22A01: Exam Report

Outline the effects of critical illness on drug pharmacokinetics, including examples

47% of candidates passed this question.

The effects of critical illness on the physiological factors that influence drug pharmacokinetics was used to analyse the candidates understanding of this core pharmacological principle. 

Better responses were able to identify the key elements perturbed by critical illness as well as outlining outline the potential cause and effect on the specific PK aspect being discussed.

Stronger answers also included specific drug examples. The failure to utilise a structure (absorption, distribution, metabolism, and elimination) with very superficial detail and limited examples limited marks and was common in poorly scoring answers.

B SYL2017 / 22A01: Outline the effects of critical illness on drug pharmacokinetics, including examples

Critical illness:

A life-threatening condition that requires pharmacological and/or mechanical support of vital organ functions without which death would be imminent

Pharmacokinetics

A branch of pharmacology describing the movement of drugs in the body, described in terms of absorption, distribution, metabolism and elimination

Pharmacokinetics

Effect

Example

Absorption

IV

Effect

Unchanged

Example

PO

Effect

  • Reduced in gut inflammation
  • Concomitant drug administration may reduce intestinal transporters/hepatic enzymes
  • If hepatic failure, reduced 1st pass (= increased PO BA)
  • Reduced splanchnic BF (2o to vasopressors/shock) = reduced absorption = increased PO BA
  • Gastric stasis reduces the rate of absorption

Example

  • Aminoglycosides
  • Amiodarone inhibits P glycoprotein
  • Aspirin

IM / SC

Effect

  • Reduced peripheral BF 2o to shock
    • Vasopressors cause peripheral vasoconstriction and reduced skin and subcut tissue blood flow

Example

  • IM suxamethonium will have delayed onset
  • Subcut opioids and patches e.g. GTN, buprenorphine, will have delayed absorption

Distribution

Protein binding

Effect

  • Low albumin (acute phase reactant) = increased function of protein bound drugs
  • Increased alpha1 glycoprotein e.g. sepsis = reduced protein binding of other drugs

Example

  • Propofol, acidic drugs
  • Local anaesthetics / lignocaine, Basic drugs

pKa

Effect

  • Acids ionised when pH > pKa
  • Bases ionised when pH < pKa
  • Affects permeability through cell membranes

Example

  • Na+ channel blockers less effective in acidic environments

Vd

Effect

  • Renal/hepatic failure and fluid resus = oedema
    • Increased Vd of hydrophilic drugs
    • Increased distributed to EC compartment
  • Hepatic failure = reduced albumin
    • Increased plasma concentration of highly bound drugs
    • Competition between drugs for binding sites

Example

  • Phenytoin
  • Warfarin

Metabolism

Effect

Hepatic phase I (zone 3) susceptible to ischaemia

  • Reduced phase I metabolism in shock

Example

  • Fentanyl metabolised by CYP450 3A4

  • Paracetamol metabolised by glutathione in zone 3

Effect

Increased global reduction hepatic function in failure

Example

Any drug that is hepatically metabolized e.g.

  • Benzylisoquinilone neuromuscular blockers
  • Morphine
  • Diazepam

Effect

Concurrent administration of drugs can interact e.g. cytochrome p450 inducers and inhibitors

  • Enzyme inhibitors increase the plasma concentration of drugs metabolized through the same pathway
  • Enzyme inducers decrease the plasma concentration of drugs metabolized through the same pathway

Example

Enzyme inhibitors:

  • Valproate
  • Carbamazepine
  • Amiodarone
  • Ciprofloxacin
  • Zzole antifungals
  • Quinidine

Enzyme inducers:

  • Phenytoin
  • Barbiturates
  • Metronidazole
  • Alcohol (chronic), , Aacrolides  (erythromycin, clarithromycin)
  • Sulfonamides

Elimination

Renal

Effect

  • Shock = reduced RBF (increased in distributive shock) = reduced GFR of drugs = reduced clearance
  • Reduced plasma proteins = increased glomerular filtration of free drug
  • ATN = reduced tubular secretion = reduced clearance

Example

  • Atenolol
  • Warfarin (and other highly protein bound drugs)
  • Penicillin (cleared by tubular secretion)

Biliary

Effect

  • Hepatic failure = reduced secretion

Example

  • Hydrocortisone

Sources

  • Peck and Hill. Pharmacology for Anaethesia and intensive Care. 4th edition
  • Scath and Smith. Drugs in anaesthetics and Intensive Care. 5th edition
  • Flood and Rathmell. Stoelting’s Pharmacology and Physiology in anaesthetic practice. 6th edition, Chapter 47
  • Deranged physiology: https://derangedphysiology.com/

Author: Erin Maylin