Pharmacology of Antimuscarinics and Acetylcholine

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Questions and Answers

What characteristic distinguishes atropine from shorter-acting antimuscarinics like cyclopentolate and tropicamide?

It is less effective for accommodation in individuals over 40.

It causes prolonged mydriasis for 7-14 days. (correct)

It has a shorter duration of action.

It is primarily eliminated in the urine.

Which adverse effect is specifically dangerous for children when using atropine?

Dry mouth

Hallucinations

Blurred vision

Rapid increases in body temperature (correct)

What is a primary therapeutic use of scopolamine?

As an antispasmodic for the GI tract

For prevention of motion sickness (correct)

To treat glaucoma

To block secretions prior to surgery

Which of the following effects can result from taking atropine?

Tachycardia Signup and view all the answers

What differentiates scopolamine's action on the CNS compared to atropine's action?

CNS effects of scopolamine occur at therapeutic doses. Signup and view all the answers

How is atropine primarily eliminated from the body?

In the urine Signup and view all the answers

What potential condition can atropine exacerbate in susceptible individuals?

Narrow-angle glaucoma Signup and view all the answers

For which condition is atropine NOT used?

Motion sickness Signup and view all the answers

What is a primary characteristic of acetylcholine in therapeutic contexts?

It is rapidly inactivated by cholinesterases. Signup and view all the answers

Which of the following best describes the actions of acetylcholine on the cardiovascular system?

It induces negative chronotropy and vasodilation. Signup and view all the answers

What is the primary therapeutic application of pilocarpine?

Lowering intraocular pressure in glaucoma Signup and view all the answers

What is the primary effect of opening K+ channels in cardiac myocytes?

Hyperpolarization of the membrane Signup and view all the answers

Which of the following effects is NOT associated with pilocarpine?

Dry mouth Signup and view all the answers

What is the role of nitric oxide in acetylcholine-mediated vasodilation?

It triggers hyperpolarization of vascular smooth muscle cells. Signup and view all the answers

Which drug is noted for having a greater selectivity for M1 muscarinic receptors?

Pirenzepine Signup and view all the answers

What is the mechanism by which nicotinic receptors cause depolarization in effector cells?

Entry of sodium ions Signup and view all the answers

Which direct-acting cholinergic drug is primarily known for its muscarinic activity and longer duration of action than acetylcholine?

Pilocarpine Signup and view all the answers

How does pilocarpine affect vision during its administration?

Creates a fixed focus at a particular distance Signup and view all the answers

What major side effect can result from pilocarpine use?

Profuse sweating Signup and view all the answers

Which of the following is a competitive muscarinic receptor antagonist with higher affinity for M3 receptor?

Darifenacin Signup and view all the answers

What effect does atropine have regarding acetylcholine's actions?

It blocks the effects of acetylcholine on muscarinic receptors. Signup and view all the answers

What occurs during rapid infusion of pirenzepine?

Reflex tachycardia due to M2 blockade Signup and view all the answers

Which of the following mechanisms does NOT describe an action of acetylcholine?

Increasing heart rate. Signup and view all the answers

What distinguishes pilocarpine from acetylcholine in terms of potency?

Pilocarpine is far less potent than acetylcholine Signup and view all the answers

What classification do choline esters belong to?

Direct-acting cholinergic agonists Signup and view all the answers

What is the mechanism of action for physostigmine?

Inhibits acetylcholinesterase Signup and view all the answers

Which group of drugs is characterized by a lack of specificity in their actions, limiting clinical usefulness?

Direct-acting agonists Signup and view all the answers

What primary action does acetylcholine have in the gastrointestinal tract?

Increases intestinal motility. Signup and view all the answers

Which type of glaucoma can pilocarpine be used in to lower intraocular pressure?

Both narrow-angle and wide-angle glaucoma Signup and view all the answers

Which receptors are selectively blocked by hexamethonium?

Nn ganglionic receptors Signup and view all the answers

What intermediate is formed when physostigmine interacts with acetylcholinesterase?

Carbamoylated intermediate Signup and view all the answers

Which of the following describes the effect of direct-acting cholinergic agonists?

Mimicking the effects of acetylcholine Signup and view all the answers

What is the primary effect of mecamicylamine as an oral antihypertensive agent?

Decrease in cardiac output Signup and view all the answers

What is the mechanism of action of nondepolarizing neuromuscular blocking drugs at low doses?

They prevent the binding of acetylcholine Signup and view all the answers

Which of the following describes the primary use of neuromuscular blocking agents during surgery?

