Pharmacology of Cholinergic Agents

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Questions and Answers

Which compound is a non-selective muscarinic and nicotinic agonist with high hydrolysis by cholinesterase?

Bethanechol

Muscarine

Carbachol (correct)

Methacholine

Which of the following agents is known to have muscarinic activity but no nicotinic activity?

Arecoline

Oxotremorine

Nicotine

Cevimeline (correct)

What is the common characteristic of compounds like Bethanechol and Muscarine?

Low muscarinic activity

Resistant to cholinesterase

High nicotinic activity

No nicotinic activity (correct)

Identify the agent with the highest muscarinic activity and moderate nicotinic activity.

Acetylcholine Signup and view all the answers

Which of these compounds has a unique property of being a selective muscarinic agonist that is hydrolyzed less effectively by cholinesterase than Methacholine?

Pilocarpine Signup and view all the answers

What is the primary therapeutic use of neostigmine in the context of muscle disorders?

Reversal of non-depolarizing neuromuscular blocking drugs Signup and view all the answers

Which of the following distinguishes pyridostigmine from neostigmine?

Pyridostigmine is better absorbed and has a longer duration of action Signup and view all the answers

What is the mechanism of action of reversible long anticholinesterases like donepezil?

Inhibition of acetylcholinesterase, leading to increased acetylcholine levels Signup and view all the answers

Which of the following is NOT a characteristic of physostigmine?

Has longer duration of action than neostigmine Signup and view all the answers

What role do carbamyl groups play in the action of intermediate acting anticholinesterases?

They replace acetyl groups in binding to the enzyme Signup and view all the answers

Which of the following accurately describes the natural substrate of plasma cholinesterase?

Fatty acyl esters Signup and view all the answers

What is the primary location of acetylcholinesterase within the body?

Cholinergic nerve terminals Signup and view all the answers

What differentiates short-acting anticholinesterases from others?

They only bind to the anionic site of the enzyme. Signup and view all the answers

What clinical condition is most commonly treated using cholinesterase inhibitors?

Myasthenia gravis Signup and view all the answers

Which of the following is NOT classified as a short-acting anticholinesterase?

Neostigmine Signup and view all the answers

What is the effect of anticholinesterase inhibitors on acetylcholine levels in the body?

They increase the levels and duration of action of ACh. Signup and view all the answers

Which compound is primarily used as an antidote in anticholinergic poisoning?

Physostigmine Signup and view all the answers

Which active site of the cholinesterase enzyme binds the acetyl group during hydrolysis?

Esteric site Signup and view all the answers

What is the primary mechanism through which Pralidoxime (2-PAM) reactivates the phosphorylated enzyme?

It releases the phosphate group from the esteric site. Signup and view all the answers

What limitation affects the efficacy of Pralidoxime in treating organophosphate poisoning?

Ageing of the enzyme renders it no longer susceptible to reactivation. Signup and view all the answers

Which statement about Pralidoxime is true regarding its impact on the nervous system?

It does not affect the central actions of organophosphate poisoning. Signup and view all the answers

In conjunction with Pralidoxime, which drug is commonly used to relieve neuromuscular weakness caused by organophosphate poisoning?

Atropine Signup and view all the answers

Why is Pralidoxime not approved for the treatment of carbamate poisoning?

It is ineffective against the mechanisms of carbamate action. Signup and view all the answers

What is a significant contraindication for muscarinic agonists?

Asthma Signup and view all the answers

Which muscarinic antagonist primarily reduces gastric acid secretion?

Pirenzepine Signup and view all the answers

What effect do muscarinic antagonists have on the heart?

Increase heart rate Signup and view all the answers

Which of the following is a central nervous system effect of atropine?

Hyperactivity and hyperthermia from sweating loss Signup and view all the answers

Which muscarinic antagonist is specifically used for motion sickness?

Hyoscine Signup and view all the answers

What is the primary clinical use of Tiotropium?

