Drug Dosage

DRUG DOSAGE

‘Dose’ is the appropriate amount of a drug needed to produce a certain degree of response in a patient. Accordingly, dose of a drug has to be qualified in terms of the chosen response, e.g. the analgesic dose of aspirin for headache is 0.3–0.6 g, its antiplatelet dose is 60–150 mg/day, while its antiinflammatory dose for rheumatoid arthritis is 3–5 g per day. Similarly there could be a prophylactic dose, a therapeutic dose or a toxic dose of the same drug.

The dose of a drug is governed by its inherent potency, i.e. the concentration at which it should be present at the target site, and its pharmacokinetic characteristics. The recommended doses are based on population data and cater to an ‘average’ patient. However, individual patients may not be ‘average’ in respect to a number of pharmacokinetic and pharmacodynamic parameters, emphasizing the need for individualizing drug dose. The strategies adopted for different types of drugs and conditions are:

1. Standard Dose

The same dose is appropriate for most patients—individual variations are minor or the drug has a wide safety margin so that large enough dose can be given to cover them, e.g. oral contraceptives, penicillin, chloroquine, mebendazole, amantadine.

2.   Regulated Dose

The drug modifies a finely regulated body function which can be easily measured. The dosage is accurately adjusted by repeated measurement of the affected physiological parameter, e.g. antihypertensives, hypoglycaemics, anticoagulants, diuretics, general anaesthetics. In their case, measurement of plasma drug concentration is not needed.

3. Target Level Dose

The response is not easily measurable but has been demonstrated to be obtained at a certain range of drug concentration in plasma. An empirical dose aimed at attaining the target level is given in the beginning and adjustments are made later by actual monitoring of plasma concentrations. When facilities for drug level monitoring are not available, crude adjustments are made by observing the patient at relatively long intervals, e.g. antidepressants, antiepileptics, digoxin, lithium, theophylline.

4.   Titrated Dose

The dose needed to produce maximal therapeutic effect cannot be given because of intolerable adverse effects. Optimal dose is arrived at by titrating it with an acceptable level of adverse effect. Low initial dose and upward titration (in most noncritical situations) or high initial dose and downward titration (in critical situations) can be practised. Often a compromise between submaximal therapeutic effect but tolerable side effects can be struck, e.g. anticancer drugs, corticosteroids, levodopa.

Fixed Dose Ratio Combination Preparations

A large number of pharmaceutical preparations contain two or more drugs in a fixed dose ratio. Advantages offered by these are:

§  Convenience and better patient compliance— when all the components present in a formulation are actually needed by the patient. It may also be cost saving compared to both/all the components administered separately.

§  Certain drug combinations are synergistic, e.g. sulfamethoxazole + trimethoprim; levodopa + carbidopa/benserazide; combination oral contraceptives.

§  The therapeutic effect of two components being same may add up while the side effects being different may not, e.g. amlodipine + atenolol as antihypertensive.

§  The side effect of one component may be counteracted by the other, e.g. a thiazide + a potassium sparing diuretic. However, the amount of the latter may not be sufficient in all cases.

§  Combined formulation ensures that a single drug will not be administered. This is important in the treatment of tuberculosis and HIVAIDS.

Before prescribing a combination, the physician must consider whether any of the ingredients is unnecessary; if it is, the combination should not be prescribed. It can never be justified that a drug is given to a patient who does not need it in order to provide him another one that he needs.

There are many inbuilt disadvantages of fixed dose ratio combinations:

§  The patient may not actually need all the drugs present in a combination: he is subjected to additional side effects and expense (often due to ignorance of the physician about the exact composition of the combined formulations).

§  The dose of most drugs needs to be adjusted and individualised. When a combined formulation is used, this cannot be done without altering the dose of the other component(s).

§  The time course of action of the components may be different: administering them at the same intervals may be inappropriate.

§  Altered renal or hepatic function of the patient may differently affect the pharmacokinetics of the components.

§  Adverse effect, when it occurs, cannot be easily ascribed to the particular drug causing it.

§  Contraindication to one component (allergy, other conditions) contraindicates the whole preparation.

§  Confusion of therapeutic aims and false sense of superiority of two drugs over one is fostered, specially in case of antimicrobials whose combinations should be avoided. Corticosteroids should never be combined with any other drug meant for internal use. Drug combinations that are banned in India are listed in Appendix 4.

Thus, only a handful of fixed dose ratio combinations are rational and justified, while far too many are available and vigorously promoted. In fact, the latest WHO essential medicines list incorporates only 21 fixed dose ratio combinations.