Christopher P Alderman

Adverse Effects of the Angiotensin-Converting Enzyme Inhibitors

OBJECTIVE: To review current literature relating to the adverse effects of the angiotensin-converting enzyme (ACE) inhibitors. DATA SOURCES: Online drug information sources, including MEDLINE (1966–November 1994), Iowa Drug Information Service, and the Australasian Medical Index (AMI), were used to identify relevant literature, including reviews. DATA EXTRACTION: Data were extracted from studies described in the English-language literature dealing with the adverse effects of ACE inhibitors. Comprehensive reviews and relevant case reports also were included. DATA SYNTHESIS: Important adverse effects of ACE inhibitors include first-dose hypotension, renal dysfunction, hyperkalemia, and cough. Less common adverse effects include angioedema, hepatotoxicity, skin rashes, and dysgeusia. ACE inhibitors also are associated with adverse fetal effects; thus, this class of drugs is contraindicated in pregnancy. Some adverse effects of ACE inhibitors are predictable on the basis of the fundamental pharmacology of this class of drugs. However, other effects are idiosyncratic in nature, although these reactions are generally much less common. CONCLUSIONS: Attention to the principles of risk assessment, risk minimization, and patient monitoring are important when ACE inhibitor therapy is used for any indication. Provided these steps are taken, ACE inhibitors are generally a safe and effective class of drugs.

Abnormal Platelet Aggregation Associated with Fluoxetine Therapy

OBJECTIVE: To document the development of abnormal hemostasis in a patient treated with fluoxetine. CASE SUMMARY: A 49-year-old man developed a release-type defect in platelet aggregation during treatment with fluoxetine. Abnormal platelet aggregation was observed during platelet viability testing, in which adenosine diphosphate, epinephrine, ristocetin, arachidonic acid, and collagen were used as agonists. Two days after the withdrawal of fluoxetine, platelet function returned to normal. DISCUSSION: Fluoxetine is an antidepressant that is thought to act through inhibition of serotonin reuptake in the central nervous system. Fluoxetine also inhibits the reuptake of serotonin in platelets, significantly decreasing granular storage and potentially influencing platelet aggregation characteristics. Clinical manifestations of abnormal platelet function have been reported in association with fluoxetine therapy. CONCLUSIONS: The rapid normalization of platelet aggregation after the withdrawal of fluoxetine in this patient does not conform to the known clinical pharmacokinetics of norfluoxetine. The half-life of fluoxetine is shorter, suggesting that the parent drug (rather than norfluoxetine) was the causative agent. Serum fluoxetine and norfluoxetine concentrations were not measured in this patient.

Effects of Serotonin Reuptake Inhibitors on Hemostasis

OBJECTIVE: To examine the hematologic safety profile of the selective serotonin reuptake inhibitors (SSRIs), with particular emphasis on the effects of these drugs on platelet aggregation. METHODS: Platelet aggregation studies were undertaken at baseline, and repeated 2 and 4 weeks after the initiation of treatment with an SSRI. Other investigations undertaken included analysis of serum electrolyte and liver enzyme concentrations, complete blood count, and coagulation studies. Patients were also assessed for clinical signs of bleeding. Eight patients (7 treated with fluoxetine, 1 with paroxetine) completed the study protocol. RESULTS: Repeated ANOVA revealed no abnormalities in platelet aggregation, hematopoiesis, or coagulation profile. No patient developed clinical signs of abnormal hemostasis during the study period. A statistically significant elevation in the mean serum bilirubin concentration was detected, but this was not of clinical significance. CONCLUSIONS: Although the SSRIs may cause abnormal hemostasis, this effect is probably rare. Another possibility is that abnormal hemostasis is more likely to occur when high doses of SSRIs are administered.

Digoxin-itraconazole interaction : Possible mechanisms

Objective To document a case in which the administration of itraconazole was associated with an apparent decrease in digoxin clearance, resulting in an increase in the serum digoxin concentration. Case Summary A man receiving digoxin for atrial fibrillation was concurrently treated with itraconazole 200 mg/d for esophageal candidiasis. The estimated urinary digoxin clearance was decreased during this combination therapy. Discussion Digoxin is primarily cleared by the kidneys, and the mechanism of renal clearance involves both glomerular filtration and tubular secretion. We postulate that itraconazole or a metabolite of this compound may have resulted in decreased tubular secretion of digoxin, accounting for decreased urinary digoxin clearance. Conclusions Monitoring of serum digoxin concentrations should be performed if patients taking digoxin are treated with itraconazole. Further investigation is necessary to elucidate the nature of the interaction between digoxin and itraconazole.

Topiramate in Combat-Related Posttraumatic Stress Disorder:

Background: Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that is common among combat veterans and may lead to very poor sleep and disturbing nightmares. Objective: To examine the safety and effectiveness of topiramate as add-on therapy for the management of combat-related PTSD and to examine the effects of topiramate on sleep and alcohol consumption. Methods: We conducted an 8-week open-label pilot study of topiramate (or male combat veterans (N = 43) with PTSD, with analysis of veterans who completed the protocol. Psychometric, sleep, and alcohol consumption assessments were conducted at baseline and at week 8. Results: Twenty-nine subjects completed the 8-week study. Significant reductions in Clinician Administered PTSD Scale scores were observed at the 8-week endpoint (from 86,3 ± 21.1 to 67.1 ± 25.1; p < 0.01). Decreases were seen in both Stanford Sleepiness Scale scores (from 10.5 ± 0.72 to 9.0 ± 0.58; p = 0.08) and Mississippi PTSD scores (from 120.4 ± 6.5 to 111.5 ± 20.9; p = 0.08), but the extent of the changes did not attain statistical significance for either scale. There was a significant reduction in the proportion of patients with nightmares (from 100% to 62%; p < 0.001) and patients who experienced anxiety that interfered with falling asleep (from 90% to 62%; p < 0.05). The proportion of patients with high-risk drinking patterns also decreased (from 31% to 14%). Two serious adverse events were reported during the study: an increase in tow back pain and an episode of acute confusion. Conclusions: When used in addition to other empiric therapy, topiramate may be effective at reducing general symptoms of combat-related PTSD and reducing high-risk alcohol intake and nightmares. Further randomized controlled trials of topiramate for the treatment of combat-related PTSD are warranted.

