• Antiarrhythmic Agents Notes 
• Antihyperlipidemic Agents Notes
• Coagulants And Anticoagulants Notes
• Congestive Heart Failure Notes
• Drugs Affecting the Endocrine System Notes
• Antidiabetic Drugs Classification & Mechanism of Action Notes
• Local Anesthesia Notes

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Local anesthetics are the drugs when given either topically or parenterally to a localized area, produce loss of sensation with or without loss of consciousness by reversibly blocking the generation and conduction of nerve impulses.

• They do not interact with the pain receptors or inhibit the release or the biosynthesis of pain mediators. The anesthesia produced by local anesthetics is without loss of consciousness or impairment of vital central cardiorespiratory functions.
• Local anesthetics block nerve conductance by binding to selective sites on the Na+ channels in the excitable membranes, thereby reducing Na+ passage (i.e., conductance) through the pores and, thus, interfering with the generation of action potentials.
• Although local anesthetics decrease the excitability of nerve membranes, they do not affect the neuron’s resting potential.
• Local anesthetics, in contrast to analgesic compounds, do not interact with the pain receptors or inhibit the release or the biosynthesis of pain mediators.

Read and Learn More Medicinal Chemistry II Notes

Characteristics of an Ideal Local Anesthetic

1. The action of local anesthetic must be reversible.
2. It must be non-irritating to the tissues and should not produce any secondary local reaction.
3. It should have a low degree of systemic toxicity and have sufficient potency to provide
   complete anesthesia.
4. It should have a rapid onset and be of sufficient duration to be advantageous.
5. It should have sufficient penetrating properties to be effective as a topical anesthetic
6. It should be relatively free from producing allergic reactionss.
7. It should be stable in solution and undergo biotransformation readily within the body
8. It should be either sterile or capable of being sterilized by heat without deterioration.

“What is local anesthesia? A detailed question and answers guide”

No local anesthetic fulfills all of these requirements, particularly regarding the duration of action.

Local Anesthetic Mechanism of Action

1. The nerve fiber is a long cylinder surrounded by a semipermeable (allows only some substances to pass) membrane. This membrane is made up of proteins and lipids (fats). Some of the proteins act as channels, or pores, for the passage of sodium and potassium ions through the membrane.
2. The movement of nerve impulses along a nerve fiber is associated with a change in the permeability of the membrane. The pores widen, and sodium ions (Na+) move to the inside of the fiber. At the same time, potassium ions (K+) diffuse out through other pores.
   • The entire process is called depolarization. Immediately after the nerve impulse has passed, the pores again become smaller.
   • Sodium ions (Na+) are now “pumped” out of the fiber. At the same time, potassium ions are actively transported into the fiber. The nerve membrane is then ready to conduct another impulse.
3. Local anesthetics block sodium channels. When the local anesthetic binds, it blocks sodium ion passage into the cell and thus blocks the formation and propagation of the action potential.
   • This blocks the transmittance of the message of “pain” or even “touch” from getting to the brain.
   • The ability of a local anesthetic to block action potentials depends on the ability of the drug to penetrate the tissue surrounding the targeted nerve as well as the ability of the drug to access the binding site on the sodium channel.

“Understanding types of local anesthesia through FAQs: Q&A explained”

Structure-Activity Relationships

All local anesthetics contain 3 structural components:

1. Lipophilic aromatic group (usually substituted)
2. A connecting group that is either an ester or an amide
3. An ionizable amino group (hydrophilic group)

“How does local anesthesia work in medical procedures? FAQ answered”

1. Lipophilic aromatic group

The aromatic ring adds lipophilicity to the anesthetic and helps in penetration through biological membranes. It is also having direct contact with the local anesthetic binding site on the sodium channel.

• Substituents on the aromatic ring may increase the lipophilicity of the aromatic ring. Lipophilic substituents and electron-donating substituents in the para position increased anesthetic activity.
• The lipophilic substituents are thought to both increase the ability of the molecule to penetrate the nerve membrane and increase their affinity at the receptor site.
• The electron-donating groups on the aromatic ring created a resonance effect between the carbonyl group and the ring, resulting in the shift of electrons from the ring to the carbonyl oxygen.
• As the electronic cloud around the oxygen increases, it increases the affinity of the molecule with the receptor. When the aromatic ring was substituted with an electron-withdrawing group, the electron cloud around the carbonyl oxygen decreased and the anesthetic activity decreased.

2. Connecting group

The linker is usually an ester or an amide group along with a hydrophobic chain of various lengths. When the number of carbon atoms in the linker is increased, the lipid solubility, protein binding, duration of action, and toxicity increase.

• Esters and amides are bioisosteres having similar sizes, shapes, and electronic structures. The similarity in their structures means that esters and amides have similar binding properties and usually differ only in their stability in vivo and in vitro.
• For molecules that only differ at the linker functional groups, amides are more stable than esters and thus have longer half-lives than esters.

3. An ionizable amino group

Most local anesthetics contain tertiary nitrogen with a pKa between 7.5 and 9.5. Therefore, at physiological pH, both the cationic and neutral form of the molecule exists.

• The molecule can penetrate the nerve membrane in its neutral form and then re-equilibrate with its cationic form on the internal side of the membrane which then blocks the sodium channels.
• To keep the anesthetic soluble in commercial solutions, most preparations are acidified. To decrease pain on injection and to increase the onset of action, sodium bicarbonate is added to the commercial preparation.
• By adding sodium bicarbonate, the solution will become less acidic and more of the drug will be found in the neutral form. The neutral form will thus cross the nerve membrane quicker and have a quicker onset of action.

“Importance of studying local anesthesia for healthcare professionals: Questions explained”

Vasoconstrictors Used in Combination with Local Anesthetics

Many anesthetic preparations are commercially available combined with the vasoconstrictor epinephrine. Some anesthetics are also combined with other agents such as norepinephrine, phenylephrine, oxymetolazone, or clonidine to achieve the desired formulation.

• The epinephrine in the anesthetic solution has multiple purposes. As a vasoconstrictor, the injected epinephrine will constrict capillaries at the injection site and thus limit blood flow to the area.
• The local anesthetic will thus stay in the immediate area of injection longer and not be carried away to the general circulation. This will help keep the drug where it is needed and allow the minimal drug to be absorbed systemically.
• This will reduce the systemic toxicity from the anesthetic and increase the duration of anesthetic activity at the site of injection.

The lack of blood flow in the immediate area will also decrease the presence of metabolizing enzymes and this also increases the duration of action of the anesthetic locally.

Classification Of Local Anaesthetics

• Esters
• Esters of benzoic acid.
  • For Example. Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine, Piperocaine.
• Esters of Para Amino Benzoic acid.
  • For Example. Benzocaine, Butamben, Procaine, Butacaine, Propoxycaine,Tetracaine, Benoxinate.
• Anilide Amides
  • For Example. Xylocaine (Lidocaine), Mepivacaine, Prilocaine, Etidocaine
• Miscellaneous
  • For Example. Phenacaine, Diperodon, Dibucaine.
• Esters
• Esters of benzoic acid

Cocaine: Cocaine is a tropane alkaloid ester isolated from the coca leaves with central nervous system(CNS) stimulation And local anesthetic activity. Cocaine was the first agent used for topical anesthesia.

“Common challenges in understanding local anesthesia effectively: FAQs provided”

Cocaine IUPAC name: methyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate.

Cocaine MOA: Cocaine is a tropane alkaloid with central nervous systems (CNS) stimulating and local anesthetic activity. Cocaine binds to and blocks the voltage-gated sodium channels in the neuronal cell membrane.

• By stabilizing neuronal membranes, cocaine inhibits the initiation and conduction of nerve impulses and produces a reversible loss of sensation.
• Cocaine binds to the dopamine, serotonin, and norepinephrine transport proteins and inhibits the reuptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons.
• This leads to an accumulation of the respective neurotransmitters in the synaptic cleft and may result in increased postsynaptic receptor activation. Its effect on dopamine levels is most responsible for the addictive properties of cocaine.

Cocaine Metabolism: Cocaine is metabolized in the liver. It is metabolized to benzoylecgonine and ecgonine methyl ester, which are both excreted in the urine. In the presence of alcohol, a further active metabolite, cocaethylene is formed and is more toxic than cocaine itself. Half-life hour.

Cocaine Uses: Cocaine is a local anesthetic indicated for the introduction of local (topical) anesthesia of accessible mucous membranes of the oral, laryngeal, and nasal cavities. It was originally used as a local anesthetic but is no longer used because of its potent addictive qualities.

Cocaine Adverse Effects: When given in high doses systemically, cocaine has mood-elevating effects that have led to its abuse potential. High doses of cocaine can be associated with toxic reactions including hyperthermia, rhabdomyolysis, shock, and acute liver injury which can be severe and even fatal.

Hexylcaine: Hexylcaine also called cyclaine or osmocaine, is a short-acting local anesthetic. Hexylcaine is a benzoate ester.

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Hexylcaine IUFAC name: 1-(cyclohexylamino)propan-2-yl benzoate.

Hexylcaine MOA: Hexylcaine acts mainly by inhibiting sodium influx through voltage-gated sodium channels in the neuronal cell membrane of peripheral nerves.

• When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited.
• The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel.

Hexylcaine Metabolism: Hydrolyzed by plasma esterase to benzoic acid and other derivatives. Half-life is <10 minutes.

Hexylcaine Uses: It is a short-acting local anesthetic

Hexylcaine Overdose: Overdose can lead to headache, tinnitus, numbness and tingling around the mouth and tongue, convulsions, inability to breathe, and decreased heart functions.

Meprylcaine: Meprylcaine (also known as Epirocaine and Oracaine) is a local anesthetic with stimulant properties that is structurally related to dimethocaine.

Meprylcaine IUPAC name: [2-methyl-2-(propylamino)propyl] benzoate.

Meprylcaine MOA: Meprylcaine has a relatively potent inhibitory action on the monoamine transporter and inhibits the reuptake of dopamine, norepinephrine, and serotonin

Cyclomethycaine

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Cyclomethycaine IUPAC name: 3-(2-methylpiperidin-1-yl)propyl 4-cydohexyloxybenzoate

Cyclomethycaine MOA: It acts mainly by inhibiting sodium influx through voltage-gated sodium channels in the neuronal cell membrane of peripheral nerves. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited.

Piperocaine

Piperocaine IUPAC name: 3-(2-methylpiperidin-1-yl) propylbenzoate.

Piperocaine MOA: It is primarily a sodium channel blocker. It acts by inhibiting sodium influx through voltage-gated sodium channels in the neuronal cell membrane of peripheral nerves due to which when the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited.

Esters of Para Amino Benzoic acid

Benzocaine: Benzocaine is a unique local anesthetic becauseit does not contain a tertiary amine.

“Steps to explain types of local anesthetics: Esters vs amides: Q&A guide”

Benzocaine IUPAC name: Eethyl 4-aminobenzoate.

Benzocaine MOA: Benzocaine binds to sodium channels and reversibly stabilizes the neuronal membrane which decreases its permeability to sodium ions. Depolarization of the neuronal membrane is inhibited thereby blocking the initiation and conduction of nerve impulses.

Benzocaine Metabolism: Like most amino ester-type local anesthetics, it is easily hydrolyzed by plasma cholinesterase. The pKa of the aromatic amine is 3.5 ensuring that benzocaine is uncharged at physiological pH.

Because it is uncharged, it is not water-soluble but is ideal for topical applications. The onset of action is within 30 seconds and the duration of drug action is 10 to 15 minutes,

Benzocaine Uses: Benzocaine is used for endoscopy, bronchoscopy, and topical anesthesia. It is used topically by itself or in combination with menthol or phenol in non-prescription dosage forms such as gels, creams, ointments, lotions, aerosols, and lozenges to relieve pain or irritation caused by such conditions as sunburn, insect bites, toothache, teething, cold sores or canker sores in or around the mouth, and fever blisters.

Benzocaine Adverse effects: Toxicity can occur when the topical dose exceeds 200 to 300 mg resulting in methemoglobinemia.

Infants and children are more susceptible to this and methemoglobinemia has been reported after benzocaine lubrication of endotracheal tubes and after topical administration to treat a painful diaper rash.

Benzocaine Synthesis:

Butamben: Butamben is a local anesthetic in the form of n-butyl-p-aminobenzoate. Its structure corresponds to the standard molecule of a hydrophilic and hydrophobic domain separated by an intermediate ester found in most of the local anesthetics.

Due to its very low water solubility, butamben was considered of low usability as it is only suitable to be used as a topical anesthesia.

“Role of lidocaine in local anesthesia: Questions answered”

Butamben IUPAc name: Butyl 4-aminobenzoate.

Butamben MOA: Butamben acts by inhibiting the voltage-gated calcium channels in dorsal root ganglion neurons. It is reported as well that butamben is an inhibitor of the sodium channels and a delayed rectifier of potassium currents.

All the effects of butamben are performed in the root ganglion neurons which suggests that the related anesthetic effect may be caused by the reduced electrical excitability.

Butamben Metabolism: It is hydrolyzed via cholinesterase for the formation of inert metabolites.

Butamben Uses: Butamben was indicated for the treatment of chronic pain due to its long-duration effect. It is also indicated as a surface anesthetic for skin and mucous membranes and for the relief of pain and pruritus associated with anorectal disorders.

Butamben Toxicity: In studies, the most common effect was related to the generation of a prolonged effect. It was also shown in preclinical trials to produce tissue necrosis and neuritis.

Procaine: Procaine was synthesized to overcome the chemical instability of cocaine. pKa of procaine is 8.9; it has low lipid solubility and the ester group is unstable in basic solutions. It has a slow onset and a short duration of action.

Procaine is available in concentrations ranging from 25% to 10% with pHs adjusted to 5.5 to 6.0 for chemical stability. Procaine is also included in some formulations of Penicillin G to decrease the pain of intramuscular injection.

“How do amide anesthetics differ from ester anesthetics? FAQ explained”

Procaine IUPAC name: 2-(diethylamino)ethyl 4-aminobenzoate.

Procaine MOA: Procaine acts mainly by inhibiting sodium influx through voltage-gated sodium channels in the neuronal cell membrane of peripheral nerves.

• When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel.
• Procaine has also been shown to bind or antagonize the function of N-Methyl-D-aspartate (NMDA) receptors as well as nicotinic acetylcholine receptors and the serotonin receptor-ion channel complex.

Procaine Metabolism: Metabolism- Procaine is very quickly metabolized in the plasma by cholinesterases and in the liver via ester hydrolysis by a pseudocholinesterase. The in vitro elimination half-life is approximately 60 seconds.

Procaine Uses: Procaine is an anesthetic agent indicated for the production of local or regional anesthesia, particularly for oral surgery. Procaine (like cocaine) has the advantage of constricting blood vessels which reduces bleeding.

It is used for infiltration anesthesia, peripheral nerve block, and spinal block. Procaine has also been investigated as an oral entry inhibitor in the treatment of experienced HIV patients.

Procaine Synthesis:

Butacaine

“Early warning signs of gaps in understanding local anesthesia basics: Common questions”

Butacaine IUPAC name: 4-aminobenzoic acid 3-(dibutylamino) propyl ester.

Butacaine MOA: It blocks sodium ion channels thereby preventing the entry of sodium ions into nerve cells. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited.

Propoxycalne: Propoxycaine is a local anesthetic of tire ester type that has a rapid onset of action and a longer duration of action than procaine hydrochloride

Propoxycalne IUPAC name: 2-(diethylamino)ethyl4-anrino-2-propoxybenzoate.

Propoxycalne MOA: Propoxycaine is a para-aminobenzoic acid ester with local anesthetic activity. Propoxycaine binds to and blocks voltage-gated sodium channels, thereby inhibiting the ionic flux essential for the conduction of nerve impulses. This results in a loss of sensation.

Propoxycalne Metabolism: This drug is hydrolyzed in both the plasma and the liver by plasma esterases.

Propoxycalne Uses: It was used beginning in the 1950s during dental procedures. This medication was used in combination with procaine to aid in anesthesia during dental procedures.

Used in combination with procaine, it was the only dental local anesthetic available in cartridge form. It has been combined with procaine to accelerate its onset of action and provide longer-lasting anesthetic effect.

Tetracaine: Tetracaine is an ester local anesthetic currently available in combination with lidocaine as a cream and patch.

“Asymptomatic vs symptomatic effects of ignoring local anesthesia principles: Q&A”

Tetracaine IUPAC name: 2-(dimethylamino) ethyl 4-(butylamino)benzoate.

Tetracaine MOA: Tetracaine is an ester-type anesthetic and produces local anesthesia by blocking the sodium ion channels involved in the initiation and conduction of neuronal impulses.

Tetracaine Metabolism: It is rapidly hydrolyzed by plasma esterases to the primary metabolites: para-aminobenzoic acid and diethylaminoethanol. The activity of both metabolites is unspecified.

Tetracaine Uses: The combination of lidocaine and tetracaine patch is indicated for local dermal analgesia for superficial dermatological procedures and superficial venous access. The combination of lidocaine and tetracaine cream is intended to provide topical local analgesia for superficial dermatological procedures.

Tetracaine Adverse Effects: The most common adverse effects with the combination cream are localized reactions such as erythema (47%), skin discoloration (16%), and edema (14%).

Systemic adverse events were less common, occurring at a rate of <1%, and included vomiting, headache, dizziness, and fever. Similar to other amide and ester anesthetics, CNS excitation and/or depression may occur.

Benoxinate (Oxybuprocaine): Oxybuprocaine is a benzoate ester in which 4-amino-3-butoxybenzoic acid and 2-(diethylamino) ethanol have combined to form the ester bond. It may be less irritating than tetracaine, and the onset and duration of action are similar to tetracaine.

Benoxinate IUPAC name: 4-Amino-3-butoxy-benzoic acid 2-diethylamino-ethyl ester.

Benoxinate MOA: Oxybuprocaine binds to sodium channel and reversibly stabilizes the neuronal membrane which decreases its permeability to sodium ions. Depolarization of the neuronal membrane is inhibited thereby blocking the initiation and conduction of nerve impulses.

Benoxinate Uses: Oxybuprocaine is the name of a local anesthetic, which is used especially in ophthalmology and otolaryngology. It is an ester-based local anesthetic.

Anilide amides derivatives

Lidocaine: A local anesthetic and cardiac depressant used as an anti-arrhythmic agent. Lidocaine is the most commonly used amino amide-type local anesthetic.

• Lidocaine is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester types local anesthetics, such as procaine and tetracaine.
• It can be administered parenterally (with or without epinephrine) or topically either by itself or in combination with prilocaine or etidocaine as a eutectic mixture.

“Can targeted interventions improve outcomes using local anesthesia knowledge? FAQs provided”

Lidocaine IUPAC name: 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide.

Lidocaine MOA: Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby affecting local anesthetic, action.

• Lidocaine alters signal conduction in neurons by blocking the fast voltage-gated sodium (Na+) channels in the neuronal cell membrane that are responsible for signal propagation.
• With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential.
• This creates the anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their birth in the first place.

Lidocaine Metabolism: Absorption of lidocaine will be decreased with the addition of epinephrine to the local anesthetic. Lidocaine is primarily metabolized by de-ethylation of the tertiary nitrogen to form monoethylglycinexylidide. (MEGX).

Lidocaine Uses: For the production of local or regional anesthesia. It is also frequently used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias, both because it binds and inhibits Na+ channels in the cardiac muscle and because of its longer duration of action than amino ester-type local anesthetic.

Mepivacaine: Mpivacaine has a reasonably rapid onset (more rapid than that of procaine) and medium duration of action (shorter than that of procaine) and is marketed under various trade names including Carbocaine and Polocaine.

It is supplied as the hydrochloride salt of the racemate, which consists of R(-)-mepivacaine and S(+)-mepivacaine in equal proportions. These two enantiomers have markedly different pharmacokinetic properties.

Mepivacaine IUPAC name: N-(2,6-dimethylphenyl)-l-methylpiperidine-2-carboxamide.

Mepivacaine MOA: Mepivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, slowing the propagation of the nerve impulse, and reducing the rate of rise of the action potential.

In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: pain, temperature, touch.

Mepivacaine Metabolism: Rapidly metabolized in the liver by CYP3A4 and CYP1A2 with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted, unchanged in the urine.

The major metabolic biotransformations of mepivacaine are N-dealkylation (to give the N-demethylated compound 2′,6′-pipecoloxylidide) and aromatic hydroxylations. These metabolites are excreted as their corresponding glucuronides.

Mepivacaine Uses: Mepivacaine is used to provide regional analgesia and anesthesia by local infiltration, peripheral nerve block, and epidural and caudal blocks.

• The pharmacologic and toxicologic profile of mepivacaine is quite similar to that of lidocaine, except that mepivacaine is less lipophilic (logDpH 7.4 = 1.95) and has a slightly longer duration of action but lacks the vasodilator activity of lidocaine.
• For this reason, it serves as an alternate choice for lidocaine when the addition of epinephrine is not recommended in patients with hypertensive vascular disease.

Prilocaine: Prilocaine is a local anesthetic that is similar pharmacologically to lidocaine: Prilocaine hydrochloride is a water-soluble salt available as a solution for nerve block or infiltration in dental procedures.

The pKa of the secondary amine is 7,9 and commercial preparations have a pH of 5.0 to 5.6. Prilocaine has only one ortho substitution on the aromatic ring, making it more susceptible to amide hydrolysis and giving it a shorter duration.

“Differential applications of topical vs injectable local anesthesia: Questions answered”

Prilocaine IUPAC name: N-(2-methylphenyiV2-(propylamino)propanamide.

Prilocaine MOA: Prilocaine acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers.

Prilocaine Metabolism: Prilocaine is metabolized in both the liver and the kidney and excreted via the kidney.

Prilocaine Uses: Currently, it is used most often for infiltration anesthesia in dentistry. Prilocaine is used for intravenous regional anesthesia as the risk of CNS toxicity is low because of its quick metabolism.

Etidocaine: Etidocaine is a local anesthetic with rapid onset and long action, similar to BUPIVACAINE.

Etidocaine IUPAC name: N-(2,6-dimethylphenyl)-2-[ethyl(propyl)amino]butanamide.

Etidocaine MOA: Etidocaine is the most potent amino amide local anesthetic. Etidocaine differs from lidocaine by the addition of an alkyl chain and the extension of one ethyl group on the tertiary amine to a butyl group.

The additional lipophilicity gives etidocaine a quicker onset, longer half-life, and an increased potency compared with lidocaine. The tertiary nitrogen pKa is 7.74, which is similar to lidocaine’s pKa (7.8)

Etidocaine Uses: It is used for epidural anesthesia, topical anesthesia, and for peripheral nerve or plexus block. Etidocaine blocks large fast-conducting neurons quicker than the sensory neurons. It is given by injection during surgical procedures and labor and delivery.

Etidocaine Adverse effect: Etidocaine has the same potential for cardiac toxicity as bupivacaine.

Miscellaneous

Phenacaine

“Steps to apply local anesthesia knowledge in clinical practice: Diagnosis vs treatment: Q&A guide”

Phenacaine IUPAC name: N,N’-bis(4-ethoxyphenyl)ethanimidamide.

Phenacaine MOA: It is a sodium channel blocker. It blocks sodium ion passage into the cell and thus blocks the formation and propagation of the action potential.

Phenacaine Use: It is a local anesthetic approved for ophthalmic use.

Diperodon

Diperodon IUPAC name: [2-(phenylcarbamoyloxy)-3-piperidin-1-ylpropyl] N-phenylcarbamate.

Dibucaine: Dibucaine is a topical amide anesthetic available in over-the-counter creams and ointments used to treat minor conditions such as sunburns and hemorrhoids. Dibucaine is a quinoline derivative and amino amide with anesthetic activity.

Dibucaine is a Standardized Chemical Allergen. The physiologic effect of dibucaine is through Increased Histamine Release, and Cell-mediated Immunity, The chemical classification of dibucaine is Allergens.

“Role of nerve blocks in surgical procedures: Questions answered”

Dibucaine IUPAC name: 2-butoxy-N-[2-(diethylamino)ethyl]quinoline-4-carboxamide.

Dibucaine MOA: Dibucaine reversibly binds to and inactivates sodium channels in the neuronal cell membrane.

Inhibition of sodium channels prevents the depolarization of nerve cell membranes and inhibits subsequent propagation of impulses along the course of the nerve, thereby limiting the excitation of nerve endings. This results in loss of sensation.

Dibucaine Metabolism: Metabolites of dibucaine identified in the urine of rats, rabbits, and humans included hydroxylated metabolites of the quinoline ring, monohydroxylated and dihydroxylated metabolites of the O-alkyl side chain (2-and 3-position), and the N-de-ethylated dibucaine metabolite.

Dibucaine Uses: It is a local anesthetic of the amide type now generally used for surface anesthesia. It is one of the most potent and toxic of the long-acting local anesthetics and its parenteral use is restricted to spinal anesthesia.

Dibucaine Toxicity: It is highly toxic when taken orally, inducing seizures, coma, and death in several children who accidentally ingested it.

Dibucaine Synthesis:

“How does epinephrine prolong the effects of local anesthesia? FAQ explained”

Local Anaesthetics Multiple Choice Questions And Answers

Question 1. Local anesthetics produce:

1. Analgesia, amnesia, loss of consciousness
2. Blocking pain sensation without loss of consciousness
3. Alleviation of anxiety and pain with an altered level of consciousness
4. A stupor or somnolent state

Answer: 2. Blocking pain sensation without loss of consciousness

Question 2. Which one of the following drugs has an allergenic effect?

1. Lidocaine
2. Procaine
3. Dibucaine
4. Bupivacaine

Answer: 3. Dibucaine

Question 3. Most local anesthetic agents consist of:

1. Lipophilic group
2. Intermediate chain
3. Amino group
4. All of the above

Answer: 4. All of the above

Question 4. Which one of the following groups is responsible for the duration of the local anesthetic action?

1. Intermediate chain
2. Lipophilic group
3. Ionizable group
4. All of the above

Answer: 1. Intermediate chain

“Early warning signs of complications from ignoring local anesthesia protocols: Common questions”

Question 5. Which one of the following groups is responsible for the potency of local anesthetics?

1. Ionizable group
2. Intermediate chain
3. Lipophilic group
4. All of the above

Answer: 3. Lipophilic group

Question 6. The primary mechanism of action of local anesthetic is _________.

1. Activation of ligand-gated potassium channels
2. Blockade of voltage-gated sodium channels
3. Stimulation of voltage-gated N-type calcium channels
4. Blockade the GABA-gated chloride channels

Answer: 2. Blockade of voltage-gated sodium channels

Question 7. Which one of the following local anesthetics is an ester of benzoic acid?

1. Lidocaine
2. Procaine
3. Ropivacaine
4. Cocaine

Answer: 4. Cocaine

Question 8. Local anesthetics are:

1. Weak bases
2. Weak acids
3. Salts
4. None of the above

Answer: 1. Weak bases

Question 9. For therapeutic application local anesthetics reasons of:

1. Less toxicity and higher potency
2. Higher stability and greater lipid solubility
3. Less local tissue damage and more potency
4. More stability and greater water solubility

Answer: 4. More stability and greater water solubility

“Asymptomatic vs symptomatic effects of outdated local anesthesia practices: Answered”

Question 10. Which of the following statements is not correct for local anesthetics?

1. In a tissue, they exist either as an uncharged base or as a cation
2. A charged cationic form penetrates biological membranes more readily than an uncharged form
3. Local anesthetics are much less effective in inflamed tissues
4. Low pH in inflamed tissues decreases the dissociation of nonionized molecules

Answer: 2. A charged cationic form penetrates biological membranes more readily than an uncharged form

Question 11. Which of the following anesthetic agents shows antiarrhythmic action?

1. Lidocaine
2. Bupivacaine
3. Procaine
4. Etidocaine

Answer: 1. Lidocaine

Local Anaesthetics Short Questions And Answers

Question 1. Define Local Anesthetics

Answer:

Local anesthetics are the drugs when given either topically or parenterally to a localized area, produce loss of sensation with or without loss of consciousness by reversibly blocking the generation and conduction of nerve impulses.

Question 2. Write the characteristics of an ideal Local Anesthetic

Answer:

The following are the characteristics of an ideal Local Anesthetic.

1. The action of local anesthetic must be reversible.
2. It must be non-irritating to the tissues and should not produce any secondary local reaction
3. It should have a low degree of systemic toxicity and have sufficient potency to provide complete anesthesia.
4. It should have a rapid onset and be of sufficient duration to be advantageous.
5. It should have sufficient penetrating properties to be effective as a topical anesthetic.
6. It should be relatively free from producing allergic reactions.
7. It should be stable in solution and undergo biotransformation readily within the body.
8. It should be either sterile or capable of being sterilized by heat without deterioration.

“Can preventive measures reduce risks of local anesthesia side effects? FAQs provided”

Question 3. Write the structural requirements for Local Anesthetics

Answer:

Following are the structural requirements for Local Anesthetic.

1. Lipophilic aromatic group (usually substituted)
2. A connecting group that is either an ester or an amide
3. An ionizable amino group (hydrophilic group).

