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REVIEW EPILEPSY and Over-the-Counter medications Fae Farrer, BPharm Abstract Epilepsy is a condition manifested by seizures. These seizures have an impact on the patient’s quality of life. As patients with epilepsy may receive antiepileptic drugs for a long period, up to a lifetime, and they will require treatment with other agents for various other conditions at some stage, it is important that both patients and health professionals are aware of possible interactions with their anti-epilepsy medication. This article is a brief review of epilepsy, its treatment, seizure threshold, possible interactions of anti-epileptic medications with other medicines, and medications that may alter seizure threshold. What is epilepsy? A seizure is a massive disruption of electrical communication between the neurons in the brain. This leads to the temporary release of excessive energy in a synchronized form. This abnormal activity is intermittent and usually self-limiting, lasting a few seconds to several minutes. An individual is considered to have epilepsy if the seizures recur over a period of time without an obvious cause. Seizures resulting from fever, toxins or intracranial bleeding or other specific causes are not classified as epilepsy unless they become recurrent after the acute problem has been resolved. Epilepsy is not a specific disease, but more a condition that results from pathological problems within the cortex, such as tumours or genetic disorders. Types of epileptic seizures Epileptic seizures are classified as partial or generalised seizures. Partial seizures Partial seizures are those that are considered to be limited to one hemisphere. These seizures are further classified as simple partial seizures in which consciousness is fully maintained, or complex partial seizures, in which consciousness is impaired. Clinical symptoms of partial seizures allow further subdivision: • Motor seizures may manifest with focal motor activity, arrest of speech, turning of the head, trunk or eyes. • Sensory seizures may cause the patient to experience vertigo, olfactory, auditory or visual disturbances. • Autonomic seizures may induce sweating or papillary changes. Simple partial seizures may also induce feelings of familiarity (“deja-vu”), distortions of time, illusions and hallucinations. Complex partial seizures involve regions of both hemispheres, and may manifest as a variety of repetitive movements such as, chewing, swallowing, kicking movements, running, jumping or flailing of arms. 26 Generalised seizures Generalised seizures are those that involve both hemispheres. Impairment of consciousness is often the initial manifestation. Motor involvement is bilateral. Generalised seizures may be convulsive or non-convulsive. • Major motor seizures (tonic-clonic seizures) manifest with bilateral movement of the entire body, clonic jerking of the extremities and/or tonic rigidity of the entire body. This is usually accompanied by a period of unconsciousness. • Minor motor seizures may be subdivided: 1. Absence seizures may begin in childhood or adolescence. During these seizures there is sudden onset of altered consciousness, lasting 10-45 seconds. These may occur frequently (up to hundreds of times) in a day. 2. Myoclonic seizures involve lightening-like jerks of one or more extremities, and may occur singly or in bursts. These seizures are accompanied by alteration of consciousness. 3. Atonic seizures manifest as sudden onset of altered consciousness with loss of postural tone, lasting up to 30 seconds. Status epilepticus is a prolonged seizure (lasting more than 20 minutes) of any type. The most common is generalised tonic-clonic status epilepticus, which may be life threatening. Seizure threshold A seizure may result from abnormal discharges of neurons in the cerebral cortex. Neurons communicate with each other by firing electrical impulses that travel along the axon, and stimulate the release of neurotransmitters that flow across the synaptic cleft to the receiving cell. If more excitatory than inhibitory transmitters are released, the cell will fire; if more inhibitory neurotransmitters are released the cell will not fire. In a situation where there is a consistently higher level of excitatory transmitters, or too few inhibitory ones, then the likelihood of uncontrolled, continuous firing of neurons in the brain – a seizure – is increased. A sudden burst of neuronal firing may not be enough to SA Pharmaceutical Journal – October 2009 REVIEW precipitate an obvious seizure, but it may produce symptoms characteristic of the area in which the discharge took place, e.g. a muscle jerk or distorted vision. If the disturbance flashes across the entire brain it may temporarily