Narrow therapeutic index

Improvements in asthma treatment include the development of more effective, safer formulations of known dmgs. The aerosol adrninistration of P2-agonists or corticosteroids results in a decrease in side effects. Also, the use of reUable sustained release formulations has revolutionized the use of oral xanthines which have a very narrow therapeutic index (see Controlled release technology). For many individuals, asthma symptoms tend to worsen at night and the inhaled bronchodilatots do not usually last through an entire night s sleep (26,27). 

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. It is important for clinicians to understand AF, because it is associated with substantial morbidity and mortality and because many strategies for drug therapy are available. Drugs used to treat AF often have a narrow therapeutic index and a broad adverse effect profile. 

Warfarin has been the primary oral anticoagulant used in the United States for the past 60 years. Warfarin is the anticoagulant of choice when long-term or extended anticoagulation is required. Warfarin is FDA-approved for the prevention and treatment of VTE, as well as the prevention of thromboembolic complications in patients with myocardial infarction, atrial fibrillation, and heart valve replacement. While very effective, warfarin has a narrow therapeutic index, requiring frequent dose adjustments and careful patient monitoring.15,29... 

Theophylline is also considered an alternative to inhaled corticosteroids for the treatment of mild persistent asthma however, limited efficacy compared to inhaled corticosteroids, a narrow therapeutic index with life-threatening toxicity, and multiple clinically important drug interactions have severely limited its use. Theophylline causes bronchodilation through inhibition of phosphodiesterase and antagonism of adenosine and appears to have anti-inflammatory and immunomodulatory properties as well.36... 

Theophylline is a non-specific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle resulting in bronchodilation. It has a modest bronchodila-tor effect in patients with COPD, and its use is limited due to a narrow therapeutic index, multiple drug interactions, and adverse effects. Theophylline should be reserved for patients who cannot use inhaled medications or who remain symptomatic despite appropriate use of inhaled bronchodilators. 

Benet and Goyan [34] have presented a clear exposition on bioequivalence and narrow therapeutic index drugs. Among other papers of relevance to this topic are those by Tsang and coworkers [35], el-Tahtawy and associates [36], and Midha and collaborators [37],... 

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

M. Burns, Management of narrow therapeutic index drugs, J. Thromb. Thrombolysis, 7, 137 (1999). 

Lithium is commonly used for bipolar affective disorders. Lithium however has a narrow therapeutic index and high risk for toxicity (Groleau 1994). The use of loop diuretics or ACE-inhibitors significantly increases the risk of hospitalisation for lithium toxicity in the elderly (Juurlink et al. 2004). Treatment of elderly patients with lithium should be thoroughly monitored. 

With types D and C, twofold increments in dose are uniformly made throughout the whole dose range. This is in contrast to type E, in which the size of dosage increments over the dose range within subjects varies between 2- and 16-fold. Thus type E might be an unwise choice for a drug anticipated to have a narrow therapeutic index or a steep dose response. 

Implementation of dissolution testing by BP was in a tiered program similar to that employed at the time by USP. For the first category, products would conform to 75% release in 45 min. Where the drug had a narrow therapeutic index and should not release too rapidly, was known to exhibit a brief plasma half-life, or have site-specific absorption, additional testing to satisfy the need for greater control would be considered. Dissolution tests were included in 1980 for 14 tablet and four capsule monographs (15,16). 

If a drug has a narrow therapeutic index, it may be appropriate to stratify on the basis of pharmacogenetics and pharmacogenomics. If the therapeutic index is wide, some large effects may not be important enough to warrant stratification. 

Phenytoin is an anti-epileptic drug. Patients taking anti-epileptic drugs are advised to take the medicine routinely, as directed, to stabilise and to avoid epileptic attacks as much as possible. Phenytoin has a narrow therapeutic index so it is important to identify side-effects. It may cause blood disorders. Patients are therefore advised to report immediately any symptoms of bruising or unexplained bleeding. Visual symptoms as a result of phenytoin do not commonly occur. Their occurrence may indicate overdosage. 

Q73 Drugs that have a narrow therapeutic index include ... 

Lithium is a drug with a narrow therapeutic index and therefore plasma concentrations are regularly monitored. Lithium is used in the prophylaxis and treatment of mania. Concurrent administration of lithium and diuretics, particularly the thiazides, is contraindicated as lithium excretion is reduced, resulting in increased plasma-lithium concentration and hence toxicity. 

Lithium is used in the prophylaxis and treatment of mania and in the prophylaxis of bipolar disorders and recurrent depression. Lithium should be stopped 24 hours before major surgery but the normal dose can be continued for minor surgery, with careful monitoring of fluids and electrolytes. After major surgery, renal function is reduced and this may compromise clearance of lithium. Lithium is a drug with a narrow therapeutic index and it should be avoided if possible in patients with renal impairment. Renal function should be tested before initiating treatment. If lithium is given to patients with renal impairment, a reduced dose should be used and serum lithium concentrations should be monitored closely. 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Is the drug likely to he co-prescribed with a drug of narrow therapeutic index For example, a drug for angina, cardiac failure or an antiarrhythmic agent is likely to be co-prescribed with warfarin. If there is any evidence of enzyme induction or inhibition, a clinical study with warfarin may be required. 

The content uniformity and the finished product specifications are critical for drugs with a very narrow therapeutic index. In such cases, the specifications may have to be tightened. 

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