Cholinergic and Anticholinesterase Drugs

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Questions and Answers

Which of the following is true regarding cholinergic agents?

  • Cholinergic agents directly inhibit the action of the parasympathetic nervous system (PSNS).
  • Cholinergic agents exclusively activate motor neurons without affecting the autonomic nervous system.
  • Cholinergic agents act at different sites than acetylcholine.
  • Cholinergic agents mimic the action of the parasympathetic nervous system (PSNS). (correct)

A drug is described as acting on muscarinic receptors, leading to increased smooth muscle contraction in the bladder and increased salivation. How would this drug be classified?

  • An adrenergic agonist.
  • A muscarinic agonist. (correct)
  • A cholinergic antagonist.
  • A nicotinic antagonist.

Which structural group within acetylcholine is directly involved in its rapid hydrolysis by cholinesterase?

  • The ester group. (correct)
  • The muscarinic ring.
  • The nicotinic ring.
  • The quaternary ammonium group.

A researcher is investigating the effects of a novel compound on cellular signaling pathways activated by muscarinic receptors. Which of the following cellular responses would be associated with stimulation of $M_2$ muscarinic receptors?

<p>Inhibition of adenylyl cyclase. (B)</p> Signup and view all the answers

A patient presents with symptoms of increased gastrointestinal motility, bronchial constriction, and increased watery secretion from the salivary glands. Which receptor subtype is primarily responsible for mediating these effects?

<p>$M_3$ (C)</p> Signup and view all the answers

How does parasympathetic stimulation affect accommodation of vision for close objects?

<p>It contracts the ciliary muscles, allowing the lens to become more rounded. (B)</p> Signup and view all the answers

Which of the following mechanisms explains how activation of $M_2$ receptors in the cardiovascular system leads to vasodilation?

<p>Release of nitric oxide (NO) via endothelium-dependent mechanisms. (B)</p> Signup and view all the answers

A patient with glaucoma is prescribed pilocarpine eye drops. What is the primary mechanism by which pilocarpine reduces intraocular pressure?

<p>By contracting the ciliary muscle, facilitating the outflow of aqueous humor. (D)</p> Signup and view all the answers

A patient exhibits the following symptoms: lacrimation, excitation/emesis, salivation, sweating, diarrhea, urination, miosis and bronchoconstriction. Which of the following conditions is most aligned with these symptoms?

<p>Muscarinic agonist overdose. (A)</p> Signup and view all the answers

A researcher aims to design a muscarinic agonist with high specificity for bladder emptying and gastrointestinal motility. Which of the following agents should they consider as a lead compound?

<p>Bethanechol (C)</p> Signup and view all the answers

How does the chemical structure of acetylcholine relate to its susceptibility to cholinesterases?

<p>The ester linkage is readily hydrolyzed by cholinesterases. (B)</p> Signup and view all the answers

Why is asthma a contraindication for muscarinic agonists?

<p>Muscarinic agonists can exacerbate bronchoconstriction. (C)</p> Signup and view all the answers

What is the key difference between reversible and irreversible anticholinesterases in terms of their mechanism of action?

<p>Reversible anticholinesterases involve carbamoylation, while irreversible agents involve phosphorylation of the enzyme. (A)</p> Signup and view all the answers

Which of the following describes the mechanism of action of cholinesterase?

<p>It hydrolyzes acetylcholine into choline and acetate. (D)</p> Signup and view all the answers

Which structural feature within the active site of cholinesterase is responsible for binding the quaternary ammonium group of acetylcholine?

<p>Anionic Site (C)</p> Signup and view all the answers

What is the role of the esteratic site in the mechanism of action of cholinesterase?

<p>It facilitates the hydrolysis of the ester bond in acetylcholine. (A)</p> Signup and view all the answers

A chemist is designing a novel cholinesterase inhibitor. They want to create a drug with intermediate duration of action. Which of the following mechanisms should inform their design?

<p>An agent which carbamoylates the enzyme (A)</p> Signup and view all the answers

A patient is brought to the emergency department exhibiting signs of organophosphate poisoning. Which of the following is the fundamental mechanism of action of organophosphates.

<p>They phosphorylate cholinesterase, leading to a very stable bond. (A)</p> Signup and view all the answers

What is the mechanism of action of pralidoxime in treating organophosphate poisoning?

<p>It regenerates active cholinesterase by breaking the phosphate bond. (D)</p> Signup and view all the answers

In the treatment of organophosphate poisoning, why is it crucial to administer pralidoxime as soon as possible?

