US Pharm. 2010;35(1):20-23.
It has been established that the elderly, particularly those with some degree of neurologic disease, are especially susceptible to the actions of medications.1 In light of the ubiquity of polypharmacy in seniors, this column has previously presented an overview of the causes of seizures in the elderly with reference to the risk of drug-induced events.2 In this issue, which focuses on neurologic diseases, a narrower discussion regarding seizures will be presented. The scope is a focus on specific agents associated with drug-induced seizures. Recognizing their potential risk and raising awareness about this problem may assist with the development of appropriate medication regimens and associated monitoring parameters to better tailor the pharmaceutical care plan to the individual patient.
The term epilepsy refers to a family of different recurrent seizure disorders causing discharge of cerebral neurons that is sudden, excessive, and synchronous, resulting in short-lasting abnormal movements or perceptions.3 Any central nervous system (CNS) disorder that causes a predisposition to recurrent seizures may be labeled epilepsy.4 It is possible, however, to experience a seizure as a single event without having epilepsy.5 Nonepileptic seizures are provoked by a stressor or an acute or temporary disorder such as drug toxicity, infection of the CNS, or a metabolic or cardiovascular disorder (TABLE 1). Fever, especially in children, can also provoke a seizure; febrile seizures also do not constitute epilepsy.6 The more prolonged the seizure, the more likely that the brain will experience ischemia with the potential for neuronal destruction and brain damage.5
In seniors, causes of seizures may be multifactorial, including cerebrovascular disease, neurodegenerative disorders, CNS infections, metabolic disorders, head trauma, and tumors.5 Lack of awareness of one’s surroundings, or a sudden and temporary loss of consciousness (syncope), may occur with seizure activity.7 While the patient is unconscious, loss of bladder or bowel control may result.7 It may take patients a considerable amount of time to “clear their thoughts” after they regain consciousness.7
One group of investigators, Thundiyil et al, were interested in determining if the causes and consequences of drug-induced seizures had changed in the last decade.8 Their retrospective review compared the causes of recently reported seizures to those found in previous investigations.8 According to the records of the California Poison Control System in 2003, tricyclic antidepressants, antihistamines, stimulants, and isoniazid continue to be classified as common causes of drug-induced seizures. Of the 386 cases evaluated that were related to poisoning or drug intoxication in which seizures occurred, the leading causes were the following in order of frequency: bupropion, diphenhydramine, tricyclic antidepressants, tramadol, amphetamines, isoniazid, and venlafaxine. Patients exposed to a stimulant were found to be at a statistically significant increased risk of death.8 Further, it had emerged that poison control centers were being consulted regarding three agents commonly causing drug-induced seizures: bupropion, tramadol, and venlafaxine.8
Select Common Causes of Drug-Induced Seizures
It is not difficult to imagine seniors at risk for drug-induced seizures when an offending agent is used in circumstances that may increase their risk, including comorbidities, polypharmacy, medication-adherence problems, errors in administration (i.e., due to vision difficulties, misunderstanding, dementia), and age-related reduced medication clearance (e.g., renal and hepatic impairment). Pharmacists should note these considerations in an attempt to identify, resolve, and prevent medication-related problems in this population. Although it is beyond the scope of this article to discuss the pharmacologic management of seizures, the interested reader is referred to References 2, 5, and 6. The following information is provided for pharmacists as a supplement to the most currently available prescribing guidelines—including those for renal and hepatic dosing—and specific precautions, warnings, and contraindications.
