Sally Usdin Yasuda

Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients

Many drugs prolong the QT interval and increase the risk of torsade de pointes. Concurrent use of two or more of these drugs can further increase the risk, but the prevalence of concurrent prescription of QT-prolonging drugs is not known. Using the administrative claims database of a national pharmaceutical benefit manager, we conducted a retrospective cohort study in 4,825,345 subjects aged 18 years or older. After identifying 50 drugs with QT-prolonging potential, and an additional 26 drugs that inhibit the metabolic clearance of QT-prolonging drugs, we measured the frequency of overlapping prescriptions for two or more of these drugs in the outpatient setting in 1999. Nearly 1.1 million subjects (22.8%) filled 4.4 million prescriptions for QT-prolonging drugs. Of these, 103,119 subjects (9.4%) filled overlapping prescriptions for two or more of the drugs or for a QT-prolonging drug and another drug that inhibits its clearance; 7249 subjects (0.7%) filled overlapping prescriptions for three or more of these drugs. Twenty-two percent of subjects who filled overlapping prescriptions were aged 65 or older; 74% were women. Antidepressants were involved in nearly 50% of the cases. Concurrent prescription of QT-prolonging drugs is common in the outpatient setting, and antidepressants are involved in half of these cases. Large pharmaceutical claims databases are useful for detecting potentially harmful prescribing behaviors, but better clinical evidence on medication safety is needed before such a system can be implemented fully.

Visual Hallucination and Tremor Induced by Sertraline and Oxycodone in a Bone Marrow Transplant Patient

The authors report a case of probable serotonin syndrome caused by the coadministration of sertraline and oxycodone. A 34 year‐old male patient experienced visual hallucinations and severe tremor after dramatically increasing his dosage of oxycodone while on stable amounts of sertraline and cyclosporin. Discontinuation of cyclosporin did not result in resolution of his symptoms. Consideration of a possible sertraline‐oxycodone interaction led to withholding sertraline, which resulted in symptom resolution. Serotonin syndrome has been noted with sertraline in combination with other drugs, but this is the first report in combination with a narcotic analgesic. Possible pharmacological mechanisms are discussed. In complicated patients that are taking multiple medications, physicians should be aware of this possible interaction to avoid delay in the diagnosis of serotonin syndrome.

Olanzapine-Induced Rhabdomyolysis

OBJECTIVE: To report a possible case of olanzapine-induced rhabdomyolysis with concomitant lithium-induced pseudo-infarction electrocardiogram changes. CASE SUMMARY: A 13-year-old white boy was admitted to the hospital with profound weakness and electrocardiogram (ECG) changes suggestive of myocardial damage after starting olanzapine and lithium. An adverse medication effect was not considered at the time of the patients admission. The time course of onset of weakness was coincident with administration of olanzapine. ECG abnormalities are a known manifestation of lithium therapy. DISCUSSION: This is a case description of olanzapine-induced rhabdomyolysis. Although other antipsychotic agents have been reported to cause rhabdomyolysis, an adverse drug reaction was not initially part of this patients differential diagnosis. The patient had begun reporting myalgias six days after starting olanzapine. Fourteen days later, these symptoms forced him to bed rest; lithium was added for behavior misinterpreted as disobedience and oppositional disorder. Only when medications were considered as cause of the weakness and ECG changes, was the true nature of the patients illness discovered. CONCLUSIONS: Olanzapine, like other neuroleptic agents, can cause rhabdomyolysis. Lithium can cause multiple ECG changes that can be misinterpreted as myocardial damage. Medication effects and adverse effects must always be considered in any disease complex.

Chlorpheniramine plasma concentration and histamine H1‐receptor occupancy

The plasma concentration‐response relationship of the antihistamine chlorpheniramine is poorly characterized. This study examined concurrently the concentrations of chlorpheniramine and presence of H1‐receptor antagonist in plasma after administration of 8 mg chlorpheniramine in normal volunteers. Six extensive metabolizers and five poor metabolizers, as judged by CYP2D6 phenotype (dextromethorphan metabolic ratio), were enrolled in the study. More than 80% occupancy of H1‐receptors by antagonist in plasma was observed for 12 hours after the dose in extensive metabolizers and greater than 60% from 12 to 30 hours in poor metabolizers, when plasma concentrations had fallen below those that should result in 50% occupancy of receptors. The results suggest that (±)‐chlorpheniramine plasma concentrations do not predict H1‐receptor antagonist in plasma. In addition, a role is suggested for CYP2D6 in formation of a potent active metabolite of chlorpheniramine.