<p>To prevent the aging process of phosphorylated cholinesterase. (C)</p> Signup and view all the answers

A toxicologist investigating a case of suspected poisoning identifies a compound that inhibits acetylcholinesterase, leading to CNS effects such as excitation, convulsions, and ultimately, respiratory failure. Which of the following properties of the compound would best explain its ability to cause these CNS effects?

<p>Non-polar nature allowing it to cross the blood-brain barrier. (C)</p> Signup and view all the answers

A researcher is investigating potential treatments for myasthenia gravis. Which mechanism would be most consistent with a drug used to manage myasthenia gravis?

<p>Inhibiting cholinesterase to increase acetylcholine levels at the neuromuscular junction. (C)</p> Signup and view all the answers

Why is Edrophonium used for diagnostic purposes in Myasthenia Gravis?

<p>It is short acting allowing for quick assessment of muscle strength (C)</p> Signup and view all the answers

How do reversible anticholinesterase drugs improve glaucoma?

<p>By facilitating the outflow of aqueous humor through contraction of the ciliary muscle. (B)</p> Signup and view all the answers

Tarcrine and Tetrahydroaminoacridine (THA) have fallen out of favour as treatments for Alzheimers, why is this?

<p>They caused liver toxicities (D)</p> Signup and view all the answers

What is the significance of the term 'aging' in the context of organophosphate poisoning?

<p>It describes a conformational change in phosphorylated cholinesterase that reduces its susceptibility to reactivators. (C)</p> Signup and view all the answers

Which of the following explains why patients with anticholinesterase poisoning often exhibit both muscarinic and nicotinic effects?

<p>Excessive acetylcholine affects both muscarinic and nicotinic receptors. (B)</p> Signup and view all the answers

A researcher discovers a new compound that exhibits anticholinesterase activity. Animal studies show that the compound is effective in increasing acetylcholine levels in the brain but causes severe peripheral side effects. Which structural modification would be most likely to improve the drug's selectivity for the CNS and reduce peripheral side effects?

<p>Increasing its polarity to limit its ability to cross the blood-brain barrier. (A)</p> Signup and view all the answers

Parathion requires what to become active?

<p>Metabolism to active metabolites (B)</p> Signup and view all the answers

Flashcards

Cholinergic / Muscarinic Agents

Chemicals that act at the same site as acetylcholine.

Parasympathomimetic drugs

Drugs that mimic the action of the parasympathetic nervous system (PSNS).

Acetylcholine (ACh)

The main neurotransmitter of the parasympathetic nervous system.

Choline Group

A quaternary ammonium group that is positively charged and very polar, making it lipid insoluble.

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Ester Group

The part of the acetylcholine molecule that is rapidly hydrolysed by cholinesterase into choline and acetate.

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Gastrointestinal tract response to Cholinergic Stimulation

Increased contractility and motility. Also increases gastric acid secretions.

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Lungs response to Cholinergic Stimulation

Constriction of the tracheal and bronchial smooth muscle, increased mucous secretion.

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Urinary Bladder response to Cholinergic Stimulation

Contraction of the detrusor muscle.

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Salivary glands response to Cholinergic Stimulation

Watery secretion.

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Erectile tissue response to Cholinergic Stimulation

Release of nitric oxide (NO), leading to vasodilation and erection.

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Eye response to Cholinergic Stimulation

Accommodation for close vision by tightening the ciliary muscles, due to parasympathetic activation.

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Cardiovascular response to Cholinergic Stimulation

Vasodilation in coronary vessels and the lungs.

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Pilocarpine

Muscarinic agonists used to treat glaucoma by reducing intraocular pressure.

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Contraindications of Muscarinic Agonists

Asthma, hyperthyroidism, coronary insufficiency and peptic ulcer diseases.

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Anticholinesterase

Drugs that inhibit the enzyme cholinesterase.

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Cholinesterase (ChE)

Serine hydrolases that hydrolyze acetylcholine and other choline esters. It has anionic and esteratic active sites.

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Edrophonium

Reversible, short-acting cholinesterase inhibitor used to diagnose Myasthenia Gravis.

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Neostigmine and Pyridostigmine

Cholinesterase inhibitors, given orally, that can be used to treat Myasthenia Gravis.

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Donepezil and Rivastigmine

Drugs used to treat Alzheimer's disease by improving cognitive function by its selective and lipophilic properties.

