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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