Question 4. Draw the structures of Propoxycaine and Butamben

Answer:

Question 5. Write the mechanism of action of local anesthetics.

Answer:

Local anesthetics block sodium channels. When the local anesthetic binds, it blocks sodium ion passage into the cell and thus blocks the formation and propagation of the action potential.

• This blocks the transmittance of the message of “pain” or even “touch” from getting to the brain.
• The ability of a local anesthetic to block action potentials depends on the ability of the drug to penetrate the tissue surrounding the targeted nerve as well as the ability of the drug to access the binding site on the sodium channel.

“Differential applications of short-acting vs long-acting local anesthetics: Q&A”

Question 6. Write the uses of Lidocaine and Tetracaine

Answer:

Lidocaine– For the production of local or regional anesthesia. Lidocaine is also frequently used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias.

Tetracaine -The combination of lidocaine and tetracaine patch is indicated for local dermal analgesia for superficial dermatological procedures and superficial venous access. The combination of lidocaine and tetracaine cream is intended to provide topical local analgesia for superficial dermatological procedures.

The post Local Anesthesia: Types, Benefits, and Side Effects appeared first on BDS Notes.

The pancreas secretes digestive enzymes, glucagon, and insulin. An isolated group of cells within a cell’s pancreas is called an islet of Langerhans. These cells are divided into three types (secretes glucagon), β cells (secretes insulin), and γ cells (secretes somatostatin).

Insulin plays an important role in the digestion and utilization of food substances. It is essential for the phosphorylation of glucose to glucose-6-phosphate. Glucose-6-phosphate is further catabolized to give energy.

In some individuals glucose levels in blood increase due to lack of sufficient insulin. This condition is called hyperglycemia. The disease is known as diabetes mellitus.

Some of the more important- symptoms associated with the disease are polydipsia, polyurea, ketonemia, and ketonuria. Most patients can be classified clinically as:

1. Insulin-dependent diabetes mellitus (Type-1 diabetes)-Type-1 diabetes is an auto-immune disease caused by the destruction of pancreatic islet cells.
2. Non-insulin-dependent diabetes mellitus (Type-2 diabetes). – Type-2 diabetes the cause of hyperglycemia is a combination of insulin resistance and a loss of secretory function by the pancreatic β-cells.

Read and Learn More Medicinal Chemistry II Notes

“Understanding antidiabetic drug classification through FAQs: Q&A explained”

Hypoglycemic Agents

Hypoglycemic agents or antihyperglycemic or antidiabetic agents lower the blood sugar and are used to treat the symptoms of diabetes mellitus.

• Pharmacologic treatment for type 1 diabetics requires intensive insulin therapy. The large number of short- and long-acting insulin analogs allows for the use of multiple doses of basal and prandial (at meals) doses of insulin.
• Therefore, patients can match their dose of prandial insulin to carbohydrate intake, pre-meal plasma glucose, and anticipated activity.

The most common side effect of the use of insulin is severe hypoglycemia; however, the development of quick-acting and long-acting insulin analogs has moderated this side effect while still maintaining equal HbAic (Hemoglobin A) lowering.

• Medical treatment of the type 2 diabetic requires management of hyperglycemia as measured by the patient’s HbA1c below 7%.
• Obesity and a sedentary lifestyle are the major risk factors for diabetes; therefore, weight Ions, dietary changes, and Increased activity levels should be the initial approach to treating type 2 diabetes. In addition to Insulin, there are several classes of oral hypoglycemic agents available.

Antidiabetic Agents Classification

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Insulin and its Preparations

Structure of insulin

The insulin molecule is composed of two polypeptide chains (A and B) linked together by two disulfide bonds. There is an additional disulfide bond in chain A.

• Chain A contains 21 amino acid residues, and chain B has 30 amino acids, giving a molecular weight of 5,734 Daltons. Insulin is biosynthesized in the b-cells of the pancreas from preproinsulin, a 110 amino acid chain with a molecular weight of 12,000 Daltons.
• Preproinsulin is cleaved in the endoplasmic reticulum, losing a 24- -amino acid unit from the N-terminus. The product is called proinsulin (molecular weight =*ÿ 9,000 Daltons), which folds to allow the disulfide bonds to form.
• And undergoes further proteolytic modification in the Golgi apparatus, losing four basic amino acids (ArgB31, ArgB32, LysA64, and ArgA65) and releasing connector C-chain by the action of prohormone convertases PCI and PC2.

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The biologically active form of insulin is the monomer. However, in solution, insulin can exist as a dimer and as a hexamer (six monomeric units attached).

The hexamer is formed by its coordination with two zinc ions, the storage form of insulin in the granules of the b-cells. When released from the granules, the hexamer gets diluted in the plasma (nanomolar) and dissociates into monomers.

Sources and stability of insulin

• Historically, patients only had the option of administering either bovine-based or porcine-based insulin, which were alternatives to human insulin because their amino acid sequence homology between species was superb.
• However, animal sources have become less relevant and have fallen into disuse. Today, the following sources of insulin are available: biosynthetic human, semisynthetic human, and analogs of human insulin. Human insulin is the least antigenic of the available insulins and tends to be more soluble than animal insulin.

Types of Insulin

The insulin analogs available for the treatment of diabetes are classified according to their rate of onset and duration of action.

Structure-activity relationship studies revealed that variations or removal of amino add residues from the C-terminus of the B chain could influence the rate of dimer formation while not drastically changing the biological activity.

1. Rapid-acting insulin analogs include insulin lispro, insulin aspart, and insulin glulisine. All have changes made to the amino add residues in the C-terminus of the B chain.
   • Insulin lispro– the LysB29 is switched with ProB28.
   • Insulin aspart– the ProB28 has been substituted with an Asp.
   • Insulin Glulisinc-ValB3 is substituted with a Lys, and LysB29 is changed to glutamate (Glu).
2. Short-acting insulin– Regular human insulin is the prototype. Making regular insulin a good choice for intravenous treatment of diabetics
3. Intermediate-acting insulin-Include Insulin NPH and insulin lente.
   • Insulin NPH is prepared by adding stoichiometric (equal) amounts of the positively charged
     polypeptide protamine to regular insulin.
   • Insulin lente is Prepared by combining regular insulin and zinc in an acetate buffer to form a crystalline complex that dissolves slowly in subcutaneous fluids.
4. Long-acting insulin)
   • Insulin glargine analog results from the replacement of AsnA21 by glycine (Gly) and the addition of two Arg amino acids to the C-terminus of the B chain.
   • Insulin ultralente– is a long-acting insulin that is a four-zinc acetate crystalline product.
   • Insulin detemir is the newest long-acting analog. This analog results from the N-acylation of the LysB29 with the 14-carbon myristic acid.
   • A new long-acting insulin analog currently in phase 3 clinical trials is insulin degludec. Insulin deglude results from the removal of GluB30 and N-acylation of LysB29 with L-g-Glu amidated with hexadecanoic acid.
5. Premixed insulins– Different types of insulin can be premixed in the same syringe and are usually prescribed for patients needing a simple insulin treatment plan. NPH insulin can be premixed with either aspart or lispro rapid-acting insulins.
   • Mixtures of NPH and lispro can be 50:50 or 75:25, whereas NPH and aspart are available in 70:30 ratios. A 70:30 NPH/regular insulin premix is also available.
   • The benefit of using premixed insulin is that rapid-acting and long-acting insulin can be administered at the same time and can be given twice a day, usually at breakfast and supper.
   • The drawback of using such a regimen is that to be effective, the amount of carbohydrates to be eaten at each meal is preset.

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Classification of insulin preparations with their pharmacokinetics

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Non-insulin antidiabetic or oral hypoglycemic agents

A characteristic of type 2 diabetes is diminished insulin secretion due to impaired b-cell function and or insulin resistance of peripheral tissues such as the liver, adipose, and skeletal muscle, which causes hyperglycemia. The current line of treatment includes:

• Insulin secretagogucs
• Insulin sensitizers
• Bigunnldes
• a-glucosidase inhibitors
• GLIM analogs and DPP-IV inhibitors
• Amylin agonists
• Insulin secretagogucs

The insulin secretagogues include sulfonylureas and meglitinides, and both increase insulin release from the pancreas by a common mechanism.

Non-Insulin antidiabetic MOA: All the sulfonylureas and meglitinides stimulate the release of insulin from the B-cells of the pancreas. These cells metabolize glucose in the mitochondria to produce ATP, which increases the intracellular ratio of ATP/ADP, resulting in the closure of the ATP-sensitive K⁺ channel on the plasma membrane.

• Closure of this channel triggers the opening of voltage-sensitive Ca²⁺ channels, leading to a rapid influx of Ca²⁺.
• Increased intracellular Ca²⁺ causes an alteration in the cytoskeleton and stimulates the translocation of insulin-containing granules to the plasma membrane and the exocytotic release of insulin.
• The ATP-sensitive K⁺ channel is an octameric heterocomplex consisting of two units of the binding site for both sulfonylureas and ATP designated as the sulfonylurea receptor type 1 (SUR1) and an inwardly rectifying K⁺ channel.

Sulfonylurea binding to the SURl causes the same effect as an increase in the ATP/ADP ratio, which is to close the channel leading to the secretion of insulin.

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Sulfonylureas

Sulfonylureas are classified as First generation For Example. Tolbutamide, Chlorpropamide.

Second generation For Example. Glipizide, Glimepiride.

Sulfonylureas SAR: The benzene ring should contain one substituent, preferably at the para position (R). The substituents that seem to enhance hypoglycemic activity are methyl, amino, acetyl, chloro, bromo, methylation, and trifluoromethyl groups.

1. Compounds with p-(-β-arylcarboxamidoethyl) substituents (the second-generation agents) have better activity than the first-generation agents. It is believed that this is because of a specific distance between the nitrogen atom of the substituent and the sulfonamide nitrogen atom.
2. The group attached to the terminal nitrogen (R₂) should be of a certain size and should impart lipophilic properties to the molecule. The N-methyl is inactive, N-ethyl has low activity, while N-propyl to N-hexyl is most active. Activity is lost if the N-substituent contains 12 or more carbons.

Sulfonylureas Adverse effects: Sulfonylureas are associated with weight gain, though less so than insulin. Due to their mechanism of action, sulfonylureas may cause hypoglycemia and require consistent food intake to decrease this risk. The risk of hypoglycemia is increased in elderly, debilitated, and malnourished individuals.

Tolbutamide

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Tolbutamide IUPAC name: 3-butyl-1-(4-methylbenzenesulfonyl)urea.

Tolbutamide Metabolism: Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea.

• May also be metabolized to 4- 4-hydroxy tolbutamide. Unchanged drugs and metabolites are eliminated in the urine and feces.
• Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the l-butyl-3-p-carboxyphenylsulfonylurea within 24 hours.

Tolbutamide Uses: For treatment of NIDDM (non-insulin-dependent diabetes mellitus) in conjunction with diet and exercise.

Tolbutamide Synthesis:

Chlorpropamide

Chlorpropamide IUPAC name: 1-(4-chlorobenzenesulfonyl)-3-propylurea.

Chlorpropamide Metabolism: Chlorpropamide has a considerably longer half-life than the other sulfonylureas and, as a result, has a greater tendency for adverse effects. One explanation for the long half-life is that its metabolism (w and w-1 hydroxylation of the propyl group) is slow. A significant amount of the drug (~20%) is excreted unchanged.

Chlorpropamide Uses: For treatment ofNIDDMin conjunction with diet and exercise.

Glipizide

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Glipizide IUPAC name: N-[2-(4-{[(cyclohexylcarbamoyl)amino]sulfonyl}phenyl)ethyl]-5-methylpyrazine-2-carboxamide.

Glipizide Metabolism: It undergoes hepatic metabolism. The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity 3-cis-Hydroxyglipizide, 4-transHydroxyglipizide, and 4-trans-OH-glipizide.

A minor metabolite that accounts for less than 2% of a dose, an acetylamino ethyl benzene derivative is reported to have 1/10 to 1/3 as many hypoglycemic activities as the parent compound.

Glipizide Uses: For use as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with non-insulin-dependent diabetes mellitus (NIDDM; type II), formerly known as maturity-onset diabetes, after an adequate trial of dietary therapy has proved unsatisfactory.

Glimepiride

Glimepiride IUPAC name: 3-ethyl-2,5-dihydro-4-methyl-N-[2-[4[[[[(trans-4-methylcyclohexyl) amino] -carbonyl] amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-l-carboxamide.

Glimepiride Metabolism: Glimepiride is metabolized in the liver, primarily by CYP2C9, to the active metabolite cyclohexyl hydroxymethyl derivative (M-l) which is then further metabolized to the inactive metabolite carboxyl derivativ (M-2).

Glimepiride Uses: For concomitant use with insulin for the treatment of noninsulin-dependent (type 2) diabetes mellitus.

Meglitinides: It is the benzoic acid derivative of the non-sulfonylurea moiety of glibenclamide.

Repaglinide

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Repaglinide IUPAC name: 2-ethoxy-4-({[(lS)-3-methyl-1-[2-(piperidin-l-yl) phenyl] butyl] carbamoyl) methyDbenzoic acid.

Repaglinide Metabolism: Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (Ml).

Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites do not possess appreciable hypoglycemic activity.

Repaglinide Uses: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Repaglinide Adverse effects: Repaglinide has a rapid onset and short duration of action compared to other hypoglycemic drugs.

It is not associated with the prolonged hyperinsulinemia seen with the sulfonylureas, and possibly for this reason, it produces fewer side effects, including weight gain and potentially dangerous hypoglycemia.

Nateglinide

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Nateglinide IUPAC name: (2R)-2-({hydroxy[(1r,4r)-4-(propan-2yl)cyclohexyl]methylidene}amino)-3-phenylpropanoic acid.

Nateglinide Metabolism: It is metabolized in the liver, with 16% excreted in the urine unchanged. The major metabolites are hydroxyl derivatives (CYP2C9, 70%; CYP3A4, 30%) that are further conjugated to glucuronide derivatives. The drug has an elimination half-life of 1.5 hours.

Nateglinide Uses: For the treatment of non-insulin dependent-diabetes mellitus in conjunction with diet and exercise.

Nateglinide Adverse Effects: May cause weight gain and hypoglycemia but lower than that of sulfonylurea.

Insulin sensitizers (peroxisome proliferatoiÿactivated receptor [PPAR] agonists)

• The thiazolidinediones (TZDs) are classic examples of PPARg agonists and are commonly referred to as the “glitazones.” Thiazolidinediones (TZD) are ligands of the peroxisome proliferator-activated receptor-γ (PPAR-γ) that is expressed in the nucleus of adipocytes, myocytes, and hepatocytes.
• PPAR regulates the expression of genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte differentiation. In diabetics, a major site of TZD action is adipose tissue.

Insulin sensitizers MOA: These drugs are synthetic ligands for the transcription factor PPARγ, a member of a superfamily of nuclear receptors including thyroid and steroid receptors. PPARγ is expressed in multiple tissue types (For Example. skeletal muscle, fat, and liver).

• Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin.
• As illustrated, one mechanism contributing to the hypoglycemic effect of thiazolidinediones is an increased expression of the glucose transporter GLUT4.
• The increased expression of GLUT4 (in addition to mediators of insulin signal transduction) increases the ability of cells (For Example. adipocytes) to take up glucose when stimulated by insulin.

Rosiglitazone

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Rosiglitazone IUPAC name: 5-[4-[2-(N-methyl-N-(2-pyridyl) amino)ethoxy]benzyl]thiazolidine-2,4-dione.

Rosiglitazone Metabolism: It undergoes hepatic metabolism. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid.

In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone.

Rosiglitazone Uses: Rosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Rosiglitazone Adverse effects: Side effects include fluid retention, congestive heart failure (CHF), and liver disease.

Pioglitazone

Pioglitazone IUPAC name: 5-({4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}methyl)-l/3-thiazolidine-2,4-dione

Pioglitazone Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-3 and M-4 are the major circulating active metabolites in humans.

The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1.

Pioglitazone Uses: Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Pioglitazone Adverse effects: Side effects include fluid retention, congestive heart failure (CHF), and liver disease.

Biguanides: The biguanides are chemically represented by the linkage of two guanidine groups with different side chains. The biguanides include metformin, phenformin, and buformin.

Metformin

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Metformin IUPAC name: 1-carbamimidamido-N, N-dimethylinethanimidamide

Metformin MOA: Although the mechanism of action is not completely understood, Metformin reduces hepatic glucose output by decreasing gluconeogenesis and stimulating glycolysis Current evidence suggests that results from a combination of intracellular effects in the liver.

• When metformin is taken orally, it is absorbed into hepatocytes from the portal vein through plasma membrane transporters, including the organic cation transporter 1 (OCT1).
• Inside the cell metformin inhibits mitochondrial respiratory-chain complex 1, resulting in reduced ATP levels and increased AMP.

Increased AMP levels activate Adenosine Monophosphate-Activated Protein Kinase (AMPK), which contributes to the lowering of glucose production by at least 2 pathways:

1. Increased AMPK phosphorylates CBP and CRTC2 transcription factors, which inhibits genes involved in the production of glucose (“gluconeogenic genes”);
2. Increased AMPK also inhibits mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), leading to an increase in cytosolic NADH, which both stimulates the conversion of pyruvate to lactate and simultaneously decreases gluconeogenesis.
3. An accumulation of lactate to dangerous levels (lactic acidosis) can occur when metformin is taken by patients with other conditions resulting in metabolic acidosis

Metformin Metabolism: Metformin is excreted in the urine, via tubular excretion, as an un-metabolized drug with a half-life of approximately 2 to 5 hours; therefore, renal impairment and hepatic disease are contraindications for the drug.

Metformin Uses: For use as an adjunct to diet and exercise in adult patients (18 years and older) with non-insulin-dependent diabetes mellitus.

Metformin may also be used for the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome (PCOS). Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults

Metformin Adverse effects: The most common adverse effects of metformin include: epigastric discomfort, nausea, flatulence, and vomiting. Diarrhea, drowsiness, weakness, dizziness, malaise, and headache may also occur.

• Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis
• In patients with decreased renal function, the plasma and blood half-life of metformin is
  prolonged and the renal clearance is decreased.

α-glucosidase inhibitors

α-Amylase and α -α-glucosidase are key enzymes responsible for the metabolism of carbohydrates.

α-glucosidase inhibitors MOA: α-Glucosidase, which consists of maltase, sucrase, isomaltase, and glucoamylase, is a membrane-bound enzyme present in the brush border of the small intestine in relatively high concentrations in the proximal part of the jejunum.

• This enzyme catalyzes the conversion of the disaccharides sucrose and maltose into glucose.
• The resulting monosaccharides are then absorbed by the enterocytes of the jejunum and enter systemic circulation, as well as various biochemical pathways for the production of energy.
• Thus, inhibiting a-glucosidase will delay the process of carbohydrate absorption in the gut by moving these undigested disaccharides into the distal sections of the small intestine and colon. The result is the prevention of glucose production, thereby reducing postprandial hyperglycemia.

Acarbose 

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Acarbose IUPAC name: 0-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]a-D-glucopyranosyl-(1→4)-O- α -D-glucopyranosy-(1→4)D-glucose.

Acarbose Metabolism: Acarbose is only metabolized within the gastrointestinal tract by intestinal bacteria and also digestive enzymes to a lesser extent.

4-methyl pyrogallol derivatives (sulfate, methyl, and glucuronide conjugates) are the major metabolites. One metabolite (formed by cleavage of a glucose molecule from acarbose) also has α-glucosidase inhibitory activity.

Acarbose Uses: For treatment and management of diabetes type II (used in combination therapy as a second or third line agent).

Acarbose Adverse effects: Gastrointestinal symptoms are the most common reactions to acarbose.

Voglibose

Voglibose IUPAC name: (1S,2S,3R,4S,5S)-5-[(1,3-dihydroxypropan-2-yl)amino]-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol.

Voglibose Metabolism: Little metabolism occurs and no metabolites have as yet been identified. The half-life of voglibose is very similar to the one found for metformin and it is reported to be 4.08 hours.

Voglibose Uses: For the treatment of diabetes. It is specifically used for lowering post-prandial blood glucose levels thereby reducing the risk of macrovascular complications.

Its use can be extended to the treatment of glycosphingolipid lysosomal storage disease, HIV infections, and certain tumors.

Voglibose Adverse Effects: Gastrointestinal irritation, bloating, and flatulence caused by fermentation of undigested sugars in the large bowel by intestinal microflora.

GLP-1 analogs and DPP-4 inhibitors

GLP-1(Glucagon-like peptide) is a 36-amino acid peptide secreted by L-cells of the gut in response to a meal. It exerts control over glucose levels by promoting insulin secretion in a glucose-dependent manner.

• The role of GLP-1 was first proposed based on the observation that the amount of insulin secreted following an oral glucose dose exceeded that of an equivalent glucose dose administered intravenously in both diabetic and nondiabetic individuals.
• This observation was termed the incretin effect and is the result of two gut hormones, GLP-1 and GIP (glucose-dependent insulinotropic polypeptide.)

GLP-1 analogs and DPP-4 inhibitors MOA:

GLP-1 secretion from L-cells is similar to that of glucose-induced insulin secretion from pancreatic B-cells. Metabolism of glucose in the intestinal L-cells leads to the closure of ATP-linked potassium (K+) channels, resulting in depolarization of the membrane and entry of Ca2+, which leads to the secretion of GLP-1.

• GLP-1 is rapidly metabolized, with a half-life of 1 to 2 minutes, by an aminopeptidase enzyme, DPP-IV (dipeptidyl peptidase-IV), yielding an inactive peptide that is two amino acids shorter.
• It follows, therefore, that GLP-1 agonists or DDP-IV inhibitors would be effective agents to control blood glucose levels in diabetic patients.

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GLP-1 agonists– Exenatide, Liraglutide, Albiglutide (The major problem with GLP-1 analogs is their need for subcutaneous administration, which can limit patient compliance.)

DDP-IV inhibitors– Sitagliptin, Vildagliptin, Linagliptin, and Saxagliptin.

Amylin agonists: Amylin is a hormone that consists of a single chain of 37 amino acids and is released from pancreatic b-cells, co-secreted with insulin, and primarily involved in controlling postprandial glucose levels.

• Amylin, like insulin, shows similar fasting and postprandial patterns in healthy individuals by a variety of mechanisms, including delayed gastric emptying and suppression of glucagon secretion (not normalized by insulin alone).
• Which leads to a suppression of endogenous glucose output from the liver. Amylin also regulates food intake by modulating the appetite center of the brain.

The observation that amylin was deficient in both type 1 and type 2 diabetics stimulated research and development of amylin analogs that would be able to control postprandial glucose levels by:

1. Modulation of gastric emptying.
2. Prevention of postprandial rise in glucagon.
3. Inhibition of caloric intake and potential weight gain.

Amylin itself is unsuitable as a drug because it aggregates and is insoluble in solution, which encouraged the development of chemical analogs.

Pramlintide is a chemical analog of amylin given enhanced water solubility and reduced aggregation liability by replacing the Ala25, Ser28, and Ser29 of the amylin peptide chain with prolines

Antidiabetic Agents Multiple Choice Questions And Answers

Question 1. What Oral Antidiabetic stimulates beta cells to secrete more insulin and increase receptor sites in the tissue?

1. Alfa-Glucosidase Inhibitors
2. Biguanides
3. Sulfonylureas
4. Thiazolidinediones
5. Meglitinides

Answer: 3. Sulfonylureas

Question 2. What Oral Diabetic Medication has the following side effects: Diarrhea, Stomach upset, and Lactic acidosis?

1. Miglitol
2. Orinase
3. Acarbose
4. Metformin
5. Tolinase

Answer: 4. Tolinase

Question 3. What Oral Medication should not be taken with Dairy products?

1. Glyset
2. Metformin
3. Repaglinide
4. Pioglitazone
5. Glyburide

Answer: 2. Metformin

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Question 4. What drug increases blood sugar by stimulating glycogenolysis (glycogen breakdown) in the liver?

1. Glimepiride
2. Glyburide
3. Acarbose
4. Miglitol
5. Glucagon

Answer: 5. Glucagon

Question 5. What decreases the rate of liver glucose production, augments glucose uptake by tissues, and lowers lipids?

1. Miglitol
2. Nateglinide
3. Pioglitazone
4. Metformin
5. Repaglinide

Answer: 4. Metformin

Question 6. What classification of OAD (Oral Anti-diabetic) medication delays the absorption of carbohydrates from the GI TRACT?

1. Biguanides
2. Thiazolidinediones
3. Alpha- Glucosidase
4. Meglitinides
5. Sulfonylureas

Answer: 3. Meglitinides

Question 7. What increased glucose uptake in muscle, decreases glucose production in the liver?

1. Meglitinides
2. Thiazolidinediones
3. Sulfonylureas
4. Glucagon
5. Biguanides

Answer: 2. Sulfonylureas

Question 8. What are the side effects of Meglitinides?

1. Edema
2. Weight gain
3. Hypertension
4. Diarrhea
5. Weight loss

Answer: 2. Hypertension

Question 9. What are the Side effects of Thiazolidinediones?

1. Weight loss
2. Edema
3. Hypoglycemia
4. Hyperglycemia
5. Diarrhea

Answer: 2. Hypoglycemia

Question 10. What stimulates the rapid and short-lived release of insulin from the pancreas

1. Meglitinides
2. Thiazolidinediones
3. Biguanides
4. Alpha- Glucosidase
5. Sulfonylureas

Answer: 1. Meglitinides

Antidiabetic Agents Short Questions And Answers

Question 1. Give the types of insulin preparations.

Answer:

• Rapid-acting insulin analogs
  • Insulin lispro
  • Insulin Aspart
  • Insulin Glulisine
• Short-acting insulin
  • Regular insulin
• Intermediate-acting insulin
  • Insulin NPH
  • Insulin Lente
• Long-acting insulin
  • Insulin glargine
  • Insulin Ultralite
  • Insulin detemir
  • Insulin degludec
• Premixed insulins-D

“Asymptomatic vs symptomatic effects of ignoring new trends in antidiabetic drug research: Answered”

Question 2. Classify insulin secretagogues with examples.

Answer:

Insulin secretagogues are classified as:

1. Sulfonylureas
   • First generation For Example. Tolbutamide, Chlorpropamide.
   • Second generation For Example. Glipizide, Glimepiride.
2. Meglitinides
   • For Example. Repaglinide, Nateglinide.

Question 3. Write adverse effects of Metformin.

Answer:

The most common adverse effects of metformin include epigastric discomfort, nausea, flatulence, and vomiting. Diarrhea, drowsiness, weakness, dizziness, malaise, and headache may also occur.

• Metformin decreases liver uptake of lactate, thereby increasing lactate blood levels which may increase the risk of lactic acidosis.
• In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased.

Question 4. Give the mode of action of GLP-1 analogs and DPP-4 inhibitors.

Answer:

GLP-1 secretion from L-cells is similar to that of glucose-induced insulin secretion from pancreatic B cells. Metabolism of glucose in the intestinal L-cells leads to the closure of ATP-linked potassium (K+) channels, resulting in depolarization of the membrane and entry of Ca2+, which leads to the secretion of GLP-1.

• GLP-1 is rapidly metabolized, with a half-life of 1 to 2 minutes, by an aminopeptidase enzyme, DPP-4 (dipeptidyl peptidase-4), yielding an inactive peptide that is two amino acids shorter.
• It follows, therefore, that GLP-1 agonists or DDP-4 inhibitors would be effective agents to control blood glucose levels in diabetic patients.

The post Antidiabetic Drugs Classification And Mechanism of Action appeared first on BDS Notes.

The human endocrine system is a group of ductless glands that regulate body processes by secreting chemical substances called hormones. Hormones act on nearby tissues or are carried in the bloodstream to act on specific target organs and distant tissues.

• Diseases of the endocrine system can result from the oversecretion or undersecretion of hormones or from the inability of target organs or tissues to respond to hormones effectively.
• Many different glands make up the endocrine system. The hypothalamus, pituitary gland, and pineal gland are in your brain. The thyroid and parathyroid glands are in your neck.
• The thymus is between your lungs, the adrenals are on top of your kidneys, and the pancreas is behind your stomach. Your ovaries (if you’re a woman) or testes (if you’re a man) are in your pelvic region.
• The steroid is any of a class of natural or synthetic organic compounds characterized by a molecular structure of 17 carbon atoms arranged in four rings. Steroids are important in biology, chemistry, and medicine.

The steroid group includes all the sex hormones, adrenal cortical hormones, bile acids, and sterols of vertebrates, as well as the molting hormones of insects and many other physiologically active substances of animals and plants.

“What are drugs affecting the endocrine system? A detailed question and answers guide”

Read and Learn More Medicinal Chemistry II Notes

• Among the synthetic steroids of therapeutic value are a large number of different categories of steroids that are frequently distinguished from each other by names that relate to their biological source For Example., phytosterols (found in plants).
• Adrenal steroids, bile acids, or some important physiological function For Example., progesterones (promoting gestation), androgens (favoring development of masculine characteristics), and cardiotonic steroids (facilitating proper heart function).
• Steroids vary from one another like attached groups, the position of the groups, and the configuration of the steroid nucleus (or gonane). Small modifications in the molecular structures of steroids can produce remarkable differences in their biological activities.

