A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

DRUGS FOR WHICH THERAPEUTIC DRUG MONITORING IS USED 43
25
20
Life-threatening toxicity possible
Coma
Dysrythymias
Convulsions
Dependent on drug concentration
Sinus tachycardia
Excitement
Hypokalaemia
Vomiting
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: Ciclosporin compliance is a
particular problem in children, and deterioration in renal
function can reflect either graft rejection due to inadequate
ciclosporin concentration or toxicity from excessive
concentrations. Sirolimus use should be monitored,
especially when used with ciclosporin or when there is
hepatic impairment or during or after treatment with
inducers or inhibitors of drug metabolism.
Key points
10
Partially dependent on drug concentration
Nausea
Dyspepsia
Insomnia
Headache
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.)
• 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.
Decreased
Increased
Case history
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
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.)
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 preparation
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.