Biosynthesis of Acetylcholine

• Acetylcholine (ACh) is synthesized in cholinergic neurons.

• Key Enzymes:

  • Choline Acetyl Transferase (ChAT): Synthesizes acetylcholine from choline and acetyl coenzyme A.

  • Acetylcholinesterase (AChE): Metabolizes acetylcholine into choline and acetate.

• Choline Transport: Choline is transported into the neurons via Choline Transporter (CHT), which is sodium-dependent.

• Rate Limiting Step: The transport of choline and transfer of acetyl group are the rate-limiting steps in acetylcholine synthesis.

Storage and Release of Acetylcholine

• Acetylcholine is stored in vesicles within cholinergic neurons.

• Vesicle Associated Transporter (VAT): Transports ACh into vesicles driven by proton efflux.

• Release of acetylcholine is calcium-dependent, triggered by action potentials leading to calcium influx via N-type calcium channels.

Fate of Acetylcholine

• Desirable: Binding to post-synaptic receptors.

• Undesirable: Hydrolysis by acetylcholinesterase, yielding choline and acetate.

Drugs Affecting Acetylcholine Synthesis

1. Hemicolinium: Inhibits active uptake of choline.

2. Visamicol: Inhibits vesicle storage of acetylcholine.

3. Botulinum Toxin: Inhibits the release of acetylcholine; leads to paralysis.

Cholinergic Receptors

• Types: Nicotinic receptors and Muscarinic receptors.

• Nicotinic Receptors:

  • Coupled to ion channels.

  • Two types: N1 (NM) for skeletal muscular contraction and N2 (NN) found in post-ganglionic neurons.

• Muscarinic Receptors:

  • Stimulate secretions and contractions in various organs.

  • Subtypes:

  • M1: CNS effects, gastric secretion.

  • M2: Cardiac effects, decreases heart rate.

  • M3: Gland secretions and smooth muscle contractions.

  • M4: Regulates adenylyl cyclase and decreases cAMP levels.

  • M5: Research stage, regulates dopamine release.

Cholinergic Agonists (Cholinomimetics)

• Mimic acetylcholine action.

• Direct Acting: Interact directly with receptors.

  • Classification: Alkaloids (e.g., nicotine) and choline esters (e.g., acetylcholine, carbacol).

• Indirect Acting: Inhibit acetylcholinesterase, increasing acetylcholine levels.

Structure-Activity Relationship (SAR) of Cholinomimetics

• Key Groups:

  • Onion Group: Quaternary ammonium cation; essential for receptor affinity.

  • Ester Function: Distance between groups affects muscarinic activity.

  • Choline Moiety: Alpha and beta substitutions can alter potency and activity.

Specific Drugs

• Acetylcholine: Not used clinically due to rapid hydrolysis and non-selectivity.

• Methacholine: Used in asthma testing, more stable than ACh.

• Carbacol: Treats glaucoma, acts on both nicotinic and muscarinic receptors.

• Bethanechol: M-selective, used for urinary retention.

• Pilocarpine: M-selective, treats glaucoma, increases glandular secretions.

Indirect Acting Cholinomimetics (Anti-Cholinesterases)

• Edrophonium: Short-acting, used for diagnosing myasthenia gravis.

• Physostigmine: Used for glaucoma and atropine poisoning.

• Pyridostigmine: Used for myasthenia gravis, longer duration than edrophonium.

• Neostigmine: Also treats myasthenia gravis, antidote for neuromuscular blockers.

• Organophosphates: Used in pesticides and nerve gases, irreversible inhibitors.

2. Toxicology and Management

• Antidote for Acetylcholine Toxicity: Atropine, a non-selective muscarinic antagonist.

• Organophosphates: Malathion and Parathion used as insecticides. Parathion metabolizes to paraoxon, a toxic form.

Nerve Gases

• Synthesis of nerve agents for chemical warfare, highly volatile and toxic. Generally categorized by a series (G-series agents like Tabun, Sarin, Soman). Risk exists via dermal exposure or inhalation.

CNS Acting Anti-Cholinesterases

• Used for treating Alzheimer’s disease (Tacrine, Donepezil).

• Indirect Acting Anticholinesterases in Alzheimer's Disease

  • Tacrine:

  • Reversible cholinesterase inhibitor.

  • Used for mild to moderate Alzheimer's disease.

  • Conflicting efficacy results.

  • Donepezil:

  • Reversible acetylcholinesterase inhibitor.

  • Used for mild to moderate Alzheimer's disease.

  • Half-life: 70 hours.

  • 96% bound to plasma proteins.

  • Galantamine:

  • Alkaloid from Leucojum aestivum and Narcissus pseudonarcissus.

  • Also a reversible cholinesterase inhibitor for Alzheimer's disease.

  • Rivastigmine:

  • Pseudo irreversible, non-competitive carbamate inhibitor.

  • Half-life: 2 hours.

  • Duration of action: 10 hours.

  • Approved for Alzheimer’s and Parkinson’s-associated dementia.

• Acetylcholine Toxicity:

  • Increased levels lead to symptoms summarized by mnemonic "DUMBELLS":

  • D: Diarrhea, U: Urination, M: Miosis, B: Bradycardia,

  • B: Bronchoconstriction, E: Emesis, L: Lacrimation, S: Salivation.

• Antidotes for Acetylcholine Toxicity:

  • Atropine: Acts at receptor level.

  • Pralidoxime: Reactivates enzymes if given within 36 hours of exposure.

• Cholinergic Antagonists:

  • Competitive antagonists of acetylcholine (muscarinic receptors).

  • Actions: Reduced GI motility, mydriasis, decreased salivation (antisialogue), and gastric acid secretion.

• Major Cholinergic Antagonists:

  • Atropine: Antidote for acetylcholine toxicity.

  • Scopolamine: Used for motion sickness.

  • Oxybutynin: For overactive bladder, but may cause dry mouth.

• Therapeutic Classifications:

  • Solanaceous Alkaloids: Atropine, hyoscyamine, scopolamine.

  • Synthetic Agents: Amino alcohols (benztropine), amides (tropicamide), esters (glycopyrrolate).

• Therapeutic Actions of Anticholinergics:

  • Respiratory: Ipratropium for COPD.

  • GI Tract: Glycopyrrolate.

  • Ocular: Homatropine/cyclopentolate for pupil dilation.

  • CNS: Scopolamine for motion sickness (prophylactic use).

• Adverse Effects:

  • Common: Dry mouth (xerostomia), blurred vision, constipation, cognitive impairment.

  • Contraindications: Urinary obstruction, GI obstruction, angle-closure glaucoma, prostatic hyperplasia.