Bupropion: Bupropion, like other antidepressant agents, lowers seizure threshold.9 Pharmacists should note that the risk of seizures with this agent is dose-dependent and that elderly patients receiving bupropion may be at greater risk of accumulation during chronic dosing.10 Seizure risk is increased in patients with the following: a history of seizures, head trauma, anorexia/bulimia, CNS tumor, severe hepatic cirrhosis, abrupt discontinuation of a sedative hypnotic or alcohol, and medications that lower the seizure threshold (e.g., neuroleptics). It has been recommended that when possible, clinicians consider discontinuing bupropion prior to elective surgery.10 Also, this agent may increase the risks associated with electroconvulsive therapy.10
It was reported in a 2002 study that bupropion-induced seizures were the third most common cause of drug-induced seizures after cocaine ingestion and benzodiazepine withdrawal.11 Additionally, according to a 3-year, multicenter retrospective analysis, approximately 21% of individuals admitted with intentional bupropion IR (immediate release) overdose presented with seizures.12 In 2007, Rissmiller and Campo first published a case of seizures induced by bupropion ER (extended release) even though the patient was already receiving two anticonvulsants, including clonazepam, a medication efficacious in preventing bupropion-induced seizures.9,13 The authors suggest that while bupropion ER (a once-daily alternative for bupropion IR and SR [sustained release]) offers a convenient once-daily dosing option, its prolonged half-life may cause seizures to have a more protracted course, as in the case they reported.9 According to published reports, this long-acting formulation might prolong neurologic toxicities, including seizures occurring in overdose.14 (For details of this case, refer to Reference 9.)
Clinicians are advised to avoid concomitant use of bupropion with monoamine oxidase (MAO) inhibitors.10 If appropriate, pharmacists should alert patients that the antidepressant bupropion is used as an adjunct in smoking cessation regimens, so that caution is used regarding risk of duplicative therapy.
Diphenhydramine: Among its many uses, the antihistamine diphenhydramine is contained in many OTC products commonly used in the treatment of allergies and as a nighttime sleep aid; it is also used in the management of parkinsonian syndrome, as well as drug-induced extrapyramidal symptoms.10 Its use in the elderly is discouraged when possible owing to its highly sedative and anticholinergic effects (e.g., dry mouth, constipation, blurred vision, urinary constipation, risk of delirium), and it may not be considered the antihistamine of choice for prolonged use in the elderly.10 Diphenhydramine should be used with caution in patients with increased intraocular pressure and cardiovascular disease (including hypertension and tachycardia), commonly seen in the elderly.10 Furthermore, use of diphenhydramine as an anxiolytic or sedative in long-term care facilities is discouraged, according to the interpretive guidelines from the Centers for Medicare and Medicaid Services.10
Nine and Rund reviewed fatalities due to diphenhydramine monointoxication in the following databases: 1) the English-language literature (PubMed) from 1946 through 2003; and 2) the Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System from 1983 through 2002.15 Adult (mean 35.6 years; range 18-84 years) and pediatric (mean 8.6 years; range 1.25-17 years) patients were both involved in the review. The researchers found that while most deaths were a result of accident or suicide, six infant homicides were reported.15 The most common symptoms reported for all cases were cardiac dysrhythmias, seizure activity, and/or sympathetic pupil responses; pulmonary congestion was the most common finding on autopsy.15
Tramadol: Tramadol is a synthetic codeine analogue classified as a centrally acting analgesic agent; it also weakly inhibits reuptake of norepinephrine and serotonin.3 Tramadol is commonly prescribed because of its relatively lower risk of addiction and favorable safety profile compared with other opiate agents.16 This agent is associated, however, with two significant adverse reactions—seizures and serotonin syndrome (fever, flushing, diaphoresis, tremors, and delirium).6,16 Sansone and Sansone report that although these two adverse reactions may develop during tramadol monotherapy, they are much more likely to emerge during misuse or overdose, as well as with the concomitant use of other drugs—especially antidepressants (e.g., tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs]).3,16 Researchers suggest that this issue is of clear clinical relevance to psychiatrists and primary care clinicians alike.16
Hersh et al point out evidence of less well-known and potentially clinically significant drug–drug interactions.17 The authors describe the potential of SSRIs to inhibit the analgesic activity of tramadol and codeine (via inhibition of their metabolic activation), causing serotonin syndrome with chronic use in the presence of high-dose tramadol therapy, which induces a synergistic serotonergic action.17
There may be a greater risk of adverse events in patients who are elderly (particularly >75 years of age), are debilitated, or have chronic respiratory disorders.10 Tramadol should be avoided in patients taking serotonergic agents (such as MAO inhibitors, TCAs, SSRIs, serotonin/norepinephrine reuptake inhibitors [SNRIs] such as venlafaxine, triptans, trazodone, lithium, sibutramine, meperidine, dextromethorphan, and St. John’s wort); the development of serotonin syndrome is associated with concomitant use.3,10
Venlafaxine: Venlafaxine is a potent inhibitor of serotonin reuptake; at higher doses, it is an inhibitor of norepinephrine reuptake.3 While the most common side effects are nausea, dizziness, insomnia, sedation, and constipation, high doses may cause an increase in blood pressure; sustained increase in blood pressure or tachycardia may be seen.3,10 There is a potential for severe reactions when venlafaxine is used with MAO inhibitors, SSRIs/SNRIs, or triptans: myoclonus, diaphoresis, hyperthermia, features of neuroleptic malignant syndrome, seizures, and death. In renal and hepatic impairment, caution is advised and dosage adjustments are recommended.