Steroid Numbering System Nomenclature And Stereochemistry

All steroids are related to a characteristic molecular structure composed of 17 carbon atoms arranged in four rings conventionally denoted by the letters A, B, C, and D bonded to 28 hydrogen atoms.

Gonane

This parent structure, named gonane (also known as the steroid nucleus), may be modified in a practically unlimited number of ways by removal, replacement, or addition of a few atoms at a time.

• Hundreds of steroids have been isolated from plants and animals, and thousands more have been prepared by chemical treatment of natural steroids or by synthesis from simpler compounds. The steroid nucleus is a three-dimensional structure, and atoms or groups are attached to it by spatially directed bonds.
• Although many stereoisomers of this nucleus are possible (and maybe synthesized), the saturated nuclear structures of most classes of natural steroids are alike, except at the junction of rings A and B.
• Simplified three-dimensional diagrams may be used to illustrate stereochemical details. For example, androstane, common to several natural and synthetic steroids, exists in two forms (2 and 3), in which the A/B ring fusions are called cis and trans, respectively.

“Understanding drugs affecting the endocrine system through FAQs: Q&A explained”

In the cis isomer, bonds to the methyl group, CH3, and the hydrogen atom, H, both project upward from the general plane defined by the rest of the molecule, whereas in the trans isomer.

The methyl group projects up and the hydrogen project down. Usually, however, steroid structures are represented as plane projection diagrams such as 4 and 5, which correspond to 2 and 3, respectively.

Stereochemistry of steroids

The stereochemistry of the rings markedly affects the biological activity of a given class of steroids There are six asymmetric carbon atoms 5,8,9,10,13,14 in the nucleus. Therefore 64 optically active forms are possible.

“How do drugs regulate hormone levels in the body? FAQ answered”

It can exist in two conformations namely chair form and boat form. Chair conformation is more stable than boat conformation due to less angle strain. Hence all cyclohexane rings exist in chair form.

Hydrogen or functional groups on the (3 side of the molecule are denoted by solid lines and the a side is denoted by dotted lines.

Stereoisomerism based on

1. How the rings are fused.
2. How configuration of substituent groups, particularly those at C3 and C17.

A and B Fusion: Fusion of rings A and B may either trans or cis to give 2 isomeric (alio and normal) C27hydrocarbon.

B and C Fusion: The fusion of the rings B and C was trans. The CIO angular methyl group must be trans to the C9 hydrogen atom.

C and D Fusion: The complete X-ray crystallographic analysis of cholesteryl iodide reveals that the ring union is trans in the sterols, bile acids, and related steroids.

Nomenclature

1. Above the plane of the nucleus – β configuration.
2. Below the plane of the nucleus – α configuration.
3. Configuration of substituents is unknown -wavy line.
4. If some carbon atoms are missing in the steroid nucleus, the numbering of the remainder will not change.

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If the side chain doesn’t contain a methylene group, this is indicated by the prefix “nor”, proceeded by the no.of the carbon atom that has disappeared. 23-nor 5α/β cholane.

If the steroid nucleus doesn’t contain an angular methyl group, this is indicated by the prefix “nor”, proceeded by the number that designates the methyl group. 10-nor 5α/β androstane.

“Common challenges in understanding endocrine drug mechanisms effectively: FAQs provided”

If the ring contraction occurs in the steroid nucleus, this is again indicated by the prefix “nor”, preceded by a capital letter indicating the ring affected. A- nor 5α/β androstane.

If there is an enlargement of the ring in the steroid nucleus, indicated by the prefix “homo”, proceeded by a capital letter indicating the ring affected. B- homo 5 α/β pregnane.

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If there is a ring fission or breaking occurs, indicated by the prefix “seco”, proceeded by several positions of a bond broken. 2,3 Seco 5α/β-androstane-2,3-dioic acid.

If the steroid nucleus contains 3 membered rings, indicated by the prefix “cyclo”. 3α,5α-Cyclocholestane.

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Metabolism of steroids: Steroids are primarily oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring, allowing the cholesterol to be broken up by other enzymes into bile adds.

• These acids then be eliminated by secretion from the liver in bile. The expression of the oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.
• Steroid hormones, lacking the side chain of cholesterol and bile adds., are typically hydroxylated at various ring positions or oxidized at die 17 positions, corrugated with sulfate or glucuronic add, and excreted in the urine.

Sex Hormones

A hormone is a chemical released into the blood and transported to affect cells in other parts of the body. Hormones regulate many things in the body, such as Growth and development.

• Male and female development How tire body uses energy. Levels of salts and sugars in the blood. The amount (volume) of fluid in the body.
• Sex hormone is a chemical substance produced by a sex gland or other organ that affects the sexual features of an organism. Like many other kinds of hormones, sex hormones may also be artificially synthesized.

Types of male and female hormones

Estrogen

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Estrogen IUPAC name: (17β)-estra-1,3,5(10)-triene-3,17-diol.

• Estrogen, or estrogen, is the primary female sex hormone. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics.
• Three major endogenous estrogens in females have estrogenic hormonal activity: estrone, estradiol, and estriol The estrane steroid estradiol is the most potent and prevalent of these.
• The three major naturally occurring forms of estrogen in females are estrone (El), estradiol (E2), and estriol (E3). Another type of estrogen called estetrol (E4) is produced only during pregnancy.
• Quantitatively, estrogens circulate at lower levels than androgens in both men and women. While estrogen levels are significantly lower in males compared to females, estrogens nevertheless also have important physiological roles in males.

Estrogen MOA: The actions of estrogen are mediated by the estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls gene expression.

• Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor.
• The estrogen complex binds to specific DNA sequences called a hormone response element to activate the transcription of target genes.
• Since estrogen enters all cells, its actions are dependent on the presence of the ER in the cell. The Er is expressed in specific tissues including the ovary, uterus, and breast.

Estrogen SAR:

1. Each estrogen contains a phenolic A ring with a hydroxyl group at carbon 3 and a beta-OH or ketone in position 17 of ring D.
2. The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to both receptors.
3. Ring A and 3-OH, 17β-OH groups are necessary for activity.
4. Activity depends on the mode of action Subcutaneous= Estradiol > Estrone > Estriol
   Oral = Estriol > Estradiol > Estrone. Ethinyl estradiol has the greatest activity, because of resistance to metabolism in the liver and degradation by enzymes in GIT.
5. Removal of the 3-OH group, epimerization of 17(3-OH group, the introduction of unsaturation in the ‘B’ ring, and expansion of the rD’ ring drastically decrease the activity.
6. Compound without steroid nuclei also shows activity.

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Estrogen Metabolism: Estrogens are metabolized via hydroxylation by cytochrome P450 enzymes such as CYP1A1 and CYP3A4 and via conjugation by estrogen sulfotransferases (sulfation) and UDPglucuronyltransferases (glucuronidation).

In addition, estradiol is dehydrogenated by 17β- hydroxysteroid dehydrogenase into the much less potent estrogen estrone. These reactions occur primarily in the liver, but also in other tissues.

Estrogen Therapeutic Use: Estrogen is a type of medication that is used most commonly in hormonal birth control and menopausal hormone therapy.

They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens.

Estrogen Adverse Reactions: Side effects of estrogens include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema among others.

• other side effects of estrogens include an increased risk of blood clots, cardiovascular disease, and when combined with most progestogens, breast cancer.
• In men, estrogens can cause breast development, feminization, infertility, low testosterone levels, and sexual dysfunction among others.

Estradiol

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Estradiol IUPAC name: (8R,9S,13S,14S,17S)-13-Methyl 6,7,8,9,ll,12,14,15,16,17decahydrocyclopenta[a]phenanthrene-3,17-diol.

Estradiol MOA: Estradiol acts primarily as an agonist of the estrogen receptor (ER), a nuclear steroid hormone receptor. There are two subtypes of the ER, ERα and ERβ, and estradiol potently binds to and activates both of these receptors.

The result of ER activation is a modulation of gene transcription and expression in ER-expressing cells, which is the predominant mechanism by which estradiol mediates its biological effects in the body.

Estradiol Metabolism: Estradiol is also metabolized via hydroxylation into catechol estrogens. In the liver, it is non-specifically metabolized by CYP1A2, CYP3A4, and CYP2C9 via 2-hydroxylation into 2- hydroxyestradiol.

• And by CYP2C9, CYP2C19, and CYP2C8 via 17p-hydroxy dehydrogenation into estrone, with various other cytochrome P450 (CYP) enzymes and metabolic transformations also being involved.
• Estradiol is additionally conjugated with an ester into lipoidal estradiol forms like estradiol palmitate and estradiol stearate to a certain extent; these esters are stored in adipose tissue and may act as a very long-lasting reservoir of estradiol.

Estradiol Therapeutic uses: Estradiol is used as a medication, primarily in hormone therapy for menopausal symptoms as well as transgender hormone replacement therapy.

Oestriol

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Oestriol IUPAC name: (8R,9S,13S,US,16R,17R)-13-methyl-6<7,8,9,11,12,14,15,16,17-decahydrocycI0penta [a]phenanthrene-3,16,17-triol.

Oestriol MOA: Estriol is an estrogen, specifically an agonist of the estrogen receptors ERα and ERβ. It is a far less potent estrogen than estradiol, and as such is a relatively weak estrogen.

Oestriol Metabolism: Estriol is metabolized via glucuronidation and sulfation.

Oestriol Therapeutic uses: Estriol is used as a medication, primarily in hormone therapy for menopausal symptoms.

Oestriol Adverse reaction: Post-menopausal estrogen therapy is carcinogenic to humans.

Oestrione

Estrone (El), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads.

Oestrione IUPAC name: (8R,9S,13S,14S)-3-hydroxy-lS-methyl-ÿ,9,11,12,14,15,16-octahydro-6Hcyclopenta[a]phenanthren-17-one.

Oestrione MOA: Estrone is an estrogen, specifically an agonist of the estrogen receptors ERα and ERβ. it is a far less potent estrogen than estradiol, and as such, is a relatively weak estrogen.

Oestrione Metabolism: Estroen is conjugated into estrogen conjugates such as estrone sulfate and estrone glucuronide by sulfotransferases and glucuronidase, and can also be hydroxylated by cytochrome P450 enzymes into catechol estrogens such as 2-hydroxyestrone and 4-hydroxyestrone or into estriol. Both of these transformations take place predominantly in the liver.

Oestrione Therapeutic uses: Estrone has been available as an injected estrogen for medical use, for instance in hormone therapy for menopausal symptoms, but it is now mostly no longer marketed.

Oestrione Adverse reactions: Bloating, breast tenderness or swelling, swelling in other parts of the body, nausea, leg cramps.

Diethyl stilbestrol

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Diethyl stilbestrol IUPAC name: 4-[(E)-4-(4-hydroxyphenyl)hex-3-en-3-yl]phenol.

Diethyl stilbestrol MOA: Estrogens diffuse into their target cells and interact with a protein receptor, the estrogen receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary.

• The effect of Estrogen binding their receptors causes downstream increases in the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
• The combination of estrogen with progestin suppresses the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH).

Diethyl stilbestrol Metabolism: DES is metabolized mainly by glucuronidation and oxidation, with the latter including aromatic hydroxylation of the ethyl side chains and dehydrogenation into (Z, Z)-dienestrol. It is also known to produce paroxypropione as a metabolite.

Diethyl stilbestrol Therapeutic Uses: DES has been used in the past for the following indications: Recurrent miscarriage in pregnancy Menopausal hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy.

• Hormone therapy for hypoestrogenism (For Example., gonadal dysgenesis, premature ovarian failure, and after oophorectomy). Postpartum lactation suppression to prevent or reverse breast engorgement.
• Gonorrheal vaginitis (discontinued following the introduction of the antibiotic penicillin). Prostate cancer and breast cancer.

Diethyl stilbestrol Adverse Reaction: DES is associated with high rates of side effects including nausea, vomiting, abdominal discomfort, headache, and bloating, with an incidence of 15 to 50%.

Progesterone

Progesterone is considered the counterpart to estrogen. It is the antagonizer to estrogen-driven growth in the lining of the uterus. Progesterone is essential to the premenstrual cycle. It rises during the second part of the cycle to reduce premenstrual syndrome and prepares the uterus for the implantation of a fertilized egg. Additionally, progesterone is needed to support a healthy pregnancy, as low levels can result in a miscarriage.

“Can targeted interventions improve outcomes using endocrine drug knowledge? FAQs provided”

Progesteron IUPAC name: (8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-l,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one.

Progesteron MOA: Progesterone shares the pharmacological actions of the progestins. Progesterone binds to the progesterone and estrogen receptors. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary.

• Once bound to the receptor, progestins like Progesterone will slow the frequency of release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge.
• In women who have adequate endogenous estrogen, progesterone transforms a proliferative endometrium into a secretory one. Progesterone is essential for the development of decidual tissue and is necessary to increase endometrial receptivity for the implantation of an embryo.
• Once an embryo has been implanted, progesterone acts to maintain the pregnancy. Progesterone also stimulates the growth of mammary alveolar tissue and relaxes uterine smooth muscle. It has little estrogenic and androgenic activity.

Progesteron SAR: Steroidal nucleus is essential for activity.

1. Substitution at 17 α with ethynyl, methyl, and ethyl reduces activity.
2. Ethindrone is more active orally than progesterone.
3. Removal of CH3 at C19 is more active. For Example. (Norethindrone)
4. Unsaturation of the B or C ring of 19-Androstane derivates increases activity.
5. Acetylation of the 17β-OH of norethindrone long duration of action.

Progesterone Metabolism: Progesterone is metabolized primarily by the liver largely to pregnanediol and pregnanolones.

Progesteron Therapeutic Uses: Taking progesterone by mouth, and applying progesterone gel into the vagina are effective strategies for treating the absence of menstrual periods in premenopausal women.

Hormone replacement therapy (HKD. Intravaginal progesterone gel (Crinone 8%) is FDA-approved for use as a part of infertility treatment in women.

Progesterone Adverse reactions: Progesterone can cause many side effects including stomach upset, changes in appetite, weight gain, fluid retention, swelling (edema), fatigue, acne, drowsiness or insomnia, allergic skin rashes, hives, fever, headache, depression, breast discomfort or enlargement, premenstrual syndrome (PMS)-like symptoms.

Nandrolone

Nandrolone is an anabolic steroid (a muscle-building chemical) that occurs naturally in the human body, but only in tiny quantities.

It is very similar in structure to the male hormone testosterone and has many of die same effects in terms of increasing muscle mass, without some of the more unwanted side effects.

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Nandralone IUPAC name: (8R,9S,10R,13S,14S,17S)-17-hydroxy-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one.

Nandralone MOA: Nandrolone is an androgen receptor agonist. The drug is bound to the receptor complexes which allows it to enter the nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA.

The areas of binding are called hormone response (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.

Nandralone SAR:

1. Some of the structural modifications have been introduced into testosterone in an
   attempt to maximize the anabolic effect and minimize the androgenic.
2. Structural modifications to the A- and B-rings of testosterone increase anabolic activity.
3. Substitution at C-17 confers oral or depot activity (i.m.).

Nandralone Metabolism:

Nandrolone is unusual in that unlike most anabolic steroids, it is not broken down into the more reactive DHT by the enzyme 5a-reductase, but rather into a less effective product known as Dihydronandrolone.

Nandrolone Therapeutic Use: Nandrolone esters are used clinically, although increasingly rarely, for people in catabolic states with major bums, cancer, and AIDS, and an ophthalmological formulation was available to support cornea healing.

• The positive effects of nandrolone esters include muscle growth, appetite stimulation increased red blood cell production,[medical citation needed], and bone density.
• Clinical studies have shown them to be effective in treating anemia, osteoporosis, and breast cancer. Nandrolone sulfate has been used in an eye drop formulation as an ophthalmic medication.

Nandrolone Adverse reactions: Side effects of nandrolone esters include masculinization among others. Other side effects of high doses of nandrolone can include erectile dysfunction and cardiovascular damage.

As well as several ailments resulting from the drug’s effect of lowering levels of luteinizing hormone through negative feedback.

Testosterone

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Testosterone IUPAC name: (8R,9S,10R,13S,14S,17S)-17-hydroxy-13-methyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one.

Testosterone MOA: The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.

• Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5a-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5a-reductase.
• DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA.
• The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.

Testosterone SAR:

1. It lacks the 2-carbon side chain attached to the 17 position, making it a 19-carbon steroid (an androstane).
2. 17 alpha methyl group increases the duration of action and improves bioavailability. But this change increases hepatotoxicity.
3. The esterification of 17 in the beta OH group increases the duration of action and bioavailability.
4. The removal of 19^th carbon led to more anabolic selective molecules and less androgenic selectivity.

Testosterone Metabolism: Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT).

Testosterone Therapeutic Uses:

• Use in males: For management of congenital or acquired hypogonadism, hypogonadism associated with HIV infection, and male climacteric (andropause).
• Use in females: For the palliative treatment of androgen-responsive, advanced, inoperable, metastatic (skeletal) carcinoma of the breast in women who are 1-5 years postmenopausal.
• Testosterone esters may be used in combination with estrogens in the management of moderate to severe vasomotor symptoms associated with menopause in women who do not respond adequately to estrogen therapy alone.

Testosterone Adverse Reactions: Common side effects from testosterone medication include acne, swelling, and breast enlargement in males. Serious side effects may include liver toxicity, heart disease, and behavioral changes.

Women and children who are exposed may develop virilization. It is recommended that individuals with prostate cancer not use the medication. lt can cause harm if used during pregnancy or breastfeeding.

Drugs For Erectile Dysfunction

Erectile dysfunction is the consistent or recurrent inability of a man to attain and/or maintain an erection sufficient for sexual performance. ED happens when blood doesn’t flow well to the penis, or when the nerves in the penis are harmed.

ED can signal an underlying health or emotional problem. Finding and treating the cause(s) of your ED can improve your overall health and your sex life.

Sildenafil

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Sildenafil IUPAC Name: 5-{2-Ethoxy-5-[(4-methylpiperazin-l-yl)sulfonyl]phenyl}-1-methyl-3-propyl-1,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

Sildenafil MOA: Sildenafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis.

• Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle.
• This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells.
• Cyclic GMP causes smooth muscle relaxation and increases blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by sildenafil enhances erectile function by increasing the amount of cGMP.

Sildenafil Metabolism: Sildenafil appears to be completely metabolized in the liver to 16 metabolites. Its metabolism is mediated mainly by cytochrome P450 microsomal isozymes 3A4 (major route) and 2C9 (minor route).

• The major circulating metabolite, N-demethylated metabolite, has PDE selectivity similar to the parent drug and ∼50% of its in vitro potency.
• The N-demethylated metabolite is further metabolized to an N-dealkylated N, N-de-ethylated metabolite. Sildenafil also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

Sildenafil Therapeutic Uses: The primary indication of sildenafil is the treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse).

Its use is now one of the standard treatments for erectile dysfunction, including for men with diabetes mellitus. Sildenafil and other PDE5 inhibitors are used off-label to alleviate vasospasm and treat severe ischemia and ulcers in fingers and toes for people with secondary Raynaud’s phenomenon.

Sildenafil Adverse reactions: Adverse effects of sildenafil use included headache, flushing, indigestion, nasal congestion, and impaired vision, including photophobia and blurred vision.

Some sildenafil users have complained of seeing everything tinted blue (cyanopsia). Some complained of blurriness and loss of peripheral vision.

Tadalafil

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Tadalafil IUPAC name: (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a hexahydropyrazino [1′,2′:1,6] pyrido[3,4-b]indole-1,4-dione.

Tadalafil MOA: Tadalafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus callosum located around the penis.

• Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle.
• This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells.
• Cyclic GMP causes smooth muscle relaxation and enhances the corpus callosum. The inhibition of phosphodiesterase-type erectile function by increasing the amount of cGMP.

Tadalafil Metabolism: Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation
to form the methyl catechol and methyl catechol glucuronide conjugate, respectively.

In vitro data suggests e metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Tadalafil Therapeutic Uses: Tadalafil is used to treat male sexual function problems (impotence or erectile dysfunction ED). In combination with sexual stimulation, tadalafil works by increasing blood flow to the perns to help a man get and keep an erection.

• Tadalafil is also used to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia-BPH).
• It helps to relieve symptoms of BPH such as difficulty in beginning the flow of urine, weak stream, and the need to urinate frequently or urgently (including during the middle of the night). Tadalafil is thought to work by relaxing the smooth muscle in the prostate and bladder.

Tadalafil Aderse Reactions: The most common side effects when using tadalafil are headache, stomach discomfort or pain, indigestion, burping, add reflux, back pain, muscle aches, flushing, and stuffy or runny nose.

• These side effects reflect the ability of PDE5 inhibition to cause vasodilation (causing blood vessels to widen) and usually go away after a few hours.
• Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and the symptom usually disappears after 48 hours.

Oral Contraceptives

Oral contraceptives, also called birth control pills, are a safe and reliable option for preventing unwanted pregnancy. Most oral contraceptives contain a combination of 2 types of hormones estrogen and progestin.

• Both of these hormones are naturally found in women’s bodies. There are many different types of estrogen and progestin.
• Both of these hormones are naturally found in women’s bodies. There are many different types of estrogens, and different types of pills contain different combinations, but they all work similarly. some pills contain only progestin, sometimes called the “mini-pill”.

“Early warning signs of complications from ignoring endocrine drug protocols: Common questions”

Mifepristone

Mifepristone IUPAC name: (8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenanthren-3-one.

Mifepristone MOA: The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites.

Based on studies with various oral does in several animal species (mouse, rat, rabbit, and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results.

Mifepristone Metabolism: Hepatic, by Cytochrome P450 3A4 isoenzyme to the N-monomethylated metabolite (RU 42 633); RU 42 698, which results from the loss of two methyl groups from position 11 beta; and RU 42 698, which results from terminal hydroxylation of the 17-propynyl chain.

Mifepristone Therapeutic Uses: Mifepristone followed by a prostaglandin analog (misoprostol or gemeprost) is used for medical abortion. Medical organizations have found this combination to be safe and effective.

Mifepristone is used for the medical treatment of high blood sugar (hyperglycemia) caused by high cortisol levels in the blood (hypercortisolism) in adults with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot have surgery. Mifepristone is used for emergency contraception.

Mifepristone Adverse Reactions: Nausea or vomiting, decreased appetite, dry mouth, tiredness, dizziness, headache, or joint or muscle pain may occur.

Norgestril

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Norgestril IUPAc name: (8R,9S,10R,13S,14S)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one.

Norgestril MOA: Norgestrel (and more specifically the active stereoisomer levonorgestrel) binds to the progesterone and estrogen receptors with the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary.

Once bound to the receptors, progestins like levonorgestrel will slow the frequency of release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge. Loss of the LH surge inhibits ovulation and thereby prevents pregnancy.

Norgestrel Therapeutic Uses: Norgestrel is used in combination with ethinylestradiol or quinestrol in combined birth control pills, alone in progestogen-only birth control pills, and in combination with estradiol or conjugated estrogens in menopausal hormone therapy.

Norgestril Adverse Reactions: Side effects of norgestrel include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others.

Levonorgestrol

Levonorgestrol IUPAC name: (8R,9S,10R,13S,14S)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,ll, 12,14,15, 16-dodecahydrocyclopenta[a]phenanthren-3-one.

Levonorgestrol MOA: Binds to the progesterone and estrogen receptors. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary.

Once bound to the receptor, progestins like levonorgestrel will slow the frequency of release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge.

Levonorgestrol Therapeutic Uses: Levonorgestrel is a hormonal medication that is used in several birth control methods. In pill form, sold under the brand name Plan B among others, it is useful within 120 hours as emergency birth control.

• It becomes less effective the longer after sex and only works before pregnancy has occurred. It is also combined with estrogen to make combined oral birth control pills.
• Within an intrauterine device (IUD), sold as Mirena among others, it is effective for long-term prevention of pregnancy.

Levonorgestrel Adverse Reaction: Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding.

Corticosteroids

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogs of these hormones.

• Two main classes of corticosteroids, glucocorticoids, and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, and immune response.
• And regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.
• Glucocorticoids (anti-inflammatory) which suppress inflammation and immunity and assist in the breakdown of fats, carbohydrates, and mineralocorticoids (salt retaining) that regulate the balance of salt and water in the body.

Cortisone

“Can preventive measures reduce risks of hormone imbalances? FAQs provided”

Cortisone IUPAC Name: (8S,9S,10R,13S,14S,17R)-17-Hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8, 9,12,14,15,16-decahydrocydopenta[a]phenanthrene-3,11-dione.

Cortisone MOA: Cortisone suppresses the immune system, thus reducing inflammation and attendant pain and swelling at the site of the injury.

Cortisone Therapeutic Uses: Cortisone, a glucocorticoid, and adrenaline are the main hormones released by the body as a reaction to stress. They elevate blood pressure and prepare the body for a fight-or-flight response.

• A cortisone injection can also be used to give short-term pain relief and reduce the swelling from inflammation of a joint, tendon, or bursa in, for example, the joints of the knee, or elbow, and response in person with autoimmune diseases or following an organ transplant to prevent transplant rejection. [citation needed]
• The suppression of the immune system may also be important in the treatment of inflammatory conditions.

Cortisone Adverse Reactions: Oral use of cortisone has several potential systemic side-effects: Asthma, hyperglycemia, insulin resistance, diabetes mellitus, osteoporosis, anxiety, depression, amenorrhoea, cataracts, Cushing’s syndrome, and glaucoma, among other problems.

Local side effects are rare but can include: pain, infection, skin pigment changes, loss of fatty tissue, and tendon rupture.

Hydrocortisone

“Differential applications of estrogen vs progesterone therapies: Q&A”

Hydrocortisone IUPAC name: (11β)-11,17,21-trihydroxypregn-4-ene-3,20-dione.

Hydrocortisone MOA: Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding the receptor the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes.

• The DNA-bound receptor then interacts with basic transcription factors, causing an increase in the expression of specific target genes.
• The anti-inflammatory actions of corticosteroids are thought to involve lipocortins and phospholipase A2 inhibitory proteins which, through inhibition of arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes.

Hydrocortisone Metabolism: Metabolism primarily hepatic via CYP3A4.

Hydrocortisone Therapeutic Uses: Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD.

It is the treatment of choice for adrenocortical insufficiency. It can be given by mouth, topically, or by injection. Stopping treatment after long-term use should be done slowly.

Hydrocortisone Adverse reactions: Side effects may include mood changes, increased risk of infection, and swelling. With long-term use common side effects include osteoporosis, upset stomach, physical weakness, easy bruising, and yeast infections. While used, it is unclear if it is safe during pregnancy.

Prednisolone

Prednisolone IUPAC name: (11(β)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione.

Prednisolone MOA: Glucocorticoids such as Prednisolone can inhibit leukocyte infiltration at the site of inflammation interfere with mediators of inflammatory response, and suppress humoral immune responses.

• The antiinflammatory actions of glucocorticoids are thought to involve phospholipase A2 inhibitory proteins, and lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.
• Prednisolone reduces inflammatory reactions by limiting the capillary dilatation and permeability of the vascular structures.

Prednisolone Metabolism: Excreted in the urine as either free or glucoconjugate.

Prednisolone Therapeutic Uses: useful for the treatment of a wide range of inflammatory and autoimmune conditions such as asthma, uveitis, pyoderma gangrenosum, rheumatoid arthritis, urticaria, angioedema, ulcerative colitis.

Pericarditis, temporal arteritis, Crohn’s disease, Bell’s palsy, multiple sclerosis, cluster headaches, vasculitis, acute lymphoblastic leukemia and autoimmune hepatitis, systemic lupus erythematosus, Kawasaki disease dermatomyositis, sarcoidosis.

Prednisolone Adverse Reactions: Increased appetite, weight gain, nausea and malaise. Increased risk of infection. Cardiovascular events in children.

• Dermatological effects include reddening of the face, brushing or skin discoloration, impaired wound healing, thinning of the skin, skin rash, fluid buildup, and abnormal hair growth. Hyperglycemia; patients with diabetes may need increased insulin or diabetic therapies for menstrual abnormalities.
• Less response to hormones, especially during stressful instances such as surgery or illness. change in electrolytes: rise in blood pressure.

Betamethasone

“Difference between thyroid drugs and corticosteroids: Q&A explained”

Betamethasone IUPAC name: (8S,9R,10S,11S,13S,14S,16S,17R)-9-Fluoro- 11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl- 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro- 3H-cyclopenta[a]phenanthren-3-one.

Betamethasone MOA: Betamethasone is a glucocorticoid receptor agonist. This leads to changes in genetic expression once this complex binds to the GRE.

• The antiinflammatory actions of corticosteroids are thought to involve lipocortins and phospholipase A2 inhibitory proteins which, through inhibition of arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes.
• The immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding.
• Betamethasone binds to plasma transcortin, and it becomes active when it is not bound to transcortin.

Betamethasone Therapeutic Uses: It is used for several diseases including rheumatic disorders such as rheumatoid arthritis and systemic lupus erythematosus, skin diseases such as dermatitis and psoriasis, allergic conditions such as asthma and angioedema.

