2000A14 Discuss the roles of plasma esterases on drugs used in anaethesia.

Activity

·  Ester hydrolysis: ester -> acid + alcohol

Source

·  Mostly liver

Capacity

·  High

Metabolites

·  Mostly inactive (exception: laudanosine -> neurotoxicity)

Factors ↑ activity

·  ↑temp

·  ±↓pH (benzylisoquinoliniums)

Factors ↓ activity

·  Deficiency

·  Drug inhibitors

Drugs metabolised

·  Suxamethonium

·  Mivacurium

·  Ester local anaesthetics e.g. tetracaine

·  Acetylcholinesterases e.g.neostigmine

Sux metabolism

·  Sux -> succinylmonocholine + choline

·  S’monocholine -> succinic acid + choline

Rapid metabolism

·  Rapid offset of paralysis for sux (~5-10mins) and mivacurium

·  Lower risk of systemic toxicity with ester LAs (e.g. prilocaine IV for Bier’s block)

Polymorphism

·  Two copies

·  Four types: usual, dibucaine-resistant (DR), chloride resistant, silent

·  Usual-usual: (~96% population): dibucaine number (DN) 80, offset ~5 mins

·  Usual-DR: (a few %): DN 60, offset ~30mins

·  DR-DR: (<<1%): DN 20, offset 8-12 hours

Inhibition of production

·  Disease states: heart failure, liver failure, renal failure, cancer

·  Pregnancy: same amount, higher blood volume hence lower concentration

Inhibition of activity

·  Acetylcholinesterase inhibitors

·  Other drugs: metoclopramide, ketamine, oral contraceptive pill, Lithium, lignocaine, ester local anaesthetics, cytotoxics

Stimulation of production

·  Obesity

·  Alcohol abuse

Drug target

·  Esmolol (ester-methyl-olol)

Rapid rate

·  Accounts for short t_1/2β of esmolol 10 mins

Drug targets

·  Benzylisoquinoliniums

·  Remifentanil

Benzylisoquinolinium metabolism

·  Atracurium -> monoquaternary alcohol + monoquaternary acid + laudanosine

·  Independent of kidney and liver, unlike aminosteroids

·  Less important for cisatracurium

Remifentanil

·  Metabolism by non-specific esterases in plasma and tissue, especially muscle

·  One minimally active carboxylic acid metabolite (activates TLR-4 -> hyperalgaesia)

·  Accounts for very short max context sensitive half time (CSHT 10 min), hence suitable for TIVA