Asthma and COPD Signup and view all the answers

Which of the following effects is NOT produced by muscarinic antagonists?

Bronchoconstriction Signup and view all the answers

What is the mechanism of action for muscarinic antagonists?

Blockade of cholinergic receptors Signup and view all the answers

Which medication is associated with the treatment of excessive salivation?

Glycopyrrolate Signup and view all the answers

Which of the following agents is a selective M3 antagonist?

Darifenacin Signup and view all the answers

What adverse effect is most commonly associated with overdose of muscarinic antagonists?

Dry mouth and skin Signup and view all the answers

Which muscarinic antagonist is primarily used in the management of organophosphate poisoning?

Atropine Signup and view all the answers

Which of the following substances is a toxic alkaloid found in mushrooms?

Muscarine Signup and view all the answers

What is the primary mechanism by which irreversible anticholinesterases exert their action?

They phosphorylate the esteric site of the enzyme. Signup and view all the answers

Which of the following statements about the aging process of organophosphate-inhibited cholinesterases is true?

Aging decreases the potential for reactivation of the inhibited enzyme. Signup and view all the answers

Which compound is classified as a pseudo-irreversible anticholinesterase and is used in treating glaucoma?

Ecothiophate Signup and view all the answers

What is the core reason for the toxicity of Dyflos?

It has a highly toxic nature with prolonged action. Signup and view all the answers

Under what condition can organophosphate poisoning become particularly dangerous?

When aging of the phosphorylated enzyme starts to occur. Signup and view all the answers

Which of the following statements correctly describes the action of irreversible anticholinesterases?

They irreversibly inhibit acetylcholinesterase by binding to the esteric site. Signup and view all the answers

What type of compounds are primarily used in pesticides and biowarfare, related to irreversible anticholinesterases?

Organophosphates Signup and view all the answers

What is the elimination half-life of the compounds discussed in relation to anticholinesterases?

70 hours Signup and view all the answers

Study Notes

Cholinergic Pharmacology

Cholinergic pharmacology studies agents that act on the cholinergic system.
The cholinergic system is composed of nerve cells that use acetylcholine as a neurotransmitter for action potentials.
Acetylcholine is the neurotransmitter released during nerve impulse propagation

Cholinergic Nerve Anatomy

A cholinergic nerve has a presynaptic neuron and a postsynaptic neuron separated by a synaptic cleft.
Vesicles containing acetylcholine (ACh) are present in the presynaptic neuron.
Acetylcholinesterase (AChE) is located in the synaptic cleft.

Anabolism of Acetylcholine

Biosynthesis: Acetylcholine (ACh) is synthesized within cholinergic neurons by transferring an acetyl group from acetyl CoA to choline.The enzyme choline-acetyltransferase (ChAT) catalyzes this reaction.
Uptake into storage vesicles: Synaptic vesicles, primarily located at nerve endings, store the synthesized neuronal acetylcholine (ACh). Vesicular ACh transporter (VACHT) transports ACh into these vesicles.
Release: Calcium influx is essential for acetylcholine (ACh) release from synaptic vesicles.
Neurotransmission: After release, ACh diffuses across the synaptic cleft and binds to postsynaptic receptors, triggering a physiological response

Catabolism of Acetylcholine

Degradation (Hydrolysis): Acetylcholinesterase (AChE) in the synaptic cleft breaks down ACh into choline and acetate.
Recycling: Choline transporter (ChT) returns choline to the presynaptic neuron to synthesize new ACh. Acetate is also recycled for further ACh synthesis.