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Antiglaucoma

Drugs (DFP, Echothiophate)

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Irreversible Anticholinesterase

Organophosphates and nerve gas.

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Pralidoxime

Antidote for organophosphate poisoning that reactivates phosphorylated acetylcholinesterase.

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AntiChE Poisoning

bradycardia, hypotension, breathing difficulties, depolarizing block + CNS effects.

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Neuromuscular junction effects (nmj)

Muscle fasciculation and increased twitch tension.

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CNS effects

Demyelination that ends excitation, convulsion, depression until unconsciousness + respiratory failure (muscarinic).

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Study Notes

Cholinergic and Anticholinesterase Drugs

  • Cholinergic and anticholinesterase drugs are important in pharmacology
  • Professor Dr Ahmad Rohi Ghazali is credited with this information

Parasympathomimetic Agents

  • Parasympathomimetic agents can be direct-acting or indirect-acting
  • Cholinergic or muscarinic agents are direct-acting
    • Include definitions, clinical uses, side effects, and contraindications
  • Anticholinesterase agents are indirect-acting
    • Include reversible and irreversible anticholinesterase, clinical uses, side effects, contraindications, and cholinesterase reactivation

Cholinergic / Muscarinic Agents Definitions

  • Chemicals act at the same site as acetylcholine
  • These are also parasympathomimetic drugs, mimicking the parasympathetic nervous system (PSNS)
  • Cholinergic agents have both direct and indirect actions
  • Acetylcholine (ACh) is a neurotransmitter
  • All motor neurons activating skeletal muscle utilize ACh
  • All preganglionic neurons of the autonomic nervous system (ANS) use ACh
  • Postganglionic neurons of the parasympathetic nervous system also use ACh

Muscarinic Drugs

  • Muscarine is derived from Amanita muscaria (fly agaric)
  • Functions as a cholinergic drug

Acetylcholine

  • Ach has activity on muscarinic (5 subtypes: metabotropic) and nicotinic (7 subtypes: ionotropic) receptors
  • The choline group is a quaternary ammonium group (+ve) and very polar (lipid insoluble)
  • Ester group is negatively charged and rapidly hydrolyzed by cholinesterase into choline and acetate

The Parasympathetic Nervous System

  • Gastrointestinal tract: M1 and M3 stimulation causes increased contractility, motility, and gastric acid secretion
  • Lungs: M1 and M3 stimulation causes constriction of tracheal and bronchial smooth muscles and increased mucous secretion from bronchial glands
  • Urinary Bladder: M3 stimulation causes contraction of the detrusor muscle
  • Salivary glands: M3 stimulation increases watery secretion
  • Erectile tissue: M3 stimulation causes release of NO, leading to vasodilation and erection, mediated by endothelial dilatation releasing factor (EDRF), increasing blood pooling

Parasympathetic Innervation to the Eye

  • Acetylcholine causes the sphincter pupillae to contract, resulting in miosis (pupil constriction)
  • The eye accommodates for close vision by tightening the ciliary muscles
    • This allows the pliable crystalline lens to become more rounded

Acetylcholine Pharmacological Responses

  • Cardiovascular (M2): Causes Vasodilation
    • Coronary vasodilatation, also in the lungs
    • Mechanisms include coronary vasodilation via reflex action or direct vagus electrical stimulation (M2)
    • M3 mediates vasodilation by endothelium dilatation releasing factor
    • Decreases Heart Rate (Negative Chronotropic Effects)
    • Decreases Conduction Rate (Negative Dromotropic Effects)
    • Decreases Cardiac Contraction Force (Negative Inotropic Effects)

Summary of Parasympathetic Actions

  • Remembered with the acronym: LESS DUMB
    • Lacrimation, Excitation/Emesis, Salivation, Sweating, Diarrhea, Urination, Miosis, Bronchoconstriction, Bradycardia

Muscarinic Agonists

  • Can be Parasympathomimetic or Cholinomimetic
  • Alkaloids:
    • Arecoline (betel nut, Areca catechu)
    • Muscarine (Amanita muscarina)
    • Pilocarpine (Pilocarpus jaborandi): Used as an antiglaucoma agent, is a tertiary amine and bladder emptying agent
  • Synthetic Agents:
    • Oxotremorine
    • Methacholine: Used for lab purposes
    • Carbachol
    • Bethanechol: Used for bladder emptying and as a GIT motility agent
    • Cevimeline: Used for dry mouth

Muscarinic Agonists - Contraindications

  • Include asthma, hyperthyroidism, coronary insufficiency, and peptic ulcer diseases