disrupt many functions of the brain and produce a convulsive seizure. The concept exists that each person has a certain balance (possibly genetically determined) between excitatory and inhibitory forces in the brain. The relative proportions of each determine whether a person has a low threshold for seizures (high level of excitatory transmitters) or a high threshold (greater inhibitory forces). A low threshold for seizures may make it easier for epilepsy to develop, or easier for a person to experience a seizure. Drug interactions Medications to treat epilepsy As patients with epilepsy will receive AEDs for a long period, up to a lifetime, and they will require treatment with other agents for various conditions at some stage, it is important that they are aware that certain substances may interact with their anti-epilepsy medication. Several possibilities exist for altered blood concentrations of the various medications: 1. The level of the AED may be increased, with possible toxicity. 2. The level of the AED may be decreased, with increased seizure risk. 3. The level of the other medication may be increased, with possible toxicity. 4. The level of the other medication may be decreased, with possible treatment failure. 5. The other medication may not interact directly with the AED, but may lower the seizure threshold, with increased seizure risk. Selecting the correct anti-epileptic drug (AED) for each patient depends on their individual epilepsy syndrome, age, gender and other factors. The goal of treatment with AEDs is to completely control seizures, without side effects. Where this is not possible, the aim is to reduce frequency and/or intensity of seizures with the fewest possible adverse effects. Monotherapy is preferred. If a single agent is not effective a second medication may be prescribed, and the first withdrawn. In situations where seizures are resistant to single drug therapy, two or more antiepileptic drugs may be used, however interactions may occur and the levels of one or more medications may have to be adjusted. Table I is a list of some of the medications commonly used in the treatment of epilepsy. Table I: Medications to treat epilepsy Trade Names Common Names Carbamazepine Tegretol®, Degranol®, Sandoz-Carbamazepine® Clonazepam Rivotril® Diazepam Valium® Ethosuximide Zarontin ® Gabapentin Neurontin ® , Neurexal ® , Epleptin ® , RanGabapentin ® Lamotrigine Lamictin®, Lamitor®, Sandoz-Lamotrigine®, Arrow-Lamotrigine®, Aspen-Lamotrigine®, AustellLamotrigine®, Dyna-Lamotrigine®, Epitec® Levetiracetam Keppra® Oxcarbazepine Trileptal® Phenobarbitone Adco-Phenobarbitone® Phenytoin Epanutin® Pregabalin Lyrica ® Primidone Mysoline Topiramate Topamax ® , Adco-Topiramate ® , Piramax ® , Sandoz-Topiramate ®, Toplep ® Valproate Epilim® Vigabatrin Sabril® Drug interactions may occur whenever two or more medications are taken at the same time. A drug interaction occurs whenever one medication alters the activity of another. This may result in either enhanced or reduced activity. The outcome may be beneficial if the therapeutic effect is enhanced, or harmful if the interaction causes an increase in adverse effects or a reduction in efficacy. Interactions may occur during absorption, distribution, metabolism and elimination of the medications, or at the site of action of the particular drug by means of effects on the target receptor. Interactions between anti-epileptic drugs and other medications There are well-documented interactions between antiepileptic drugs, but these may be used to advantage when Table II: AEDs and medications increasing AED levels AED Carbamazepine Valproic acid, fluoxetine, trazodone, propoxyphene, clarithromycin, erythromycin, chloramphenicol, sulphonamides, trimethoprim, fluconazole, isoniazid, ketoconazole, metronidazole, ritonavir, verapamil, cimetidine, danazol, diltiazem, risperidone Ethosuximide Isoniazid Lamotrigine Valproic acid, sertraline Phenobarbitone Valproic acid, phenytoin, chloramphenicol, isoniazid, dextropropoxyphene Phenytoin Oxcarbazepine, topiramate, fluoxetine, imipramine, sertraline, trazodone, chloramphenicol, fluconazole, isoniazid, metronidazole, ritonavir, tamoxifen, allopurinol, amiodarone, cimetidine, chlorpheniramine, dextropropoxyphene, diltiazem, disulfiram, omeprazole, phenylbutazone, tolbutamide, ibuprofen Valproate Isoniazid, sertraline, cimetidine ® SA Pharmaceutical Journal – October 2009 Drug increasing AED level 27 REVIEW polytherapy is required for the treatment of epilepsy. It is the possibility of interactions with other medications that may pose more of a problem for the epileptic patient. Table III: AEDs and medications decreasing AED levels AED Interactions increasing AED levels Drug decreasing AED level Carbamazepine Phenytoin, phenobarbitone, antacids, St