5.3 Anticonvulsants Flashcards
What is the definition of a seizure?
Seizures are the clinical manifestation of epilepsy – these can be manifestations of sensory, motor or autonomic phenomena, memory disturbances and emotion changes
What is the definition of epilepsy?
Epilepsy is a condition defined as a tendency to recurrent, unprovoked seizures.
what is the epileptogenic zone in focal epilepsy?
defined localized cortical region, capable of triggering an epileptic seizure
What is required for the diagnosis of epileps?
The diagnosis of epilepsy requires an evaluation of seizure type (semiology), underlying predispositions, medical and family history and the electroencephalogram and brain imaging findings.
How are seizures classified under the ILAE guidelines
Seizures, the clinical manifestations, are classified into focal, generalized or unknown onset.
Which drugs enhance GABA mediated inhibition?
Benzodiazepines and phenobarbitone
Which drugs inhibits fast excitatory neurotransmission, principally that mediated by the excitatory neurotransmitter glutamate
Gabapentin and topiramate
Which drug inhibits neuronal action potentials by blocking voltage-gated sodium channels?
Phenytoin, carbamazepine, lamotrigine
Which drugs are neuronal calcium channels?
ethosuximide
Which drug has more than one mechanism of action?
topiramate
Which drugs are usually used as first line agents for focal epilepsy?
carbamazepine (CBZ), lamotrigine (LTG) or levetiracetam (LEV)
Which drugs are usually used for generalized epilepsies?
valproic acid (VPA), lamotrigine (LTG), levetiracetam (LEV)
which drugs worsen seizures in generalized epilepsies?
Carbamazepine (CBZ), vigabatrin (VGB) and gabapentin (GPT)
What drugs to use when in doubt what type of epilepsy?
Valproic acid (VPA), topiramate (TPM), lamotrigine (LTG) or levetiracetam (LEV).
Where is therapeutic drug monitoring mainly useful in?
- Phenytoin (but 1/3 still controlled on “sub-therapeutic” levels)
- Polytherapy (complex drug interactions)
- Assessing of compliance
- Suspected toxicity
- Intensive care setting
Phenytoin is a commonly used anti-epileptic drug. It undergoes hepatic metabolism and displays saturable kinetics. It is highly protein bound, hence free levels of phenytoin need to be monitored or calculated in low albumin states.
- Hepatic metabolism: oxidation (______________), followed by hydroxylation then conjugation and renal excretion of non-active metabolites
- Large inter-individual variation in metabolism
- ___________ kinetics, that is concentration dependent. ie., non-linear kinetics (rising quickly after point of enzyme saturation)
- Dosage: Start low (In UK, usual adult dose is 100-200mg daily, with increments of 50mg every 2/52 to 300mg daily, then 25mg increment. In Singapore usually started at _____________mg once daily, to about ______________ maintenance dose)
- If urgent, can load IV (20mg/kg at a rate of less than 50mg/min). Requires cardiac monitoring
- Highly (70-90%) protein bound so free PHT levels helpful in some circumstances (displacement by some drugs, low albumin states)
- P450 enzyme inducer - hence large number of important D/Is
- Phenytoin is a p450 enzyme inducer (CYP2C9 and CYP2C19) and hence may lower drug levels of other drugs such as oral contraceptive pills.
CYP2C9 >2C19;
Saturable;
230 – 400;
5mg/kg/day ;
Indication for PHT?
Partial epilepsy and status epilepticus
Mechanism of PHT?
Blockade of v-gated Na channels
Elimination half life of PHT?
Mean 20 hours (once or twice daily dosing)
What are possible allergic reactions to PHT?
rash, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, vasculitis, fever, hepatitis
What are dose related effects of PHT?
Ataxia, sedation,
What are chronic side effects of PHT?
gingival hypertrophy, folate deficiency, megaloblastic anaemia,vit K deficiency, depression, hirsutism, peripheral neuropathy, hypocalcaemic and osteomalacia/osteoporosis
Why drug interaction does amiodarone and Isoniazide have with PHT?
Potent inhibitors of PHT metabolism, with increased PHT levels
Why drug interaction does asparin has with PHT?
displaces PHT from protein binding - only a problem when phenytoin is near saturation
Why drug interaction does valproate has with PHT?
displaces PHT from protein binding and also inhibits PHT metabolism. A problem if PHT levels are near saturation, leading to PHT toxicity despite total PHT levels (measuring free PHT levels with this drug combination would be more accurate). Avoid this combination where possible.
Why drug interaction does warfarin has with PHT?
Induction of CYP450 system so concentration of warfarin decreases. Monitor INRs closely after addition of PHT or if there is any change in PHT dose
Which drugs have its levels lowered when interacting with PHT?
AEDs (e.g., lamotrigine), corticosteroids, cyclosporin, eostradiol
What are the indications of carbamazepine?
Partial and secondary generalized seizures
What are the mechanisms of action for carbamazepine?
Blockade of v-gated Na channels
What is the half life for carbamazepine?
5-26 hours (x3 daily dosing, unless SR preparations)
What are the hypersensitivity reactions for carbamazepine?
rash, hepatitis, nephritis
What are dose related side effects for CBZ?
Ataxia, dizziness, sedation, diplopia
What are chronic side effects of CBZ?
Vit K deficiency, depression, impotence, osteomalacia, hyponatraemia, osteoporosis and SIADH
Which drugs induce CBZ metabolism by reducing CBZ levels?
PHT, PB
How does VPA cause 4 fold increase in active metabolite of CBZ (CBZ- epoxide) levels?
inhibition of epoxide hydrolase
What are the drugs can increase CBZ levels?
LTG; macrolide antibiotics (e.g. erythromycin), Ca2+ channel blockers (diltiazem/verapamil) , Fluoxetine
What are the indications of Valproate?
Partial or generalized epilepsy - wide spectrum
What is the elimination half life of Valproate?
4-12 hrs (tds dosing)
What are the side effects of VPA?
- Valproic acid side effects include hepatotoxicity, pancreatitis, thrombocytopenia and encephalopathy.
- Common side effects include weight gain, hair loss and tremors. In addition, for women of childbearing age, valproic acid should be avoided in view of high teratogeneicity and risk of poor cognition of the child
Why does VPA increase levels of PHT, PB, LTG and CBZ epoxide?
VPA is a potent inhibitor of both oxidation and glucuronidation
What drugs impair absorption of VPA?
Antacids
Which drugs displace VPA from its albumin binding sites and may result in toxicity?
NSAIDs, aspirin, phenylbutazone
In Singapore, __________ genotype testing is required prior to initiation of carbamazepine in view of the relatively high prevalence of this genotype and its association with Stevens-Johnson syndrome
HLAB1502
carbamazepine-induced hypersensitivity syndrome and found that the presence of the _____________- allele was associated with this among subjects of Northern European ancestry.
HLA-A*3101