Preterm labor to speed the development of the baby’s lungs, Crohn’s disease, cancers such as leukemia, and fludrocortisone for adrenocortical insufficiency.

Betamethasone Adverse reactions: Serious side effects include an increased risk of infection, muscle weakness, severe allergic reactions, and psychosis. Long-term use may cause adrenal insufficiency.

Stopping the medication suddenly following long-term use may be dangerous. The cream commonly results in increased hair growth and skin irritation. Betamethasone belongs to the glucocorticoid class of medication.

Dexamethasone

“Most common complications of poorly understood endocrine drug concepts: FAQs”

Dexamethasone MOA: Dexamethasone is a glucocorticoid agonist. Unbound dexamethasone crosses cell membranes and binds with high affinity to specific cytoplasmic glucocorticoid receptors.

• This complex binds to DNA elements (glucocorticoid response elements) which results in a modification of transcription and, hence, protein synthesis to achieve inhibition of leukocyte infiltration at the site of inflammation.
• Interference in the function of mediators of inflammatory response, suppression of humoral immune responses, and reduction in edema or scar tissue.
• The antiinflammatory actions of dexamethasone are thought to involve phospholipase A2 inhibitory proteins, and lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.

Dexamethasone Therapeutic Uses: It is used in the treatment of many conditions, including rheumatic problems, several skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, and along with antibiotics in tuberculosis.

In adrenocortical insufficiency, it should be used together with a medication that has greater mineralocorticoid effects such as fludrocortisone. In preterm labor, it may be used to improve outcomes in the baby.

Dexamethasone Adverse Reactions: The long-term use of dexamethasone may result in thrush, bone loss, cataracts, easy bruising, or muscle weakness. Acne, Insomnia, Vertigo, Increased appetite, weight gain, impaired skin healing, Depression, Euphoria, Hypertension, etc.

Thyroid And Antithyroid Drugs

The thyroid gland produces thyroid hormones. These Hormones are essential for life and have many effects on body metabolism, growth, and development. Thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodine. The two principal thyroid hormones are Thyroxine (also known as T4 or L-3,5,3′,5′-tetraiodothyronine).

• Triiodotyronine (T3 or L-3,5,3′-triiodothyronine)
• Thyroid hormones have two major physiological effects. They increase protein synthesis in virtually every body tissue and increase oxygen consumption dependent upon Na+-K+ATPsae (Na pump).
• Hyperthyroidism occurs seven to nine times more likely in women than in men. Hyperthyroidism often occurs between the ages of twenty and forty, while hypothyroidism often appears after the age of fifty.
• Certain types of thyroid tumors appear to be more prevalent in certain age groups. In the last few years, case studies of patients with hyperthyroidism in their youth have shown that, thirty years later, the same individuals have a greater tendency to develop hypothyroidism.
• Thyroid problems have a strong genetic component, and may “skip” generations. Family histories may be useful in suggesting the nature of thyroid problems at early stages.
• Prematurely gray hair, hair that starts to go gray before the age of thirty, is often a sign of thyroid dysfunction. Patchy hair loss, usually temporary, is often observed by persons with Graves’ or Hashimoto’s disease.

Hypothyroidism in Adults: It is a state of low serum thyroid hormone resulting from hypothalamic, pituitary, or thyroid insufficiency. Untreated, can lead to life-threatening myxedema coma (early signs of fatigue, forgetfulness, sensitivity to cold, unexplained weight gain.

Constipation progresses to decreasing mental stability, dry, flaky inelastic skin; puffy face, hands, and feet; hoarseness; periorbital edema; upper eyelid droop; dry, sparse hair Most common in women, incidence rising significantly in persons aged 40 to 50.

Hypothyroidism in Children (Cretinism): This is a Deficiency of thyroid hormone secretion during fetal development or early infancy that results in infantile cretinism (congenital hypothyroidism).

• Respiratory difficulties, persistent jaundice; and hoarse crying in infants; stunted growth (dwarfism), bone and muscle dystrophy, and mental deficiency in older children.
• 3 times more common in girls than in boys. Infants not treated within the first 3 months or children within two years suffer irreversible mental retardation.

Thyroiditis: Thyroiditis is the inflammation of the thyroid gland and can be divided into categories of autoimmune (Long-term inflammatory disease; Grave’s Disease, Hashimoto’s Disease).

Subacute granulomatous (Self-limiting inflammation), Riedel’s (rare, invasive fibrotic process), and miscellaneous (acute suppurative, chronic infective, chronic non-infective). More common in women than in men (5 to 7 times more common.)

“Why are endocrine drug mechanisms often misunderstood in practice? Questions answered”

Hyperthyroidism (Grave’s Disease, Basedow’s disease, Parry’s disease, thyrotoxicosis): Hyperthyroidism is a metabolic imbalance that results from thyroid hormone overproduction. The most common is Grave’s Disease. Only 5% of hyperthyroid patients are under age 15.

Grave’s Disease

Toxic goiter is a cause of 80% of hyperthyroidism. A diffusely enlarged thyroid gland associated with hyperthyroidism is known as Grave’s disease. Autoimmune disease. The highest incidence is between the ages of 30 and 40.

Disorder of unknown etiology characterized by exophthalmos, enlarged pulsating thyroid gland, marked acceleration of heart rate, tendency to profuse sweats, nervous symptoms (fine muscular tremors, restlessness, irritability), psychic disturbances, emaciation, and increased metabolic rate.

Anti-thyroid Drugs

Anti-thyroid drugs (ATDs) are compounds that interfere with the body’s production of thyroid hormone, thereby reducing symptoms of hyperthyroidism.

ATDs were discovered accidentally in the mid-1940s when thiocyanate compounds used for heart disease were found to cause hypothyroidism. This led to the development of several compounds specifically tailored to reduce thyroid hormone production.

1. L-Thyroxine

“Cost of ignoring endocrine drug principles vs benefits of systematic approaches: Q&A”

L-Thyroxine IUPAC name: (S)-2-Amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl] propanoic acid.

L-Thyroxine SAR:

1. Levothyroxine is a synthetic form of thyroxine (T4), an endogenous hormone secreted by the thyroid gland, which is converted to its active metabolite, L-triiodothyronine (T3).
2. T4 and T3 bind to thyroid receptor proteins in the cell nucleus and cause metabolic effects through the control of DNA transcription and protein synthesis.

L-Thyroxine SAR:

1. The ether oxygen can be replaced isosterically by sulphur or methylene which also provide an angle of 120 °C. This change does not qualitatively impair the activity.
2. A phenolic hydroxyl group at the 4′ position is important for hydrogen bonding to transport proteins. It can, however, be replaced by isosteric groups like NH2 or by a group that generates a hydroxyl group after metabolism (OCH3 or OCOCH3). However such a change results in reduced hormonal activity.
3. The S’-position ortho to the hydroxyl and away from the other aromatic ring must be substituted by a lipophilic group. This can be a halogen (preferably Iodine) or any alkyl group approximately of the same size as Iodine such as an isopropyl group.
4. The iodine atoms at 3 and 5 positions can be replaced by non-polar groups (such as methyl), as long as they keep the aromatic rings perpendicular to each other.
5. The amino add side chain can be varied but should be para to the aromatic ring.

L-Thyroxine Metabolism: The primary pathway of thyroid hormone metabolism is through sequential deiodination. The liver is the main site of T4 deiodination, and along with the kidneys is responsible for about 80% of circulating T3.

In addition to deiodination, thyroid hormones are also excreted through the kidneys metabolized through conjugation and glucuronidation, and excreted directly into the bile and the gut where they undergo enterohepatic recirculation.

L-Thyroxine Therapeutic Use: Levothyroxine is typically used to treat hypothyroidism, and is the treatment of choice for people with hypothyroidism, who often require lifelong thyroid hormone therapy.

It may also be used to treat goiter via its ability to lower thyroid-stimulating hormone (TSH), a hormone that is considered goiter-inducing.

L-Thyroxine Adverse reactions: Adverse events are generally caused by incorrect dosing. Long-term suppression of TSH values below normal values will frequently cause cardiac side effects and contribute to decreases in bone mineral density (low TSH levels are also well known to contribute to osteoporosis).

• Too high a dose of levothyroxine causes hyperthyroidism. Overdose can result in heart palpitations, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia, weight loss, and increased appetite.
• Allergic reactions to the drug are characterized by symptoms such as difficulty breathing, shortness of breath, or swelling of the face and tongue. Acute overdose may cause fever, hypoglycemia, heart failure, coma, and unrecognized adrenal insufficiency.

2. L-Thyronine

“Is endocrine-related risk reversible if addressed promptly? Answer provided”

L-Thyronine IUPAC name: (2S)-2-amino-3-[4-(4-hydroxyphenoxy)phenyllpropanoic acid.

3. Propylthiouracil

Propylthiouracil IUPAC name: 6-propyl-2-sulfanylpyrimidin-4-one.

Propylthiouracil MOA: Propylthiouracil binds to thyroid peroxidase and thereby inhibits the conversion of iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (via hydrogen peroxide as a cofactor) and also catalyzes.

• The incorporation of the resulting iodide molecule onto both the 3 and or 5 positions of the phenol rings of tyrosines found in thyroglobulin.
• Thyroglobulin is degraded to produce thyroxine (T4) and tri-iodothyronine (T3), which are the main hormones produced by the thyroid gland. Therefore propylthiouracil effectively inhibits the production of new thyroid hormones.

Propylthiouracil Metabolism: Propylthiouracil is readily absorbed and is extensively metabolized. Approximately 35% of the drug is excreted in the urine, in intact and conjugated forms, within 24 hours.

Propylthiouracil Therapeutic Uses: Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves’ disease and toxic multinodular goiter.

In a thyrotoxic crisis, it is generally more effective than methimazole. Otherwise, it is typically only used when methimazole surgery and radioactive iodine is not possible.

Propylthiouracil Adverse Reactions: Common side effects include itchiness, hair loss, swelling vomiting, muscle pains, numbness, and headache. Other severe side effects include liver problems and low blood cell counts.

Use during pregnancy may harm the baby. Propylthiouracil is in the antithyroid family of medications. It works by decreasing the amount of thyroid hormone produced by the thyroid gland and blocking the conversion of thyroxine(T4) to triiodothyronine(T3).

Methimazole

“Success rate of interventions using modern endocrine drug techniques: FAQ”

Methimazole IUPAC name: 1-Methyl-3H-imidazole-2-thione.

Methimazole MOA: It inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I-) to iodine (12), hypoiodous acid (HOI).

Enzyme-linked hypoioctate (EOI) facilitates iodine’s addition to tyrosine residues on the hormone precursor thyroglobulin, a necessary step in the synthesis of triiodothyronine (T3) and thyroxine (T4)

Methimazole Metabolism: Primarily hepatic. Metabolized rapidly, requiring frequent administration.

Methimazole Therapeutic Uses: Methimazole is a drug used to treat hyperthyroidism such as in Graves’ disease, a condition that occurs when the thyroid gland begins to produce an excess of thyroid hormone.

The drug may also be taken before thyroid surgery to lower thyroid hormone levels and minimize the effects of thyroid manipulation.

Methimazole Adverse reaction: It is important to monitor any symptoms of fever or sore throat while taking thiamazole; this could indicate the development of agranulocytosis, an uncommon but severe side effect resulting from a drop in the white blood cell count (to be specific, neutropenia, a deficiency of neutrophils).

A complete blood count (CBC) with differential is performed to confirm the suspicion, in which case the drug is discontinued.

Drugs Acting On Endocrine System Multiple Choice Questions And Answers

Question 1. Hormone production is a function related to ___________.

1. Hypothalamus
2. Pons
3. Hippocampus
4. Medulla

Answer: 1. Hypothalamus

Question 2. The mode of action of steroid hormones involves _____________.

1. A second messenger
2. Modification of
3. Stimulation of DNA replication
4. Stimulation of mRNA enzyme activity

Answer: 4. Stimulation of mRNA enzyme activity

Question 3. Prostaglandins are local regulators whose basic structure is derived from __________.

1. Oligosaccharides
2. Fatty acids
3. Steroids
4. Amino acids

Answer: 2. Fatty acids

Question 4. One reason a person might be several overweight is due to __________.

1. An under-secretion of thyroxine
2. A defect in hormone release from the posterior pituitary
3. A lower-than-normal level of insulin-like growth factors
4. Hyposecretion of oxytocin

Answer: 1. An under-secretion of thyroxine

Question 5. All of the following are steroid hormones except ________.

1. Androgen
2. Cortisol
3. Estrogen
4. Insulin

Answer: 4. Insulin

Question 6. Testosterone is an example of __________.

1. An androgen
2. An estrogen
3. A progestin
4. A catecholamine

Answer: 1. An androgen

Question 7. In children, hypothyroidism (underactive thyroid gland) can lead to _________.

1. Goiter
2. Acromegaly
3. Cretinism
4. Myxedema

Answer: 3. Cretinism

Question 8. In Males, the sex hormone that maintains sexual organs and secondary sex characteristics is ________.

1. Progesterone
2. Estrogen
3. Testosterone
4. Relaxin

Answer: 3. Testosterone

Question 9. Anabolic steroids are ________ versions of testosterone.

1. Effective
2. Synthetic
3. Natural
4. Ineffective

Answer: 2. Synthetic

Question 10. Which of the following is characteristic of Male Erectile Disorder?

1. A failure to attain an erection from the outset of sexual activity
2. First experiencing an erection but then losing tumescence before penetration
3. Losing tumescence during penetration but before orgasm
4. All of the above

Answer: 1. A failure to attain an erection from the outset of sexual activity

Drugs Acting On Endocrine System Short Questions And Answers

Question 1. What is the endocrine system?

Answer:

Many different glands make up the endocrine system. The hypothalamus, pituitary gland, and pineal gland are in your brain. The thyroid and parathyroid glands are in your neck.

The thymus is between your lungs, the adrenals are on top of your kidneys, and the pancreas is behind your stomach. Your ovaries (if you’re a woman) or testes (if you’re a man) are in your pelvic region.

Question 2. What is estrogen? and give therapeutic uses of it.

Answer:

Estrogen, or estrogen, is the primary female sex hormone. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics.

• Three major endogenous estrogens in females have estrogenic hormonal activity: estrone, estradiol, and estriol. Estrogen is a type of medication that is used most commonly in hormonal birth control and menopausal hormone therapy.
• They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens.

Question 3. What are Atv anabolic steroids?

Answer:

Anabolic steroid (a muscle-building chemical) occurs naturally in the human body, but only in tiny quantities.

• It is very similar in structure to the male hormone testosterone, and has many of the same effects in terms of increasing muscle mass, without some of the more unwanted side-effects For Example. Nandrolone esters an used clinically.
• Although increasingly rarely, for people in catabolic states with major bums, cancer, and AIDS, an ophthalmological formulation was available to support cornea healing.

Question 4. Give SAR points for testosterone.

Answer:

1. It lacks the 2-carbon side chain attached to the 17 position, making it a 19-carbon steroid (an androstane).
2. 17 alpha methyl group increases the duration of action and improves bioavailability. But this change increases hepatotoxicity.
3. The esterification of the 17 beta OH group increases the duration of action and bioavailability.
4. The removal of 19th carbon led to more anabolic selective molecules and less androgenic selectivity.

5. What are oral contraceptives?

Answer:

Oral contraceptives, also called birth control pills, are a safe and reliable option for preventing unwanted pregnancy. Most oral contraceptives contain a combination of 2 types of hormones: estrogen and progestin.

Both of these hormones are naturally found in women’s bodies. There are many different types of estrogens and progestins, and different types of pills contain different combinations, but they all work similarly. Some pills contain only progestin, sometimes called the “mini-pill.”

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Congestive heart failure (CHF) is a chronic progressive condition that affects the pumping power of your heart muscles. Cardiac failure is the inability of the heart to pump blood effectively at a rate that meets the needs of metabolizing tissues.

• This occurs due to reduced contractility of the cardiac muscles, especially those of the ventricles, which cause a decrease in cardiac output, increasing the blood volume of the heart.
• As a result, systemic blood pressure and renal blood flow are both reduced, which often leads to the development of edema in the lower extremities and the lung (pulmonary edema) as well as renal failure.

Types of CHF

1. Left-sided CHF is the most common type of CHF. It occurs when the left ventricle doesn’t properly pump blood out to the body. As the condition progresses, fluid can build up in the lungs, which makes breathing difficult. There are two types of left-sided heart failure:
   • Systolic heart failure occurs when the left ventricle fails to contract normally. This reduces the level of force available to push blood into circulation.
   • Diastolic failure or diastolic dysfunction happens when the muscle in the left ventricle becomes stiff. Because it can no longer relax, the heart can’t quite fill with blood between beats.
2. Right-sided CHF occurs when the right ventricle has difficulty pumping blood to the lungs. Blood backs up in blood vessels, which causes fluid retention in the lower extremities, abdomen, and other vital organs.
   • It’s possible to have left-sided and right-sided CHF at the same time. Usually, the disease starts on the left side and then travels to the right when left untreated.

“What are drugs for congestive heart failure? A detailed notes and Q&A guide”

Read and Learn More Medicinal Chemistry II Notes

Drugs Used In Congestive Heart Failure

Drugs that increase the force of contraction allow greater amounts of blood to be distributed throughout the body and, in turn, reduce the symptoms associated with CHF.

Most of the positive inotropic agents show their effects on the force of contraction by modifying the coupling mechanism involved in the myocardial contractile process.

Cardiac Glycosides

Cardiac glycosides have both beneficial and toxic effects on the heart. Digoxin is one of the oldest compounds used in cardiovascular medicine.

Chemistry of the Cardiac Glycosides Cardiac glycosides are composed of two portions the sugar moiety and the non-sugar (aglycone) moiety.

• Aglycones- The aglycone portion of the cardiac glycosides is a steroid nucleus containing 4 rings A, B, C, and D. Rings A and C-D are cis fused, whereas rings B-C have a trans configuration.
• The cardiac glycosides include two distinct classes of compounds the cardenolides and the bufadienolides.
• These differ in the substitutions at the C-17 position; where the cardenolides possess an unsaturated butyrolactone ring, the bufadienolides, possess a six-membered lactone ring with two conjugated double bonds.

“Understanding CHF medications through FAQs: Notes and explanations”

Glycone or Sugar moiety – Hydroxyl group of aglycone at the 3 position is conjugated with sugar moiety via 1,4- glucosidic linkage. Commonly found sugar moieties are 1-rhamnose, d-digitoxose, d-glucose, and d-cymarose. These sugars existin β- conformation.

Cardiac Glycosides MOA: Cardiac glycosides show a positive inotropic effect. They inhibit the membrane-bound Na⁺/K⁺– adenosine triphosphatase (Na⁺/K⁺ ATPase) pump which is responsible for sodium/potassium exchange.

• Normally, these Na⁺/K⁺-ATPase pumps move potassium ions in and sodium ions out of the myocardium. At the resting state, sodium is located outside the cell.
• On membrane depolarization, Na+ goes inside, leading to an immediate elevation of the action potential.
• Increased intracellular sodium stimulates the influx of Ca2⁺⁺ which is represented by the plateau region of the cardiac action potential. The influx of calcium causes the efflux of potassium out of the myocardial membrane.
• The Na⁺/K⁺ exchange is an energy-dependent process and is catalyzed by the enzyme Na⁺/K⁺– ATPase.

Cardiac glycosides inhibit this enzyme, due to which less amount of sodium is exchanged with potassium which in turn results in increased intracellular calcium. Elevated intracellular calcium concentration causes an increase in myocardial contraction.

“How do drugs for congestive heart failure improve cardiac function? FAQ answered”

Digoxin

A cardiotonic glycoside obtained mainly from Digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity.

“Importance of studying CHF drugs for cardiology students: Questions explained”

Dlgoxin MOA: Digoxin inhibits the Na⁺/K⁺-ATPase membrane pump, increasing intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote the activation of contractile proteins (For Example., actin, and myosin).

Dlgoxin Metabolism: Hepatic (but not dependent upon the cytochrome P-450 system). The end metabolites, which include 3 b-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar and are postulated to be formed via hydrolysis, oxidation, and conjugation.

Dlgoxin Uses: It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation.

• Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small.
• Digoxin is usually given orally, but can also be given by 4 injections in urgent situations. The half-life is about 3b hours for patients with normal renal function.

Toxicity

In mild to moderate toxicity, the common symptoms are anorexia, nausea and vomiting, muscular weakness, bradycardia, and ventricular premature contractions. The nausea is a result of the excitation of the chemoreceptor trigger zone in the medulla.

• In severe toxicity, the common symptoms are blurred vision, disorientation, diarrhea, ventricular tachycardia, and AV block, which can progress into ventricular fibrillation.
• It is usually accepted that the toxicity of the cardiac glycosides results from inhibition of the Na⁺/K⁺-ATPase pump, which results in increased intracellular levels of Ca²⁺.
• Hypokalemia (decreased potassium), which can be induced by co-administration of thiazide diuretics, glucocorticoids, or by other means, can be an important factor in initiating a toxic response.

Digitoxin

“Common challenges in understanding CHF drug mechanisms effectively: FAQs provided”

Digitoxin MOA: Digitoxin inhibits the Na-K-ATPase membrane pump, increasing intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote the activation of contractile proteins (For Example., actin, and myosin).

Digitoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.

Digitoxin Uses: For the treatment and management of congestive cardiac insufficiency, arrhythmias, and heart failure.

Digitoxin is sometimes used in place of digoxin. It has a longer half-life than digoxin. It is eliminated via the liver, so could be used in patients with poor or erratic kidney function.

Toxicity

Toxic effects, which are similar to those of digoxin namely; anorexia, nausea, vomiting, diarrhea, confusion, visual disturbances, and cardiac arrhythmias are longer lasting.

Nesiritide

“Why is early learning of CHF drugs critical for patient care? Answered”

Nesiritide MOA: Nesiritide is a recombinant human B (brain)-type natriuretic peptide (rhBNP) that exerts a direct vasodilator}ÿ effect on arterial and venous blood vessels, along with potent natriuretic and diuretic effects on the kidney.

• These effects result from the binding of rhBNP to natriuretic peptide receptors A and B on vascular smooth muscle cells, endothelial cells, and kidneys.
• And adrenal gland; inhibition of peripheral vascular sympathetic neurotransmission; and inhibition of the renin-angiotensin-aldosterone pathway.
• Binding to natriuretic peptide receptors A and B activates guanylyl cyclase, resulting in an intracellular rise in cGMP. cGMP regulates vascular smooth muscle relaxation via a decrease in intracellular calcium

“Factors influencing success with CHF drug knowledge: Q&A”

Nesiritide Metabolism: Nesiritide undergoes proteolytic cleavage of the peptide by endopeptidases, such as neutral endopeptidase, which are present on the vascular lumenal surface.

Nesiritide Uses: For the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

Nesiritide Adverse effect: Symptomatic hypotension has been reported in approximately 4% of adult patients receiving nesiritide.

• Careful blood pressure monitoring is therefore advised, and nesiritide is not recommended in adults with baseline systolic blood pressure less than 100 mm Hg.
• Nesiritide may decrease renal function in patients with severe CHF whose kidney function is dependent on renin-angiotensin-aldosterone function.

Bosentan

“Steps to explain types of CHF drugs: Diuretics vs ACE inhibitors vs beta-blockers: Notes guide”

Bosentan IUPAC name: 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl] benzene-1-sulfonamide.

Bosentan MOA: Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B receptors in the endothelium and vascular smooth muscle.

• ET-1 concentrations are elevated in the plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease.
• Bosentan is a specific and competitive antagonist at endothelin receptor types ET_A and ET_B– Bosentan has a slightly higher affinity for ET_A receptors than for ET_B receptors.

Bosentan Metabolism: Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

Bosentan Uses: Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class 3 or 4 symptoms).

Bosentan Adverse effects: The most common side effect was headache of mild to moderate intensity, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.

Tezosentan

“Role of spironolactone in managing CHF symptoms: Questions answered”

Tezosentan IUPAC name: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2H-1,2,3,4-tetrazol-5-yl) pyridin-4-yl] pyrimidin-4-yl] -5-(propan-2-yl) pyridine-2-sulfonamide.

Tezosentan MOA: Tezosentan is an intravenous and non-selective ETA and ETB receptor antagonist. It acts as a vasodilator and was designed as a therapy for patients with acute heart failure.

Tezosentan Uses: Investigated for use or treatment in congestive heart failure, liver disease, and heart disease.

Drugs Used In Congestive Heart Failure Multiple Choice Questions And Answers

Question 1. Cardiac glycosides inhibit which of the following?

1. Na-H-ATPase
2. Na-K-ATPase
3. Na-H-Symporter
4. All of the above

Answer: 2. Na-K-ATPase

Question 2. Ncsiritlde is metabolized by proteolytic cleavage of the peptide by ________

1. Exopepticwses
2. Lipase
3. Endopeptidases
4. Pepsin

Answer: 3. Endopeptidases

Question 3. Clinical efficacy of digitalis glycosides is based on _________

1. Decreased transmission through the AV node
2. Increased myocardial contractility
3. Both
4. Neither

Answer: 3. Both

Question 4. Cardiac output is directly dependent upon _________

1. Peripheral vascular resistance
2. Intravascular blood volume
3. Heart rate alone
4. Heart rate and stroke volume

Answer: 4. Heart rate and stroke volume

“How does lisinopril reduce afterload in CHF patients? FAQ explained”

Question 5. Component of digitalis responsible for Na/K ATPase binding ________

1. Genin or aglycone moiety
2. Sugar residues
3. Steroid component
4. All of the above

Answer: 1. Genin or aglycone moiety

Question 6. The most common symptom of heart failure.

1. Tachycardia
2. Oliguria
3. Hepatomegaly
4. Dyspnea

Answer: 4. Dyspnea

Question 7. Clinical efficacy of digitalis glycosides is based on _________

1. Decreased transmission through the AV node
2. Increased myocardial contractility
3. Both
4. All of the above

Answer: 3. Both

Question 8. Primarily excreted in the urine; digitalis glycosides with half-life of 16 days.

1. Digoxin
2. Digitoxin
3. Both
4. None of the above

Answer: 1. Digoxin

Question 9. Inhibitors of Na/K ATPase used in the management of CHF.

1. Enalapril
2. Digoxin
3. Minoxidil
4. Amrinone

Answer: 2. Digoxin

“Early warning signs of gaps in understanding CHF drug basics: Common questions”

Question 10. The mechanism by which vasodilators improve myocardial performance in CHF.

1. Increase heart rate
2. Promote diuresis
3. Reduce afterload
4. Reduce pulmonary blood flow

Answer: 3. Reduce afterload

Question 11. Which of the following is an intravenous endothelin receptor antagonist?

1. Tezosentan
2. Digoxin
3. Nesiritide
4. Digitoxin

Answer: 4. Digitoxin

Drugs Used In Congestive Heart Failure Short Questions And Answers

Question 1. Explain the different types of CHF

Answer:

1. Left-sided CHF is the most common type of CHF. It occurs when the left ventricle doesn’t properly pump blood out to the body. As the condition progresses, fluid can build up in the lungs, which makes breathing difficult. There are two types of left-sided heart failure:
   • Systolic heart failure occurs when the left ventricle fails to contract normally. This reduces the level of force available to push blood into circulation.
   • Diastolic failure or diastolic dysfunction, happens when the muscle in the left ventricle becomes stiff. Because it can no longer relax, the heart can’t quite fill with blood between beats.
2. Right-sided CHF occurs when the right ventricle has difficulty pumping blood to the lungs. Blood backs up in blood vessels, which causes fluid retention in the lower extremities, abdomen, and other vital organs.
   • It’s possible to have left-sided and right-sided CHF at the same time. Usually, the disease starts on the left side and then travels to the right when left untreated.

“Asymptomatic vs symptomatic effects of ignoring CHF drug principles: Q&A”

Question 2. Write the mechanism of action of cardiac glycosides.

Answer:

Cardiac glycosides show a positive inotropic effect. They inhibit the membrane-bound Na+/K+- adenosine triphosphatase (Na⁺/K⁺ ATPase) pump which is responsible for sodium/potassium exchange.

• Normally, these Na⁺/K⁺-ATPase pumps move potassium ions in and sodium ions out of the myocardium. At the resting state, sodium is located outside the cell. On membrane depolarization, Na⁺ goes inside, leading to an immediate elevation of the action potential.
• Increased intracellular sodium stimulates the influx of Ca2⁺⁺ which is represented by the plateau region of the cardiac action potential.
• The influx of calcium causes the efflux of potassium out of the myocardial membrane. The Na⁺/K⁺ exchange is an energy-dependent process and is catalyzed by the enzyme Na⁺/K⁺-ATPase.
• Cardiac glycosides inhibit this enzyme, due to which less amount of sodium is exchanged with potassium which in turn results in increased intracellular calcium. Elevated intracellular calcium concentration causes an increase in myocardial contraction.

Question 3. Write the mechanism of action of Nesiritide

Answer:

Nesiritideis a recombinant human B (brain)-type natriuretic peptide (rhBNP) that exerts a direct vasodilatory effect on arterial and venous blood vessels, along with potent natriuretic and diuretic effects on the kidney.

