2020B15 Discuss the pharmacokinetic implications of severe chronic kidney disease,
using examples of drugs used in anaesthesia to illustrate your answer.

 

List:

·         Intro

·         Absorption

·         Distribution

·         Metabolism

·         Excretion

 

Intro:

Definition

·      Kidney damage or dysfunction of any cause for ≥3/12

Staging by GFR

1.         >90mL/min

2.         60-90

3.         30-60

4.         15-30

5.         <15 or dialysis-dependent (= failure)

Implications

·      Disturbs all aspects of pharmacokinetics

·      Unpredictable drug behaviour

   ->> titrate to effect ± ↓dose ± ↓frequency

Risk factors for toxicity

·      Severe ↓GFR

·      Renal clearance of parent or active/toxic metabolite

·      Low therapeutic index


   ->> e.g. digoxin in ESKD

 

Absorption:

Oral

·      ↑Urea -> delayed gastric emptying

   ->> Risk of dose stacking (e.g. PO metoprolol)

Inhaled

·      Volatile uptake unaffected

SC / IM / topical

·      ↑TBW -> oedema -> ↑diffusion distance -> ↓rate of onset

·      ±Cardiorenal syndrome -> ↓blood flow -> ↓rate of onset

   ->> Risk of dose stacking (e.g. GTN patch, IM ephedrine)

 

Distribution:

Volume of distribution

·      ↑ECF volume -> ↑VD water-soluble drugs -> ↑loading dose
(e.g. suxamethonium)

Acid-base

·      ±Metabolic acidosis

o  ↑unionised % of acidic drugs (e.g. thiopentone -> CVS toxicity)

o  ↓unionised % of basic drugs (e.g. morphine -> ↓effect)

Plasma proteins

Important for highly bound drugs.

·      ↓Albumin -> ↑free acidic drug (e.g. diazepam -> CNS depression)

·      ↑AAG -> ↓free basic drug (e.g. morphine -> ↓effect)

 

Metabolism:

Hepatic

·      Urea -> inhibition of CYP enzymes (e.g. fentanyl -> ↑duration)

·      ±Hepatorenal syndrome

Renal

·      ↓Drug metabolism (e.g. insulin -> ↑duration)

 

Excretion:

Renal

Renal drug clearance ∝ GFR:

·      Parent: e.g. pancuronium -> ↑↑duration) prefer atracurium

·      Active metabolite: e.g. M6G -> opioid toxicity (prefer fentanyl)

·      Toxic metabolite: e.g. norpethidine -> seizure (prefer fentanyl)

Haemodialysis

Variable clearance:

·      Small, unbound particles cleared-> give after dialysis

·      Large, bound drugs unaffected -> same schedule

Normalisation of TBW:

·      ↓VD water-soluble drugs

 

 

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