For muscle relaxation without higher anesthetic doses Signup and view all the answers

In what way does mecamylamine differ from trimethaphan regarding drug absorption?

Mecamylamine has good oral absorption Signup and view all the answers

Which drug was the first documented neuromuscular blocker used in clinical practice?

Tubocurarine Signup and view all the answers

What occurs in the body at higher doses of mecaylmine?

GI and bladder activity decreases Signup and view all the answers

What is a key characteristic of neuromuscular blockers used during surgery?

They facilitate intubation and muscle relaxation Signup and view all the answers

How does the use of neuromuscular blockers enhance the safety of anesthesia?

By reducing the required doses of anesthetic Signup and view all the answers

Which drug is favored for producing mydriasis in ocular examinations but is not preferred if cycloplegia is needed?

Phenylephrine Signup and view all the answers

How does atropine affect gastric motility?

It reduces gastric motility. Signup and view all the answers

What cardiovascular effect does atropine produce at low doses?

Decreased cardiac rate Signup and view all the answers

Which statement is correct regarding the effect of atropine on salivary glands?

It produces xerostomia. Signup and view all the answers

At what dose does atropine start to increase the cardiac rate by blocking M2 receptors?

1 mg Signup and view all the answers

What is a notable side effect of atropine regarding temperature regulation?

Hyperthermia due to reduced sweating Signup and view all the answers

Which drug is an M1-muscarinic antagonist that reduces gastric acid secretion?

Pirenzepine Signup and view all the answers

Which of the following is a therapeutic use of topical atropine?

To measure refractive errors without accommodative interference Signup and view all the answers

Study Notes

Autonomic Nervous System

The autonomic nervous system (ANS) is a division of the nervous system that controls involuntary bodily functions.
Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the ANS.
Cholinergic drugs act on receptors activated by acetylcholine.
Cholinomimetic (cholinergic) drugs can be direct-acting or indirect-acting.

Cholinergic Agonists and Parasympathetic System

Cholinergic drugs act on receptors activated by acetylcholine.
Cholinergic and adrenergic drugs act by either stimulating or blocking receptors of the ANS.
Cholinomimetic (cholinergic) drugs are categorized as direct-acting or indirect-acting.
Direct-acting drugs include muscarinic and nicotinic subgroups.
Indirect-acting drugs include organophosphates (very long-acting), carbamates (intermediate, long-acting), and edrophonium (short-acting).
Cholinergic receptors on effector organs are categorized as muscarinic and nicotinic.

The Cholinergic Neuron

Preganglionic fibers terminating in the adrenal medulla and the autonomic ganglia (both parasympathetic and sympathetic), and the postganglionic fibers of the parasympathetic division use acetylcholine as a neurotransmitter.
Cholinergic neurons innervate somatic system muscles and play a role in the central nervous system (CNS).
Patients with Alzheimer's disease experience a substantial loss of cholinergic neurons in the temporal lobe and entorhinal cortex.

Neurotransmission at Cholinergic Neurons

Neurotransmission in cholinergic neurons follows six sequential steps: synthesis, storage, release, binding to a receptor, degradation of the neurotransmitter, and recycling of choline.
Synthesis of acetylcholine involves choline transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system.
Acetylcholine is packaged into presynaptic vesicles by an active transport process.
When an action potential arrives at a nerve ending, calcium levels increase, promoting the fusion of synaptic vesicles with the membrane for release of their contents into the synaptic space.

Binding to the Receptor

Acetylcholine released from synaptic vesicles diffuses across the synaptic space and binds to postsynaptic receptors on the target cell or presynaptic receptors.
Postsynaptic cholinergic receptors are categorized as muscarinic and nicotinic.

Degradation of Acetylcholine

The signal at the post-junctional site is rapidly terminated by acetylcholinesterase, which cleaves acetylcholine to choline and acetate in the synaptic cleft.

Recycling of Choline

Choline is recaptured by a sodium-coupled, high-affinity uptake system, transported back into the neuron, and acetylated into acetylcholine, stored until released by a subsequent action potential.

Muscarinic Receptors

Muscarinic receptors recognize acetylcholine and muscarine, an alkaloid in some poisonous mushrooms.
Muscarinic receptors have five subclasses: M1, M2, M3, M4, and M5.
M1, M2, and M3 receptors have been functionally characterized.
Muscarinic receptors are found on ganglia, peripheral nervous system, smooth muscle, brain, and exocrine glands.
- M1 receptors are also present in gastric parietal cells.
- M2 receptors are found in the cardiac cells and smooth muscles.
- M3 receptors are located in the bladder, exocrine glands, and smooth muscles.
Drugs with muscarinic actions preferentially stimulate muscarinic receptors; at high concentrations, they can show some activity with nicotinic receptors.

