A Textbook of Clinical Pharmacology and Therapeutics

for atrial dysrhythmias (0.5–1.5 mg/L). The clinical utility

of predicting toxicity by measuring a metabolite (desethyl

amiodarone) is under evaluation.

8.Immunosuppressants: Ciclosporincompliance is a

particular problem in children, and deterioration in renal

function can reflect either graft rejection due to inadequate

ciclosporinconcentration or toxicity from excessive

concentrations.Sirolimususe should be monitored,

especially when used with ciclosporinor when there is

hepatic impairment or during or after treatment with

inducers or inhibitors of drug metabolism.

DRUGS FORWHICHTHERAPEUTICDRUGMONITORING ISUSED 43

Life-threatening toxicity possible

Coma

Dysrythymias

Convulsions

Dependent on drug concentration

Sinus tachycardia

Excitement

Hypokalaemia

Vomiting

Partially dependent on drug concentration

Nausea

Dyspepsia

Insomnia

Headache

25

20

10

Figure 8.2:Theophylline plasma concentrations (mg/L). Note that
there is a wide variation in the incidence and severity of adverse
effects. (Adapted from Mant T, Henry J, Cochrane G. In: Henry J,
Volans G (eds). ABC of poisoning. Part 1: Drugs. London: British
Medical Journal.)

Decreased

Cirrhosis

Heart failure

Age >50 years

Neonates

Obesity

Severe renal failure

Cimetidine

Erythromycin

Ciprofloxacin

Smoking

Marijuana

Age 1–20 years

High protein diet

Phenobarbitone

Prolonged half-life Shortened half-life

Increased

Figure 8.3:Theophylline clearance. (Adapted from Mant T, Henry
J, Cochrane G. In: Henry J, Volans G (eds). ABC of poisoning. Part
1: Drugs. London: British Medical Journal.)

Key points

• Determining the plasma concentrations of drugs in
  order to adjust therapy is referred to as therapeutic
  drug monitoring. It has distinct but limited applications.


• Therapeutic drug monitoring permits dose
  individualization and is useful when there is a clear
  relationship between plasma concentration and
  pharmacodynamic effects.


• The timing of blood samples in relation to dosing is
  crucial. For aminoglycosides, samples are obtained for
  measurement of peak and trough concentrations. To
  guide chronic therapy (e.g. with anticonvulsants),
  sufficient time must elapse after starting treatment or
  changing dose for the steady state to have been
  achieved, before sampling.


• Drugs which may usefully be monitored in this way
  include digoxin, lithium, aminoglycosides, several
  anticonvulsants, methotrexate, theophylline, several
  anti-dysrhythmic drugs (including amiodarone) and
  ciclosporin.


• Individualization of dosage using therapeutic drug
  monitoring permits the effectiveness of these drugs to
  be maximized, while minimizing their potential toxicity.

Case history

A 35-year-old asthmatic is admitted to hospital at 6 a.m.

because of a severe attack of asthma. She has been treated

with salbutamol and beclometasone inhalers supplemented

by a modified-release preparation of theophylline, 300 mg

at night. She has clinical evidence of a severe attack and

does not improve with nebulized salbutamol and oxygen.

Treatment with intravenous aminophylline is considered.

Comment

Aminophylline is a soluble preparation of theophylline (80%)

mixed with ethylenediamine (20%), which has a role in

patients with life-threatening asthma. However, it is essential

to have rapid access to an analytical service to measure plasma

theophylline concentrations if this drug is to be used safely,

especially in this situation where the concentration of

theophylline resulting from the modified-release prepar-

ation that the patient took the night before admission must

be determined before starting treatment. Theophylline

toxicity (including seizures and potentially fatal cardiac

dysrhythmias) can result if the dose is not individualized in

relation to the plasma theophylline concentration.