Pharmacology of Antimuscarinics and Acetylcholine

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..

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.