Therapeutic Monitoring

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The issues that concern the practising doctor are not primarily those of changing drug plasma concentration but relate to drug effect: to the onset, magnitude and duration of action of individual doses. Accurate information about the time course of drug action is less readily obtained than that about plasma concentration. This immediately raises implications about the relation between plasma concentration and drug effect and, particularly, the extent to which useful response may be predicted by measuring the concentration of drug in plasma.

Experience shows that patients differ greatly in the amount of drug required to achieve the same response. The dose of warfarin that maintains a therapeutic concentration may vary as much as 5fold between individuals, and there are many other examples. This is hardly surprising considering known variation in rates of drug metabolism, in disposition and in tissue responsiveness, and it raises the question of how optimal drug effect can be achieved quickly in each patient, i.e. can drug therapy be individualised? A logical approach is to assume that effect is related to drug concentration at the receptor site in the tissues and that in turn the plasma concentration is likely to be constantly related to, though not necessarily the same as, tissue concentration. Indeed, for many drugs, correlation between plasma concentration and clinical effect is better than that between dose and effect. Yet monitoring therapy by measuring drug in plasma is of practical use only in selected instances. The reasons for this repay some thought.

Plasma concentration may not be worth measuring.

This is the case where dose can be titrated against a quickly and easily measured effect such as blood pressure (antihypertensives), body weight (diuretics), INR (oral anticoagulants) or blood sugar (hyp-oglycaemics).

Plasma concentration has no correlation with effect. This is the case with drugs that act irreversibly and these have been named 'hit and run drugs' because their effect persists long after the drug has left the plasma. Such drugs destroy or inactivate target tissue (enzyme, receptor) and restoration of effect occurs only after days or weeks, when resynthesis takes place, e.g. some monoamine oxidase inhibitors, aspirin (on platelets), some anticholinesterases and anticancer drugs.

Plasma concentration may correlate poorly with effect. Inflammatory states may cause misleading results if only total drug concentration is measured. Many basic drugs, e.g. lidocaine, disopyramide, bind to acute phase proteins, e.g. cXj-acid glycoprotein, which are present in greatly elevated concentration in inflammatory states. The consequent rise in total drug concentration is due to increase in bound (inactive) but not in the free (active) concentration and correlation with effect will be poor if only total drug is measured. The best correlation is likely to be achieved by measurement of free (active) drug in plasma water but this is technically more difficult and total drug in plasma is usually monitored in routine clinical practice.

The assay procedure may not measure metabolites of a drug that are pharmacologically active, e.g. some benzodiazepines, or may measure metabolites that are pharmacologically inactive; in either event correlation between plasma concentration and effect is weakened.

Plasma concentration may correlate well with effect.

When this is the case, and when the therapeutic effect is inconvenient to measure, dosage may best be monitored according to the plasma concentration (in relation to a previously defined optimum range).

Plasma concentration monitoring has proved useful in the following situations:

• As a guide to the effectiveness of therapy, e.g. plasma gentamicin and other antimicrobials against sensitive bacteria, plasma theophylline for asthma, blood ciclosporin to avoid transplant rejection

• When the desired effect is suppression of infrequent sporadic events such as epileptic seizures or episodes of cardiac arrhythmia

• To reduce the risk of adverse drug effects, e.g. otic damage with aminoglycoside antibiotics or adverse CNS effects of lithium, when therapeutic doses are close to toxic doses (low therapeutic index)

• When lack of therapeutic effect and toxicity may be difficult to distinguish. Digoxin is both a treatment for, and sometimes the cause of, cardiac supraventricular tachycardia; a plasma digoxin measurement will help to distinguish whether an arrhythmia is due to too little or too much digoxin

• When there is no quick and reliable assessment of effect, e.g. lithium for mood disorder

• To check patient compliance on a drug regimen, when there is failure of therapeutic effect at a dose that is expected to be effective, e.g. antiepilepsy drugs

• To diagnose and treat drug overdose.

of 50-200 micrograms/I when the drug is given by mouth.

Recommended plasma concentrations for drugs appear throughout this book where these are relevant.

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