Cholinergic Drugs and Their Effects

Autonomic Nervous System

• The autonomic nervous system is responsible for involuntary functions like heart rate, digestion, and breathing
• Cholinergic and adrenergic drugs act by either stimulating or blocking receptors in the autonomic nervous system
  • Cholinergic drugs act on receptors activated by acetylcholine
  • Adrenergic drugs act on receptors activated by adrenaline/epinephrine

Cholinergic Agonists and Parasympathetic system

• Cholinergic drugs act on receptors activated by acetylcholine
• Cholinergic drugs are categorized as cholinomimetics
  • Direct-acting (acting on receptors directly):
    • Muscarinic
    • Nicotinic
  • Indirect-acting (acting on the breakdown/synthesis of acetylcholine):
    • Organophosphates
    • Carbamates
    • Edrophonium

The Cholinergic Neuron

• Preganglionic fibers in the autonomic ganglia (parasympathetic and sympathetic) use acetylcholine as a neurotransmitter
• Cholinergic neurons also innervate somatic system muscles and play a role in the central nervous system (CNS)
• Alzheimer's disease is characterized by loss of cholinergic neurons in the temporal lobe and entorhinal cortex
• Many Alzheimer's treatments are cholinesterase inhibitors

Neurotransmission at Cholinergic Neurons

• Neurotransmission at cholinergic neurons follows six sequential steps: synthesis, storage, release, binding to a receptor, degradation of the neurotransmitter, and recycling of choline
  • Choline is transported from the extracellular fluid into the neuron's cytoplasm by an energy-dependent carrier system
    • This system co-transports sodium and can be inhibited by hemicholinium
  • Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form acetylcholine
  • Acetyl CoA is derived from mitochondria and is produced by the Krebs cycle and fatty acid oxidation
  • Acetylcholine is packaged into presynaptic vesicles by active transport
    • Mature vesicles also contain ATP

Release of Acetylcholine

• When an action potential arrives at a nerve ending, voltage-sensitive calcium channels open, increasing intracellular calcium levels
• Elevated calcium levels cause synaptic vesicles to fuse with the cell membrane, releasing acetylcholine into the synaptic space
• Botulinum toxin blocks this release, while black widow spider venom causes all acetylcholine to empty into the synaptic gap

Binding to the receptor

• Acetylcholine released diffuses across the synaptic space and binds to either presynaptic or postsynaptic receptors
• Postsynaptic cholinergic receptors on effector organs are divided into muscarinic and nicotinic classes

Degradation of Acetylcholine

• The signal at the post-junctional effector site is rapidly terminated by acetylcholinesterase
  • It breaks down acetylcholine into choline and acetate
  • The cleft is this where this process occurs

Recycling of Choline

• Choline may be recaptured by a sodium-coupled, high-affinity uptake system to be transported back into the neuron
  • It will then be acetylated, to form acetylcholine, which is stored until subsequent action potentials occur

Cholinergic Receptors (Cholinoceptors)

• Two families of cholinoceptors, muscarinic and nicotinic, are distinguished based on their affinities for acetylcholine mimetics and parasympathomimetics
• Muscarinic receptors show affinity for muscarine, while nicotinic receptors have affinity for nicotine

Muscarinic Receptors

• These receptors bind acetylcholine and recognize muscarine that is found in certain poisonous mushrooms.
• They have a weak affinity for nicotine.
  • Subclasses: M1, M2, M3, M4, and M5
  • Only M1, M2, and M3 receptors have been functionally characterized.

Locations of muscarinic receptors

• Located on ganglia of the peripheral nervous system, autonomic effector organs (heart, smooth muscle, brain, and exocrine glands), gastric parietal cells, cardiac cells, smooth muscle, and bladder, exocrine glands, and smooth muscle

Mechanisms of Acetylcholine Signal Transduction

• Activation of M1 or M3 receptors triggers a conformational change, initiating interaction with a G protein (Gq)
  • Gq activates phospholipase C.
  • This leads to the hydrolysis of phosphatidylinositol-4,5-bisphosphate, generating diacylglycerol and inositol triphosphate.
  • This increases intracellular Ca2+ levels
  • The resultant action: may stimulate or inhibit enzymes, cause hyperpolarization, secretion, or contraction
• Activation of M2 receptors triggers a different response, involving a different G protein (Gi). -Gi inhibits adenylyl cyclase and increases K+ conductance,
  • leading to a decrease in the heart's rate and force of contraction.

