Download EPILEPSY and Over-the

 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.
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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
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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)
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Reduced antifungal activity
Reduced antiretroviral efficacy, increased viral replication, development of resistance
Reduced immunosuppressant activity
Reduced efficacy, potential for poorer prognosis for patient
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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).
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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.
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