Seniors, particularly those with some degree of neurologic disease, are especially susceptible to the effects of medications. While the causes of seizures in the elderly may be multifactorial, many age-related issues are potential contributors to the risk of drug-induced seizures in this population. Pharmacists should note the common causes of seizures in seniors and be able to identify those drugs that place a senior at particular risk in light of the individual’s history, clinical status, and risk for drug interactions.
1. Changes in the brain. Merck Manual of Geriatrics. www.merck.com/mkgr/mmg/sec6/ch42/ch42a.jsp#ind06-042-2312. Accessed December 15, 2009.
2. Zagaria ME. Causes of seizures in the elderly. US Pharm. 2008;33(1):27-31.
3. Howland RD, Mycek MJ. Pharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:139-148,170-171.
4. Ferrendelli AJ, Lim HL. Epilepsy in the elderly. In: Hazzard WR, Blass JP, Halter JB, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York, NY: McGraw-Hill, Inc; 2003:1431-1441.
5. Gidal BE, Garnett WR. Epilepsy. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill Inc; 2005:1023-1048.
6. Seizure disorders. Merck Manual. www.merck.com/mmpe/sec16/ch214/ch214a.html?qt=seizure%20disorders&alt=sh. Accessed December 15, 2009.
7. Beers MH, Jones TV, Berkwits M, et al, eds. The Merck Manual of Health & Aging. Whitehouse Station, NJ: Merck Research Laboratories; 2004:239,828,830.
8. Thundiyil JG, Kearney TE, Olson KR. Evolving epidemiology of drug-induced seizures reported to a poison control center system. J Med Toxicol. 2007;3:15-19.
9. Rissmiller DJ, Campo TJ. Extended-release bupropion induced grand mal seizures. J Am Osteopath Assoc. 2007;107:441-442.
10. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 14th ed. Hudson, OH: Lexi-Comp, Inc; 2009.
11. Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med. 2002;22:235-239.
12. Spiller HA, Ramoska EA, Krenzelok EP, et al. Bupropion overdose: a 3-year multi-center retrospective analysis [review]. Am J Emerg Med. 1994;12:43-45.
13. Tutka P, Mróz T, Klucha K, et al. Bupropion-induced convulsions: preclinical evaluation of antiepileptic drugs. Epilepsy Res. 2005;64:13-22.
14. Jepsen F, Matthews J, Andrews FJ. Sustained release bupropion overdose: an important cause of prolonged symptoms after an overdose. Emerg Med J. 2003;20:560-561.
15. Nine JS, Rund CR. Fatality from diphenhy-dramine monointoxication: a case report and review of the infant, pediatric, and adult literature. Am J Forensic Med Pathol. 2006;27:36-41.
16. Sansone RA, Sansone LA. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry (Edgmont). 2009;6:17-21.
17. Hersh EV, Pinto A, Moore PA. Adverse drug interactions involving common prescription and over-the-counter analgesic agents. Clin Ther. 2007;29(suppl):2477-2497.
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