• These effects result from the binding of rhBNP to natriuretic peptide receptors A and B on vascular smooth muscle cells, endothelial cells, kidney, and adrenal gland; inhibition of peripheral vascular sympathetic neurotransmission; and inhibition of the renin-angiotensin-aldosterone pathway.
• Binding to natriuretic peptide receptors A and B activates guanylyl cyclase, resulting in an intracellular rise in cGMP. cGMP regulates vascular smooth muscle relaxation via a decrease in intracellular calcium.

“Differential applications of ARBs vs ACE inhibitors in CHF: Notes explained”

Question 4. Write the uses of Tezosentan and bosentan.

Answer:

Tezosentan uses– Investigated for use or treatment in congestive heart failure, liver disease, and heart disease.

Bosentan uses– Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease tire rate of clinical worsening (in patients with WHO Class 3 or 4 symptoms).

The post Drugs for Congestive Heart Failure Notes appeared first on BDS Notes.

A theory of blood clotting introduced in 1905 was based on the existence of four factors: thromboplastin (thrombokinase), prothrombin, fibrinogen, and ionized calcium.

• The clotting sequence proposed was that when tissue damage occurred, thromboplastin entered the blood from the platelets and reacted with prothrombin in the presence of calcium to form thrombin.
• Thrombin then reacted with fibrinogen to form insoluble fibrin, which enmeshed red blood cells (RBCs) to create a clot.

Blood coagulation: factors involved

“Understanding coagulants and anticoagulants through FAQs: Q&A explained”

Mechanism Of Blood Coagulation

The process of blood coagulation involves a series of steps that occur in a cascade and terminate in the formation of a fibrin clot.

• Blood coagulation occurs by activation of either an intrinsic pathway, a relatively slow process of clot formation, or an extrinsic pathway, which has a much faster rate of fibrin formation.
• Both pathways merge into a common pathway for the conversion of prothrombin to thrombin and the subsequent transformation of fibrinogen to the insoluble strands of fibrin.
• Lysis of intravascular clots occurs through a plasminogen plasmin system, which consists of plasminogen, plasmin, urokinase, kallikrein, plasminogen activators, and some undefined inhibitors.
• The intrinsic pathway refers to the system for coagulation that occurs from the interaction of factors circulating in the blood. It is activated when blood comes into contact with a damaged vessel wall or a foreign substance.
• Each of the plasma coagulation factors, except factor 3 (tissue thromboplastin), circulates as an inactive proenzyme.

Read and Learn More Medicinal Chemistry II Notes

Except for fibrinogen, which precipitates as fibrin, these factors are usually activated by enzymatic removal of a small peptide in the cascade of reactions that make up the clotting sequence.

• The extrinsic clotting system refers to the mechanism by which thrombin is generated in plasma after the addition of tissue extracts.
• When various tissues, such as the brain or lungs (containing thromboplastin), are added to blood, a complex between thromboplastin and factor 7 in the presence of calcium ions activates factor 10, bypassing the time-consuming steps of the intrinsic pathway that form factor 10.
• The intrinsic and extrinsic pathways interact in vivo. Small amounts of thrombin formed early after stimulation of the extrinsic pathway accelerate clotting by the intrinsic pathway by activating factor 8.
• Thrombin also speeds up the clotting rate by activating factor V, located in the common pathway. Thrombin then converts the soluble protein fibrinogen into a soluble fibrin gel by acting on GlyArg bonds to remove small fibrinopeptides from the N-terminus, enabling the remaining fibrinogen molecule to polymerize.

It also activates factor XHI, which stabilizes the fibrin gel in the presence of calcium by cross-linking between the chains of the fibrin monomer through intermolecular y-glutamyl- lysine

“Importance of studying coagulants and anticoagulants for pharmacology students: Questions explained”

“Common challenges in understanding coagulation mechanisms effectively: FAQs provided”

Coagulant drugs: Coagulant drugs, also called anti-inhibitor coagulant complexes, also help regulate blood coagulation. Some diseases, such as hemophilia, lead to defects in blood bleed uncontrollably in response to coagulation and patients suffering from the disorder can have relatively minor injuries.

Anticoagulant drugs: Although anticoagulants are called blood thinners, these medicines do not thin your blood. Instead, they decrease the blood’s ability to clot. Decreased clotting keeps fewer harmful blood clots from forming and from blocking blood vessels.

Classification Of Drugs Used In Clotting Disorders

“Factors influencing success with coagulant and anticoagulant knowledge: Q&A”

Menadione

“Steps to explain types of coagulants: Vitamin K vs clotting factors: Q&A guide”

Menadione IUPAC name: 2-methyl-1,4-dihydronaphthalene-l,4-dione.

Menadione MOA: Menadione (vitamin K3) is involved as a cofactor in the posttranslational gamma-carboxylation of glutamic acid residues of certain proteins in the body.

• These proteins include the vitamin K-dependent coagulation factors 2 (prothrombin), 7 (proconvertin), 9 (Christmas factor), 10 (Stuart factor), protein C, protein S, protein Zv, and a growth-arrest-specific factor (Gas6).
• In contrast to the other vitamin K-dependent proteins in the blood coagulation cascade, protein C and protein S serve anticoagulant roles. The two vitamin K-dependent proteins found in bone are osteocalcin, also known as bone Gla (gamma-carboxyglutamate) protein or BGP, and the matrix Gla protein or MGP.
• Gamma-carboxylation is catalyzed by the vitamin K-dependent gamma-carboxylases. The reduced form of vitamin K, vitamin K hydroquinone, is the actual cofactor for the gamma carboxylases

Menadione Uses: The primary known function of vitamin K is to assist in the normal clotting of blood, but it may also play a role in normal bone calcification.

Menadione Adverse effect: Menadione (vitamin K3), which is not used as a nutritional supplemental form of vitamin K for humans, has been reported to cause adverse reactions, including hemolytic anemia. Large doses have also been reported to cause brain damage.

Acetomenaphthone

“Role of warfarin in preventing blood clots: Questions answered”

Acetomenaphthone IUPAC name: (4-acetyloxy-3-methylnaphthalen-1-yl) acetate.

Acetomenaphthone MOA: Acetomenaphthone (Vitamin K3) is a synthetic analogue, involved as a cofactor in the posttranslational gamma-carboxylation of glutamic acid residues of certain proteins in the body.

• These proteins include the vitamin K-dependent coagulation factors 2 (Prothrombin), 7 (proconvertin), 9 (Christmas factor), 10 (Stuart factor), protein C, Protein S, protein Zv, and a growth-arrest-specific factor (Gas6).
• In contrast to the other vitamin K-dependent proteins in the blood coagulation cascade, protein C and protein S serve anticoagulation roles. The two vitamin K-dependent proteins found in bone are osteocalcin, also known as bone G1a (gamma-carboxyglutamate) protein or BGP, and the matrix G1a protein or MGP.
• gamma-carboxylation is catalyzed by the vitamin K-dependent gamma-carboxylases. The reduced form of vitamin K, vitamin K hydroquinone, is the actual cofactor for the gamma-carboxylases.

Warfarin

“Early warning signs of gaps in understanding coagulant basics: Common questions”

Warfarin IUPAC name: 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one.

Warfarin MOA: Warfarin inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2).

• As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins.
• The synthesis of vitamin K-dependent coagulation factors 2, 7, 9, and X and anticoagulant proteins C and S is inhibited.
• Depression of three of the four vitamin K-dependent coagulation factors (factors 2, 7, and 10) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

Warfarin Metabolism: Hepatic CYP2C9 isozyme is responsible for metabolizing (S)-warfarin and other coumarin derivatives to give 6- and 7-hydroxywarfarins as the major inactive metabolites.

• Whereas hepatic CYP3A4, CYP1A2, and CYP2C19 isozymes inactivate (R)-warfarin, the less active enantiomer, to give 4′-, 6-, and 8-hydroxywarfarins, respectively.
• Warfarin also undergoes, to a lesser extent, reductive metabolism of the ketone on the C-3 side chain to a pair of pharmacologically active, diastereomeric 2′-hydroxywarfarins.

Warfarin Uses: For the treatment of retinal vascular occlusion, pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, transient cerebral ischemia, arterial embolism and thrombosis.

The clinically used preparation of warfarin is racemic, but the (S)- and (R)-enantiomers are not equipotent. (S)-warfarin is at least fourfold more potent as an anticoagulant than (R)-warfarin.

Warfarin Adverse Effect: Warfarin can cross the placental barrier during pregnancy which can result in fetal bleeding, spontaneous abortion, preterm birth, stillbirth, and neonatal death.

Additional adverse effects such as necrosis, purple toe syndrome, osteoporosis, valve and artery calcification, and drug interactions have also been documented with warfarin use.

Warfarin Synthesis:

“Asymptomatic vs symptomatic effects of ignoring coagulant principles: Q&A”

Anisindione

Anisindione IUPAC name: 2-(4-methoxyphenyl)-2/3-dihydro-1H-indene-1/3-dione.

Anisindione MOA: Anisindione exercises its therapeutic action by reducing the prothrombin activity of the blood.

• Anisindione prevents the formation of active pro-coagulation factors 2, 7, 9, and 10, as well as the anticoagulant proteins C and S, in the liver by inhibiting the vitamin K-mediated gamma-carboxylation of precursor proteins.
• Anisindione has no direct thrombolytic effect and does not reverse ischemic tissue damage, although it may limit the extension of existing thrombi and prevent secondary thromboembolic complications.

Anisindione Uses: For the prophylaxis and treatment of venous thrombosis and its extension, the treatment of atrial fibrillation with embolization, the prophylaxis and treatment of pulmonary embolism, and as an adjunct in the treatment of coronary occlusion.

Anisindione Adverse Effect: An overdose is likely to cause abnormal bleeding, for which the symptoms include: bleeding from gums or nose, blood in urine or stools, excessive bleeding from minor cuts, and patches of discoloration or bruises on the skin.

Clopidogrel

“Differential applications of direct vs indirect anticoagulants: Questions answered”

Clopidogrel IUPAC name: methyl (2S)-2-(2-chlorophenyl)-2-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-yl}acetate.

Clopidogrel MOA: The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GP 2b/3a complex.

• It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane.
• The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in the aggregation of platelets and cross-linking by the protein fibrin.
• No direct interference occurs with the GP 2b/3a receptor. As the glycoprotein GP 2b/3a complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation.
• By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of clopidogrel.

Clopidogrel Metabolism: Hepatic, extensive, and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid derivative, which accounts for approximately 85% of the circulating drug-related compounds.

A glucuronic acid derivative of the carboxylic acid derivative has also been found in plasma and urine. Neither the parent compound nor the carboxylic acid derivative has a platelet-inhibiting effect. The active metabolite of clopidogrel is 2- oxoclopidogrel.

Clopidogrel Uses: For the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.

Clopidogrel Adverse Effect: Clopidogrel use is associated with several serious adverse drug reactions such as severe neutropenia, various forms of hemorrhage, and cardiovascular edema.

“Role of diagrams in understanding coagulation cascade: Questions answered”

Coagulants And Anticoagulants Multiple Choice Questions And Answers

Question 1. What are the steps in fibrin formation?

1. “Tissue factor” or thromboplastin is released from the endothelial wall.
2. Contact of blood with collagen.
3. Clots bind thromboxane A2.
4. (1) and (2)

Answer: 4. (1) and (2)

Question 2. Proteins C and S are dependent on which vitamin for synthesis?

1. Vitamin C
2. Vitamin B
3. Vitamin E
4. Vitamin K

Answer: 4. Vitamin K

Question 3. What might cause a deficiency In Prothrombin (factor 2) or Stuart-Power factor (factor 10)?

1. Liver disease
2. Vitamin K deficiency
3. (1) and (2)
4. Renal disease

Answer: 3. (1) and (2)

“Steps to master coagulants and anticoagulants for exams: Study plans vs mock tests: Q&A guide”

Question 4. Which drug acts by competitive inhibition of vitamin K reductase?

1. Desirudin (Iparavask)
2. Warfarin
3. Heparin
4. Ezetimibe
5. Niacin

Answer: 2. Heparin

Question 5. How much time is required for the peak anticoagulant effect of Warfarin?

1. 3 hours
2. 1 day
3. 1 week
4. 3 days

Answer: 4. 3 days

Coagulants And Anticoagulants Short Questions And Answers

Question 1. Define coagulant.

Answer:

Coagulant drugs, also called anti-inhibitor coagulant complexes, also help regulate blood coagulation.

Some diseases, such as hemophilia, lead to defects in blood coagulation and patients suffering from the disorder can bleed uncontrollably in response to relatively minor injury.

“Differential applications of traditional vs digital study resources: Q&A”

Question 2. Draw the structure and IUPAC name of Menadione.

Answer:

IUPAC name: 2-methyl-1,4-dihydronaphthalene-1,4-dione.

“Steps to incorporate AI into analyzing anticoagulant drug efficacy: Questions and answers”

Question 3. Write the MOA of warfarin.

Answer:

Warfarin inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2).

• As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins.
• The synthesis of vitamin K-dependent coagulation factors 2, 7, 9, and 10 and anticoagulant proteins C and S is inhibited.
• Depression of three of the four vitamin K-dependent coagulation factors (factors 2, 7, and 10) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

The post Coagulants And Anticoagulants appeared first on BDS Notes.

Hyperlipidemia is the most prevalent indicator of susceptibility to atherosclerotic heart disease; it is a term used to describe elevated plasma levels of lipids that are usually in the form of lipoproteins.

• Lipoproteins are macromolecules consisting of lipid substances (cholesterol, triglycerides) non-covalently bound with protein and carbohydrates.
• These combinations solubilize the lipids and prevent them from forming insoluble aggregates in the plasma. Each lipoprotein is associated with an additional protein known as apolipoproteins.
• The various lipoproteins found in plasma can be separated by ultra-centrifugal techniques into chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
• The excess plasma concentration of one or more of these compounds is known as hyperlipidemia.
• Because all lipids require the presence of soluble lipoproteins to be transported in the blood, hyperlipidemia ultimately increases the concentration of these transport molecules.

A condition known as hyperlipoproteinemia and it is strongly associated with atherosclerotic lesions and coronary heart disease.

Read and Learn More Medicinal Chemistry II Notes

“Understanding antihyperlipidemic drugs through FAQs: Q&A explained”

Lipoprotein Metabolism

The rate at which cholesterol and triglycerides enter the circulation from the liver and small intestine depends on the supply of the lipids and proteins necessary to form the lipoprotein complexes.

• Although the protein component must be synthesized, the lipids can be obtained either from de novo biosynthesis in the tissues or from the diet. Reduction of plasma lipids by diet can delay the development of atherosclerosis.
• Furthermore, the use of drugs that decrease assimilation of lipids into the body plus diet decreases mortality from cardiovascular disease.
• The lipid transport mechanisms that exist shuttle cholesterol and triglycerides among the liver, intestine, and other tissues.
• Normally, plasma lipids, including lipoprotein cholesterol, are cycled in and out of plasma and do not cause extensive accumulation of deposits in the walls of arteries.
• Genetic factors and changes in hormone levels affect lipid transport by altering enzyme concentrations and apoprotein content, as well as the number and activity of lipoprotein receptors.

Lipids are transported by both exogenous (dietary intake) and endogenous (synthetic) pathways. The exogenous pathway begins after the ingestion of a fat-containing meal or snack.

“Importance of studying antihyperlipidemic agents for pharmacology students: Questions explained”

• Dietary lipids are absorbed in the form of cholesterol and fatty acids. The fatty acids are then reesterified within the intestinal mucosal cells and, along with the cholesterol, are incorporated into chylomicrons, the largest lipoprotein.
• During circulation, chylomicrons are degraded into remnants by the action of lipoprotein lipase, a plasma membrane enzyme located on capillary endothelial cells in adipose and muscle tissue.
• The interaction of chylomicrons with lipoprotein lipase requires apolipoprotein (apo) C-II, and the absence of either the enzyme or the apolipoprotein can lead to hypertriglyceridemia and pancreatitis.
• The liberated free acids are then available for either storage or energy generation by these tissues. The remnants are predominantly cleared from the plasma by liver parenchymal cells via recognition of the apo E portion Of the carrier.
• In the endogenous pathway of lipid transport, lipids are secreted from the liver. These are triglycerides and cholesterol combined with apoprotein B-100 and apoprotein E to form VLDL.

“Common challenges in understanding antihyperlipidemic mechanisms effectively: FAQs provided”

The VLDL is acted on by lipoprotein lipase in the capillaries of adipose tissue to generate free fatty acids (FFAs) and an IDL. Some IDL binds to LDL receptors in the liver and is cleared from plasma by endocytosis.

• Approximately half of the circulating IDL is converted to LDL in the plasma by additional loss of triglycerides. This LDL has a half-life in plasma of about 1.5 days and represents 60% to 70% of the cholesterol in plasma.
• These LDL particles bind to LDL receptors in extrahepatic tissues and are removed from the plasma. Levels of LDL receptors vary depending on the need of extrahepatic tissues to bind- LDL to use cholesterol.
• The extrahepatic tissue subsequently releases HDL. Free plasma cholesterol can be adsorbed onto HDL and the cholesterol esters formed by the enzyme lecithin-cholesterol acyltransferase (LCAT).
• These esters are transferred from HDL to VLDL or LDL in plasma to complete the cycle.

“Factors influencing success with antihyperlipidemic agent knowledge: Q&A”

Drug Therapy Affecting Lipoprotein Metabolism

In general, successful use of these compounds depends on proper identification and classification of the hyperlipoproteinemia affecting the patient.

HMG- CoA reductase inhibitors (Statins) For Example. Lovastatin, Atorvastatin.

Lipoprotein lipase activators (Fibrates) For Example. Clofibrate.

Bile acid sequestrants (resins) For Example. Cholestyramine, Colestipol.

Lipolysis and triglyceride synthesis inhibitors For Example. Nicotinic acid.

Cholesterol absorption inhibitor For Example. Ezetimibe

HMG-CoA Reductase Inhibitors (Statins)(HMGRIs)

“Steps to explain types of antihyperlipidemic agents: Statins vs fibrates vs bile acid sequestrants: Q&A guide”

• The development and use of HMGRIs began in 1976 with the discovery of mevastatin. Several years later, a structurally similar compound was isolated from Monascus ruber and Aspergillus terreus.
• This compound was originally known as mevinolin, was later renamed lovastatin, and was more than twofold more potent than mevastatin.

Statins SAR: Mevastatin and lovastatin served as lead compounds in the development of additional HMGRIs.

1. The activity of HMGRIs is sensitive to the stereochemistry of the lactone ring, the ability of the lactone ring to be hydrolyzed, and the length of the bridge connecting the two ring systems.
2. The bicyclic ring could be replaced with other lipophilic rings and the size and shape of these other ring systems were important to the overall activity of the compounds.
3. Pravastatin, a ring-opened dihydroxy acid with a 6’a-hydroxyl group, is much more hydrophilic than either lovastatin or simvastatin.
4. Proposed advantages of this enhanced hydrophilicity are minimal penetration into the lipophilic membranes of peripheral cells better selectivity for hepatic tissues, and a reduction in the incidence of side effects seen with lovastatin and simvastatin.
5. The replacement of the bicyclic ring with various substituted, aromatic ring systems led to the development of atorvastatin (substituted pyrrole), fluvastatin (indole), pitavastatin (quinolone), and rosuvastatin (pyrimidine).
6. Methyl substitution at the R2″ position increases activity (i.e., simvastatin is more potent than lovastatin).

Statins MOA: Inhibitors of HMG-CoA reductase lower plasma cholesterol levels by three related mechanisms: inhibition of cholesterol biosynthesis, enhancement of receptor-mediated LDL uptake, and reduction of VLDL precursors.

• As previously discussed, HMG-CoA reductase is the rate-limiting step in cholesterol biosynthesis. Inhibition of this enzyme causes an initial decrease in hepatic cholesterol.
• Compensatory mechanisms result in an enhanced expression of both HMG-CoA reductase and LDL receptors.
• The net result of all these effects is a slight to modest decrease in cholesterol synthesis, a significant increase in receptor-mediated LDL uptake, and an overall lowering of plasma LDL levels.

Lovastatin

“Role of statins in lowering LDL cholesterol: Questions answered”

Lovastatin IUPAC name: 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy6oxo-2H-pyran-2- yl)ethyl]-l-naphthalenyl ester.

Lovastatin Metabolism: Lovastatin is hepatically metabolized by CYP3A4 isozyme to the major active metabolites, the (3- hydroxy acid of lovastatin, the 6′-hydroxy derivative.

Lovastatin Uses: For management as an adjunct to diet to reduce elevated total -C, LDL-C, apo B, and TG levels in patients with primary hypercholesterolemia and mixed dyslipidemia.

For primary prevention of coronary heart disease and to slow the progression of coronary atherosclerosis in patients with coronary heart disease.

Lovastatin Adverse Effects: Gastrointestinal disturbances are the most common complaint; however, these and other adverse reactions tend to be mild and transient.

• Approximately 5% to 10% of patients will experience a mild increase in creatine phosphokinase levels; however, less than 1% will develop symptoms of myalgia and myopathy (For Example., fever, muscle aches or cramps, and unusual tiredness or weakness).
• Tests for creatine phosphokinase levels should be performed in patient muscle complaints.

Lipoprotein lipase activators (Fibrates)

A random screening test on a series of aryloxyisobutyric acids demonstrated that these compounds could lower both plasma cholesterol and total lipid levels.

• The compound that produced the best balance between activity and toxicity was ethyl p-chlorophenoxyisobutyrate.
• Later renamed clofibrate, this compound was subsequently shown to be a prodrug for p-chlorophenoxyisobutyric acid (clofibric acid).

Fibrates SAR:

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1. The isobutyric acid group is essential for activity.
2. Compounds containing an ester such as Fenofibrate, are required for vivo hydrolysis.
3. Substitution at the para position of the aromatic ring with a chloro group or a chlorine-containing cyclopropyl ring produces compounds with significantly longer half-lives.
4. Compounds contain a phenoxyisobutyric acid, the addition of an n-propyl spacer, as seen in gemfibrozil, results in an active drug.

Fibrates MOA: The mechanism of action has been proposed to be mediated through the activation of peroxisome proliferator-activated receptors (PPARs) and an alteration of gene expression.

• Specifically, fibrates bind to PPARa Decreases in plasma VLDL primarily result from the ability of these compounds to stimulate the activity of lipoprotein lipase, the enzyme responsible for removing triglycerides from plasma VLDL.
• Additionally, fibrates can lower VLDL levels through PPARa-mediated stimulation of fatty acid oxidation, inhibition of triglyceride synthesis, and reduced expression of apo C-3.
• This latter effect enhances the action of lipoprotein lipase because apo C-3 normally serves as an inhibitor of this enzyme.
• Favorable effects on HDL levels appear to be related to increased transcription of apoA-I and apo A-2 as well as a decreased activity of cholesteryl ester transfer protein.

Clofibrate

Clofibrate IUPAC name: ethyl 2-(p-chlorophenoxy)2-methylpropionate.

Clofibrate Metabolism: It undergoes rapid de-esterification in the gastrointestinal tract and or on first-pass metabolism to produce the active form, clofibric acid (chlorophenoxy isobutyric acid [CPIB]).

Clofibrate Uses: For Primary Dysbetalipoproteinemia (Type III hyperlipidemia) that does not respond adequately to diet. This helps control high cholesterol and high triglyceride levels.

Clofibrate Adverse effect: Clofibrate is tolerated well by most patients; the most common side effects are nausea and, to a lesser extent, other gastrointestinal distress.

The dosage of anticoagulants, if used in conjunction with this drug, should be reduced by one-third to one-half, depending on the individual response, so that the prothrombin time may be kept within the desired limits.

Bile acid sequestrants (resins)

Cholestyramine, colestipol, and colesevelam are chemically classified as anion-exchange resins. This term arises from their ability to selectively bind and exchange negatively charged atoms or molecules with one another.

• The selectivity comes from the fact that these positively charged resins do not bind equally to all anions.
• For example, the chloride ion of cholestyramine can be displaced by, or exchanged with, other anions (For example., bile acids) that have a greater affinity for the positively charged functional groups on the resin.

Resins SAR:

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1. Cholestyramine is a copolymer consisting primarily of polystyrene, with a small amount of divinylbenzene as the cross-linking agent.
2. It contains quaternary ammonium groups that function as binding sites for anions.
3. Increasing the amount of divinylbenzene from 2% to 4% to 8% increases the cross-linkage and reduces the porosity of the resin. This prevents the binding of bile acids and decreases the efficacy of the compound.
4. Colestipol is a copolymer of tetraethylenepentamine and epichlorohydrin contains basic secondary and tertiary amines.
5. The total nitrogen content of colestipol is greater than that of cholestyramine, the functional anion-exchange capacity of the resin depends on intestinal pH and may be less than cholestyramine.
6. Cholestyramine has a higher adsorption capacity than colestipol for bile salts.
7. Colesevelam is a more diverse polymer. In the case of colesevelam, poly (allylamine) is initially cross-linked with epichlorohydrin and then alkylated with 1-bromodecane and (6-bromohexyl)- trimethylammonium bromide.

Resins MOA: They bind the two major bile acids, glycocholic acid, and taurocholic acid, and greatly increase their fecal excretion. As a result, decreased concentrations of these compounds are returned to the liver.

• This removes the feedback inhibition of 7a-hydroxylase and increases the hepatic conversion of cholesterol to bile acids.
• The decrease in hepatic cholesterol concentrations leads to several compensatory effects: increased expression of LDL receptors, increased hepatic uptake of plasma LDL, induction of HMG-CoA reductase, and increased biosynthesis of cholesterol.
• The latter two effects are insufficient to counteract the increases in cholesterol clearance and catabolism; however, concurrent use of an HMGRI can provide an additive effect in lowering LDL cholesterol.
• The decreased return of bile acids to the liver also will produce an increase in triglyceride synthesis and a transient rise in VLDL levels.
• Subsequent compensatory mechanisms will increase VLDL removal, most likely through the increased LDL receptors, and return VLDL levels to predrug levels.

Cholestyramine

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Cholestyramine MOA: Cholestyramine binds bile in the gastrointestinal tract to prevent its reabsorption.

• The resin is a strong anion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix.
• The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

Cholestyramine Uses: Indicated as adjunctive therapy to diet for the reduction of elevated serum cholesterol in patients with primary hypercholesterolemia (elevated low-density lipoprotein [LDL] cholesterol) who do not respond adequately to diet. Also for the relief of pruritus associated with partial biliary obstruction.

Cholestyramine Adverse Effect: Constipation is by far the most frequent patient complaint. Increasing dietary fiber or using bulk-producing laxatives, such as psyllium, often can minimize this adverse effect.

• Other gastrointestinal symptoms, such as bloating and abdominal discomfort, usually disappear with continued use; however, the possibility of fecal impaction requires that extreme caution be used in patients with preexisting constipation.
• All three of these compounds release chloride ions as part of their exchange mechanism and can cause hyperchloremic acidosis.
• This is not a common occurrence, but it may limit the use of bile acid sequestrants in patients with renal disease. Hypoprothrombinemia and bleeding are caused by the ability of bile acid sequestrants to bind with and impair the absorption of dietary vitamin K.
• These effects also are rare, but they may limit the use of these agents in patients with preexisting clotting disorder and those being concurrently treated with anticoagulants.

Colestipol

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Colestipol MOA: It functions as an anion-exchange, resin-requesting gent like that of cholestyramine resin.

Colestipol hydrochloride reduces cholesterol levels without affecting triglycerides and seems to be especially effective in the treatment of type 2 hyperlipoproteinemias.

Lipolysis and triglyceride synthesis inhibitors

Nicotinic Acid

Nicotinic Acid IUPAC name: pyridine-3-carboxylic acid.

Nicotinic Acid MOA: The mechanism by which niacin exerts its lipid-lowering effects is not entirely understood, but may involve several actions, including a decrease in the esterification of hepatic triglycerides.

Niacin treatment also decreases the serum levels of apolipoprotein B-100 (apo B), the major protein component of the VLDL (very low-density lipoprotein) and LDL fractions.

Nicotinic Acid Metabolism: Nicotinic acid is a B-complex vitamin that is converted to nicotinamide, nicotinamide adenine dinucleotide (NAD+), and NADP+.

• The latter two compounds are coenzymes and are required for oxidation or reduction reactions in a variety of biochemical pathways.
• Additionally, nicotinic acid is metabolized into several inactive compounds, including nicotinic acid and N-methylated derivatives.

Nicotinic Acid Uses: Nicotinic acid is approved for the treatment of hypercholesterolemia, hypertriglyceridemia, and familial combined hyperlipidemia in patients who have not responded to diet, exercise, and other non-pharmacologic methods.

• It also is approved for nutritional supplementation, for the prevention of pellagra, and as an adjunct therapy for peripheral vascular disease and circulatory disorders.
• It is contraindicated in patients with hepatic disease and peptic ulcer disease. Additionally, because of its ability to elevate glucose and uric acid levels.
• Especially when taken in large doses, nicotinic acid should be used with caution in patients who have or are predisposed to diabetes mellitus and gout.

