Mechanism of action of ACH Inhibitors

 Acetylcholinesterase (AChE) inhibitors work by preventing the breakdown of the neurotransmitter acetylcholine (ACh) in the synaptic cleft, thereby increasing its levels and prolonging its action. Here’s a detailed mechanism of action:

1. Inhibition of Acetylcholinesterase

Acetylcholinesterase (AChE) is the enzyme responsible for breaking down acetylcholine into acetate and choline at cholinergic synapses. AChE inhibitors bind to the active site of AChE, preventing it from hydrolyzing acetylcholine.

• Reversible AChE inhibitors: These inhibitors form non-covalent bonds with AChE, temporarily blocking its activity.
• Irreversible AChE inhibitors: These inhibitors covalently bond with AChE, causing long-lasting or permanent inactivation of the enzyme.

2. Accumulation of Acetylcholine

As acetylcholine is no longer degraded, its concentration increases at cholinergic synapses. This results in enhanced cholinergic transmission, meaning more acetylcholine is available to bind to cholinergic receptors (muscarinic and nicotinic receptors).

3. Enhanced Cholinergic Effects

The elevated levels of acetylcholine lead to prolonged stimulation of:

• Muscarinic receptors: Found in smooth muscles, cardiac tissue, and glands, leading to effects like increased glandular secretions, bradycardia (slower heart rate), and bronchoconstriction.
• Nicotinic receptors: Found in skeletal muscle and the autonomic ganglia, causing increased muscle contraction and, at high levels, muscle fatigue or paralysis.

4. Therapeutic Uses

• Alzheimer’s Disease: AChE inhibitors (e.g., donepezil, rivastigmine) are used to increase acetylcholine levels in the brain, helping improve cognition and memory.
• Myasthenia Gravis: Drugs like pyridostigmine increase acetylcholine at the neuromuscular junction, enhancing muscle strength.
• Glaucoma: AChE inhibitors (e.g., echothiophate) reduce intraocular pressure by increasing cholinergic tone in the eye.
• Reversal of Neuromuscular Blockade: AChE inhibitors are used to reverse the effects of non-depolarizing muscle relaxants in anesthesia.

5. Side Effects

Excess acetylcholine can lead to cholinergic crisis, characterized by muscle weakness, bradycardia, hypotension, excessive salivation, bronchoconstriction, and respiratory depression.

This mechanism outlines how acetylcholinesterase inhibitors enhance cholinergic transmission and the therapeutic roles they play in various conditions.