Anti convulsants Flashcards
Examples of Anti convulsants
Phenytoin, carbamazepine, sodium valproate, lamotrigine, levitaracetam
How do Anti convulsants work?
The mechanism of action of phenytoin is incompletely understood. Phenytoin reduces neuronal excitability and electrical conductance among brain cells, which inhibits the spread of seizure activity. It appears to do this by binding to neuronal Na+ channels in their inactive state, prolonging inactivity and preventing Na+ influx into the neuron. This prevents a drift in membrane potential from the resting (−70 mV) to the threshold (−55 mV) value required to trigger an action potential. A similar effect in cardiac Purkinje fibres may account for both antiarrhythmic and cardiotoxic effects of phenytoin.
Sodium valproate
It appears be a weak inhibitor of neuronal sodium channels, stabilising resting membrane potentials and reducing neuronal excitability (see Phenytoin). It also increases the brain content of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter, which regulates neuronal excitability.
Indications for Anti convulsants
Phenytoin
1) To control seizures in status epilepticus where benzodiazepines are ineffective.
2) To reduce the frequency of generalised or focal seizures in epilepsy, although drugs with fewer adverse effects and interactions (e.g. valproate, lamotrigine, levetiracetam) are usually preferred.
Carbamazepine
1) Epilepsy, as a first choice treatment for focal seizures with and without secondary generalisation and for primary generalised seizures.
2) Trigeminal neuralgia, as first choice treatment to control pain and reduce frequency and severity of attacks.
3) Bipolar disorder, as an option for prophylaxis in patients resistant to or intolerant of other medication.
Sodium valproate
1) Epilepsy, as a first choice drug for the control of generalised or absence seizures and as a treatment option for focal seizures.
2) Bipolar disorder, for the acute treatment of manic episodes and prophylaxis against recurrence.
Contraindications for Anti convulsants
Phenytoin is metabolised by the liver with zero-order kinetics (i.e. at a constant rate irrespective of plasma concentrations) for concentrations at or above the therapeutic range. Moreover, the therapeutic index is low, implying that the safety margin between therapeutic and toxic doses is narrow. Phenytoin dosage should therefore be reduced in hepatic impairment. In utero phenytoin exposure is associated with craniofacial abnormalities and reduced IQ (fetal hydantoin syndrome). Women with epilepsy planning pregnancy should discuss treatment with a specialist and take high-dose folic acid before conception (see Valproate).
Carbamazepine (see above also) exposure in utero is associated with neural tube defects, cardiac and urinary tract abnormalities and cleft palate. Prior antiepileptic hypersensitivity syndrome is a contraindication to both carbamazepine and phenytoin, due to potential cross-sensitivity. Carbamazepine should be prescribed with caution in patients with hepatic, renal or cardiac disease, due to increased risk of toxicity.
Sodium valproate
Valproate should be avoided where possible in women of child-bearing age, particularly around the time of conception and in the first trimester of pregnancy. It is the antiepileptic drug associated with the greatest risk of fetal abnormalities, including neural tube defects, craniofacial, cardiac and limb abnormalities and developmental delay. It should be avoided in patients with hepatic impairment and dose reduction is required in patients with severe renal impairment.
Side effects of Anti convulsants
Long-term phenytoin treatment can cause a change in appearance, with skin coarsening, acne, hirsutism and gum hypertrophy. Dose-related neurological effects include cerebellar toxicity (e.g. nystagmus, ataxia and discoordination) and impaired cognition or consciousness. Phenytoin can cause haematological disorders and osteomalacia by inducing folic acid and vitamin D metabolism. Hypersensitivity reactions to phenytoin range from mild skin rash to the rare life-threatening antiepileptic hypersensitivity syndrome (see Carbamazepine). Phenytoin toxicity (due to overdose or injudicious IV infusion) can cause death through cardiovascular collapse and respiratory depression.
Carbamazepine (see above also)
The most common dose-related adverse effects are gastrointestinal upset (e.g. nausea and vomiting) and neurological effects (particularly dizziness and ataxia).
Interactions of Anti convulsants
Phenytoin is an enzyme inducer, so reduces plasma concentrations and efficacy of drugs metabolised by P450 enzymes, e.g. warfarin, and oestrogens and progestogens. Phenytoin is itself metabolised by these enzymes, so its plasma concentrations and adverse effects are increased by cytochrome P450 inhibitors, e.g. amiodarone, diltiazem and fluconazole. Complex interactions can occur with other antiepileptic drugs as most alter drug metabolism. The efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold (e.g. SSRIs, tricyclic antidepressants, antipsychotics, tramadol).
Elimination of Anti convulsants
Phenytoin is an enzyme inducer, so reduces plasma concentrations and efficacy of drugs metabolised by P450 enzymes, e.g. warfarin, and oestrogens and progestogens. Phenytoin is itself metabolised by these enzymes, so its plasma concentrations and adverse effects are increased by cytochrome P450 inhibitors, e.g. amiodarone, diltiazem and fluconazole. Complex interactions can occur with other antiepileptic drugs as most alter drug metabolism. The efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold (e.g. SSRIs, tricyclic antidepressants, antipsychotics, tramadol).
Patient information
Explain that treatment aims to reduce seizure frequency. Warn the patient to look out for signs of severe hypersensitivity, including skin rashes; bruising, bleeding, a high temperature or mouth ulcers (blood toxicity); reduced appetite or abdominal pain (liver toxicity). If any of these occur they should seek urgent medical advice. For women, discuss contraception and pregnancy (see Valproate). Advise patients that they must not drive unless they have been seizure-free for 12 months (or have at least a three-year pattern of seizures while asleep only). They should not drive for 6 months after changing or stopping treatment.