Nicotinic Acid Adverse effects: The most common (and, often, dose-limiting) side effects of nicotinic acid treatment are cutaneous vasodilation (flushing and pruritus) and gastrointestinal intolerance, which may occur in 20% to 50% of treated patients.

• Flushing and pruritus are prostaglandin-mediated effects and may be prevented by taking aspirin or indomethacin before nicotinic acid.
• Gastrointestinal side effects, such as flatulence, nausea, vomiting, and diarrhea, can be minimized if nicotinic acid is taken either with or immediately after meals.

Cholesterol Absorption Inhibitor

Ezetimib

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Ezetimib IUPAC name: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

Ezetimib MOA: Ezetimibe lowers plasma cholesterol levels by inhibiting the absorption of cholesterol at the brush border of the small intestine.

• Specifically, ezetimibe has been proposed to bind to a specific transport protein located in the wall of the small intestine, resulting in a reduction of cholesterol transport and absorption.
• Ezetimibe appears to be selective in its actions in that it does not interfere with the absorption of triglycerides, lipid-soluble vitamins, or other nutrients.
• The decreased absorption of cholesterol eventually leads to enhanced receptor-mediated LDL uptake similar to that seen with bile acid sequestrants and HMGRIs.

Ezetimib Metabolism: ezetimibe is rapidly and extensively metabolized in the intestinal wall and the liver to its active metabolite, a corresponding phenol glucuronide.

This glucuronide is excreted in the bile back to its active site. A small amount (<5%) of ezetimibe undergoes oxidation to convert the benzylic hydroxyl group to a ketone; however, ezetimibe does not appear to exert any significant effect on the activity of CYP450 enzymes.

Ezetimib Adverse Effect: Abdominal pain, diarrhea, arthralgia, back pain, cough, pharyngitis, sinusitis, fatigue, and viral infection.

Antihyperlipidemic Agents Multiple Choice Questions And Answers

Question 1. Which of the following is true concerning lipoproteins?

1. They serve to transport lipids from tissue to tissue and participate in lipid metabolism.
2. The inside of the particles has varying amounts of neutral lipids, cholesterol esters, and triacylglycerols.
3. 5 major classes have specific physiological and anatomical significance. The classes are chylomicrons, VLDL, IDL, LDL, and HDL.
4. All of the above are true concerning lipoproteins.

Answer: 4. All of the above are true concerning lipoproteins.

Question 2. Which apolipoprotein components of chylomicrons stimulate lipase?

1. C2 and E
2. A1 and A2
3. B-48 and E
4. C3 and A4

Answer: 1. C2 and E

Question 3. Which drug to treat hyperlipidemia acts by inhibiting the mobilization of free fatty acids (FFA) from peripheral adipose tissue to the liver?

1. Statins
2. Fabric Acids
3. Niacin (Nicotinic Acid)
4. Bile acid-binding Resins

Answer: 3. Niacin (Nicotinic Acid)

Question 4. Which antihyperlipidemic is most effective when given in combination with other drugs?

1. Niacin
2. Bile acid-binding resins
3. Ezetimibe
4. Statins

Answer: 1. Niacin

“Early warning signs of outdated methods in antihyperlipidemic studies: Common questions”

Question 5. What is the drug of choice for lowering VLDL levels in patients at risk of pancreatitis and for mixed elevations of LDLs and VLDLs and low levels of HDLs?

1. Fabric Acids
2. Ezetimibe
3. Statins
4. Niacin

Answer: 4. Niacin

Question 6. How can you avoid some of the adverse effects seen with Niacin (dyspepsia, skin flushing, itching)?

1. By taking an NSAID like Aspirin concurrently.
2. By taking the medication at night.
3. By taking the medication with food.
4. By taking the medication on an empty stomach.

Answer: 1. By taking an NSAID like Aspirin concurrently.

Question 7. What do the fibrous acid derivatives do?

1. Enhance oxidation of FA in the liver and muscle.
2. Reduce the rate of lipogenesis in the liver.
3. Increase synthesis of Apo AI and II for more HDL.
4. All of the above.

Answer: 4. All of the above.

Question 8. How do the Bile Acid-Binding Resins (Cholestyramine, Colestipol, and Colesevelam) function?

1. By binding LDLs and removing them from circulation.
2. By anionic exchange.
3. By attacking the plaque directly.
4. By cationic exchange.

Answer: 4. By cationic exchange.

“Asymptomatic vs symptomatic effects of ignoring new trends in antihyperlipidemic research: Answered”

Antihyperlipidemic Agents Short Questions And Answers

Question 1. What are lipoproteins? Classify them.

Answer:

Lipoproteins are macromolecules consisting of lipid substances (cholesterol, triglycerides) noncovalently bound with protein and carbohydrates.

The various lipoproteins found in plasma are chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).

Question 2. Write MOA of HMG CoA reductase inhibitor.

Answer:

Inhibitors of HMG-CoA reductase lower plasma cholesterol levels by three related mechanisms: inhibition of cholesterol biosynthesis, enhancement of receptor-mediated LDL uptake, and reduction of VLDL precursors.

• As previously discussed, HMG-CoA reductase is the rate-limiting step in cholesterol biosynthesis. Inhibition of this enzyme causes an initial decrease in hepatic cholesterol.
• Compensatory mechanisms result in an enhanced expression of both HMG-CoA reductase and LDL receptors.
• The net result of all these effects is a slight to modest decrease in cholesterol synthesis, a significant increase in receptor-mediated LDL uptake, and an overall lowering of plasma LDL levels.

Question 3. Discuss the S AU of Flbrates.

Answer:

“Differential applications of traditional vs cutting-edge antihyperlipidemic techniques: Questions answered”

1. The isobutyric acid group is essential for activity.
2. Compounds containing an ester such as Fenofibrate, are required for vivo hydrolysis.
3. Substitution at the para position of the aromatic ring with a chloro group or a chlorine-containing.
4. Cyclopropyl ring produces compounds with significantly longer half-lives.
5. Compounds contain a phenoxyisobutyric acid, the addition of an n-propyl spacer, as seen in gemfibrozil, results in an active drug.

Question 4. Give clinical uses of Cholestyramine.

Answer:

Indicated as adjunctive therapy to diet for the reduction of elevated serum cholesterol in patients with primary hypercholesterolemia (elevated low-density lipoprotein [LDL] cholesterol) who do not respond adequately to diet. Also for the relief of pruritus associated with partial biliary obstruction.

The post Antihyperlipidemic Agents appeared first on BDS Notes.

Arrhythmia

Arrhythmia is an alteration in the normal sequence of electrical impulse rhythm that leads to the contraction of the tire myocardium.

• It is manifested as an abnormality in the rate, in the site from which the impulses originate, or in tire conduction through the myocardium.
• The rhythm of the heart normally is determined by a pacemaker site called the SA node, which consists of specialized cells that undergo spontaneous generation of action potentials at a rate of 100 to 110 action potentials (“beats”) per minute.
• This intrinsic rhythm is strongly influenced by the vagus nerve, overcoming the sympathetic system at rest. This “vagal tone” brings the resting heart rate down to a normal sinus rhythm of 60 to 100 beats per minute.

Sinus rates below this range are termed “sinus bradycardia,” and sinus rates above the tins range are termed “sinus tachycardia.” The sinus rhythm normally controls both atrial and ventricular rhythm.

• Action potentials generated by the SA node spread throughout tire atria, depolarizing this tissue and causing atrial contraction. The impulse then travels into the ventricles via the AV node.
• Specialized conduction pathways within the ventricle rapidly conduct the wave of depolarization throughout the ventricles to elicit ventricular contraction.
• Therefore, Normal cardiac rhythm is controlled by the pacemaker activity of the SA node.
• Abnormal or irregular cardiac rhythms (heartbeats) can occur when the SA node fails to function normally, when other pacemaker sites (For Example., ectopic pacemakers) trigger depolarization, or when dysfunction occurs along the normal conduction pathways.

Normal Physiologic Action

Normal cardiac contractions largely are a function of the action of a single atrial pacemaker, a fast and usually uniform conduction in predictable pathways and a normal duration of the action potential and refractory period.

• The depicts a normal cardiac action potential from a Purkinje fiber. The resting cell has a membrane potential of approximately -90 mV, with the inside of the cell being electronegative relative to the outside of the cell.
• This is termed the “transmembrane resting potential.” On excitation, the transmembrane potential reverses, and the inside of the membrane rapidly becomes positive concerning the outside.
• On recovery from excitation, the resting potential is restored. These changes have been divided into five phases: Phase 0 represents depolarization and reversal of the transmembrane potential, phases 1 to 3 represent different stages of repolarization, and phase 4 represents the resting potential.

Read and Learn More Medicinal Chemistry II Notes

During phase 0, which is also referred to as rapid depolarization, the permeability of the membrane for sodium ions increases, and sodium rapidly enters the cell, causing it to become depolarized.

• Phase 1 results from the ionic shift, which creates an electrochemical and concentration gradient that reduces the rate of sodium influx but favors the influx of chloride and efflux of potassium.
• Phase 2, the plateau phase, results from the slow inward movement of calcium, which is triggered by the rapid inward movement of sodium in phase 0. During this time, there is also an efflux of potassium that balances the influx of calcium, thus resulting in little or no change in membrane potential.
• Phase 3 is initiated by a slowing of the calcium influx coupled with a continued efflux of potassium. This continued efflux of potassium from the cell restores the membrane potential to normal resting potential levels.
• During phase 4, the Na+, K+-ATPase pump restores the ions to their proper local concentrations.

The action potential is a coordinated sequence of ion movements in which sodium initially enters the cell, followed by a calcium influx, and finally, a potassium efflux returns the cell to its resting state. Several antiarrhythmic agents exert their effects by altering these ion fluxes.

Antiarrhythmic Agents

It is widely accepted that most currently available antiarrhythmic drugs can be classified into four categories, which are grouped based on their effects on the cardiac action potential and, consequently, on the electrophysiologic properties of the heart.

Antiarrhythmic Agents Classification

• Class 1 Membrane depressant drugs (Na+ Channel blockers)
  • Class 1 (1A) – For Example. Quinidine, Procainamide, Disopyramide.
  • Class 1 (1B) – For Example. Lidocaine, Phenytoin, Tocainide, Mexiletine.
  • Class 1 (1C) – For Example. Encainide, lorcainide, Moricizine.
• Class 2 β- Adrenergic blocking agents
  • For Example. Propranolol.
• Class 3 Repolarization prolongation (K⁺ Channel blockers)
  • For Example. Amiodarone, Bretylium, Sotalol.
• Class 4 Ca⁺⁺ Channel blockers
  • For Example. Verapamil, Diltiazem.

Class 1 membrane depressant drug (Na⁺ channel blockers)

• Drugs in this class act on the fast Na⁺ channels and interfere with the process by which the depolarizing charge is transferred across the membrane.
• It is assumed that these drugs bind to the Na+ channel and block its function, preventing Na+ conductance as long as the drug is bound.

Class 1 antiarrhythmic drugs can be subdivided based on the relative ease with which they dissociate from the Na⁺ ion channel. The action of class 1 local anesthetic-type antiarrhythmic drugs is pH-dependent and may vary with each drug.

• Class 1A-Quinidine, procainamide, and disopyramide are drugs that have an intermediate rate of dissociation from Na+ channels.
• Class 1B-Lidocaine, tocainide, and mexiletine dissociate rapidly from the Na+ channels and thus have the lowest potency as sodium channel blockers. They produce little, if any, change in action potential duration.
• Class 1C– Encainide, lorcainide, and moricizine, are the most potent sodium channel blocking agents. They slowly dissociate from the Na+ channel, causing a slowing of the conduction time of the impulse through the heart.

Class 1A

Quinidine sulphate

Quinidine sulphate IUPAC name: (5-ethenyl-l-azabicyclo[2.2.2] octan-2-yl) -(6-methoxyquinolin-4-yl) methanol; sulphuric add.

Quinidine sulfate MOA: It reduces Na⁺ current by binding the open ion channels. The decreased Na⁺ entry into the myocardial cell depresses phase 4 diastolic depolarization and shifts the intracellular threshold potential toward zero.

• These combined actions diminish the spontaneous frequency of pacemaker tissues, depress the automaticity of ectopic foci, and, to a lesser extent, reduce impulse formation in the SA node.
• This last action results in bradycardia. During the spike action potential, quinidine’s phase decreases transmembrane permeability to the passive influx of Na⁺, thus slowing the process of phase 0 depolarization, which decreases conduction velocity.
• This is shown as a prolongation of the QRS complex of electrocardiograms. Quinidine sulfate also prolongs action potential duration, which results in a proportionate increase in the QT interval.

Quinidine sulfate Metabolism: Quinidine is metabolized primarily in the liver by hydroxylation, and a small amount is excreted by the liver.

• The metabolites are hydroxylated derivatives at either the quinoline ring through first-pass O-demethylation or at the quinuclidine ring through oxidation of the vinyl group.
• These metabolites possess only about one-third of the activity of quinidine. Metabolites are 3- hydroxyquinidine and quinidine-N-oxide.

Quinidine sulphate Uses: It is used to treat supraventricular and ventricular ectopic arrhythmias, such as atrial and ventricular premature beats, atrial and ventricular tachycardia, atrial flutter, and atrial fibrillation.

Quinidine sulphate Adverse effects: The most frequent adverse effects associated with quinidine therapy are gastrointestinal disturbances, such as nausea, diarrhea, and vomiting.

Procainamide hydrochloride

Procainamide hydrochloride IUPAC name: p-amino-N-[2-(diethylamino)ethyl]benzamide monohydrochloride

Procainamide hydrochloride MOA: Procainamide is a sodium channel blocker. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby affecting local anesthetic action.

Procainamide hydrochloride Metabolism: Procainamide hydrochloride is metabolized through the action of N-acetyltransferase The product of enzymatic metabolism of procainamide hydrochloride is N-acetylProcainamide (NAPA), which possesses only 25% of the activity of the parent compound.

A study of the disposition of procainamide hydrochloride showed that 50% of the drug was exerted unchanged in the urine, with 7% to 24% recovered as NAPA.

Procainamide hydrochloride Uses: For the treatment of life-threatening ventricular arrhythmias.

Procainamide hydrochloride Adverse effects: If therapy is continued, a drug-induced lupus syndrome. These adverse effects which are attributed to the aromatic amino group, are observed more frequently and more rapidly m “slow acetylators.”

As a rule, the symptoms associated with procainamide-induced lupus syndrome subside fairly rapidly after the drug is discontinued.

Disopyramide phosphate

Disopyramide phosphate IUPAC name: α-[2(diisopropylamino)ethyl]- α -phenyl-2-pyridineacetamide phosphate.

Disopyramide phosphate MOA: Disopyramide is a type 1A antiarrhythmic drug (i.e. similar to procainamide and quinidine). It inhibits the fast sodium channels.

• In animal studies, Disopyramide decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells.
• Decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.

Disopyramide phosphate Metabolism: The drug undergoes hepatic CYP3A4 metabolism, principally to the corresponding N-dealkylated metabolite. This metabolite retains approximately half the antiarrhythmic activity of disopyramide and is also subject to renal excretion.

Disopyramide phosphate Uses: For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, ventricular pre-excitation, and cardiac dysrhythmias.

Disopyramide phosphate Adverse effects: Adverse effects are primarily anticholinergic and include dry mouth, blurred vision constipation, and urinary retention.

Disopyramide phosphate Synthesis:

Lidocaine hydrochloride

Lidocaine hydrochloride IUPAC name: 2-(diethylamino)-2′,6′-acetoxylidide monohydrochloride.

Lidocaine hydrochloride MOA: Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby affecting local anesthetic action.

• Lidocaine alters signal conduction in neurons by blocking the fast voltage-gated sodium (Na⁺) channels in the neuronal cell membrane that are responsible for signal propagation.
• With sufficient blockage the membrane of the postsynaptic neuron will not depolarize and will thus fail to transmit an action potential.
• This creates the anesthetic effect by not merely preventing pain signals from propagating to the brain but by aborting their birth in the first place.

Lidocaine hydrochloride Metabolism: Hepatic metabolism is rapid (plasma half-life, ~15 to 30 minutes) and primarily involves Ndeethylation to yield monoethylglycinexylide, followed by amidase-catalyzed hydrolysis into Nethylglycine and 2,6-dimethylaniline (2,6-xylidine).

Lidocaine hydrochloride Uses: For the production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks.

Lidocaine hydrochloride Adverse effects: The adverse effects of lidocaine include emetic and convulsant properties that predominantly involve the central nervous system and heart. The central nervous system effects can begin with dizziness and paresthesia and, in severe cases, ultimately lead to epileptic seizures.

Phenytoin sodium

Phenytoin sodium IUPAC name: 5,5diphenyl-2,4-imidazolidinedione.

Phenytoin sodium MOA: Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation.

• By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient.
• This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

Phenytoin sodium Metabolism: Phenytoin metabolism is relatively slow and predominantly involves aromatic hydroxylation by the CYP2C family of enzymes to p-hydroxylated inactive metabolites.

• Phenytoin also induces its metabolism and is subject to large inter-individual variability.
• The major metabolite, 5-phydroxyphenyl5-phenylhydantoin, accounts for approximately 75% of a dose. This metabolite is excreted through the kidney as the b-glucuronide conjugate.

Phenytoin sodium Uses: For the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

Tocainide hydrochloride

Tocainide hydrochloride IUPAC name: 2-amino-2′,6,-propionoxyxylidide hydrochloride.

Tocainide hydrochloride MOA: Tocainide acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation.

Tocainide binds preferentially to the inactive state of the sodium channels. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers.

Tocainide hydrochloride Metabolism: Negligible first pass hepatic degradation. Tocainide hydrochloride is hydrolyzed like that of lidocaine. No active metabolites have been found.

Tocainide hydrochloride Uses: For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, those, in the judgment of the physician, are life-threatening.

Tocainide hydrochloride Adverse effects: Adverse effects associated with tocainide are like those observed with lidocaine —specifically, gastrointestinal disturbances and central nervous system effects.

Mexiletine hydrochloride

Mexiletine hydrochloride IUPAC name: 1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride.

Mexiletine hydrochloride MOA: Mexiletine, like lidocaine, inhibits the inward sodium current required for the initiation and conduction of impulses, thus reducing the rate of rise of the action potential, Phase 0.

• It achieves this reduced sodium current by inhibiting sodium channels. Mexiletine decreases the effective refractory period (ERP) in Purkinje fibers in the heart.
• The decrease in ERP is of lesser magnitude than the decrease in action potential duration (APD), which increases the ERP/APD ratio.
• It does not significantly affect resting membrane potential or sinus node automaticity, left ventricular function, systolic arterial blood pressure, atrioventricular (AV) conduction velocity, or QRS or QT intervals.

Mexiletine hydrochloride Metabolism: Mexiletine hydrochloride is metabolized by oxidative and reductive processes by CYP2D6 in the liver. Its metabolites, p-hydroxymexiletine and hydroxymethylmexiletine, are not pharmacologically active as antiarrhythmic agents.

Mexiletine hydrochloride Uses: For the treatment of ventricular tachycardia and symptomatic premature ventricular beats and prevention of ventricular fibrillation.

Lorcainide hydrochloride

Lorcainide hydrochloride IUPAC name: N-(4-chlorophenyl)-N- (1-isopropylpiperidin-4-yl) -2-phenylacetamide, hydrochloride.

Lorcainide hydrochloride MOA: Irreversibly binding and reducing the fast Na+ influx. Interactions of Lorcainide with Nav1.5 are time and voltage-dependent.

• Class lc drugs have a characteristically slow dissociation rate, which will slow the upstroke duration and amplitude of ventricular myocytes’ action potential and prolong the PR, QRS, and QT intervals of an ECG.
• Lorcainide also increases the fibrillation threshold in a dose-dependent fashion. Overall, Lorcainide ventricular causes a decrease in tachycardiac events but also reduced ventricular contractility ejection fraction.
• The effect on sinus node function is controversial, as some researchers have noted a decreased sinus cycle length and an increase in sinus node recovery.

Lorcainide hydrochloride Metabolism: Noriorcainide, an N-dealkylated derivative, is an active metabolite of Lorcainide. It is as potent as its parent compound with similar antiarrhythmic efficacy, wherein it suppresses chronic premature ventricular complexes.

Lorcainide hydrochloride Uses: It is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardia, and Wolff-Parkinson-White syndrome.

Class 2 β- Adrenergic blocking agents

(3-adrenergic receptor blocking agents that block the role of the sympathetic nervous system in the genesis of certain cardiac arrhythmias.

• Their dominant electrophysiologic effect is to depress adrenergically enhanced calcium influx through β-receptor blockade.
• Drugs in this class decrease neurologically induced automaticity at normal therapeutic doses.
• At higher doses, these drugs can also exhibit anesthetic properties, which cause decreased excitability, decreased conduction velocity, and a prolonged effective refractory period.

Propranolol

Propranolol IUPAC name: 1-(naphthalen-1-yloxy)-3-[(propan-2-yl)amino]propan-2-ol.

Propranolol MOA: P-adrenergic receptor-blocking agents that block the role of the sympathetic nervous system in the genesis of certain cardiac arrhythmias. Their dominant electrophysiologic effect is to depress adrenergically enhanced calcium influx through p -p-receptor blockade.

Propranolol Uses: Its use as an antiarrhythmic is typically for the treatment of supraventricular arrhythmias, including atrial flutter, paroxysmal supraventricular tachycardia, and atrial fibrillation.

Propranolol is also reported to be effective in the treatment of digitalis-induced ventricular arrhythmias.

Class 3 Repolarizatlon prolongation (K⁺ Channel blockers)

The drugs in this class cause prolongation of the duration of the action potential. This results in a prolongation of the effective refractory period. It is believed that most class 3 antiarrhythmic agents act through phase 3 of the action potential by blocking potassium channels.

Amiodarone

Amiodarone IUPAC name: 2-butyl-3-benzofuranyl-4-[2(diethylamino)ethoxy]-3,5-diiodophenyl ketone.

Amiodarone MOA: It has a unique mechanism of action that involves the alteration of the lipid membrane in which ion channels and receptors are located. Its cardiac effects are not well characterized, but clinical studies indicate that it is primarily a class 3 agent.

Amiodarone Metabolism: Amiodarone is extensively metabolized in the liver via CYP2C8 (under 1% unchanged in urine), and can affect the metabolism of numerous other drugs.

• The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.
• The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated serum levels of amiodarone.

Amiodarone Uses: For the treatment of life-threatening ventricular arrhythmias that are refractory to other drugs.

Amiodarone Adverse Effects: Amiodarone has adverse effects involving many different organ systems. It also inhibits the metabolism of drugs cleared by oxidative microsomal enzymes.

• It contains iodine in its molecular structure and, as a result, affects thyroid hormones. Hypothyroidism occurs in up to 11% of patients receiving amiodarone.
• The principal effect is the inhibition of peripheral conversion of T4 to T3. Serum reverse T3 (rT3) is increased as a function of the dose as well as the length of amiodarone therapy.
• As a result, rT3 levels have been used as a guide for judging the adequacy of amiodarone therapy and predicting toxicity.

Sotalol

Sotalol IUPAC name: 4′[l-hydroxy-2-(isopropylamino) ethyl]methylsulfonanilide.

Sotalol MOA: Sotalol is an antiarrhythmic drug. Sotalol has both beta-adrenoreceptor blocking and cardiac action potential duration prolongation antiarrhythmic properties.

• Sotalol is a racemic mixture of dand 1-sotalol. Both isomers have similar Class 1 antiarrhythmic effects, while the 1-isomer is responsible for virtually all of the beta-blocking activity.
• Sotalol inhibits response to adrenergic stimuli by competitively blocking β₁-adrenergic receptors within the myocardium and β₂-adrenergic receptors within bronchial and vascular smooth muscle.
• The electrophysiologic effects of sotalol may be due to its selective inhibition of the rapidly activating component of the potassium channel involved in the repolarization of cardiac cells.

Sotalol Metabolism: Sotalol is not metabolized, nor is it bound significantly to proteins. Elimination occurs by renal excretion, with more than 80% of the drug eliminated unchanged.

Sotalol Uses: For the treatment of documented life-threatening ventricular arrhythmias.

Anti-Arrhythmic Agents Multiple Choice Questions And Answers

Question 1. What is an arrhythmia?

1. Accelerated heartbeat.
2. Slow heartbeat.
3. Irregular heartbeat.
4. A type of heart cancer

Answer: 3. Irregular heartbeat.

Question 2. How do anti-arrhythmic agents work?

1. They change the electrical conduction of the heart by targeting the defective myocytes.
2. They change the electrical conduction of the heart by targeting the pacemaker
3. They change the electrical conduction of the heart by targeting the ion channels.
4. They change the electrical conduction of the vasculature by targeting the ion channels.

Answer: 3. They change the electrical conduction of the heart by targeting the ion channels.

Question 3. What is the most common side effect of anti-arrhythmic therapy?

1. Pseudo arrhythmia
2. Proarrhythmia
3. Bradycardia
4. Tachycardia

Answer: 2. Proarrhythmia

Question 4. Antiarrhythmic drug: may cause hypothyroidism or hyperthyroidism (frequency-2%-4%) approved for use only in the treatment of serious ventricular arrhythmias, also used for refractory supraventricular arrhythmias.

1. Mexiletine
2. Tocainide
3. Adenosine
4. Amiodarone

Answer: 4. Amiodarone

Question 5. Antiarrhythmic drug: 37% iodine by weight, structurally similar to thyroxine.

1. Propranolol
2. Mexiletine
3. Flecainide
4. Amiodarone

Answer: 4. Amiodarone

Question 6. Side effects or toxicities of disopyramide

1. Negative inotropic- very significant
2. Dry mouth
3. Urinary hesitancy
4. Paradoxical ventricular tachycardia

Answer: 2. Dry mouth

Question 7. The most serious adverse effect with long-term treatment- is rapidly progressive pulmonary fibrosis, with a frequency: of 5%-15%.

1. Lidocaine
2. Propranolol
3. Amiodarone
4. Procainamide

Answer: 3. Amiodarone

Question 8. Major non-cardiac side effect of lidocaine (Xylocaine)

1. Hepatic
2. Renal
3. Pulmonary
4. CNS

Answer: 4. CNS

Question 9. p-adrenergic receptor blockers.

1. Increased AV induction time
2. Decreased AV nodal refractoriness
3. Both
4. Neighter

Answer: 1. Increased AV induction time

Anti-Arrhythmic Agents Short Questions And Answers

Question 1. What is transmembrane resting potential?

Answer:

The resting cell has a membrane potential of approximately -90 mV, with the inside of the cell being electronegative relative to the outside of the cell. This is termed the “transmembrane resting potential.

Question 2. What is arrhythmia?

Answer:

Arrhythmia is an alteration in the normal sequence of electrical impulse rhythm that leads to contraction of the myocardium.

Question 3. On which basis are Class 1 antiarrhythmic agents classified?

Answer:

Class 1 antiarrhythmic drugs can be classified based on the relative ease with which they dissociate from the Na⁺ ion channel.

• Class 1A drugs that have an intermediate rate of dissociation from Na⁺ channels.
• Class 1B drugs dissociate rapidly from the Na+ channels and thus have the lowest potency as sodium channel blockers. They produce little, if any, change in action potential duration.
• Class 1C drugs are the most potent sodium channel-blocking agents. They slowly dissociate from the Na⁺ channel, causing a slowing of the conduction time of the impulse through the heart.

Question 4. Write adverse effects of Amiodarone.

Answer:

Amiodarone has adverse effects involving many different organ systems. It also inhibits the metabolism of drugs cleared by oxidative microsomal enzymes.

• It contains iodine in its molecular structure and, as a result, affects thyroid hormones. Hypothyroidism occurs in up to 11% of patients receiving amiodarone.
• The principal effect is the inhibition of peripheral conversion of T4 to T3. Serum reverse T3 (rT3) is increased as a function of the dose as well as the length of amiodarone therapy.
• As a result, rT3 levels have been used as a guide for judging the adequacy of amiodarone therapy and predicting toxicity.

The post Classifications of Antiarrhythmic Agents appeared first on BDS Notes.

Antihypertension

Hypertension is a consequence of many diseases. Diseases of components of the central and peripheral nervous systems, which regulate blood pressure, and abnormalities of the hormonal system.

• Diseases of the kidney and peripheral vascular network, which affect blood volume, can create a hypertensive state in humans.
• Hypertension is generally defined as mild when the diastolic pressure is between 90 and 104 mm Hg, moderate when it is 105 to 114 mm Hg, and severe when it is above 115 mm Hg.

Antihypertensive Drugs Classification

Antihypertensive drugs are a class of drugs that are used to treat hypertension.

Antihypertensive Drugs For Hypertension

• Adrenergic receptors antagonist
  • For Example. Timolol.
• Angiotensin Converting Enzyme (ACE inhibitors)
  • For Example. Captopril, Lisinopril, Enalapril, Benazepril hydrochloride, Quinapril hydrochloride.
• Centrally-acting adrenergic drugs
  • For Example. Methyldopate hydrochloride, Clonidine hydrochloride, Guanabenz acetate
• Vasodilators
  • For Example Sodium nitroprusside, Hydralazine hydrochloride, Diazoxide, and Minoxidil.
• Adrenergic neuron-blocking agents
  • For Example Guanethidine monosulphate, and Reserpine.
• Diuretics
  • For Example. Furocemide, thiazides.
• Calcium channel blockers
  • For Example. Amlodipine, Felodipine, Verapamil.

