Therapeutic index/ratio

Therapeutic index. Ratio between the median lethal dose CLDso) and the median effective dose CED30) of a drug. 

It is unfortunate that the debate over narrow therapeutic index (ratio) or critical care drugs has been... 

Metabolic polymorphisms affect the rate of clearance of certain drugs. A good example can be seen in the pharmacogenetics haloperidol in poor and extensive metabolizers of CYP2D6 (Figure 11.2). If a drug has a narrow therapeutic index (ratio of toxic dose/therapeutic dose), the polymorphism may produce toxic levels in the PM (Figure 11.3). 

As a therapeutic agent, mechlorethamine has many toxic effects. Acutely, it causes nausea and vomiting, skin blistering, and ulceration. After a week or two, it causes leukopenia, lymphopenia, anemia, thrombocytopenia, diarrhea, oral ulcers, and hyperuricemia. It can cause sterility and after a few years, leukemia. The most susceptible tissues are those with renewable cell populations, bone marrow, lymphoid tissues, and gastrointestinal (GI) epithelium. The therapeutic dose of mechlorethamine and most of the cytotoxic chemotherapy drugs is very close to the toxic dose. The therapeutic index (ratio of beneficial effect to toxic effect) is small. 

Hundreds of retinoids have been synthesized over a period spanning almost 15 years. Several firms, research institutes, and academic institutions have dedicated efforts to synthesize retinoids with an improved therapeutic index (ratio of potency to toxicity) relative to the standards, all-trans-retinoic acid (1) and 13 -ciy-retinoic acid. The strategies have varied significantly. Two tendencies are observed (a) to synthesize retinoids with improved anti-cancer activity relative to RA with the expectancy of minimal difference in toxicity relative to RA, and (b) to synthesize retinoids with improved toxicity profiles relative to RA with the expectancy of altered but not diminished anti-cancer activity relative to RA. 

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). 

This leads to the concept of therapeutic index. The potency of a drug is almost irrelevant. It is its specificity that matters. Thus if two drugs A and B are effective at the same dose in a patient, say 1 mg, but A produces toxic effects at 10 mg which are only seen with 500 mg of B then B is clearly a much safer drug than A, in that patient. The ratio of toxic to effective dose is the therapeutic index (TI). It is often expressed as... 

The partitioning of the activated inhibitor between direct covalent inactivation of the enzyme and release into solution is an important issue for mechanism-based inactivators. The partition ratio is of value as a quantitative measure of inactivation efficiency, as described above. This value is also important in assessing the suitability of a compound as a drug for clinical use. If the partition ratio is high, this means that a significant proportion of the activated inhibitor molecules is not sequestered as a covalent adduct with the target enzyme but instead is released into solution. Once released, the compound can diffuse away to covalently modify other proteins within the cell, tissue, or systemic circulation. This could then lead to the same types of potential clinical liabilities that were discussed earlier in this chapter in the context of affinity labels, and would therefore erode the potential therapeutic index for such a compound. 

Several of these compounds, on the other hand, show greater central potency than BZ (Fig. 74). Higher potency is present in EA 3167, EA 3443, EA 3580 and possibly the less thoroughly studied 302282 and 226086. A high absolute central potency, combined witii high central to peripheral potency ratio produces a belladonnoid that has both low dose requirements and a high safety margin (therapeutic index). Such compounds would presumably be safer and more effective than BZ. 

In CONCLUSION, lithium is universally accepted as a mood-stabilizing drug and an effective antimanic agent whose value is limited by its poor therapeutic index (i.e. its therapeutic to toxicity ratio). Neuroleptics are effective in attenuating the symptoms of acute mania but they too have serious adverse side effects. High potency typical neuroleptics appear to increase the likelihood of tardive dyskinesia. Of the less well-established treatments, carbamazepine would appear to have a role, particularly in the more advanced stages of the illness when lithium is less effective. 

Hunt et al. [6] demonstrated that the DTI is also equivalent to the ratio of the therapeutic index (abbreviated to TI in Hunt et al. s paper in this chapter TI is defined differently, see Section 13.4.3) of the drug-carrier conjugate and that of the free drug. The therapeutic index (also called the therapeutic ratio) is a statistical measure defined as the ratio of the median toxic dose to the median effective dose [22]. 

The therapeutic index of (III), defined as the ratio of the LDq value divided by the dose which gives an ILS of 40 %, is about 6. 

The therapeutic index of SOF, SOPHi and SOAz, which is defined as a ratio of the LDp value divided by the dose which gives an ILS of 25% (extrapolated from the activity-dose relationships), is respectively about 2, 2 and 8. This may be compared with the values previously reported for NjPjAz (TI = 6) and N P AZg (TI = 4)... 

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

Pharmacokinetic parameters are also important in relation to toxicity. The toxicity of antimicrobial drugs varies considerably and is usually concentration dependent. The therapeutic index is the ratio between the concentration of drug that is toxic for the... 

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