System

Physiological Disturbance

Altered Pharmacokinetics

Cardiovascular

Hyperdynamic circulation

- ↑ CO and organ blood flow

- ↑ with fluids & vasoactive medications

 

Myocardial depression

- ↓ CO & organ perfusion

 

Microciruclatory failure

 

Endothelial dysfunction & Capillary leak

↑ CL

Sub-therapeutic concentrations

 

 

↓ CL

Drug accumulation / toxicity

 

↓ Target tissue penetration

 

↑ Vd (hydrophilic drugs)

 

Respiratory

↓ gas exchange

 - Hypoxemia & hypercapnoea

 

Endotracheal intubation

 

Positive Pressure Ventilation

↓ RBF

↓ Renal CL

 

Impaired aerosol delivery

 

↓ CL

↑ Vd (hydrophilic drugs)

 

Renal

Augmented Renal Clearance

 - ↑ GFR +/- tubular function

 

Acute Kidney Injury

- ↓ GFR +/- tubular function

 

 

 

Renal Replacement Therapy

↑ CL

Sub-therapeutic concentrations

 

↓ CL

Drug accumulation / toxicity

↑ Vd (hydrophilic drugs)

Altered protein binding (uraemia)

 

↓ CL

Drug accumulation / toxicity

 

Hepatobilliary

Hepatic dysfunction

- ↓ HBF

- altered enzyme (CYP450) function

 

Acute phase response

- ↑ production AAG

 

Hypoalbuminaemia

↓ CL

Drug accumulation / toxicity

 

 

Altered protein binding (Basic drugs)

 

 

↑ Free fraction

↑ CL (highly protein bound drugs)

 

Other

Gastrointestinal function

 - ↓ motility

 

Integument

 - ↓ perfusion

 

Polypharmacy

↓ drug absorption

Sub-therapeutic concentrations

 

↓ drug absorption

Sub-therapeutic concentrations

 

Enzyme inhibition / induction

Direct competition (protein binding)

Variable CL

 

AAG - α1-Acid Glycoprotein; CL – Clearance; CO – Cardiac Output; GFR - Glomerular Filtration Rate; HBF - Hepatic Blood Flow; RBF - Renal Blood Flow; Vd - Volume of Distribution
Table 1: Changes in Organ Function and Drug Pharmacokinetics in the Critically Ill.