Direct Cholinergic Drugs and Receptors

Direct Cholinergic Drugs

• Direct cholinergic drugs mimic the effects of acetylcholine by binding directly to cholinergic receptors (muscarinic or nicotinic).
• These drugs are classified into two groups: direct-acting muscarinic and direct-acting nicotinic.
• Examples of direct-acting muscarinic drugs include acetylcholine, carbachol, and pilocarpine.
• Examples of direct-acting nicotinic drugs include acetylcholine and nicotine.

Cholinergic Receptors

• Cholinergic receptors are divided into two main types: muscarinic and nicotinic.

• Muscarinic receptors are G protein-coupled receptors. Subtypes M1, M3, and M5 are excitatory; M2 and M4 are inhibitory. They are located in all target organs innervated by parasympathetic fibers, such as the heart, cardiovascular system, eyes, and bladder.

• Nicotinic receptors are ion channel-linked receptors and are located at the neuromuscular junctions of skeletal muscle (Nm), adrenal medulla (Nn), CNS (Nn), and autonomic ganglia (Nn).

• Muscarinic actions vary by receptor subtype and include effects on the eye (contraction of pupil, etc.), heart (bradycardia), endothelium (vasodilation via NO), lungs (bronchial constriction), GIT (increased motility & secretion), urinary bladder (relaxation of sphincters), and exocrine glands (increase secretions).

Cholinergic Agonists (Parasympathomimetics)

• These mimic the actions of acetylcholine.
• Cholinergic agonists are subdivided into direct-acting and indirect-acting.
• Direct-acting agonists bind directly to cholinergic receptors.
• Indirect-acting agonists inhibit the degradation of acetylcholine by acetylcholinesterase.
  • Examples of direct-acting include acetylcholine, bethanechol, and pilocarpine.
  • Examples of indirect-acting include physostigmine, and neostigmine.

Synthetic Choline Esters

• These drugs include carbachol and bethanechol.
• They are quaternary ammonium compounds.
• They are not orally absorbed and have poor distribution.
• They cannot cross the blood-brain barrier.
• They are not metabolized by cholinesterase.
• They have a longer duration of action compared to acetylcholine.
• They are administered subcutaneously, not intravenously or intramuscularly.
• Carbachol exhibits both muscarinic and nicotinic actions. It's used in glaucoma treatment via eye drops, and rarely for urinary retention or paralytic ileus. Adverse effects include stimulation of norepinephrine (NE) release from the adrenal medulla.
• Bethanechol is used for atonic bladder, postpartum urinary retention, and paralytic ileus. Adverse effects include general cholinergic stimulation—sweating, salivation, abdominal pain—and decreased blood pressure.

Pilocarpine

• A tertiary amine cholinergic agonist.
• Well-absorbed orally and crosses the blood-brain barrier.
• It's primarily used in ophthalmology (treating glaucoma—eye drops) and for xerostomia (dry mouth).
• Pilocarpine is a muscarinic agonist and has a longer duration of action. Adverse effects when given orally include blurred vision, sweating, salivation, diarrhea, and bronchospasm.

Cevimeline

• A direct-acting muscarinic agonist.
• Used for the treatment of dry mouth associated with Sjogren's syndrome.

Nicotine

• Available as gum, lozenges, inhalers, or patches.

• An agonist at both Nn and Nm cholinergic receptors.

• Clinical use: smoking cessation.

• Common adverse effects: GI issues (nausea and vomiting), diarrhea.

Neurotransmission at Cholinergic Neurons

• Cholinergic neurons involve six sequential steps: synthesis, storage, release, binding to a receptor, postsynaptic response, degradation, and recycling.
• Post-synaptic responses can include excitation (depolarization: Na+ influx) or inhibition (hyperpolarization: Cl- influx & K+ efflux). Acetylcholinesterase degrades acetylcholine in the synaptic cleft, and choline is recycled.

Explore the mechanisms and classifications of direct cholinergic drugs and their corresponding receptors. This quiz covers the effects of acetylcholine, examples of muscarinic and nicotinic drugs, and the various subtypes of cholinergic receptors. Test your understanding of this critical area in pharmacology.