Muscarinic Agonists - Adverse Reactions

  • Symptoms of poisoning manifest as parasympathetic overdrive, leading to headaches and sight disturbances
    • Remembered with the acronym: LESS DUMB

Anticholinesterase

  • Blocks the normal breakdown of Acetylcholine

MOA of Cholinesterase (ChE)

  • Serine hydrolases class hydrolyzes ACh and other choline esters
  • Has two active sites
  • Anionic active site: remaining glutamate that binds to choline (base) ACh
  • Esteratic (catalytic) site: remaining histidine + serine that binds to acetyl (acid) ACh

ACh Hydrolysis

  • Mechanism:
  • ACh binds to enzyme.
  • Acetyl group binds to serine-OH(enzyme) and converted to acetylated enzyme (spontaneous acetyl-serine) and production of free choline molecules.
  • Bound acetyl-serine is hydrolysed to produce acetyl group.
  • Hydrolysis action occurs in approximately 1ms

Cholinergic Drugs

  • These can be Direct Acting or Indirect Acting
  • Direct Acting
    • Agonists can be either Choline Esters or Alkaloids
  • Indirect Acting
    • Cholinesterase Inhibitors which can be:
      • Quarternary Alcohol (Short-acting, S)
        • Edrophonium
        • Tacrine
        • Donepezil
      • Carbamate (Middle-acting, M)
        • Physostigmine
        • Neostigmine
        • Demecarium
      • Organophosphate (Irreversible, I)
        • Ecothiophate
        • Parathion/Malathion
        • Sarin

Reversible Anticholinesterase for Glaucoma

  • Works in intra ocular pressure (IOP) increase
  • ALL parasympathomimetic agents lower IOP by pulling iris away from trabecular meshwork and aqueous humor to flow out.

Reversible Anticholinesterase for Myasthenia Gravis

  • There is no cure. Drugs provide temporary assistance to help the body function normally
  • Includes:
    • Pyridostigmine (Mestinon)
    • Neostigmine (Prostigmin)
    • Edrophonium chloride (to diagnose myasthenia, also for curare OD)

Reversible Anticholinesterase for Alzheimer's Disease

  • Alzheimer's disease characterized by loss of cholinergic neurons (basal forebrain to cerebral cortex + hippocampus)
    • Leads to profound memory disturbances and irreversible impairment of cognitive function
  • Tacrine or Tetrahydroaminoacridine (THA)
    • The first AntiChE approved for use in Alzheimer's patients
    • It can cause liver toxicities
  • Donepezil and Rivastigmine
    • Selective and lipophilic

Irreversible Anticholinesterase

  • Includes: -Drugs (DFP, Echothiophate), Antiglaucoma -Insecticides

Cholinesterase Reactivation

  • Pralidoxime: Used to reactivate phosphorylated AChE
    • Hydroxylamine group (=NOH) has high affinity for phosphorus atom
    • This is via nucleophilic site that interacts with phosphorylated site on phosphorylated-AChE

Anticholinesterase - Other Responses

  • Autonomic cholinergic synapse effects:
    • AntiChE Poisoning:
      • bradycardia, hypotension, breathing difficulties + nmj depolarizing block + CNS effects (TREATMENT with atropine)
  • Neuromuscular junction effects (nmj):
    • Muscle fasciculation + ↑ twitch tension (depolarizing block)
  • CNS effects:
    • Tertiary compounds and OP are non polar and can cross BBB (neurotoxicity: demyelination)
    • Effects: excitation, convulsion, depression until unconsciousness + respiratory failure (muscarinic).

Summary of Anticholinesterase

  • Edrophonium: Type S, acts on nmj, used for Myasthenia gravis diagnosis (too short acting for clinical).
  • Neostigmine: Type M, acts on nmj, administered IV (competes with nmj blockers) or Oral (myasthenia gravis treatment)
  • Physostigmine: Type M, targets postganglion PARA, used as Drops for the glaucoma treatment
  • Pyridostigmine: Type M, acts on nmj, administered Orally for myasthenia gravis; has better absorption from Neostigmine and longer acting
  • Dyflos: Type L, targets postganglion PARA, is Very toxic and sustained effects, and used for glaucoma
  • Ecothiopate: Type L, targets postganglion PARA, drops are used to treat treatment glaucoma with Systemic side effects (continuous)
  • Parathion: Type L, undergoes Metabolism to active metabolites (insecticide)

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