Amiodarone-induced lymphocyte toxicity and mitochondrial function.

Amiodarone is one of the most effective antiarrhythmic drugs available. However, its use is often limited by potentially life-threatening toxicities, including hepatotoxicity and pulmonary toxicity. We have used human lymphocytes as a system in which to study amiodarone-induced cytotoxicity. Using a tetrazolium dye reduction assay, we observed amiodarone-induced cytotoxicity with a lethal dose (LD)50 of 10.0 +/- 31.1 microM (mean +/- SD, n = 5) with a cellular concentration of 2.2 +/- 0.2 million/ml and of 55.5 and 39.2 microM with cellular concentrations of 8.9 and 7.2 million/ml, respectively, after only 2.75 h of drug exposure. Damage to mitochondria, but not other organelles, was observed with electron microscopy at an amiodarone concentration of 7.3 microM. Alterations in ATP synthesis and lactate dehydrogenase (LDH) release from cells had concentration-response curves similar to those for cytotoxicity. However, we did not observe extracellular accumulation of adenine nucleotides. These results suggest that amiodarone may have a direct toxic effect on mitochondria, beginning at < 10 microM, with membrane-damaging effects at higher drug concentrations.

d‐Sotalol reduces heart rate in vivo through a β‐adrenergic receptor–independent mechanism

d‐Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at β‐adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d‐sotalol was attributable to β ‐blockade. Plasma samples from normal volunteers who randomly received either atenolol, d‐sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of β‐adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologie effects. A reduction in exercise heart rate of 7.7% ± 3.8% for d‐sotalol and 15.9% ± 3.0% for atenolol occurred with β1‐adrenergic receptor occupancy of 0% and 33.9% ± 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of β1‐blockade in d‐sotalol— induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.

Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes.

Anticholinergic effects are presumed to be the mechanism for the efficacy of chlorpheniramine in symptomatic relief of the common cold. Terfenadine, a second‐generation antihistamine, reportedly lacks anticholinergic side effects. We evaluated affinities of two commonly used over‐the‐counter antihistamines, brompheniramine and chlorpheniramine, as well as terfenadine in comparison with atropine at the five human muscarinic cholinergic receptor subtypes using CHO cells stably transfected with the individual subtypes. Atropine was more potent than all three drugs at m1–m5 (p<0.01). No significant difference was observed between chlorpheniramine and brompheniramine. Atropine, brompheniramine, and chlorpheniramine could not discriminate between m1–m5. Terfenadine demonstrated subtype selectivity at m3. In vitro comparisons in human muscarinic receptor subtypes could potentially be used to predict clinical anticholinergic effects of antihistamines and to target receptor‐specific effects of such agents.

The clinical value of FDA class C drugs approved from 1981 to 1988

Clinical Pharmacology and Therapeutics (1992) 52, 577–582; doi:10.1038/clpt.1992.194

Quantification of Human H1 Histamine Receptor mRNA from Peripheral Blood

Study Objective. To develop a reverse transcription (RT)‐polymerase chain reaction (PCR) technique to detect and quantify human histamine1 (H1) receptor mRNA in peripheral blood.

Nimodipine in the Treatment of Subarachnoid Hemorrhage

Nimodipine, a calcium-channel antagonist with a relatively selective vasodilatory effect on cerebral blood vessels, has recently been approved for improvement of neurologic deficits due to spasm following subarachnoid hemorrhage. Nimodipine has low oral bioavailability (2.7–27.9 percent), a short half-life (2 h), is highly protein bound (98–99 percent), and is hepatically metabolized. Clinical studies have evaluated topical, intravenous, and oral administration of nimodipine for the treatment of cerebral artery spasm associated with subarachnoid hemorrhage. These studies document some benefit of the drug in reducing the occurrence of severe neurologic deficit, although this effect is not universal. Few adverse effects have been noted. Further studies are necessary to evaluate the pharmacologic and pharmacokinetic characteristics, the appropriate dose and route of administration, adverse effects, drug interactions, and the therapeutic efficacy of nimodipine before routine use can be recommended.