Acetylcholinesterase Inhibitors (Lecture 7)

Acetylcholinesterase Inhibitors (Lecture 7) Acetylcholine (ACh) Mechanism of Action 1. **How ACh Acts as a Neurotransmitter:** - **Synthesis:** ACh is synthesized from acetate and coenzyme A (CoA) in the presence of water. - **Storage:** ACh is stored in vesicles within the presynaptic neuron. - **Release:** ACh is released into the synaptic cleft upon presynaptic neuron stimulation. - **Receptor Activation:** ACh binds to either nicotinic or muscarinic receptors on the postsynaptic cell, depending on the cell type. - **Metabolic Inactivation:** ACh is quickly inactivated by acetylcholinesterase (AChE) into inactive substances (acetate and choline). 2. **Identifying Postsynaptic Receptors:** - The type of cholinergic receptor (nicotinic or muscarinic) depends on the target cell. Nicotinic receptors are typically present in skeletal muscle and autonomic ganglia, whereas muscarinic receptors are found in smooth muscle, cardiac muscle, and glandular tissues. 3. **ACh Synthesis and Breakdown:** - **Synthesis Reaction:** Acetate + CoA + H₂O → ACh - **Breakdown Reaction:** ACh + AChE → Acetate + Choline - Both acetate and choline are metabolic breakdown products and are not active neurotransmitters. ### Acetylcholinesterase Inhibitors (AChEIs) 1. **General Concepts:** - ACh is the active neurotransmitter. - AChE metabolizes ACh, terminating its action. - Inhibiting AChE results in increased levels of ACh in the synapse, leading to prolonged activation of nicotinic and muscarinic receptors. 2. **Neostigmine:** - **Prototype AChEI:** Inhibits the breakdown of ACh but does not stimulate or block receptors directly. - It is a quaternary ammonium compound, meaning it is always ionized and cannot cross the blood brain barrier, affecting only peripheral sites. - Acts on both muscarinic and nicotinic receptors, increasing ACh levels and receptor stimulation. 3. **Effects of AChEIs:** - Effects are **not permanent** and are reversible. - Used therapeutically for conditions such as myasthenia gravis, diagnosis of myasthenic vs. cholinergic crises, reversal of neuromuscular blockade, and as a topical agent for glaucoma. ### Myasthenia Gravis 1. **Overview:** - A neuromuscular disease characterized by weakness and fatigue of skeletal muscles due to inadequate stimulation by ACh. 2. **Treatment Rationale:** - AChEIs increase ACh availability at the neuromuscular junction, promoting better muscle activation. 3. **Crises:** - **Myasthenic Crisis:** Insufficient AChEI leads to muscle weakness or paralysis. - **Cholinergic Crisis:** Excessive AChEI overdose leads to muscle weakness due to overstimulation of nicotinic and muscarinic receptors. ### Differentiating Between Myasthenic and Cholinergic Crises: - **Diagnostic Test:** Administer a short-acting AChEI (e.g., Edrophonium). - **Improvement** in symptoms suggests myasthenic crisis. - **Deterioration** of symptoms suggests cholinergic crisis. ### Reversal of Neuromuscular Blockade: - AChEIs counteract neuromuscular blockers (like Tubocurarine) by increasing ACh concentration to overcome receptor blockade. ### Signs and Symptoms of AChEI Overdose: - **Nicotinic Symptoms:** Muscle twitching, cramps, weakness. - **Muscarinic Symptoms:** Salivation, lacrimation, urination, diarrhea, gastrointestinal distress, emesis (SLUDGE). **Treatment:** Supportive care and atropine administration to block muscarinic effects. ### Additional Information: - **Absorption of Drug Molecules:** Uncharged drug molecules are more easily absorbed than ionized ones. Ionized drugs do not penetrate the blood-brain barrier and only affect peripheral nervous system (PNS) targets. - **Atropine's Role:** Atropine blocks muscarinic effects of AChEIs, preventing excessive muscarinic activation (note: this section is left open for clarification with "Ask Andrew?"). What effects of AChEI does atropine NOT block? ️the Nicotinic receptors found on skeletal muscle Physostigmine ️Acts in peripheral nervous system just like neostigmine, but also enters CNS/brain very easily. Used for glaucoma (topical administration) and to treat antimuscar