John’s wort Most AEDs have a narrow therapeutic index and therefore even slight changes in their metabolism may result in loss of response or toxic effects. In situations where the metabolism of a particular medication is inhibited, higher levels of that particular medication in the blood result, leading to possible adverse effects or toxicity, e.g. valproic acid inhibits the metabolism of lamotrigine resulting in lamotrigine-induced skin rashes; val-proic acid may inhibit metabolism of carbamazepine, leading to signs of neurotoxicity when added to carbamazepine therapy. Medications that inhibit hepatic enzymes may increase plasma levels of AEDs metabolised in the liver. Table II lists AEDs and medications that may increase their levels (see table on previous page). Interactions decreasing AED levels Ethosuximide Carbamazepine, phenytoin, phenobarbital, primidone Gabapentin Antacids Lamotrigine Carbamazepine, phenytoin, phenobarbital, primidone, oral contraceptives Oxcarbazepine Carbamazepine, phenytoin, phenobarbital, primidone Phenytoin Cisplastin, antacids, ethanol (alcohol), folic acid, rifampin, sucralfate, vinblastine, St John’s wort Topiramate Carbamazepine, phenytoin, phenobarbital, primidone Valproate Carbamazepine, phenytoin, phenobarbital, primidone Increased hepatic clearance of a medication may result in lower levels of that substance, leading to reduced efficacy. Medication that induces hepatic metabolism such as rifampicin, ethanol and St. John’s wort may decrease levels of AEDs metabolised in the liver. Table IV: Medications decreased by AEDs, and possible outcomes Medication decreased by AED AED Outcome of interaction Oral contraceptives Carbamazepine, phenytoin, phenobarbitone, Reduced contraceptive efficacy, pregnancy oxcarbazepine, topiramate Theophylline Carbamazepine, phenytoin, phenobarbitone Reduced efficacy in asthma and chronic bronchitis Dicoumarol/warfarin Carbamazepine, phenytoin, phenobarbitone Decreased anticoagulant activity. If AED removed, possible dicoumarol/warfarin toxicity Digoxin Phenytoin, topiramate Reduced efficacy in cardiac failure Corticosteroids (e.g. dexamethasone, corti- Carbamazepine, phenytoin, phenobarbitone sone, prednisone, prednisolone, methylprednisolone) Reduced therapeutic effects Benzodiazepines (e.g. midazolam, alprazolam, Carbamazepine, phenytoin, phenobarbitone clobazam, clonazepam, diazepam) Reduced therapeutic effects of the benzodiazepine Antipsychotic agents (e.g. haloperidol, chlor- Carbamazepine, phenytoin, phenobarbitone promazine, clozapine, risperidone) Reduced therapeutic effects of the antipsychotic agent Antidepressant agents (e.g. amitriptyline, Carbamazepine, phenytoin, phenobarbitone citalopram, imipramine, mianserin, mirtazepine, nortriptyline) Reduced efficacy of the antidepressant Antimicrobials (e.g. albendazole, doxycycline, Carbamazepine, phenytoin, phenobarbitone itraconazole, metronidazole, praziquantel) Reduced antimicrobial efficacy Griseofulvin Carbamazepine, phenytoin, phenobarbitone Antiviral agents (nevirapine, indinavir, ritonavir, Carbamazepine, phenytoin, phenobarbitone saquinavir) Ciclosporin Carbamazepine, phenytoin, phenobarbitone Anticancer agents (e.g. cyclophosphamide, Carbamazepine, phenytoin, phenobarbitone etoposide, paclitaxel) 28 Reduced antifungal activity Reduced antiretroviral efficacy, increased viral replication, development of resistance Reduced immunosuppressant activity Reduced efficacy, potential for poorer prognosis for patient SA Pharmaceutical Journal – October 2009 REVIEW Table V: Medications that may lower seizure threshold Category Medication Antiasthmatics Aminophylline Theophylline Antibiotics Amphotericin-B Cephalosporins Isoniazid Metronidazole Nalidixic acid Penicillins Antidepressants Tricyclic antidepressants Selective serotonin re-uptake inhibitors Bupropion Antihistamines Azatadine Chlorpheniramine Pheniramine maleate Promethazine General anaesthetics Enflurane Ketamine Propofol Hormones Insulin Prednisone Oestrogen Immunosuppressants Chlorambucil Cyclosporine a Local anaesthetics Narcotics Psychostimulants Lidocaine Bupivicaine Procaine Fentanyl Meperidine Pentazocine Pethidine Propoxyphene Amphetamines Cocaine Methylphenidate Phenylpropanolamine Neuroleptics Clozapine Phenothiazines Butyrophenones Other Anticholinergics Anticholinesterases Baclofen Heavy metals Hyperbaric oxygen Lithium Mefenamic acid Oral hypoglycaemics Oxytocin Table VI: OTC medication and AEDs AED OTC medication Effect on AED level Phenytoin Antacids Alcohol Chlorpheniramine Folic acid and Vit B6 Aspirin Theophylline Charcoal Dietary supplements Piperine (peppers, chillies) Herbal antiepileptic Decrease Decrease Increase Decrease Decrease or increase Decrease Decrease Decrease Increase Decrease Carbamazepine