Muscarinic Agonists and Antagonists

• Example: pirenzepine; a tricyclic anticholinergic drug with selectivity for inhibiting M1 muscarinic receptors, with this specific example, primarily in the gastric mucosa
  • At therapeutic doses, pirenzepine doesn't cause many side effects (compared with non-subtype selective drugs)
  • It does, however, cause reflex tachycardia on rapid infusion due to blockade of M2 receptors in the heart.

Darifenacin

• Competitive muscarinic receptor antagonist with greater affinity for the M3 receptor than other muscarinic receptors
• Commonly used in treating overactive bladder

Nicotine Receptors

• These receptors bind acetylcholine and nicotine, but show weak affinity for muscarine.
• Two types: NM and NN
  • Nm are located in the neuromuscular junction, causing skeletal muscle contraction.
    • Nm receptors are blocked by tubocurarine.
  • Nn are located in autonomic ganglia, resulting in postsynaptic depolarization.
    • Nn receptors are blocked by hexamethonium

Direct-Acting Cholinergic Agonists

• Cholinergic agonists (also known as parasympathomimetics) mimic the effects of acetylcholine by binding directly to cholinoceptors
• These agents are broadly classified into choline esters (acetylcholine and synthetic esters of choline, e.g. carbachol and bethanechol) and naturally occurring alkaloids (pilocarpine)
• Most direct-acting cholinergic drugs have longer durations of action than acetylcholine
• Some, such as pilocarpine and bethanechol, preferentially bind to muscarinic receptors and are sometimes called muscarinic agents

Acetylcholine

• A quaternary ammonium compound that cannot penetrate membranes
• It's the neurotransmitter for parasympathetic and somatic nerves and autonomic ganglia
• It has both muscarinic and nicotinic activity
• Its actions include decreased heart rate and cardiac output (negative chronotropy)

Decrease in Blood Pressure

• Acetylcholine causes vasodilation and lowers blood pressure
• It activates M3 receptors on endothelial cells lining blood vessels, stimulating nitric oxide production from arginine
• Nitric oxide then causes smooth muscle relaxation

Other Actions

• In the gastrointestinal tract, acetylcholine stimulates intestinal secretions and motility; also increases salivary secretion
• In the genitourinary tract, the tone of the detrusor muscle is increased, causing urine expulsion
• In the eye, acetylcholine stimulates ciliary muscle contraction, aiding near vision, and constricts the pupillary sphincter, causing miosis

Bethanechol

• Structurally related to acetylcholine; not hydrolyzed by acetylcholinesterase but inactivated by other esterases
• Lacks nicotinic activity but has strong muscarinic activity
• Duration of action: 1 hour
• Actions: direct stimulation of muscarinic receptors in the intestine and urinary bladder, increasing intestinal motility and tone, stimulating the bladder's detrusor muscles, relaxing the trigone and sphincter.
• Therapeutic applications: commonly used to stimulate the atonic bladder, especially in postpartum patients

Carbachol (carbamylcholine)

• Structurally related to acetylcholine with muscarinic AND nicotinic actions
  • Lacks the methyl group present in bethanechol
• Poor substrate for acetylcholinesterase; biotransformed by other esterases but with a much slower rate
• Duration of action: up to 1 hour
• Acts on both cardiovascular and GI systems through its ganglion-stimulating activity, which can first stimulate then depress the systems. It can release epinephrine from the adrenal medulla(via its nicotinic effects).
• Therapeutic uses: ophthalmology (miotic agent for glaucoma treatment).

Pilocarpine

• Alkaloid, a tertiary amine that's stable to hydrolysis by acetylcholinesterase
  • In contrast to other cholinergic agonists, it can cross the blood-brain barrier even at therapeutic doses
• Exhibits strong muscarinic activity
  • Primarily used in ophthalmology
• Actions include rapid miosis and contraction of the ciliary muscle, causing accommodation spasm, important in treating narrow-angle glaucoma

Anticholinesterases (re-(reversible))

• Inhibit the enzyme acetylcholinesterase
  • Leading to increased acetylcholine concentrations in the synaptic cleft
• Physostigmine, pyridostigmine, ambenomium, and demecarium are some examples
  • These agents may be used for certain situations such as treating myasthenia gravis or glaucoma.

Echothiophate

• Organophosphate that inhibits acetylcholinesterase
  • A long-lasting effect of increasing acetylcholine.
  • It is extremely toxic. Used as nerve agents.
• Mechanism of action: Covalently binds via phosphate group to the serine-OH group of the active site of acetylcholinesterase.
• Treatment and reactivation: Pralidoxime can reactivate the inhibited enzyme, but it is unable to cross the blood-brain barrier.
• Adverse effects: Generalized cholinergic stimulation(sweating, salivation, decreased blood pressure).

