Ch.10 Cholinesterase Inhibitors

1. Ch.10 Cholinesterase Inhibitors R1 이송이

2. Cholinesterase Inhibitors • Primary Clinical use – to reverse nondepolarizing muscle blockade • Commonly used • Neostigmine • Edrophonium • Pyridostigmine • Physostigmine

3. Cholinergic Pharmacology • Cholinergic = the effects of the neurotransmitter Acetylcholine • Ach is the neurotransmitter for • The entire parasympathetic nervous system (parasympathetic ganglions & effector cells) • Parts of the sympathetic nervous system (sympathetic ganglions, adrenal medulla, sweat gl) • Some neurons in the CNS • Somatic nerves innervating skeletal m.

4. Cholinergic Pharmacology

5. Cholinergic Pharmacology Cholinergic Receptors – Two major groups • Nicotinic receptor -> autonomic ganglia & skeletal m -> blocked by neuromuscular blockers • Muscarinic receptor -> end-organ effector cells in bronchial smooth m, salivary gl, SA node -> blocked by anticholinergic drugs

6. Mechanism of Action • Normal Neuromuscular Transmission • Ach binds to Nicotinic Rc on motor end plate • Nondepolarizing muscle relaxants • Act by competing with Ach ; Competitive Antagonist • Reversing neuromuscular blockade-to maximize nicotinic transmission-to minimize Muscarinic side effects

7. Mechanism of Action Reversal of blockade • Spontaneous reversal • Diffusion • Redistribution • Metabolism • Excretion • Pharmacologic reversal • Cholinesterase Inhibitors increase the amount of Ach available

8. Mechanism of Action • In excessive doses - Cholinesterase inhibitors paradoxically potentiate a nondepolarizing neuromuscular blockade • Cholinesterase Inhibitors prolong the blockade of succinylcholine (Depolarizing NMB) by • An increase in Ach • Inhibition of pseudocholinesterase activity

9. Clinical Pharmacology An increase in Ach affect Nicotinic receptors of skeletal muscle but also • Cardiovascular Rc : vagal-like bradycardia, bradyarrhythmias • Pulmonary Rc : bronchospasm • Cerebral Rc : Physostigmine can cross BBB – Diffuse excitation • GI Rc : increase peristaltic activity and glandular secretion

10. Clinical Pharmacology These unwanted Muscarinic side effects can be minimized by the administration of anticholinergic medication • Atropine sulfate • Glycopyrrolate

11. Clinical Pharmacology • Dosage depend on the degree of neuromuscular block • Estimated by the response to peripheral nerve stimulation • Some evidence of spontaneous recovery (i.e.. The 1st twitch of the TOF) must be present before reversal is attempted!

12. Clinical Pharmacology • Time required for full reversal depend on • The choice and dose of the Cholinesterase Inhibitor (e.g.. Edrophonium reversal is faster than with Neostigmine// Large doses lead to faster reversal) • The choice and dose of the muscle relaxant (e.g.. Intermediate-acting relaxants reverse sooner than long acting) • The extent of blockade (e.g.. A shallow block is easier to reverse than deep blocks)

13. Clinical Pharmacology • Unless full reversal can be demonstrated or postop. plans include continued ventilation –A reversal agent should be routinely given to patients who have received nondepolarizing muscle relaxants

14. Clinical Pharmacology • Peripheral nerve stimulators should also be used (to monitor the progress and confirm the adequacy of reversal) • Suggested end points of recovery • In anesthetized pts – sustained tetanus for 5s in response to a 100-Hz stimulus • In awake pts – sustained head lift (> inspiratory force > vital capacity > tidal volume)

15. Specific Cholinesterase Inhibitors

16. Neostigmine • Physical Structure • Lipid insoluble, cannot pass BBB

17. Neostigmine • Dosage & Packaging • 0.04-0.08 mg/kg (up to 5mg in adults) • 10mL of a 1mg/mL solution • Clinical Considerations • Effects apparent in 5-10 min peak at 10 min lasts more than an hour • Pediatric and elderly pts are more sensitive  require a smaller dose

18. Neostigmine • Anticholinergics minimize Muscarinic side effects • Glycopyrrolate has similar onset of action (0.2mg per 1ml of Neostigmine) • Atropine is better choice in pregnant pts (b/c Neostigmine crosses placenta resulting in fetal bradycardia) • Side effects N/V, incontinence, delayed recovery room discharge, atropine-resistant bradycardia (higher dose, 200ug)

19. Pyridostigmine • Physical structure • Lipid insoluble, cannot pass BBB

20. Pyridostigmine • Dosage & Packaging • 0.1- 0.4mg/kg (up to total 20mg in adults) • Solution of 5mg/mL • Clinical Consideration • onset is slower (10-15 min) • duration is longer (>2h) • Glycopyrrolate (0.05mg per 1mg of Pyridostigmine) or atropine (0.1mg per 1mg of Pyridostigmine) • Glycopyrrolate is preferred

21. Edrophonium • Dosage & Packaging • Less than 10% as potent as Neostigmine • 0.5-1mg/kg • Solution of 10mg/mL • Clinical Consideration • Most rapid onset – 1~2mins • Shortest duration of effect • Higher doses prolongs duration (more than 1h) • Not as effective in reversing intense blockade • Atropine(0.014mg per 1mg of Edrophonium)

22. Physostigmine • Physical structure • lipid soluble, freely passes the BBB

23. Physostigmine • Dosage & Packaging • 0.01-0.03mg/kg • Solution of 1mg/mL • Clinical Consideration • Limited as reversal agent • Effective in treatment of central anticholinergic toxicity • Reverses CNS depression and delirium associated with use of benzodiazepine and volatile anesthetics • Preventing postoperative shivering(0.04mg/kg) • Partially antagonizes morphine induced respiratory depression

24. Physostigmine • Side Effects excessive salivation, vomiting, convulsion