Fluvoxamine-methadone interaction

Objective: The aim of this paper is to report a case of symptomatic methadone toxicity associated with fluvoxamine treatment. Clinical picture: A 28-year-old woman was admitted to hospital with severe hypoxaemia and hypercapnia indicating hypoventilation. Medication prior to admission had been stable and included methadone 70 mg daily and diazepam 2 mg twice daily. Three weeks before admission she had commenced treatment with fluvoxamine. Treatment: Methadone was decreased to 50 mg daily and diazepam was tapered to zero. Outcome: The serum methadone concentration decreased and oxygenation improved considerably. Conclusions: Clinicians should be aware of the potential for a significant drug interaction between fluvoxamine and methadone.

Venous Thromboembolism Prophylaxis in a South Australian Teaching Hospital

Background Venous thromboembolism (VTE) is relatively common among hospitalized patients, is often clinically silent, and is associated with substantial morbidity and mortality. Risk stratification and routine use of thromboprophylaxis for patients at moderate to high risk for VTE are key strategies that can be used to prevent VTE. Objective To assess the appropriateness of the selection and implementation of thromboprophylactic measures for prevention of VTE within a South Australian teaching hospital. Methods Guidelines for risk stratification and prophylaxis were compiled from a range of studies, consensus statements, and tertiary references. Using prospective, observational methodology, data collection was performed through case note audit for 130 inpatient admissions over a 4-week period. Results The decisions regarding the usage of thromboprophylaxis were considered inappropriate in 32% of cases in the study cohort. Suboptimal practices were also observed with respect to factors including the choice between mechanical and pharmacologic methods and the timing of initiation and cessation of thromboprophylaxis. Conclusions These findings provide evidence suggesting that the selection and implementation of thromboprophylaxis require improvement and that appropriate means to facilitate this improvement need to be developed and evaluated through future research.

Possible Neuroleptic Malignant Syndrome Associated with Olanzapine

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Interaction of serotonin re-uptake inhibitors with perhexiline

Objective: To report two cases of perhexiline toxicity associated with selective serotonin re-uptake inhibitor (SSRI) treatment. Clinical picture: Serum perhexiline concentrations progressively increased after a 69-year-old man was concurrently prescribed paroxetine for the treatment of depression. An 84-year-old woman was admitted to hospital with severe, symptomatic perhexiline toxicity associated with fluoxetine treatment. Treatment: In both cases, perhexiline therapy was suspended and treatment with SSRIs was withdrawn. Outcome: Serum perhexiline concentrations declined following the withdrawal of paroxetine in one case, but in the case of the second patient perhexiline concentrations were extremely slow to decrease, resulting in referral to a rehabilitative care unit for convalescence. Conclusions: Serum perhexiline concentrations may be elevated during concurrent treatment with SSRIs, potentially resulting in severe toxicity.

An Open-Label Study of Mirtazapine as Treatment for Combat-Related PTSD

Background: Posttraumatic stress disorder (PTSD) is common among war veterans. Antidepressants are effective in reducing symptoms and associated disability for some patients. Objective: To assess the effectiveness of mirtazapine for combat-related PTSD among veterans treated in an Australian hospital. Methods: This open-label prospective study assessed the effectiveness of mirtazapine as empirical treatment for combat-related PTSD. The initial dose was 15 mg at night, titrated against response to 15–45 mg. PTSD symptoms were assessed using the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder and the Clinician-Administered PTSD Scale (CAPS). Subjects also completed the Hospital Anxiety and Depression Scale (HADS). Body weight and biochemical assessments, including fasting blood glucose (FBG), total serum cholesterol, and serum triglycerides, were also measured. Baseline measurements were repeated after 12 weeks. Results: During the 18-month recruitment phase, 17 subjects were enrolled and 13 completed the protocol. The CAPS measurement decreased from a mean pretreatment score of 87.5 to 64.4 (p = 0.01). In 4 cases, the CAPS score decreased to below the diagnostic cut-point, consistent with a remission of PTSD. The Mississippi scale measurement decreased from a mean pretreatment score of 126.6 to 115.5 (p < 0.01). The mean HADS anxiety score decreased from 15.6 ± 4.2 to 13.5 ± 5.6 (p = 0.016), although the proportion of subjects with scores above the diagnostic cut-point remained high. The mean HADS depression score at baseline was not significantly different from the postintervention score. One subject had a postintervention FBG of 155 mg/dL (consistent with diabetes mellitus), which was increased from the baseline level of 83 mg/dL. All subjects experienced an increase in body weight. One subject had an increase in body weight of 8.75 kg (8.4%) from baseline. Conclusions: Although small and with methodological limitations, this study suggests that mirtazapine is an effective treatment for combat-related PTSD. Additional research incorporating an appropriately powered, double-blind, placebo-controlled study design is required.