“Understanding antihypertensive drug classification through FAQs: Q&A explained”

Adrenergic receptor antagonists (β-blockers)

β-Blockers are among the most widely employed antihypertensives and are also considered the first-line treatment for glaucoma. Most of the β-blockers are in the chemical class of aryloxypropanolamines.

Read and Learn More Medicinal Chemistry II Notes

Timolol

“Importance of studying antihypertensive agents for pharmacology students: Questions explained”

Timolol IUPAC name: l-(tert-butylamino)-3-{[4-(morpholin-4-yl)-l/2/5-thiadiazol-3-yl]oxy}propan-2-ol.

Timolol MOA: Like propranolol and nadolol, timolol competes with adrenergic neurotransmitters such as catecholamines for binding at β(1)-adrenergic receptors in the heart and vascular smooth muscle and β(2)-receptors in the bronchial and vascular smooth muscle.

• β(l)-receptor blockade results in a decrease in resting and exercise heart rate and cardiac output, a decrease in both systolic and diastolic blood pressure, and, possibly, a reduction in reflex orthostatic hypotension.
• β(2)-blockade results in an increase in peripheral vascular resistance. The exact mechanism whereby timolol reduces ocular pressure is still not known. The most likely action is by decreasing the secretion of aqueous humor.

Timolol Metabolism: Primarily hepatic (80%) via the cytochrome P450 2D6 isoenzyme. Timolol and its metabolites are primarily excreted in the urine.

Timolol Uses: In its oral form it is used to treat high blood pressure and prevent heart attacks, and occasionally to prevent migraine headaches. In its ophthalmic form, it is used to treat open-angle and occasionally secondary glaucoma.

“Common challenges in understanding antihypertensive mechanisms effectively: FAQs provided”

Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)

The Renin Angiotensin System and Hypertension

The renin-angiotensin system is a hormonal system that plays a central role in the control of sodium excretion and body fluid volume.

• It interacts closely with the sympathetic nervous system and aldosterone secretion in the regulation of blood pressure.
• Renin, an aspartyl protease cleaves the Leu-Val bond from the aspartic acid end of angiotensinogen polypeptide molecule to release the decapeptide angiotensin 1.
• The cleavage of a dipeptide from the carboxyl terminal] of angiotensin 1 by angiotensin-converting enzyme (ACE) to form the octapeptide angiotensin 2.
• It is a potent vasoconstrictor that increases total peripheral resistance through a variety of mechanisms: direct vasoconstriction, enhancement of both catecholamine release and neurotransmission with the peripheral nervous system, and increased sympathetic discharge.
• The result of all these actions is a rapid pressure response. Additionally, angiotensin 2 slows pressor response, resulting in long-term stabilization of arterial blood pressure.

This long-term effect is accomplished by the regulation of renal function. Angiotensin 2 directly increases sodium reabsorption in the proximal tubule.

• It also alters renal hemodynamics and causes the release of aldosterone from the adrenal cortex.
• causes Angiotensin 3 to be formed by the removal of the N-terminal aspartate residue of angiotensin 2, a reaction catalyzed by glutamyl aminopeptidase.
• In contrast to angiotensin 2, angiotensin 3 has a less potent but significant regulatory effect on sodium excretion by the renal tubules.
• This is primarily results from the effect angiotensin 3 has in stimulating aldosterone secretion, potent mineralocorticoids.

“Factors influencing success with antihypertensive agent knowledge: Q&A”

The regulatory action of the renin-angiotensin system in controlling sodium and potassium balance and arterial blood pressure is modified by vasodilators called kinins.

• Proteolytic enzymes that circulate in the plasma form kinins. Kallikrein is activated in plasma by noxious influences, to act on a kinin, callidin, which is converted to bradykinin by tissue enzymes.
• Bradykinin enhances the release of the prostaglandins PGE2 and PGI2 within certain tissues to produce a vasodilatory effect. Bradykinin is converted to inactive products by ACE and other carboxypeptidases.
• Although ACE causes activation of angiotensin and inactivation of bradykinin, actions that appear to be opposite, the balance of the system seems to favor vasoconstriction.

ACE inhibitors

These compounds can be sub-classified into three groups based on their chemical composition:

• Sulfhydryl-containing inhibitors
  • For Example. Captopril.
• Dicarboxylate-containing inhibitors
  • For Example. Enalapril, Lisinopril, benazepril.
• Phosphonate-containing inhibitors
  • For Example. Fosinopril.

Captopril and fosinopril are the alone representatives of their respective chemical subclassifications, whereas the majority of the inhibitors contain the di-carboxylate functionality.

SAR of ACE inhibitors:

“Steps to explain types of antihypertensive agents: ACE inhibitors vs beta-blockers vs diuretics: Q&A guide”

1. The N-ring must contain a carboxylic acid to mimic the C-terminal carboxylate of ACE substrates.
2. Large hydrophobic heterocyclic rings (i.e., the N-ring) increase potency and alter
   pharmacokinetic parameters.
3. The zinc-binding groups can be either sulfhydryl (A), a carboxylic acid (B), or a phosphinic acid (C).
4. The sulfhydryl group shows superior binding to zinc (the side chain mimicking the Phe in carboxylate and phosphinic acid compounds partially compensates for the lack of a sulfhydryl group).
5. Sulfhydryl-containing compounds produce a high incidence of skin rash and taste disturbances.
6. Sulfhydryl-containing compounds can form dimers and disulfides, which may shorten
   the duration of action.
7. Compounds that bind to zinc through either a carboxylate or phosphinate mimic the peptide hydrolysis transition state and enhance binding.
8. Esterification of the carboxylate or phosphinate produces an orally bioavailable prodrug.
9. X is usually methyl to mimic the side chain of alanine. Within the dicarboxylate series, when X equals n-butylamine (lysine side chain), this produces a compound that does not require a prodrug for oral activity.
10. Optimum activity occurs when the stereochemistry of the inhibitor is consistent with L-amino acid stereochemistry present in normal substrates.

ACE inhibitors MOA: The ACE inhibitors attenuate the effects of the renin-angiotensin system by inhibiting the conversion of angiotensin 1 to angiotensin 2.

• They also inhibit the conversion of angiotensin 1 to angiotensin 3. Inhibitors of ACE increase bradykinin levels that, in turn, stimulate prostaglandin biosynthesis.
• Both of these compounds have been proposed to contribute to the overall action of ACE inhibitors. Additionally, decreased angiotensin 2 levels increase the release of renin and the production of angiotensin 1.
• Because ACE is inhibited, angiotensin 1 is shunted toward the production of angiotensin 1-7 and other peptides. The contribution of these peptides to the overall effect of ACE inhibitors is unknown.

Sulfhydryl-containing inhibitors

Captopril

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Captopril IUPAC name: 1-[(2S)-3-mercapto-2-methyl-l-oxopropionyl]proline.

Captopril MOA: It blocks the conversion of angiotensin I (ATI) to angiotensin II (ATII) by inhibiting the converting enzyme. The rational development of captopril as an inhibitor of ACE.

• Captopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and or stimulation of reflex mechanisms via baroreceptors.
• Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI.

Captopril Metabolism: 25-30% bound to plasma proteins, primarily albumin, half-life is about 2 hours. It undergoes hepatic metabolism.

Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion.

Captopril Uses: For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics).

• May be used to treat congestive heart failure in combination with other drugs (For Example. cardiac glycosides, diuretics, β-adrenergic blockers).
• May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy.

Captopril Adverse effects: Common side effects, skin rashes and taste disturbances (For Example., metallic taste and loss of taste). These side effects usually subsided on dosage reduction or discontinuation of captopril.

Dicarboxylate-containing inhibitors

Enalapril

Enalapril IUPAC name: (2SM-[(2S)-2-{[(2S)-l-ethoxy-1-oxo-4-phenylbutan-2-yl]’ amino} propanoyl] pyrrolidine-2-carboxylic acid.

Enalapril MOA: It is a long-acting ACE inhibitor. It requires activation by hydrolysis of its ethyl ester to form the diacid enalaprilat.

Enalapril Metabolism: 50-60% of enalaprilat is bound to plasma proteins. ~ 60% of the absorbed dose is extensively hydrolyzed to enalaprilat, primarily by liver esterases.

The average terminal half-life of enalaprilat is 35-38 hours. The effective half-life following multiple doses is 11-14 hours.

Enalapril Uses: For the treatment of essential or renovascular hypertension and symptomatic congestive heart failure. It may be used alone or in combination with thiazide diuretics.

Enalapril Adverse Effects: The most common adverse effects include hypotension, headache, dizziness, and fatigue.

Lisinopril

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Lisinopril IUPAC name: (2S)-1-[(2S)-6-amino-2-{[(lS)-1-carboxy-3-phenylpropyl] amino) hexanoyl] pyrrolidine-2-carboxylic acid.

Lisinopril MOA: It is a lysine derivative of enalaprilat, the active metabolite of enalapril. Like all ACE inhibitors, it is an active site-directed inhibitor of the enzyme, with the zinc ion.

Lisinopril Metabolism: Lisinopril does not appear to be bound to serum proteins other than ACE. Does not undergo metabolism, excreted unchanged in urine. The effective half-life of accumulation following multiple dosing is 12 hours.

Lisinopril Uses: For the treatment of hypertension and symptomatic congestive heart failure. May be used in conjunction with thrombolytic agents, aspirin, and or β-blockers to improve survival in hemodynamically stable individuals following myocardial infarction.

May be used to slow the progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.

Lisinopril Adverse Effects: The most frequent adverse effects include headache, dizziness, cough, fatigue, and diarrhea.

Benazepril hydrochloride

Benazepril hydrochloride IUPAC name: (3S)-3-[[(lS)-1-carbethoxy-3-phenylpropyl]amino]-2,3,4,5tetrahydro-2-oxo-1H-1benzazepine-1-acetic acid 3-ethyl ester hydrochloride.

Benazepril hydrochloride MOA: Benazeprilat, the active metabolite of Benazepril, competes with angiotensin 1 for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin 1 to angiotensin 2.

• Inhibition of ACE results in decreased plasma angiotensin 2. Angiotensin 2 is a vasoconstrictor and a negative feedback mediator for renin activity.
• Lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion.
• Benazeprilat may also act on kininase 2, an enzyme identical to ACE that degrades the vasodilator bradykinin.

Benazepril hydrochloride Metabolism: Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat.

Benazepril and benazeprilat may be conjugated to glucuronic acid before urinary excretion. Half-life is 10-11 hours.

Benazepril hydrochloride Uses: For the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.

Benazepril hydrochloride Adverse effects: The most common adverse effects include headache, dizziness, fatigue, somnolence, postural dizziness, nausea, and cough.

Quinapril hydrochloride

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Quinapril hydrochloride IUFAC name: (S)-[(S)-N-[(S)21-carboxy3-phenylpropyl]alanyl]-l,2,3,4tetrahydro-3-isoquinolinecarboxylic acid 1-ethyl ester hydrochloride.

Quinapril hydrochloride MOA: Quinaprilat, the principal active metabolite of quinapril competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII.

Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressure effects of ATII. It is more potent than captopril and equipotent to the active form of enalapril.

Quinapril hydrochloride Metabolism: It undergoes hepatic metabolism followed by glucuronide conjugation. Elimination half-life is 2 hours with a prolonged terminal phase of 25 hours.

Quinapril hydrochloride Uses: For the treatment of hypertension and as an adjunct therapy in the treatment of congestive heart failure. May also be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

Quinapril hydrochloride Adverse effects: The most common adverse effects observed in controlled clinical trials were dizziness, cough, chest pain, dyspnea, fatigue, and nausea or vomiting.

Dicarboxylate-containing inhibitors

Tire phosphinic acid is capable of binding to ACE like enalapril. The interaction of the zinc atom with the phosphinic acid is similar to that seen with sulfhydryl and carboxylate groups.

• A feature unique to this compound is the ability of the phosphinic acid to more truly mimic the ionized, tetrahedral intermediate of peptide hydrolysis.
• Structural modification to investigate more hydrophobic, C-terminal ring systems, similar to that described earlier for the dicarboxylate compounds, led to a 4-cyclohexylproline analog of the original phosphinic acid.
• This compound, fosinoprilat, was more potent than captopril but less potent than enalaprilat.

Fosinopril

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Fosinopril IUPAC name: (4S)-4-cyclohexyl-1-[[[(RS)-1-hydroxy-2-methylpropoxy](4-phenylbutyl) phosphinyl]acetyl]-L-proline.

Fosinopril MOA: Fosinoprilat, the active metabolite of fosinopril, competes with ATI for binding to ACE and inhibits enzymatic proteolysis of ATI to ATIL Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII.

Fosinopril Metabolism: Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites.

Fosinopril Uses: For treating mild to moderate hypertension, used as an adjunct in treating congestive heart failure, and may be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes microalbuminuria.

Centrally-acting adrenergic drugs

The use of agents that directly affect the peripheral component of the sympathetic nen system represents an important approach to the treatment of hypertension.

• A second approach to modifying sympathetic influence on the cardiovascular system is through inhibition or reduction of CNS control of blood pressure.
• Several widely used medications act by stimulating a2-receptors, which in the CNS reduces sympathetic outflow to the cardiovascular system and produces a hypotensive effect.

Methyldopate hydrochloride

Methyldopate hydrochloride IUPAC name: 3-(3,4-dihydroxyphenyl)-2-methylalanine ethyl ester hydrochloride.

Methyldopate hydrochloride MOA: The current hypothesis concerning the hypotensive activity of methyldopa involves the CNS as the site of action. Methyldopa, on conversion to a-methyl norepinephrine.

• Acts on az-adrenergic receptors to inhibit the release of norepinephrine, resulting in decreased sympathetic outflow from the CNS and activation of parasympathetic outflow.
• A reduction of plasma renin activity can also contribute to the hypotensive action of methyldopa. Postural hypotension and sodium and water retention are also effects related to a reduction in blood pressure.
• If a diuretic is not administered concurrently with methyldopa, tolerance to the antihypertensive effect of the methyldopa during prolonged therapy can result.

Methyldopate hydrochloride Metabolism: If undergoes hepatic, extensively metabolized. The known urinary metabolites are a-methyldopamona-O-sulfate; 3-O-methyl-a-methyldopa; 3,4-dihydroxy phenylacetone; a-methyl dopamine; 3-O-methyl-a-methyldopamine and their conjugates. The plasma half-life of methyldopa is 2 hours.

Methyldopate hydrochloride Uses: Methyldopa is used in the management of moderate to severe hypertension and is reserved for patients who fail to achieve blood pressure goals with stage 2 drugs.

• Methyldopa is also co-administered with diuretics and other classes of antihypertensive drugs, permitting a reduction in the dosage of each drug and minimizing adverse effects while maintaining blood pressure control.
• Methyldopa has been used in the management of hypertension during pregnancy without apparent substantial adverse effects on the fetus and also for the management of pregnancy-induced hypertension.

Methyldopate hydrochloride Adverse effects: The most common adverse effect for methyldopa is drowsiness, which occurs within the first 48 to 72 hours of therapy and can disappear with continued administration of the drug. Sedation commonly recurs when its dosage is increased.

• A decrease in mental acuity, including impaired ability to concentrate, lapses of memory, and difficulty in performing simple calculations, can occur and usually necessitates withdrawal of the drug.
• Patients should be warned that methyldopa can impair their ability to perform activities requiring mental alertness or physical coordination (For Example., operating machinery or driving a motor vehicle).
• Nightmares, mental depression, orthostatic hypotension, and symptoms of cerebrovascular insufficiency can occur during methyldopa therapy and are indications for dosage reduction.

Methyldopate hydrochloride Synthesis:

“Steps to incorporate AI into analyzing antihypertensive drug efficacy: Questions and answers”

Clonidine hydrochloride

Clonidine hydrochloride IUPAC name: 2[(2,6-dichlorophenyl)imino]imidazolidine monohydrochloride.

Clonidine hydrochloride MOA: Clonidine hydrochloride acts by both peripheral and central mechanisms in the body to affect blood pressure.

• It stimulates the peripheral a-adrenergic receptors to produce vasoconstriction resulting in a brief period of hypertension.
• Clonidine Hydrochloride acts centrally to inhibit the sympathetic tone and cause hypotension that is of much longer duration than the initial hypertensive effect.
• Clonidine hydrochloride also acts centrally to cause bradycardia and to reduce plasma levels of renin.

Clonidine hydrochloride Metabolism: The half-life in humans is about 20 hours. Clonidine hydrochloride is metabolized by the body to form two major metabolites, p-hydroxy clonidine and its glucuronide.

p-Hydroxyclonidine does not cross the blood-brain barrier and has no hypotensive effect in humans.

Clonidine hydrochloride Uses: May be used as an adjunct in the treatment of hypertension, as an epidural infusion as an adjunct treatment in the management of severe cancer pain that is not relieved by opiate analgesics alone.

• For differential diagnosis of pheochromocytoma in hypertensive patients, prophylaxis of vascular migraine headaches, treatment of severe dysmenorrhea, and management of vasomotor symptoms associated with menopause.
• Rapid detoxification in the management of opiate withdrawal, treatment of alcohol withdrawal used in conjunction with benzodiazepines, and management of nicotine dependence.
• Topical use to reduce intraocular pressure in the treatment of open-angle and secondary glaucoma and hemorrhagic glaucoma associated with hypertension, and in the treatment of attention-deficit hyperactivity disorder (ADHD).

Clonidine hydrochloride Adverse effects: It has some sedative properties that are undesirable; it also may cause constipation and dryness of the mouth.

Guanabenz acetate

Guanabenz acetate IUPAC name: [(2,6-dichlorobenzylidene)amino]guanidine monoacetate.

Guanabenz acetate MOA: It is a central α₂-adrenergic agonist that reduces the release of norepinephrine from the neuron when stimulated. The effect of the drug results in decreased sympathetic tone in the heart, kidneys, and peripheral blood vessels.

Guanabenz acetate Metabolism: Guanabenz is metabolized principally by hydroxylation to its inactive metabolite, 4-hydroxy guanabenz, which is eliminated in the urine as its glucuronide (major) and sulfate conjugates.

Guanabenz acetate Uses: Guanabenz has been used in diabetic patients with hypertension without adverse effects on the control of or therapy for diabetes.

• It has been effective in hypertensive patients with chronic obstructive pulmonary disease, including asthma, chronic bronchitis, or emphysema.
• Guanabenz has been used alone or in combination with naltrexone in the management of opiate withdrawal in patients physically dependent on opiates and undergoing detoxification.
• Guababenz has also been used as an analogic in a limited number of patients with chronic pain.

Guanabenz acetate Adverse effects: Overall, the frequency of adverse effects produced by guanabenz is similar to that produced by clonidine and the other α₂-adrenergic agonists, but the incidence is lower.

As with the other centrally active sympatholytic (For Example., Considine), abrupt withdrawal of guanabenz can result in rebound hypertension, but the withdrawal syndrome symptoms appear to be less severe.

Vasodilators

Vasodilator drugs relax the smooth muscle in blood vessels, which causes the vessels to dilate. Dilation of arterial vessels leads to a reduction in systemic vascular resistance, which leads to a fall in arterial blood pressure. Dilation of venous vessels decreases venous blood pressure.

• There are three potential drawbacks to tire use of vasodilators: First, vasodilators can lead to baroreceptor-mediated reflex stimulation of tire heart (increased heart rate and inotropy) from systemic vasodilation and arterial pressure reduction.
• Second, they can impair the normal baroreceptor-mediated reflex vasoconstriction when a person stands up, which can lead to orthostatic hypotension and syncope on standing.
• Third, they can lead to renal retention of sodium and water, increasing blood volume and cardiac output. Antihypertensive agents that produce vasodilation of smooth muscle can be divided into two categories:

Direct acting: include hydralazine hydrochloride, sodium nitroprusside, potassium channel openers, and calcium channel-blocking agents.

Indirect-acting: Include sympatholytic drugs, such as reserpine, a-adrenergic antagonists, such as prazosin hydrochloride, ACE inhibitors, and angiotensin 2 receptor antagonists, such as sralysin.

Sodium nitroprusside

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Sodium nitroprusside IUPAC name: pentacyano(nitroso) ironside.

Sodium nitroprusside MOA: One molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN^– ions; methemoglobin.

• Obtained from hemoglobin, can sequester cyanide as cyanmethemoglobin; thiosulfate reacts with cyanide to produce thiocyanate; thiocyanate is eliminated in the urine; cyanide not otherwise removed binds to cytochromes.
• Cyanide ion is normally found in serum; it is derived from dietary substrates and tobacco smoke.
• Cyanide binds avidly (but reversibly) to ferric ion (Fe⁺⁺⁺), most body stores of which are found in erythrocyte methemoglobin (metHgb) and mitochondrial cytochromes.
• When CN is infused or generated within the bloodstream, essentially all of it is bound to methemoglobin until intraerythrocytic methemoglobin has been saturated.
• Once activated to NO, it activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP.
• cGMP stimulates calcium movement from the cytoplasm to the endoplasmic reticulum and reduces calcium available to bind with calmodulin. This eventually leads to vascular smooth muscle relaxation and vessel dilatation.

Sodium nitroprusside Metabolism: Sodium nitroprusside undergoes a redox reaction that releases cyanide. The cyanide that is produced is rapidly converted into thiocyanate in the liver by the enzyme thiosulfate sulfotransferase (rhodanase) and is excreted in the urine.

The rate-limiting step in the conversion of cyanide to thiocyanate is the availability of sulfur donors, especially thiosulfate. The elimination half-life of thiocyanate is 2.7 to 7.0 days.

Sodium nitroprusside Uses: For immediate reduction of blood pressure of patients in hypertensive crises, reduce bleeding during surgery, and for the treatment of acute congestive heart failure

Sodium nitroprusside Adverse effects: The most clinically important adverse effects of sodium nitroprusside are profound hypotension and accumulation of cyanide and thiocyanate can accumulate in the blood of patients receiving sodium nitroprusside therapy, especially in those with impaired renal function.

• Thiocyanate is mildly neurotoxic at serum concentrations of 60 mg/mL and can be life-threatening at concentrations of 200 mg/mL. Other adverse effects of thiocyanate include inhibition of both the uptake and binding of iodine, producing symptoms of hypothyroidism.
• Sodium nitroprusside can bind to vitamin B12, interfering with its distribution and metabolism, and it should be used with caution in patients having low plasma vitamin B12 concentrations. Excess cyanide can also bind to hemoglobin, producing methemoglobinemia.

Hydralazine hydrochloride

Hydralazine hydrochloride IUPAC name: 1-hydrazinophthalazine monohydrochloride.

Hydralazine hydrochloride MOA: The only drug in this group, hydralazine, does not fit neatly into the other mechanistic classes, in part because its mechanism of action is not entirely clear.

• It seems to have multiple, direct effects on the vascular smooth muscles (VSM). First, it causes smooth muscle hyperpolarization, quite likely through the opening of K⁺ channels.
• Activation therefore increases the efflux of potassium ions from the cells, causing hyperpolarization of VSM cells and, thus, prolonging the opening of the potassium channel and sustaining a greater vasodilation on arterioles than on veins.
• It can also inhibit the second messenger, the IP3-induced release of calcium from the smooth muscle SR (the PIP2 signal transduction pathway).
• Finally, hydralazine stimulates the formation of NO by the vascular endothelium, leading to cGMP-mediated vasodilation. The arterial vasodilator action of hydralazine reduces systemic vascular resistance and arterial pressure.
• Diastolic blood pressure is usually decreased more than systolic pressure is. The hydralazine-induced decrease in blood pressure and peripheral resistance causes a reflex response, which is accompanied by an increased heart rate.

Hydralazine hydrochloride Metabolism: Hydralazine hydrochloride undergoes benzylic oxidation, glucuronide formation, and N-acetylation by the microsomal enzymes in the tissues.

• Acetylation appears to be a major determinant of the rate of hepatic removal of the drug from the blood and, therefore, of systemic availability.
• Rapid acetylation results in a highly hepatic extraction ratio from blood and greater first-pass elimination.
• The drug is excreted rapidly by the kidneys, and within 24 hours, 75% of the total amount administered appears in the urine as metabolites or unchanged drugs.

Hydralazine hydrochloride Uses: For the treatment of essential hypertension, alone or as an adjunct. Also for the management of severe hypertension when the drug cannot be given orally or when blood pressure must be lowered immediately, congestive heart failure.

Hydralazine hydrochloride Adverse effects: Patients who engage in potentially hazardous activities, such as operating machinery or driving motor vehicles, should be warned about possible faintness, dizziness, or weakness.

Hydralazine should be used with caution in patients with cerebrovascular accidents or with severe renal damage.

Potassium channel opener

Minoxidil

“Early warning signs of outdated methods in antihypertensive studies: Common questions”

Minoxidil IUPAC name: 2,4-diamino-6-piperidinopyrimidine-3-oxide.

Minoxidil MOA: Potassium channel openers are drugs that activate (i.e., open) ATP-sensitive K+ channels in the VSM.

• By opening these potassium channels, there is increased efflux of potassium ions from the cells, causing hyperpolarization of VSM, which closes the voltage-gated calcium channels and, thereby, decreases intracellular calcium.
• With less calcium available to combine with calmodulin, there is less activation of MLCK (Myosin light chain kinase) and phosphorylation of myosin light chains. This leads to relaxation and vasodilation.

Minoxidil Metabolism: Minoxidil is absorbed from the GI tract and is metabolized to its active sulfate metabolite. Plasma concentrations for minoxidil sulfate peak within 1 hour and then decline rapidly.

• Following an oral dose of minoxidil, its hypotensive effect begins in 30 minutes, is maximal in 2 to 8 hours, and persists for approximately 2 to 5 days.
• The delayed onset of the hypotensive effect of minoxidil is attributed to its metabolism to its active metabolite. The drug is not bound to plasma proteins.
• The major metabolite for minoxidil is its N-Oglucuronide, which, unlike the sulfate metabolite, is inactive as a hypotensive agent.
• Approximately 10% to 20% of an oral dose of minoxidil is metabolized to its active metabolite, minoxidil O-sulfate, and approximately 20% of minoxidil is excreted unchanged.

Minoxidil Uses: For the treatment of severe hypertension and in the topical treatment (regrowth) of androgenic alopecia in males and females and stabilization of hair loss in patients with androgenic alopecia.

Minoxidil Adverse effects: Adverse effects include cardiovascular effects associated with hypotension such as sudden weight gain, rapid heartbeat, faintness, or dizziness.

Diazoxide

Diazoxide IUPAC name: 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide.

Diazoxide MOA: Diazoxide reduces peripheral vascular resistance and blood pressure by a direct vasodilating effect on the VSM with a mechanism similar to that described for minoxidil by activating (opening) the ATP-modulated potassium channel.

• Thus, diazoxide prolongs the opening of the potassium channel, sustaining greater vasodilation on arterioles than on veins.
• Diazoxide increases blood glucose concentration (diazoxide-induced hyperglycemia) by several different mechanisms: by inhibiting pancreatic insulin secretion, by stimulating release of catecholamines, or by increasing hepatic release of glucose

Diazoxide Metabolism: It undergoes hepatic metabolism. Its half-life is 28+8.3 hours in normal adults in patients with renal impairment, the half-life is prolonged.

Approximately 90% of the diazoxide in the blood is bound to plasma proteins. approximately 20% to 50% of diazoxide of the 3-methyl group to its 3-hydroxymethyl-and 3-carboxyl-metabolites.

Diazoxide Uses: Used parentally to treat hypertensive emergencies. Also used to treat hypoglycemia secondary to insulinoma.

Diazoxide Adverse effects: Diazoxide causes sodium and water retention and decreased urinary output, which can result in expansion of plasma and extracellular fluid volume, edema, and congestive heart failure, especially during prolonged administration.

Adrenergic Neuron-Blocking Agents

Drugs that reduce blood pressure by depressing the activity of the sympathetic nervous system have been used as effective agents in the treatment of hypertension. This can be accomplished in several ways:

1. Depleting the stores of neurotransmitters,
2. Reducing the number of impulses traveling in sympathetic nerves,
3. Antagonizing the actions of the neurotransmitter on the effector cells, and
4. Inhibiting neurotransmitter release.

“Differential applications of traditional vs cutting-edge antihypertensive techniques: Questions answered”

Guanethidine mono sulphate

Guanethidine monosulphate IUPAC name: [2-(hexahydro-1 (2H)-azocinyl)ethyl]guanidine sulfate.

Guanethidine monosulphate MOA: Guanethidine is an adrenergic neuronal blocking agent that produces a selective block of peripheral sympathetic pathways by replacing and depleting norepinephrine stores from adrenergic nerve endings, but not from the adrenal medulla.

