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