Low therapeutic index

Historically, the use of xanthines has been hampered by poor aqueous solubiUty, rapid but highly variable metaboHsm, and the existance of a low therapeutic index. SolubiUty problems were partially solved by the preparation of various salt forms, eg, aminophylline. However, it was since recognized that the added base in aminophylline only increases solubiUty by increasing pH and thus does not affect the rate of absorption from the gut (65). Thus, in more recent medical practice, theophylline is commonly dispensed in anhydrous form and aminophylline is only recommended for iv adrninistration. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

Colchicine has a long history of successful use and was the treatment of choice for many years. It is used infrequently today because of its low therapeutic index. Colchicine is thought to exert its anti-inflammatory effects by interfering with the function of mitotic spindles in neutrophils by binding of tubulin dimers this inhibits phagocytic activity. 

Low therapeutic index Anatomical or cellular barriers Commercial... 

Multiple prescribing physicians Use of drugs with a low therapeutic index Use of drugs that are enzyme inhibitors or inducers Elderly... 

For a product where it is desired or necessary to show external predictability (e.g., to bridge to the commercial product for a low therapeutic index product), the external validation batch can be included in the same study as the IVIVC batches, normally in a separate study arm (i.e., not randomized). This reduces the probability of failing to fulfill the strict external validation criteria (prediction errors for Cmax and AUC of < 10%), as the data are collected in the same study population as those used to develop and validate the IVIVC. 

Direct isolation of sufficient quantities of each metabolite for structural characterization, assay validation and pharmacological or toxicological testing from in vivo studies using biological specimens is, therefore, often impossible, particularly from dmgs with a low therapeutic index. Furthermore, many metabolites have structural modifications which are difficult to replicate by traditional chemical methods. A number of synthetic steps may be required to prepare such metabolites from the API, or, in the worst case, a completely new synthetic route may need to be developed. 

Severe cases may, however, require an intensified bronchodilator treatment with systemic jk-mimetics or theophylline (systemic use only low therapeutic index monitoring of plasma levels needed). Salmeterol is a long-acting in-halative P2-mimetic (duration 12 h onset -20 min) that offers the advantage of a lower systemic exposure. It is used prophylactically at bedtime for nocturnal asthma. 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

Highly variable (often associated with poor) bioavailability with low therapeutic index... 

In all this, it should be remembered that the role of regulatory authorities is to protect the public. For entirely justifiable reasons, they will apply very strict criteria to products with a low therapeutic index, non-linear kinetics or imfavour-able physical properties. Digoxin, phenytoin and primidone provide notable examples of drugs where bioinequivalence issues have led to clinical problems. 

What is the therapeutic index of the drug If the drug has a low therapeutic index, interactions are much more likely to have clinical consequences, so a variety of kinetic studies will be needed. 

There are small changes in serum albumin concentration with age, with concomitant small effects on protein binding of some highly bound drugs such as naproxen, salicylate, and warfarin. For such drugs the free concentration rather than the total plasma concentration is a better predictor of drug dose requirements, particularly for drugs with low therapeutic index (difference between the therapeutic... 

Chloral hydrate and triclofos are of some use as hypnotics for children. However these compounds are largely superseded by the benzodiazepines and are not recommended other than for exceptional cases. Chloral hydrate has a low therapeutic index. These agents have an unpleasant taste and odor. The hypnotic effect has a rapid onset but a short duration. Tolerance appears to occur rapidly with a loss of sleep-inducing and sleep-maintaining effects after about 2 weeks. 

Tricyclic antidepressants are cardiotoxic, inducing tachycardias and an increased tendency for ventricular arrhythmias with high doses. This dose dependent cardiotoxicity gives these agents a low therapeutic index. Overdoses are characterized by cardiac conduction disturbances, hyperpyrexia, hypertension, confusion, hallucinations, seizures and coma and there is a high mortality rate in suicide attempts. Depressed patients should therefore not be given more than one week supply of these drugs. 

Monoamine oxidase inhibitors have a low therapeutic index. Adverse effects include orthostatic hypotension, impotence and insomnia. Overdoses become manifest by symptoms of agitation, hyper-reflexia followed by convulsions. Rare but serious cases of hepatotoxicity have been associated with the use of isocarboxazid and of phenelzine. 

Adverse reactions that are not dose dependent are nausea, vomiting and diarrhoea. Lithium has a low therapeutic index. Some adverse reactions such as thirst and mild polyuria may occur at therapeutic plasma concentrations of 0.4-1.0 mEq/1. At concentrations of 1.0-1.6 mEq/1 diarrhea, nausea and incoordination become prominent. At toxic levels ataxia, confusion and stupor occur potentially leading to coma and death. 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

For a long time, muscarinic receptor-blocking drugs occupied a major place in the therapy of asthma, but they have been largely displaced by the adrenergic drugs (see Chapter 41). The problems associated with the use of antimuscarinic alkaloids in respiratory disorders are low therapeutic index and impaired expectoration. The... 

Individualization of dosing of chemotherapeutic drugs with a low therapeutic index is essential to effective, safe chemotherapy. 

To further define dose requirements, therapeutic drug monitoring should also be performed for drugs with a low therapeutic index. 

The principal disadvantages of barbiturates as hypnotics include the development of physical dependence, a relatively low therapeutic index (and the potential of poisoning, as in suicide), suppression of REM sleep, and possible hangover effects. As mentioned above, benzodiazepines (e.g., flurazepam or brotizolam) are hypnotics as effective as barbiturates and are much safer in terms of their therapeutic index, addiction potential, and REM sleep-deprivation effects. Thus benzodiazepines have displaced barbiturates as sedative hypnotics. 

Oral administration of polyether antibiotics allows, initially, for regulation of the body function at the site of digestion by positively affecting feed conversion efficiency and negatively affecting the developmental stage of coccidia. Since their activity is directed particularly towards sporozoites and merozoites, the polyethers must be fed continuously to be fully effective but are not recommended for treating established infections. They have a low therapeutic index and may... 

Hepatic metabolism is a variable factor, and other drugs that induce or inhibit metabolism will alter the drug level in the body. As it has a low therapeutic index, this can have significant effects. 

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