2009B04 Describe the effect of obesity on pharmacokinetics and the potential
clinical implications, providing relevant examples.

Definition

BMI >30kg/m² body surface area

Changes

·  ↑Fat mass

o Accounts for 60-80% excess

o  -> Chest wall compression, diaphragm displacement

·  ↑Fat-free mass

o Accounts for 20-40% excess

o ->↑Metabolic rate (BMR), ↑blood volume, ↑cardiac output (CO)

·  ↑Visceral fat

o ↑Inflammatory cytokines (e.g. TNFα, IL-1, IL-6 in metabolic syndrome)

·  Comorbid disease

Oral

·  Delayed gastric emptying -> slow onset of oral pre-med

o (e.g. midazolam for intellectually disabled adult)

·  ±-NAFLD -> liver failure -> portosystemic shunt and ↓first pass metabolism -> ↑oral bioavailability

o e.g. airway topicalization with lignocaine

Inhalational

·  ↑V_A:FRC -> ↑rate of rise F_A/F_I

o ↑Metabolic rate -> ↑VCO₂ -> ↑V_A awake

o Diaphragm compression -> ↓compliance -> ↓V_A under GA

o Diaphragm compression -> ↓↓FRC (e.g. ↓25% erect at BMI 35)

§  Worse supine, under GA

Intramuscular

·  Risk of subcut injection -> ↓onset, risk of dose stacking

↑Cardiac output

·  ↑Rate of drug distribution

o ↓Peak plasma [propofol] after bolus -> risk of awareness

o ↑Rate of onset suxamethonium

o ↓Rate of rise F_A/F_I volatile anaesthetic

Blood

·  ↑Blood volume

o ↑V_D drugs confined to plasma (e.g. heparin V_D 0.1L/kg)

·  ↑Fat content

o ↑Blood gas partition coefficient of volatile anaesthetic -> ↓rate of rise F_A/F_I

·  Plasma proteins

o ↓Albumin -> ↑unbound % of acidic drugs -> toxicity if low HER (e.g. phenytoin)

o ↑AAG -> ↓unbound % basic drugs (e.g. morphine)

Tissues

·  ↑Total body water

o ↑V_D water-soluble drug -> resistance to effect of muscle relaxants

o Note overdose likely if loading dose calculated with total body weight

·  ↑Muscle

o ↑Time constant -> slow emergence from volatile anaesthetic

o ↑Time to emergence from volatile anaesthetic

·  ↑Fat

o ↑V_D fat-soluble drugs -> ↑t_1/2β (e.g. fentanyl)

o ↑Time constant -> slow emergence if very long volatile anaesthetic

·  Hepatic extraction ratio (HER)

·  = [drug] in hepatic artery – [drug] in hepatic vein / [drug] in hepatic artery

↓Phase 1&2 reactions (if NAFLD)

·  ↓Clearance if metabolism-limited drugs (HER <0.3)

·  e.g. thiopentone -> prolonged hypnosis

·  Phase 1 affected before phase 2

↓Hepatic blood flow (if cirrhosis)

·  ↓Clearance if flow-limited (HER >0.7)

·  e.g. lignocaine -> seizure, arrhythmia, arrest

Urine

·  ↑Renal blood flow

o ↑Excretion of small and/or hydrophilic drugs and metabolites

o e.g. morphine 6 glucuronide

Bile

·  If NAFLD-associated liver failure

o ↓Bile secretion -> ↓excretion of large and/or fat-soluble drugs

o e.g. digoxin

Lung

·  ↑V_A:FRC -> ↑rate of fall F_A/F_A0 (causes as above)

Marsh TCI

·  High total body weight

o ↑Dose -> toxicity (i.e. hypotension)

Schnider TCI

·  Poor estimate of lean mass (James equation)

o Paradoxical ↓infusion rate at BMI >42 in men, >35 in women

o Risk of awareness