Agents Affecting ACh

Biosynthesis inhibition: a-ketoacids and naphthoquinones directly inhibit the enzyme choline acetyltransferase (ChAT), thus interfering with ACh synthesis.
Vesicle uptake blockage: Vesamicol blocks the specific ACh transporter (VACHT), preventing ACh from entering synaptic vesicles. This compound is poisonous.
Release inhibition: Botulinum toxin inhibits ACh release from presynaptic nerve terminals.
Release increase: Latrotoxin (from black widow spider) causes an explosive release of ACh.
Neurotransmission blockade: Atropine blocks postsynaptic muscarinic ACh receptors, preventing ACh's action. a-Bungarotoxin irreversibly binds to postsynaptic nicotinic ACh receptors. D-tubocurarine blocks nicotinic ACh receptors

Cholinergic Receptors

Nicotinic ACh receptors (nAChRs): These receptors are located at the preganglionic, ganglion, and postganglionic regions. Excess activation can result in desensitization. They are ionotropic receptors.
Muscarinic ACh receptors (mAChRs): Primarily postganglionic and not prone to desensitization after excess activation. They are metabotropic. There are five subtypes

Effects of Cholinergic Transmission

Muscarinic agonists/antagonists
Ganglion-stimulating/blocking agents
Neuromuscular-blocking agents
Anticholinesterases

Structure Activity Relationship (SAR) of Muscarinic Agonists

Key features for activity include a quaternary ammonium group (reducing CNS penetration), an ester group (susceptible to cholinesterase hydrolysis), and a choline structure (affinity for both mAChRs and nAChRs).

Muscarinic Agonists

Substances that mimic the effects of ACh on muscarinic receptors.
Types: quaternary ammonium and tertiary ammonium.
Examples: Acetylcholine, Carbachol, Methacholine, Bethanechol, Pilocarpine, Cevimeline, Oxotremorine, Arecoline, Muscarine

Muscarinic Agonists Effects

Organs/Systems: Smooth muscles (bronchi, GI tract, bladder), eye (pupil, ciliary muscles), glands (salivary, lacrimal, sweat), blood vessels, heart (SA and AV nodes).

Muscarinic Antagonists

Substances that block the effects of ACh on muscarinic receptors.
Types: tertiary and quaternary ammonium salts
Examples: Atropine, Hyoscine, Dicycloverine, Propantheline, Tolterodine, Darifenacin, Ipratropium, Glycopyrrolate

Muscarinic Antagonists Effects

Effects on smooth muscles, glands, eye, and heart are opposite to those of muscarinic agonists.

Ganglion Agonists

These agents stimulate both sympathetic and parasympathetic ganglia.
Examples: Nicotine, Varenicline, Lobeline, Epibatidine

Ganglion Blockers

These agents inhibit transmission between preganglionic and postganglionic neurons in autonomic ganglia.
Examples: Tetraethyl ammonium, Hexamethonium, Trimetaphan, Mecamylamine, D-tubocurarine, Pentamine

Neuromuscular Blockers

Agents that block neuromuscular transmission (cholinergic).
Types: non-depolarizing, depolarizing
Non-depolarizing: Act postsynaptically, block nAChRs or Na+ channels.
Examples: Mivacurium, Atracurium, Vecuronium, Pipecuronium

Depolarizing Blockers

Agents that induce persistent depolarization of the motor endplate.
Example: Suxamethonium, Decamethonium.
More rapidly in onset compared to non-depolarizing.

Cholinesterases

Enzymes in the neuromuscular junction that break down acetylcholine (ACh) and other cholinergic compounds. Two main types: AChE, BuChE

Anticholinesterases

Compounds that inhibit the cholinesterase enzyme.
Most commonly used in diseases like Alzheimer's or Parkinson's.
Two types: Reversible and Irreversible

Cholinesterase Reactivation

Pralidoxime (2-PAM) reactivates phosphorylated cholinesterase.

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Description

Explore the key concepts surrounding non-selective muscarinic and nicotinic agonists, including the characteristics and applications of various compounds. This quiz covers their mechanisms of action, therapeutic uses, and differences among agents like neostigmine and pyridostigmine. Test your knowledge on the pharmacological aspects of cholinergic agents.