Mechanisms of Acetylcholine Signal Transduction

M1 and M3 receptors, when activated, undergo conformational changes, interact with Gq proteins leading to phosphatidylinositol hydrolysis.
This hydrolysis yields diacylglycerol and inositol, causing an increase in intracellular calcium levels.
This interaction stimulates or inhibits enzymes, or causes hyperpolarization, secretion, or contraction.
M2 subtype activation leads to Gi protein activation, which inhibits adenylyl cyclase and increases potassium conductance.
This leads to a decrease in heart rate and force of contraction.

Muscarinic Agonists and Antagonists

Examples of muscarinic agonists include pirenzepine, which particularly inhibits M1 muscarinic receptors, and darifenacin, which exhibits high affinity for M3 receptors.
Pirenzepine, at therapeutic doses, does not cause many of the side effects observed in non-subtype-specific drugs and causes reflex tachycardia in the heart due to blockade of M2 receptors.
Muscarinic antagonists, such as atropine, do not block nicotinic receptors, limiting actions primarily to skeletal muscle and autonomic ganglia.

Cholinergic Agonists

Cholinergic agonists mimic the actions of acetylcholine at cholinoceptors, thereby mimicking parasympathetic actions.
Agents can be grouped broadly as choline esters and naturally occurring alkaloids.
Direct-acting cholinergic agonists, including acetylcholine, carbachol, and bethanechol have long durations of action than acetylcholine.

Acetylcholine

Acetylcholine is the major parasympathetic neurotransmitter and is present in some somatic nerves and autonomic ganglia.
It is a quaternary ammonium compound that cannot penetrate membranes.
Its short duration of action and the presence of cholinesterases limits its therapeutic importance.

Decrease in Blood Pressure

Acetylcholine causes vasodilation through the activation of M3 receptors on endothelial cells, leading to nitric oxide production from arginine by endothelial cells.

Other Actions

In the GI tract, acetylcholine stimulates secretions and motility, and increases salivary secretion.
Acetylcholine enhances bronchiolar secretions, and increases tone in the detrusor muscle of the genitourinary tract, causing urine expulsion.
In the eye, acetylcholine leads to ciliary muscle contraction needed for near-vision and pupil constriction.

Bethanechol

Bethanechol is similar structurally to acetylcholine.
It is not inactivated by acetylcholinesterase.
It generally stimulates muscarinic receptors to cause increased gastrointestinal motility and bladder tone.
Bethanechol is primarily used to stimulate an atonic bladder in postpartum or postoperative states.

Carbachol

Carbachol is structurally related to acetylcholine and exhibits both muscarinic and nicotinic actions.
It is a poor substrate for acetylcholinesterase and is biotransformed by other esterases, thus generally having a longer duration of action.
It can cause profound effects on both the cardiovascular and gastrointestinal systems, which may initially stimulate and then depress the targeted system.
It can cause epinephrine release from the adrenal medulla by its nicotinic action.
A miotic agent which is used for the treatment of glaucoma.

Pilocarpine

Pilocarpine is a tertiary amine, stable against hydrolysis by acetylcholinesterase.
It is a potent stimulator of secretions, such as sweat, tears, and saliva..

Indirect-Acting Cholinergic Agonists (Anticholinesterases)

Inhibitors of acetylcholinesterase indirectly provide a cholinergic action by increasing the concentration of acetylcholine in the synaptic space.
Physostigmine, a tertiary amine found naturally in plants, is a substrate for acetylcholinesterase, and forms a relatively stable carbamoylated intermediate that is inactivated, potentiating cholinergic activity.
Neostigmine has a quaternary nitrogen and, unlike physostigmine, does not enter the CNS, having a moderate duration of action.
It's therapeutic use is in treating symptomatic myasthenia gravis, an autoimmune disease affecting neuromuscular junctions.

Pyridostigmine and Ambenomium

Pyridostigmine and ambenomium are other cholinesterase inhibitors used for the chronic management of myasthenia gravis.
They have intermediate durations of action (3 to 6 hours and 4 to 8 hours, respectively).
Adverse effects are typical for a cholinergic agonist.

Demecarium

Demecarium is a cholinesterase inhibitor used to treat chronic glaucoma.
It is also used for diagnosing and treating accommodative esotropia.

