Anticholinesterase Drugs and Cholinergic Agonists

Cholinergic Receptors Refers to the effects of ACH ACH Responsible for neurotransmission for the entire parasympathetic NS (Parasympathetic ganglions and effector cells). Portions of the sympathetic NS (sympathetic ganglions, adrenal medulla, and sweat glands) Some neurons in the CNS. Somatic nerves innervating skeletal muscle.

Acetylcholinesterase Acetylcholinesterase promotes hydrolysis of acetylcholine (ACH) to choline and acetic acid. Acetylcholinesterase is one of the most efficient enzymes known; one molecule has the ability to hydrolyze an estimated 300,000 molecules of ACH each minute. Widely distributed , present wherever ACH is the neurotransmitter.

Cholinesterase Inhibitors Inhibit the enzyme acetylcholinesterase Indirectly increase the amount of ACH available to compete with the NDMR by reversibly binding to inactivate the acetylcholinesterase enzyme. Primary clinical use, to reverse nondepolarizing muscle blockade. The effects extend beyond the neuromuscular endplate. Neostigmine, Physostigmine and Edrophonium follow this mechanism; increasing the availability of ACH at the NMJ to compete with NDMR.

Cholinesterase Inhibitors AChE Indirectly increase amounts of ACH available for competition with NDMR This reestablishes neuromuscular transmission

Cholinergic receptors Subdivided into 2 groups depending on their reaction to muscarine and nicotine alkaloids. Nicotine – autonomic ganglia and skeletal muscle receptors are activated - Nicotinic Receptors Muscarine – end-organ effector cells in bronchial smooth muscle, salivary glands and sinoatrial node - Muscarinic Receptors. Nicotinic Receptors- blocked by NDMR. Muscarinic Receptors – blocked by anticholinergic drugs (atropine). Our goal is to maximize nicotinic transmission while, simultaneously, minimizing muscarinic effects.

Mechanism of Action NDMR act by competition with ACH at motor end plate (nicotinic) Blocks neuromuscular transmission. Reversal of blockade dependent on several factors. Gradual diffusion Redistribution Metabolism Excretion

Duration of Action of Cholinesterase Inhibitors The stability of the bond when bound to the enzyme acetylcholinesterase Edrophonium: electrostatic attraction and hydrogen bonding are short lived. Neostigmine and Physostigmine: form covalent bonds and are longer lasting Clinical duration most influenced by the rate of drug disappearance from the plasma. Can be overcome by adjusting the dosages. Excess dosages can paradoxically potentiate a nondepolarizing blockade. These drugs prolong the depolarization blockade of succinylcholine.

Pharmacology characteristics related to increased ACH Cardiovascular: vagal-like bradycardia that can progress to sinus arrest. Pulmonary: Muscarinic stimulation can lead to bronchospasm(smooth muscle contraction) and increased respiratory tract secretions. Cerebral: Physostigmine crosses the BBB can cause diffuse activation of EEG GI: Muscarinic stimulation increases peristaltic activity (esophageal, gastric and intestinal) as well as glandular secretions(salivary, parietal). Perioperative bowel anastomotic leakage, N/V, and fecal incontinence can occur. Unwanted Muscarinic side effects are minimized with usage of anticholinergic meds such as Atropine and Glycopyrrolate.

Neostigmine Provides covalent bonding to acetylcholinesterase. The effects are usually apparent in 5-10 minutes Maximum recommended dose is 0.08mg/kg (up to 5mg in adults) Duration > 1 hour Concomitant administration of glycopyrrolate 0.2mg for each 1 mg of Neostigmine. Onset of action is closer with glycopyrrolate than atropine. Atropine can be used at 0.4mg per 1mg of Neostigmine

Edrophonium Relies on noncovalent bonding to the acetylcholinesterase enzyme. Less than one tenth as potent as Neostigmine. Recommended dose is 0.5-1mg/kg. Most rapid onset of action 1-2 minutes. Shortest duration Low doses can be outlast by longer acting NDMR’s. Higher doses can prolong duration to > 1hour. In equipotent doses, the muscarinic effects are less pronounced than those of Neostigmine.

Edrophonium The rapid onset is matched with the onset of Atropine (2 minutes) Dose 0.015-0.02 mg/kg Effects on HR last 170 minutes (+/-) CNS effects are minimal after usual doses. Pts with CAD may not tolerate the increased myocardial oxygen demand and decreased oxygen supply associated with tachycardia caused by atropine.

Costs: Edrophonium: 10mg/ml, 15 ml vial ($71.00/ $65.18) Neostigmine: 1mg/ml, 10 ml vial ($87.70/ $ 66.70) Glycopyrrolate: 0.2mg/ml, 1ml ($224.61 for box of 25) ($8.98/ml) Glycopyrrolate: 0.2mg/ml, 5ml ($41.43/$88.17) ($ 8.28/ml) Atropine: 0.4mg/ml, 20ml vial ($39.67/$52.13)