SN6 SHORT NOTE 5M

Describe the principles and applications of therapeutic drug monitoring.

Biochemistry · 1st Professional — Pre-Clinical

Definition

Xenobiotic detoxification in the liver and the assessment of drug levels form the basis of therapeutic drug monitoring (TDM) — measuring plasma concentrations to individualise dosage.

When Therapeutic Drug Monitoring Is Justified

Narrow therapeutic index — the toxic level is close to the effective one
Wide interindividual variation in metabolism
No easily measured clinical endpoint
Saturable (zero-order) kinetics — small dose changes cause large level changes
Suspected toxicity or non-compliance
Altered handling — renal or hepatic disease, pregnancy, extremes of age

Drugs Commonly Monitored

Drug	Therapeutic range	Reason for monitoring
Digoxin	0.5–2.0 ng/mL	Narrow index; toxicity worsened by hypokalaemia
Phenytoin	10–20 µg/mL	Zero-order kinetics above therapeutic levels
Lithium	0.6–1.2 mEq/L	Very narrow index; renal excretion
Theophylline	10–20 µg/mL	Narrow index
Aminoglycosides	Peak and trough	Nephrotoxicity and ototoxicity
Vancomycin	Trough 10–20 µg/mL	Nephrotoxicity
Ciclosporin, tacrolimus	Trough	Rejection versus toxicity
Methotrexate	Level-guided rescue	Determines folinic acid rescue

CLINICAL PEARL

Phenytoin is the classic example. Because its metabolism saturates within the therapeutic range, a small increase in dose can produce a disproportionately large rise in plasma level and sudden toxicity — ataxia, nystagmus and confusion. This is why it cannot be dosed by weight alone.

Principles of Sampling

Take the sample at steady state — after about 5 half-lives
Trough levels (immediately before the next dose) are usual; peaks are used for aminoglycosides
Digoxin must be sampled at least 6–8 hours after a dose, or the distribution phase gives a falsely high result — a very common error
Record the exact time of sampling and of the last dose, or the result is uninterpretable

Factors Altering Drug Levels

Factor	Effect
Enzyme induction (rifampicin, phenytoin, carbamazepine, alcohol)	↓ Level, ↓ effect
Enzyme inhibition (cimetidine, erythromycin, ketoconazole, grapefruit)	↑ Level, toxicity
Hypoalbuminaemia	↑ free fraction — toxicity at a normal total level (phenytoin, warfarin)
Renal impairment	Accumulation of renally excreted drugs — digoxin, lithium, aminoglycosides
Genetic polymorphism	CYP2D6, CYP2C19, NAT2, TPMT — poor and rapid metabolisers

Applied Aspects

Total phenytoin is misleading in hypoalbuminaemia — the free fraction may be toxic while the total looks therapeutic; measure free phenytoin or correct for albumin
Lithium toxicity is precipitated by dehydration, diuretics, NSAIDs and ACE inhibitors, all reducing renal clearance
TPMT testing before azathioprine prevents severe myelosuppression in poor metabolisers — pharmacogenetics in routine practice
A level is interpreted alongside the patient: a "toxic" level in a well patient and a "therapeutic" level in a toxic one both demand clinical judgement rather than automatic dose change

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