Edrophonium

Edrophonium has similar actions to neostigmine; it is rapidly absorbed from the site of injection and has a brief duration of action.
It is used in the diagnosis of myasthenia gravis, characterized by muscle weakness.
Excessive use may potentially provoke cholinergic crisis.

Tacrine, donepezil, rivastigmine, and galantamine

These agents are anticholinesterase drugs used to treat Alzheimer's disease, aiming to improve cognitive function.
Patients with Alzheimer's disease have a deficiency of cholinergic neurons in the central nervous system.

Echothiophate

Echothiophate is an organophosphate inhibiting acetylcholinesterase, yielding long-lasting acetylcholine increase and acting similar to other cholinesterase inhibitors.
It is extremely toxic and was developed as a nerve agent.
Echothiophate is used in the treatment of open-angle glaucoma.
Pralidoxime can reactivate inhibited acetylcholinesterase by displacing the phosphate group of the organophosphate, restoring the enzyme.

Cholinergic Antagonists

Act as antagonists at cholinoceptors, preventing receptor-mediated effects.
Include anti-muscarinic and anti-nicotinic agents, both ganglionic blockers and neuromuscular blockers.
Anti-muscarinic agents block muscarinic receptors but not nicotinic receptors, and are useful in treating a variety of clinical conditions.

Antimuscarinic Agents

Examples include atropine, scopolamine, cyclopentolate, and tropicamide.
They block muscarinic receptors, limiting parasympathetic functions.
They are used in ocular examinations.

Scopolamine

Scopolamine is an anti-motion sickness drug with CNS effects such as sedation, excitement, and euphoria.
Its use is mostly preventive, rather than curative.
It is a potent anti-motion sickness drug, and its amnesic action is clinically useful in anesthetic procedures.

Ipratropium

Inhaled ipratropium is a quaternary derivative of atropine, and is useful in treating asthma and chronic obstructive pulmonary disease(COPD).

Ganglionic Blockers

Ganglionic blockers act on nicotinic receptors in sympathetic and parasympathetic ganglia.
They have complex and unpredictable responses that limits their therapeutic use, and are mostly used in experimental pharmacology.

Nicotine

Nicotine is a component of cigarette smoke and is without therapeutic benefit, it causes adverse effects on health.
Depending on the dose, it can stimulate or paralyze autonomic ganglia in different ways.
It affects both parasympathetic and sympathetic ganglia.
Nicotine's effects include increased blood pressure and cardiac rate, and increased peristalsis and secretions.

Mecamylamine

Mecamylamine is potent, oral antihypertensive agent, primarily attributed to reduced sympathetic tone, vasodilation, and lowered cardiac output.
It is used to reduce hypertension and to achieve selective blood pressure control in emergency situations following oral absorption.
It blocks nicotinic receptors of autonomic ganglia.

Neuromuscular Blocking Drugs

These drugs interfere with the transmission from motor nerves endings to skeletal muscles.
They are classified as structural analog of acetylcholine, acting either as antagonists (non-depolarizing type) or agonists (depolarizing type) at the end plate of the neuromuscular junction.
They are helpful in surgeries for muscle relaxation and facilitate intubation.

Nondepolarizing Blockers

The first drug to be capable for skeletal muscle neuromuscular junction blocking was curare.
Tubocurarine was purified and used in clinical practice in the early 1940s.
These competitive blockers interfere with acetylcholine binding to nicotinic receptors, preventing depolarization and muscular contraction.

Depolarizing Agents

The depolarizing neuromuscular blocking drug succinylcholine works by attaching to nicotinic receptors and causing depolarization of the receptor.
This effect leads to a transient muscle twitch (fasciculation) and eventually a gradual repolarization of the receptor making it resistant, resulting in flaccid paralysis.
It is short-lasting and is mostly used for its brief duration for rapid endotracheal intubation.

Adverse Effects

Adverse effects of cholinergic agonists and antagonists vary based on the agent and dose.
In general, anticholinergic agents, at toxic levels, can cause significant adverse effects, including elevated body temperature, and CNS effects..
Hyperthermia, caused by agents such as halothane with succinylcholine, is treated by rapid cooling and dantrolene administration to reduce heat production and relax muscle tone.
Deficient cholinesterase can exacerbate succinylcholine's action, leading to prolonged apnea due to diaphragm paralysis..

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Description

This quiz covers key pharmacological concepts related to antimuscarinic agents such as atropine, scopolamine, and pilocarpine. It explores their mechanisms, therapeutic uses, adverse effects, and the role of acetylcholine in the cardiovascular system. Test your knowledge on the distinctions between various drugs and their impacts on the body.