Maximum therapeutic index

Activity and toxicity both increase with the size of the groups. Branching and unsaturation decrease the duration of action. Phenobarbital and butabarbital are effective. The maximum therapeutic index (tolerated... 

The maximum therapeutic index (tolerated dose/minimum effective dose) is highest when the two groups have a total of 6 to 10 carbons. Major drawbacks of their use are their habit formation and their high toxicity when alcohol is present in the bloodstream. 

Fig. 1. Blood—drug concentration curve used to determine bioavailabiLitv and bioequivalence. C is the maximum dmg concentration in the blood and corresponds to some The AUC (shaded) represents the total amount of orally adininistered dmg the time from points A to B represents dmg onset, from points B to D, the duration MEC = minimum effective concentration MTC = minimum toxic concentration and TI = therapeutic index.

The therapeutic efficacy of a dmg is generally measured in terms of ED q or ID q which represent the concentration of dmg which produces 50% of the maximum effect or 50% of maximum inhibition. LD q represents the concentration of dmg that produces 50% fataUties in test animals. The therapeutic index is the ratio of the ED q versus LD q. Detailed descriptions of the terminology and fundamental principles of pharmacology are available (32) (see Pharmacodynamics). 

GRAPEFRUIT JUICE ANTI EPILEPTICS -CARBAMAZEPINE t in plasma concentrations of carbamazepine (AUC11.4-fold, maximum concentration t), which is of clinical significance because of the narrow therapeutic index of carbamazepine thus, toxic effects are likely, t efficacy and t adverse effects Grapefruit juice irreversibly inhibits intestinal CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited Monitor fort side-effects/toxicity and check carbamazepine levels weekly. If levels or control of fits are variable, remove grapefruit and grapefruit juice from the diet... 

Gaining maximum potency is only half the problem in drug design. The other half is to minimize unwanted side effects. Therefore, for the ultimate in maximization of the therapeutic index, regression analysis must also be applied to relate substituent effects to the various kinds of serious toxicity as these become evident. 

Use of suboptimal doses of drugs in serious disease, sacrificing efficacy for avoidance of serious adverse effects, has been documented. It particularly affects drugs of low therapeutic index (see Index), i.e. where the effective and toxic dose ranges are close, or even overlap, e.g. heparin, anticancer drugs, aminoglycoside antimicrobials. In these cases dose adjustment to obtain maximum benefit with minimum risk requires both knowledge and attentiveness. 

Fig. 7.1 Dose-response curves for two hypothetical drugs. Drug X the dose that brings about the maxinnum wanted effect is less than the lowest dose that produces the unwanted effect.The ratio EDSO (unwanted effect)/ED50 (wanted effect) indicates that drug X has a large therapeutic index it is thus highly selective in its wanted action. DrugY causes unwanted effects at doses well below those which produce its maximum benefit The ratio EDSO (unwanted effect)/ED50 (wanted effect) indicates that the drug has a small therapeutic index it is thus nonselective.

Other classes of C5d otoxic agents, e.g. cinti-metabolities, were subsequently identified and used to treat cancer patients. Their efficacy evidently was limited by their relative nonselectivity for proliferating cells the narrow therapeutic index of c5dotoxic agents means that escalation of drug doses is constrained by damage to normal cells and maximum doses which can be safely administered to patients are often suboptimal to achieve total... 

In order to attain maximum selectivity for killing cancer cells while limiting damage to the host, various methods have been adopted with a view to widening the narrow therapeutic index of cytotoxic agents ... 

To be more precise, the therapeutic index compares the drug dose levels which lead to toxic effects in 50 per cent of cases studied, with respect to the dose levels leading to maximum therapeutic effects in 50 per cent of cases studied. This is a more reliable method of measuring the index since it eliminates any peculiar individual results. 

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