Which one of the following antipsychotics is strongly implicated in deaths due to QTc prolongation?
C. Prolongation of the QT interval of the ECG is associated with the development of torsade de pointes, a ventricular arrhythmia that can cause syncope and may progress to ventricular fibrillation and sudden death. The average QTc interval is approximately 400 ms. A QTc interval of 500 ms or greater is considered to be a high risk factor for torsades de pointes, though the prediction of arrhythmia is not simply linearly dependent on QT measure. An elevated risk of serious adverse cardiac events or sudden cardiac death has been documented for thioridazine,clozapine, droperidol, pimozide, and sertindole.These are considered higher-risk antipsychoticsin terms of serious cardiac effects. Haloperidol, quetiapine, risperidone, chlorpromazine, and trifluoperazine have a tendency to extend the QT interval even at therapeutic doses, but their link with sudden cardiac death is not yet clarified. Amisulpride, aripiprazole, olanzapine, sulpride, and zotepine have not been linked with an elevated risk of sudden cardiac death or QTc prolongation. Typical neuroleptics that have lower potency, such as thioridazine and chlorpromazine, are more cardiotoxic than high-potency drugs such a haloperidol. The major effects on the electrocardiogram include prolongation of the QT and PR intervals, T wave blunting or inversion, and ST segment depression. Sudden death noted in antipsychotic recipients may also be due to seizures during sleep, sudden asphyxiation, temperature dysregulation (for example malignant hyperthermia), and neuroleptic malignant syndrome.
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Which one of the following anticonvulsants follows zero-order kinetics on dose increase within therapeutic range?
B. Drugs can undergo two different types of clearance when administered. When a constant fraction of a drug is cleared per unit time, it is called first-order kinetics. This means that when the amount of drug in plasma or dose of administered drug increases, the clearance proportionately increases as a stable fraction of plasma concentration. When the system facilitating such clearance of drugs becomes saturated, drugs follow zero-order kinetics. Here a constant amount, not a fraction, of the drug is cleared per unit time. This means that irrespective of the amount of drug in plasma or dose of drug administered, only a fixed unit of drug is cleared by the body. Thus, increasing the dose might result in serious toxicity in this case. Certain drugs have a propensity to undergo zero-order kinetics, even at therapeutic dose levels. Phenytoin metabolism is dose dependent, wherein smaller therapeutic doses follow first-order kinetics while higher doses follow zero-order kinetics. Gabapentin is not metabolized by liver and undergoes first-order renal clearance. Valproate follows first-order kinetics even in wide therapeutic dose levels. Lamotrigine, too, shows first-order linear kinetics and it is metabolized predominantly through glucuronidation.
A patient suffering from gastritis is prescribed several psychotropic medications. She wants to know which part of her body will absorb most of these orally administered drugs.
The correct answer is:
E. The small intestine has the largest surface area for drug absorption in the GI tract, and its membranes are more permeable than oral epithelium, oesophagus, or stomach. Hence most drugs are absorbed primarily in the small intestine. Gut mucosa harbours many metabolic enzymes that can breakdown active drug molecules and reduce the bioavailability of administered drugs.
A patient started on antidepressant treatment for a first episode of depression stopped the medication abruptly after an initial response.
Which one of the following medications, if prescribed, has the highest chance of causing the most troublesome discontinuation reaction?
D. The abrupt discontinuance of SSRI use is associated with a discontinuation syndrome. This is characterized by fatigue, light headedness, nausea, headache, anxiety, insomnia and poor concentration, fl u like symptoms, and electric shock-like paresthesias. In most cases, at least 6 weeks of treatment have elapsed before a discontinuation reaction takes place. The symptoms are self-resolving within 3 weeks in most cases. It is suggested that those who tolerate SSRIs poorly on initiation are more likely to develop discontinuation symptoms. Fluoxetine is the SSRI least likely to be associated with this syndrome, because it has a metabolite that is active with a half-life of more than a week. Shorter half-life medications, such as paroxetine, are associated with more discontinuation symptoms. Other classes of antidepressants, such as venlafaxine and tricyclics, are also associated with discontinuation reactions.
A patient started on paroxetine after the fi rst episode of depression stopped the medication abruptly following an initial response. Apart from short half-life, higher incidence of discontinuation reaction following paroxetine is attributed to:
A. Paroxetine has a half-life of nearly 21 hours, which is short compared to fluoxetine, which has a prolonged duration of action due to an active metabolite that remains in the body for many days. In addition, paroxetine is more anticholinergic than most other SSRIs. Too rapid a discontinuation of any drug with significant anticholinergic properties may lead to a cholinergic rebound. The symptoms are characterized by acetylcholine excess—nausea, vomiting sweating, stomach cramps, diarrhoea, anxiety, agitation, and insomnia. In some cases delirium can result. This rebound is more common with tricyclics than SSRIs, except in the case of paroxetine which has significant anticholinergic effects.
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