Antacids Terfenadine Charcoal Grapefruit Theophylline Colestipol powder Decrease Increase Decrease Increase Decrease Decrease Sodium valproate Antacids Aspirin Charcoal Cholestyramine powder Decrease Increase Decrease Decrease Phenobarbitone Alcohol Antacids Increase Decrease Vigabatrin No documented OTC interactions Topiramate No documented OTC interactions Lamotrigine Paracetamol Decrease Gabapentin Antacids Decrease Diazepam Alcohol Smoking tobacco Grapefruit Increase Decrease Increase Clonazepam Alcohol Grapefruit Increase Increase Primidone Alcohol Folic acid Increase Decrease Note: Decreased AED levels = increased seizure risk. Carbamazepine, phenytoin, phenobarbital and primidone are enzyme inducers, stimulating the metabolism and decreasing the concentration of most other co-administered AEDs. Since enzyme induction is reversible, caution is required when an enzyme-inducing agent is discontinued, as the level of a concurrently administered medication may increase to potentially toxic levels. (See Table III on page 28.) Interactions increasing levels of other medications Interactions between AEDs and other medications that result in increased levels of the non-AED are uncommon. Valproic acid may increase plasma concentrations of lorazepam. Interactions decreasing levels of other medications The older generation AEDs (carbamazepine, phenytoin, phenobarbitone and primidone) are inducers of hepatic enzymes and decrease plasma concentrations of many other medications. (See Table IV on page 28). Contd on p 52 30 SA Pharmaceutical Journal – October 2009 REVIEW Contd from p. 30 Epilepsy and OTC medications Medicines that may lower seizure threshold Patients with epilepsy have to be aware that certain factors may lower their seizure threshold, making them more liable to have seizures. These factors include stress, lack of sleep, alcohol, menstruation, and, especially in children, infections and fever. Certain medications have also been shown to provoke seizures by lowering the seizure threshold rather than by interacting directly with AEDs. Table V (page 30) lists some of the medications that may provoke seizures by lowering the seizure threshold. This does not imply that these medications should not be used in patients with epilepsy, but that there is a possibility of a change in seizure threshold and precautions should be taken where no alternative medication is suitable. Potential interactions with over-the-counter medication Over-the-counter medication and herbal products that have an effect on the central nervous system, such as stimulation or sedation, may affect a patient’s seizure threshold and may increase the risk of seizure occurrence. Stimulants of all types are implicated in seizure induction, even in patients without a pre-existing seizure disorder. Pseudoephedrine, phenylpropanolamine, as well as some OTC antihistamines e.g. diphenhydramine, have been associated with seizures, especially in overdose. Medications for nasal congestion and rhinorrhoea such as pseudoephedrine and phenylephrine are generally considered to be safe, although there are reports of these substances causing seizures. Despite interactions with certain AEDs, paracetamol and aspirin are considered the safest analgesics for OTC treatment of aches and pains. Conclusion The potential for drug-drug interactions is a problem in patients taking several medicines. Long-term therapy is the reality for the majority of patients with epilepsy. Most patients will require medication for a concomitant disease; therefore the probability that patients with epilepsy will experience a drug interaction is high. The solution to the problem of interactions is to choose preparations that do not interact. However, this may not always be possible, and potential interactions must be considered and precautions taken. There is also the possibility that certain groups of patients may have different susceptibilities to various interactions due to genetic or environmental influences on drug metabolism. Thus not all patients will experience all possible interactions. It is important that the potential for interactions or adverse effects are considered when adding or discontinuing any medication, including over-the-counter medications. The lists of interactions and medications that may lower seizure thresholds should not be regarded as exhaustive. References 1. 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Clinically relevant drug interactions with antiepileptic drugs. British Journal of Clinical Pharmacology. March 2006. 61(3) 13. Buchanan N. Medications which may lower seizure threshold. Australian Prescriber. 24. 2001 14. Epilepsy phenome/genome project. Drugs that may lower seizure threshold. Epilepsy.com 52 SA Pharmaceutical Journal – October 2009