Tacrine, donepezil, rivastigmine, galantamine

• These are anticholinesterase drugs used in treatment of Alzheimer's disease
• Tacrine was the first, but the other three are preferred due to less hepatotoxicity

Cholinergic Antagonists

• Anticholinergic drugs: bind to cholinoceptors but do not trigger intracellular effects
  • Anticholinergics are classified into: Antimuscarinic, Ganglionic blockers, and Neuromuscular blockers
• Antimuscarinics
  • Examples: Atropine, Scopolamine, Cyclopentolate, Ipratropium, Tropicamide, etc
• Ganglionic blockers
  • Examples: Mecamylamine, Nicotine, etc
• Neuromuscular blockers
  • Examples: Tubocurarine, Succinylcholine, etc

Antimuscarinic Agents

• Often called "antimuscarinics" -Examples:Atropine, Scopolamine, etc -Action: block muscarinic receptors, inhibiting muscarinic functions. -They also block some sympathetic neurons that are cholinergic (ex: glands).
  • Benefits: Beneficial in various clinical situations

Atropine

• Tertiary amine belladonna alkaloid
  • High affinity for muscarinic receptors
  • Competes with acetylcholine, preventing it from binding
  • Acts centrally and peripherally
  • Actions include:
    • Eye: increased intraocular pressure, blocks cholinergic activity(mydriasis, cycloplegia, unresponsiveness to light)
    • Gastrointestinal: reduces GI activity -Other Actions: inhibits various secretions, may cause dilated pupils, blurred vision, tachycardia, and constipation.
    • Cardiovascular: usually produces decreased cardiac rate at low doses and increased rate at higher doses.
  • Uses in ophthalmology, antispasmodic, antidote for cholinergic agent overdoses, and antisecretory agent before surgery

Scopolamine

• Tertiary amine belladonna alkaloid
  • Has greater effect on the CNS than atropine
  • Used as an anti-motion sickness drug
  • Prophylactic use is more effective
  • Therapeutic Uses: as an anti-motion sickness drug

Ipratropium

• Quaternary derivative of atropine, useful for treating asthma in patients unable to take adrenergic agonists, beneficial for COPD management
  • Inhaled
  • Useful for treating asthma

Tropicamide and Cyclopentolate

• Ophthalmic solutions for conditions similar to atropine (mydriasis and cycloplegia)
• Shorter duration of action (tropicamide: 6 hours, cyclopentolate: 24 hours) compared to atropine

Ganglionic Blockers

• Ganglionic blockers specifically act on nicotinic receptors in both parasympathetic and sympathetic ganglia.
• They display non-selectivity and are rarely used therapeutically
• Examples: Mecamylamine (potent oral antihypertensive agent)

Nicotine

• Component of cigarette smoke, without any therapeutic benefit, but rather deleterious to health
• Nicotine depolarizes autonomic ganglia at low doses and then results in paralysis of these ganglia when higher doses are used.

Neuromuscular Blocking Drugs

• These drugs block cholinergic transmission between motor nerve endings and nicotinic receptors at the neuromuscular junction
  • Structural analogs of acetylcholine
  • Antagonists (non-depolarizing type) or agonists (depolarizing type)
  • Clinically-useful for surgery to produce muscle relaxation without higher anesthetic doses
  • Helpful for facilitating intubation

Non-depolarizing (competitive) blockers

• Example: Tubocurarine, the first drug found capable of blocking the neuromuscular junction
  • Most commonly-used is tubocurarine -Mechanism of action (at low doses): interact with nicotinic receptors to prevent acetylcholine binding, preventing depolarization and muscle contraction -Mechanism of action (at high doses): can block ion channels on the end-plate, causing further weakening of neuromuscular transmission, reduces the ability of acetylcholinesterase inhibitors to reverse nondepolarizing muscle relaxants

Depolarizing Agents

• Example: Succinylcholine
• Mechanism of action: -Binds to nicotinic receptors -Acts like acetylcholine on the receptors, depolarizing the neuromuscular junction -Causes a short-lived depolarization(Phase I) followed by a sustained depolarization and eventually repolarization.

This quiz explores the pharmacological effects of cholinergic drugs, including bethanechol, carbachol, and pilocarpine. It covers therapeutic applications, mechanisms of action, and potential side effects. Test your knowledge on how these medications interact with cholinoceptors and their clinical significance.