• It prevents the release of norepinephrine from adrenergic nerve endings in response to sympathetic nerve stimulation. The chronic administration of guanethidine results in an increased sensitivity of these effector cells to catecholamines.
• Following the oral administration of usual doses of guanethidine, depletion of the catecholamine stores from adrenergic nerve endings occurs at a very slow rate, producing a more gradual and prolonged fall in systolic blood pressure than in diastolic pressure.

Guanethidine monosulphate Metabolism: Guanethidine is incompletely absorbed from the GI tract and is metabolized in the liver to several metabolites, including guanethidine N-oxide from flavin mononucleotide.

These metabolites of guanethidine are excreted in the urine and have less than 10% of its hypotensive activity. Guanethidine accumulates in the neurons with an elimination half-life of 5 days.

Guanethidine monosulphate Uses: Guanethidine is used in the management of moderate to severe hypertension and in the management of renal hypertension.

It has been administered as ophthalmic drops in the treatment of chronic open-angle glaucoma and for endocrine ophthalmopathy, ophthalmoplegia, lid lag, and lid retraction.

Guanethidine mono sulfate Adverse effects: Adverse effects of guanethidine frequently are dose-related, including dizziness, weakness, lassitude, and syncope, and resulting from postural or post-exercise hypotension.

• A hot environment(i.e., a hot bath) can aggravate postural hypotension. Patients should be warned about possible orthostatic hypotension and about the effect of rapid postural changes on blood pressure (For Example arising in the morning) that can cause fainting.
• Especially during the initial period of dosage adjustment. Sodium retention (edema) is usually controlled by the co-administration of a diuretic.

Reserpine

Reserpine MOA: Reserpine acts to replace and deplete the adrenergic neurons of their stores of norepinephrine by inhibiting the active transport Mg-ATPase responsible for sequestering norepinephrine and dopamine within the storage vesicles.

• The norepinephrine and dopamine that are not sequestered in vesicles are destroyed by MAO. As a result, the storage vesicles contain little neurotransmitter, adrenergic transmission is dramatically inhibited, and sympathetic tone is decreased, leading to vasodilation.
• Reserpine has the same effect on epinephrine storage in the adrenal medulla. Reserpine readily enters the CNS, where it also depletes the stores of norepinephrine and serotonin. The CNS neurotransmitter depletion led to the use of reserpine in treating certain mental illnesses.

Reserpine Metabolism: The elimination of reserpine appears to be biphasic, with a plasma half-life averaging 4.5 hours during the first phase and approximately 11.3 days during the second phase.

Reserpine is metabolized to unidentified inactive compounds. Unchanged reserpine and its metabolites are excreted slowly in urine and feces, with an average of 60% reserpine recovered in feces within 96 hours after oral administration of 0.25 mg of radiolabeled reserpine.

Reserpine Uses: Reserpine has been used in the management of mild to moderate hypertension, but because of very significant CNS adverse effects and its cumulative action in the adrenergic neurons, reserpine is rarely used.

Reserpine has been used in the symptomatic treatment of agitated psychotic states, such as schizophrenic disorders, although other antipsychotic agents have generally replaced reserpine and alkaloids.

Reserpine Adverse effects: The common adverse CNS effects of reserpine include drowsiness, fatigue, and lethargy.

• Mental depression is one of the most serious potential adverse effects for reserpine, which can be severe enough to require hospitalization or result in suicide attempts.
• Reserpine-induced depression can persist for several months after the drug is discontinued.

“Can bioinformatics revolutionize antihypertensive classification? FAQs provided”

Antihypertensive Agents Multiple Choice Questions And Answers

Question 1. Clinical use of clonidine:

1. Analgesic
2. Antihypertensive
3. Both
4. Neither

Answer: 3. Both

Question 2. β-blockers adverse effects:

1. Bronchoconstriction
2. Bradycardia
3. Depression
4. Mask hypoglycemia

Answer: 1. Bronchoconstriction

Question 3. Name of the drug contraindicated with digoxin.

1. Captopril
2. Atenolol
3. Furosemide
4. Losartan

Answer: 3. Furosemide

Question 4. Which one will cause heart failure when combined with verapamil?

1. Captopril
2. Atenolol
3. Aliskiren
4. Furosemide

Answer: 2. Atenolol

Question 5. This hypertension drug is the first choice for diabetic and renal failure pts.

1. K sparing diuretics
2. ACE inhibitors
3. Loop diuretics
4. Calcium channel blockers

Answer: 3. Loop diuretics

Question 6. Impotence is most commonly caused by which antihypertensive agent.

1. Calcium channel blocker
2. ACE inhibitors
3. ATI receptor antagonist
4. Beta-blockers

Answer: 4. Beta-blockers

“Asymptomatic vs symptomatic effects of ignoring new trends in antihypertensive research: Answered”

Question 7. Which drug inactivates bradykinin?

1. Lisinopril
2. Losartan
3. Gaunethedin
4. Reserpine

Answer: 1. Lisinopril

Question 8. Hydralazine works on hypertension by:

1. Decrease in sympathetic response
2. Peripheral vasodilation
3. Directly inhibits renin
4. Block Ca⁺⁺ from stimulating muscle wall

Answer: 2. Peripheral vasodilation

Antihypertensive Agents Short Questions And Answers

Question 1. Give the classification of ACE inhibitors.

Answer:

1. Sulfhydryl-containing inhibitors For Example. Captopril.
2. Dicarboxylate-containing inhibitors For Example. Enalapril, lisinopril.
3. Phosphonate-containing inhibitors For Example. Fosinopril.

Question 2. Write the uses of captopril.

Answer:

For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics).

• May be used to treat congestive heart failure in combination with other drugs (For Example. cardiac glycosides, diuretics, p-adrenergic blockers).
• May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy.

Question 3. Give MOA and metabolism of Benazepril.

Answer:

MOA– Benazeprilat, the active metabolite of Benazepril, competes with angiotensin 1 for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin 1 to angiotensin 2. Inhibition of ACE results in decreased plasma angiotensin 2.

• As angiotensin 2 is a vasoconstrictor and a negative feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and decreased aldosterone secretion.
• Benazeprilat may also act on kininase 2, an enzyme identical to ACE that degrades the vasodilator bradykinin.
• Metabolism– Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Benazepril and benazeprilat may be conjugated to glucuronic acid before urinary excretion. Half-life is 10-11 hours.

Question 4. Draw the structure and IUFAC name of Clonidine hydrochloride.

Answer:

IUPAC name: 2[(2,6-dichlorophenyl)imino]imidazolidine monohydrochloride.

Question 5. What are the adverse effects related to vasodilators?

Answer:

1. Vasodilators can lead to baroreceptor-mediated reflex stimulation of the heart (increased heart rate and inotropy) from systemic vasodilation and arterial pressure reduction.
2. They can impair the normal baroreceptor-mediated reflex vasoconstriction when a person stands up, which can lead to orthostatic hypotension and syncope on standing.
3. They can lead to renal retention of sodium and water, increasing blood volume and cardiac output.

The post Antihypertensive Agents Classification appeared first on BDS Notes.

Diuretics are drugs, which increase the rate of urine flow. However, clinically useful diuretics also increase the excretion of Na+ and an accompanying anion (negatively charged ion) like Cl^–.

• Since NaCl is the major determinant of extracellular fluid volume, diuretics reduce extracellular fluid volume (decrease in edema) by decreasing total body NaCl content.
• Although continued use of diuretics causes sustained net loss of Na⁺, the time course for this effect is limited by compensatory mechanisms including activation of the renin-angiotensin-aldosterone pathway and the sympathetic nervous system.
• When blood is filtered at the glomerulus, the fluid that enters the proximal tubule is the developing urine. As the tubular fluid passes down the tubule, solutes (Na⁺, K⁺, Cl^–) are removed from the fluid and returned to the blood (reabsorption).
• Diuretics inhibit the reabsorption of Na⁺ ions, thereby reducing the quantity of water in body fluids. The diuretics drugs are mainly used to treat two medically important conditions, edema and hypertension.

Diuretics are also useful in treating several other conditions including increased cranial or intraocular pressure, diabetes insipidus, hypercalcemia, acute mountain sickness, primary hyperaldosteronism, and osteoporosis.

Read and Learn More Medicinal Chemistry II Notes

Diuretics Classification

• Carbonic anhydrase inhibitors
  • For Example. Acetazolamide, Methazolamide, Dichlorphenamide.
• Thiazides
  • For Example. Chlorothiazide, Hydrochlorothiazide, Hydroflumethiazide, Cyclothiazide.
• Loop diuretics
  • For Example. Furosemide, Bumetanide, Ethacrynic acid.
• Potassium-sparing diuretics
  • For Example. Spironolactone, Triamterene, Amiloride.
• Osmotic diuretics
  • For Example. Mannitol.

“What is medicinal chemistry of diuretics? A detailed notes and Q&A guide”

Carbonic anhydrase inhibitors

Carbonic anhydrase (CA) inhibitors are derived from the sulphonamides. The sulfonamide group (—SO₂NH₂) is essential for its activity.

In 1937 observed that sulphanilamide not only had antibacterial activity but also produced systemic acidosis and an alkaline urine (HCO₃-excretion).

The carbonic anhydrase inhibitors must have an unsubstituted sulphamoyl (—SO₂NH₂) group. Some potent CA inhibitors have an aromatic group (phenyl or heterocycle) attached to the sulphamoyl group.

Carbonic anhydrase inhibitors MOA: This class of diuretics inhibits carbonic anhydrase enzymes in the membrane and cytoplasm of the epithelial cells. The primary site of action is the proximal tubules.

• These agents interfere with the reabsorption of HCO₃ -. HCO₃ – is reabsorbed in the proximal tubule and requires the activity of carbonic anhydrase.
• Intracellularly carbonic anhydrase converts H₂0 and CO₂ to carbonic add (H₂CO₃). H₂CO₃ dissociates into H+ and HCO₃-. The HCO₃– is transported across the basolateral membrane.
• H⁺ is secreted into the tubular lumen in exchange for Na⁺. The H⁺ combines with a filtered HCO₃– (using CA) to form H₂CO₃ which immediately dissociates into H₂O and CO₂ that, is reabsorbed.
• Therefore, filtered bicarbonate is reabsorbed for every H⁺ secreted. Carbonic anhydrase inhibitors, by blocking the enzyme, prevent the reabsorption of HCO₃-.
• Accumulation of HCCV in the tubular lumen subsequently inhibits Na⁺ -H⁺ exchange and Na⁺ reabsorption.

The increase in sodium concentration in the tubular fluid may be compensated partially by increased NaCl reabsorption m later segments of the tubule. Thus, the diuretic effect of the carbonic anhydrase inhibitors is mild.

“Understanding diuretic agents through FAQs: Medicinal chemistry explained”

Acetazolamide

Acetazolamide IUPAC name: N-(5-sulfamoyl-l,3,4-thiadiazol-2-yl)acetamide.

Acetazolamide MOA: The diuretic effect depends on the inhibition of carbonic anhydrase, causing a reduction in the availability of hydrogen ions for active transport in the renal tubule lumen.

This leads to alkaline urine and an increase in the excretion of bicarbonate, sodium, potassium, and water.

Acetazolamide Uses: For adjunctive treatment of edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; and chronic simple (open-angle) glaucoma.

Acetazolamide Synthesis:

“How do diuretics work at the molecular level? FAQ answered”

Methazolamide

Methazolamide IUPAC name: N-(3-methyl-5-sulfamoyl-2,3-dihydro-l,3,4-thiadiazol-2-ylidene)acetamide.

Methazolamide MOA: Methazolamide is a potent inhibitor of carbonic anhydrase. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport.

Methazolamide Uses: For treatment of chronic open-angle glaucoma and acute angle-closure glaucoma.

Dichlorphenamide

“Importance of studying medicinal chemistry of diuretics for pharmacology students: Questions explained”

Dichlorphenamide IUPAC name: 4,5-dichlorobenzene-l,3-disulfonamide.

Dichlorphenamide MOA: It reduces intraocular pressure by partially suppressing the secretion of aqueous humor (inflow), although the mechanism by which they do this is not fully understood.

• Evidence suggests that HCO^3- ions are produced in the ciliary body by hydration of carbon dioxide under the influence of carbonic anhydrase and diffuse into the posterior chamber which contains more Na⁺ and HCO^3- ions than dose plasma and consequently is hypertonic.
• Water is then attracted to the posterior chamber by osmosis, resulting in a pressure drop.

Dichlorphenamide Uses: For adjunctive treatment of chronic simple (OPen-angle) glaucoma, Secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired to lower intraocular pressure.

Thiazides

Thiazides are also called benzothiadiazides. Thiazides are sulfonamide derivatives.

Thiazides SAR:

“Common challenges in understanding diuretic mechanisms effectively: FAQs provided”

1. H atom at N-2 is the most acidic due to the electron-withdrawing effects of the neighboring sulfone group.
2. The sulfonamide group at C-7 provides an additional point of acidity in the molecule but is less acidic than the N-2 proton. A free sulfamoyl group at position 7 is essential for diuretic activity.
3. These acidic protons make possible the formation of a water-soluble sodium salt that can be used for I.V. dosing.
4. An electron-withdrawing group is essential at position 6.
5. The diuretic activity is enhanced by substitution at position 3.
6. Replacement of 6-Cl by 6-CF3 does not change potency but alters the duration of action.
7. Replacement of 6-Cl by electron-donating groups (For Example. CH3) reduces diuretic activity.
8. Saturation of thiadiazine ring to give 3, 4-dihydro derivative and replacement replace or removal of sulfonamide group at position C-7 yields compounds with little or no diuretic activity.

Thiazides MOA: Thiazides inhibit a Na⁺—Cl^– symport in the luminal membrane of the epithelial cells in the distal convoluted tubule. Thus, thiazides inhibit NaCl reabsorption in the distal convoluted tubule and may have a small effect on the NaCl reabsorption in the proximal tubule.

Thiazides enhance Ca⁺⁺ reabsorption in the distal convoluted tubule by inhibiting Na⁺ entry and thus enhancing the activity of Na⁺ —Ca⁺⁺ exchanger in the basolateral membrane of epithelial cells.

Chlorothiazide

Chlorothiazide IUPAC name|6-chloro-l,l-dioxo4H-lX6,2,4-benzothiadiazine-7-sulfonamide.

Chlorothiazide MOA: As a diuretic, chlorothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, increasing the excretion of sodium, chloride, and water.

• Thiazides like chlorothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide-sensitive sodium-chloride transporter.
• This results in an increase in potassium excretion via the sodium-potassium exchange mechanism.
• The antihypertensive mechanism of chlorothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

Chlorothiazide Uses: Chlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Chlorothiazide Synthesis:

“Why is early learning of diuretic medicinal chemistry critical for drug design? Answered”

Hydrochlorothiazide

Hydrochlorothiazide IUPAC name: 6-chloro-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamicle.

Hydrochlorothiazide MOA: Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption.

• Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule.
• The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane.
• Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption.
• By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Hydrochlorothiazide Uses: For the treatment of high blood pressure and management of edema.

Hydroflumethiazide

“Factors influencing success with diuretic medicinal chemistry knowledge: Q&A”

Hydroflumethiazide IUPAC name: 1,1-dioxo-6-(trifluoromethyl)-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide.

Hydroflumethiazide MOA: Hydroflumethiazide is a thiazide diuretic that inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption.

Hydroflumethiazide Uses: Used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Also used in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the severe forms of hypertension.

Cyclothiaride

“Differential applications of thiazide diuretics vs loop diuretics: Notes explained”

Cyclothiaride IUPAC name: 3-{bicyclo[2.2.1]hept-5-en-2-yl)-6-chloro-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide.

Cyclothiaride MOA: As a diuretic, cydothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, increasing the excretion of sodium, chloride, and water.

• Thiazides like cydothiazide also inhibit sodium ion transport across the renal tubular epithelium by binding to the thiazide-sensitive sodium-chloride transporter.
• This results in an increase in potassium excretion via the sodium-potassium exchange mechanism.
• The antihypertensive mechanism of cydothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle.

CyclothiarideUses: Cydothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Loop diuretics

The diuretics that produce peak diuresis than other diuretics and act distinctly on renal tubular function (at the loop of Henle) are called loop diuretics or high-ceiling diuretics. There are two major classes of loop diuretics

1. Sulfonamide derivatives such as furosemide, bumetanide and torsemide.
2. Non-sulfonamide loop diuretic such as ethacrynic acid.

Loop diuretics MOA: Loop diuretics inhibit the reabsorption of NaCl and KCl by inhibiting the Na⁺ —K⁺ —2Cl^– symport in the luminal membrane of the thick ascending limb (TAL) of the loop of Henle.

• As TAL is responsible for the reabsorption of 35% of filtered sodium, loop diuretics are highly efficacious and are thus called high-ceiling diuretics.
• The Na* —K+ —20“ symport and sodium pump together generate a positive lumen potential that drives the reabsorption of Ca⁺⁺ and Mg⁺⁺, inhibitors of the Na⁺ -K⁺ -2CI^– symport also inhibit the reabsorption of Ca⁺⁺ and Mg⁺⁺.
• Loop diuretics also have direct effects on vasculature including an increase in renal blood flow and an increase in systemic venous capacitance.

“Steps to explain types of diuretics: Loop diuretics vs thiazides vs potassium-sparing diuretics: Notes guide”

Loop diuretics SAR:

1. The substituent at 1-position must be acidic, the carboxyl group provides optimal diuretic activity, but other groups as tetrazole, may have diuretic activity.
2. A sulfamoyl group in the 5-position is essential for optimal high-ceiling diuretic activity.
3. The activating group (X-) in the 4- position can be Cl^– or CF₃-, a phenoxy-, alkoxy-, aniline-, benzyl-, orbenzoyl- group.
4. Substituents that can be tolerated on the 2-amino group series only furfuryl- >benzyl>thienylmethy.
5. substituent, on the 3-amino group series, can vary widely without affecting optimal diuretic activity.

Furosemide

“Role of Na-K-Cl symport inhibition in loop diuretics: Questions answered”

Furosemide IUPAC name: 4-chloro-2-[(furan-2-ylmethyl)ainino]-5-sulfamoylbenzoic add.

Furosemide MOA: Furosemide, a loop diuretic, inhibits water reabsorption in the nephron by blocking the sodium potassium-chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle.

• This is achieved through competitive inhibition at the chloride binding site on the cotransporter, thus preventing the transport of sodium from the lumen of the loop of Henle into the basolateral interstitium.
• Consequently, the lumen becomes more hypertonic while the interstitium becomes less hypertonic, which in turn diminishes the osmotic gradient for water reabsorption throughout the nephron.
• Because the thick ascending limb is responsible for 25% of sodium reabsorption in the nephron, furosemide is a very potent diuretic.

Furosemide Metabolism: Only a small amount is hepatically metabolized to the defurfurylated derivative, 4-chloro-5- sulfamoyl anthranilic add.

Furosemide Uses: For the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome.

Also for the treatment of hypertension alone or in combination with other antihypertensive agents.

Furosemide Synthesis:

Bumetanide

“How does furosemide differ from hydrochlorothiazide? FAQ explained”

Bumetanide IUPAC name: 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid.

Bumetanide MOA: Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium m the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in the excretion of sodium, chloride, and water and, hence, diuresis.

Bumetanide Uses: For the treatment of edema associated with congestive heart failure and hepatic and renal disease including nephrotic syndrome.

Ethacrynic acid

“Asymptomatic vs symptomatic effects of outdated diuretic practices: Answered”

Ethacrynic acid IUPAC name: 2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid.

Ethacrynic acid MOA: Ethacrynic acid inhibits the symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules.

• This pharmacological action results in the excretion of these ions, increased urinary output, and reduction in extracellular fluid Diuretics also lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases, explaining its antihypertensive action.
• Eventually, cardiac output returns to normal with an accompanying decrease in peripheral resistance. Its mode of action does not involve carbonic anhydrase inhibition.

Ethacrynic acid Uses: For the treatment of high pressure and edema caused by diseases like congestive heart failure, liver, and kidney failure.

Potassium-sparing diuretics

Potassium-sparing diuretics do not share any obvious chemical similarities, except for the steroidstructure of the aldosterone antagonists. Those in clinical use include:

Aldosterone antagonists (mostly spironolactone)- Spironolactone, Eplerenone. Epithelial sodium channel blockers- Amiloride, Triamterene.

Aldosterone antagonists

Spironolactone

“Early warning signs of gaps in understanding diuretic SAR basics: Common questions”

Spironolactone IUPAC name: (1’S, 2’R,2’R,9’R,10,R,11’S,15’S)-9′-(acetylsulfanyl)-2′,15’-dimethylspiro[oxolane-2,14′- tetracycloheptadecan]-6’-ene-5,5′-dione.

Spironolactone MOA: Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule.

Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism.

Spironolactone Uses: Used primarily to treat low-renin hypertension, hypokalemia, and Conn’s syndrome.

Epithelial sodium channel blockers

Amiloride

“Asymptomatic vs symptomatic effects of ignoring diuretic principles: Q&A”

Amiloride IUPAC name: 3,5-diamino-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide.

Amiloride MOA: Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the amiloride-sensitive sodium channels.

• This promotes the loss of sodium and water from the body, but without depleting potassium. Amiloride exerts its potassium-sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule.
• Cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion.
• Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone.

Amiloride Uses: For use as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents in congestive heart failure or hypertension.

Triamterene

Triamterene IUPAG name: 6-phenylpteridine-2,4,7-triamine.

Triamterene MOA: Triamterene inhibits the epithelial sodium channels on principal cells in the late distal convoluted tubule and collecting tubule, which are responsible for 1-2% of total sodium reabsorption.

• As sodium reabsorption is inhibited, this increases the osmolarity in the nephron lumen and decreases the osmolarity of the interstitium.
• Since sodium concentration is the main driver for water reabsorption, triamterene can achieve a modest amount of diuresis by decreasing the osmotic gradient necessary for water reabsorption from the lumen to the interstitium.
• Triamterene also has a potassium-sparing effect. Normally, the process of potassium excretion is driven by the electrochemical gradient produced by sodium reabsorption.
• As sodium is reabsorbed, it leaves a negative potential in the lumen, while producing a positive potential in the principal cell. This potential promotes potassium excretion through apical potassium channels.
• By inhibiting sodium reabsorption, triamterene also inhibits potassium excretion.

Triamterene Uses: For the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism.

Osmotic diuretics

Osmotic diuretics are the agents that mobilize fluids by increasing the osmotic pressure in tubules.

Osmotic diuretics MOA:

“Can targeted interventions improve outcomes using diuretic medicinal chemistry knowledge? FAQs provided”

• Osmotic diuretics are substances to which the tubule epithelial cell membrane has limited permeability. When administered (often in a large dosage), osmotic diuretics significantly increase the osmolarity of plasma and tubular fluid.
• The osmotic force thus generated prevents water reabsorption, and also extracts water from the intracellular compartment, expands extracellular fluid volume, and increases renal blood flow resulting in reduced medulla tonicity.
• The primary sites of action for osmotic diuretics are the Loop of Henle and the proximal tubule where the membrane is most permeable to water.

Mannitol

Mannitol IUPAC name: (2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol.

Mannitol MOA: As a diuretic mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and the renal tubular reabsorption of sodium, chloride, and other solutes.

• Mannitol promotes the urinary excretion of toxic materials and protects against nephrotoxicity by preventing the concentration of toxic substances in the tubular fluid.
• As an Antiglaucoma agent mannitol elevates blood plasma osmolarity, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure.

Mannitol Uses:

Used for the promotion of diuresis before irreversible renal failure becomes established, the reduction of intracranial pressure, the treatment of cerebral edema, and the promotion of urinary excretion of toxic substances.

Adverse Effects Of Diuretics

Loop and thiazide diuretics can cause metabolic alkalosis due to increased excretion of chloride in proportion to bicarbonate. This is more common with loop diuretics than thiazide diuretics.

• They can also cause hypokalemia, hyperglycemia and glucose intolerance, hyperlipidemia, hyponatremia, hyperuricemia, and hypomagnesemia. Thiazide diuretics can cause hypercalcemia while loop diuretics increase the excretion of calcium which can lead to hypocalcemia.
• Moreover, loop and thiazide diuretics are sulfonamides and can lead to allergic reactions. Loop diuretics also have the potential to cause ototoxicity and hearing loss. Of note, hypokalemia can cause ventricular arrhythmias and muscular weakness.
• Spironolactone’s primary adverse effect is hyperkalemia, especially in elderly patients and those with chronic kidney disease.
• Individuals at higher risk for hyperkalemia also include those on beta blockers, ACE inhibitors, angiotensin receptor blockers, and NSAIDs. It also has antiandrogenic effects, including gynecomastia, hirsutism, and sexual dysfunction.
• Acetazolamide is a sulfonamide and can lead to allergic reactions. Other adverse reactions include paresthesias, tinnitus, taste alteration, and metabolic acidosis (especially in the elderly and kidney disease.

Mannitol has complex effects on electrolytes. It initially leads to hypertonic hyponatremia when it recruits water from cells. Later as the extracellular fluid is excreted, hyperkalemic acidosis can develop. After this hypernatremic dehydration may occur.

“Differential applications of diuretics in hypertension vs edema: Notes explained”

Diuretics Multiple Choice Questions And Answers

Question 1. Which of these beverages does not have a diuretic effect?

1. Alcohol
2. Milk
3. Tea
4. Coffee

Answer: 2. Milk

Question 2. Progesterone

1. ADH
2. ANH
3. Aldosterone
4. PTH

Answer: 3. Aldosterone

Question 3. Side effects for this particular diuretic include hyperkalemic metabolic acidosis and gynecomastia.

1. Amiloride
2. Hydrochlorothiazide
3. Furosemide
4. Spironolactone

Answer: 4. Spironolactone

Question 4. One of the most powerful “high ceiling” diuretics that has a short duration of action, inhibits the Na/K/Cl transporter and can block the reabsorption of up to 30% of filtered sodium.

1. Acetazolamide
2. Hydrochlorothiazide
3. Ethacrynic acid
4. Spironolactone

Answer: 3. Ethacrynic acid

“Steps to apply diuretic medicinal chemistry in drug discovery: Design vs optimization: Notes guide”

Question 5. A drug that acts on the proximal tubule has a relatively low efficacy in blocking the reabsorption of Na but is useful in the treatment of glaucoma, and as a prophylactic to prevent acute mountain sickness.

1. Acetazolamide
2. Triamterene
3. Ethacrynic acid
4. Furosemide

Answer: 1. Acetazolamide

Question 6. A drug with modest effects that is often reserved for use in patients who develop hypokalemia in response to taking another more potent diuretic.

1. Ethacrynic add
2. Indapamide
3. Triamterene
4. Furosemide

Answer: 3. Triamterene

Question 7. Which drug causes an increase in plasma glucose, urate levels, and lipid levels?

1. Mannitol
2. Hydrochlorothiazide
3. Spironolactone
4. Furosemide

Answer: 2. Hydrochlorothiazide

Question 8. Which drug increases the risk of kidney stones? Decreases?

1. Furosemide, Spironolactone
2. Furosemide, Hydrochlorothiazide
3. Hydrochlorothiazide, Furosemide
4. Hydrochlorothiazide, Spironolactone

Answer: 2. Furosemide, Hydrochlorothiazide

Question 9 Which of the following drugs is paradoxically used to treat Diabetes insipidus?

1. Hydrochlorothiazide
2. Mannitol
3. Spironolactone
4. Furosemide

Answer: 1. Hydrochlorothiazide

“Role of SAR in improving diuretic efficacy: Questions answered”

Question 10. Which type of drug can pull water out of cells all over the body?

1. Mannitol
2. Amiloride
3. Thiazide diuretics
4. Acetazolamide

Answer: 1. Mannitol

Diuretics Short Questions And Answers

Question 1. Discuss mode of action of thiazides.

Answer:

Thiazides inhibit a Na⁺—Cl^– symport in the luminal membrane of the epithelial cells in the distal convoluted tubule. Thus, thiazides inhibit NaCl reabsorption in the distal convoluted tubule and may have a small effect on the NaCl reabsorption in the proximal tubule.

Thiazides enhance Ca++ reabsorption in the distal convoluted tubule by inhibiting Na⁺ entry and thus enhancing the activity of Na⁺ —Ca⁺⁺ exchanger in the basolateral membrane of epithelial cells.

Question 2. Outline synthesis and clinical Use of Furosemide.

Answer:

Synthesis

“How does spironolactone act as a potassium-sparing diuretic? FAQ explained”

Clinical uses: For the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome.

Also for the treatment of hypertension alone or in combination with other antihypertensive agents.

Question 3. Write MOA of osmotic diuretics.

Answer:

Osmotic diuretics are substances to which the tubule epithelial cell membrane has limited permeability. When administered (often in a large dosage), osmotic diuretics significantly increase the osmolarity of plasma and tubular fluid.

• The osmotic force thus generated prevents water reabsorption, and also extracts water from the intracellular compartment, expands extracellular fluid volume, and increases renal blood flow resulting in reduced medulla tonicity.
• The primary sites of action for osmotic diuretics are the Loop of Henle and the proximal tubule where the membrane is most permeable to water.

“Early warning signs of complications from ignoring diuretic protocols: Common questions”

Question 4. Draw the structure of any two potassium-sparing diuretics.

Answer:

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