12 Cholinesterase Inhibitors

Question 1

Purpose

Answer 1

Reverse non-depolarizing muscle blockade

Maximize nicotinic transmission with minimum muscarinic side effects

Question 2

Rx Examples

Answer 2

Neostigmine, edrophonium, pyridostigmine, physostigmine

Question 3

Where is ACh active

Answer 3

• Neurotransmitter for parasympathetic nervous system: ganglions and effector cells
• Parts of sympathetic: sympathetic ganglia, adrenal medulla, sweat glands
• Somatic nerves
• Some neurons of CNS

Question 4

2 subtypes of cholinergic receptors & locations

Answer 4

1. Nicotinic - somatic motor neurons; blocked by muscle relaxants and/or anticholinergics
2. Muscarinic - CNS & autonomic locations (specifically: bronchial smooth muscle, salivary glands, SA note); blocked by anticholinergic (e.g atropine)

Question 5

Cholinesterase inhibitors: Mechanism of Action

Answer 5

Stop degradation of ACh

Indirectly increase amount of ACh available to compete with nondepolarizing agent

In excessive doses, paradoxically potentiate nondepolarizing neuromuscular blockade

Question 6

Muscarinic Side Effects

Answer 6

Muscarinic receptors for autonomic & CNS.

Increase in ACh caused by cholinesterase inhibitors, by activating muscarinic receptors, causes:

CV - bradycardia

Pulmonary - bronchospasm, increased respiratory tract secretions

Cerebral - physostigmine crosses BBB

GI - increase peristaltic activity, PONV, fecal incontinence

Minimized by prior/concomitant admin of anticholinergic

Question 7

Cholinesterase Inhibitors Clearance

Answer 7

Hepatic metabolism (25-50%) and renal excretion (50-75%)

Question 8

Tetany and cholinesterase inhibitors

Answer 8

If no tetanic peripheral nerve stimulation, block too intense for cholinesterase inhibitor to reverse block

Palpable post-tetanic twitch appears ~10-40 min prior to first twitch of TOF

Higher frequency of stimulation, great specificifty of test: 100 Hz tetany > 50 Hz tetany or TOF > single twitch height

Question 9

Neostigmine

Answer 9

Lipid insoluble, doesn’t pass through BBB

0.04-0.08 mg/kg (up to 5 mg in adults)

Effects in 5 minutes, last ~ 1 hr

Admin with glycopyrrolate: 0.2mg / 1 mg neostigmine

Neostigmine crosses placenta, theoretically causing fetal bradycardia

Question 10

Pyridostigmine

Answer 10

20% as potent as neostigmine

0.1-0.25 mg/kg

Slower onset (10-15 min), longer duration (>2 hr)

Doesn’t cross BBB

Glycopyrrolate: 0.05 mg / 1 mg pyridostigmine

Question 11

Edrophonium

Answer 11

10% as potent as neostigmine

0.5-1 mg/kg

Rapid onset (1-2 min), shortest duration

Atropine: 0.014 mg / 1 mg edrophonium

Would need to give glycol several minutes before to avoid bradycardia

Question 12

Physostigmine

Answer 12

Lipid soluble - crosses BBB - less useful to reverse neuromuscular blockade - used for treatment of central anticholinergic toxicity

0.01-0.03 mg/kg

Question 13

Sugammadex

Answer 13

Hydrophobic interactions trap steroid (Roc, Vec, Pancuronium) in cyclodextrin cavity

Tight 1:1 complex

Terminates neuromuscular blockade

Unchanged renal excretion