Treatment for epilepsy
Epilepsy is a problem of the CORTEX
Focal Seizures
- Carbamazepine or lamotrigine
- Second line: levetiracetam, oxcarbazepine or sodium valproate
- Lamotrigine and levetiracetam is good for women of child-bearing age and also in the elderly
- Lamotrigine is favoured in the elderly with depression as a comorbidity
Generalised Tonic-Clonic Seizures
- Sodium valproate in non-childbearing aged women (due to teratogenic effects)
- Second line: lamotrigine, carbamazepine, levetiracetam
Absence Seizures* (Petit mal)
- Sodium valproate or ethosuximide
- Sodium valproate particularly effective if co-existent tonic-clonic seizures in primary generalised epilepsy
Myoclonic Seizures** (eg: juvenile myoclonic epilepsy)
- Sodium valproate
- Second line: clonazepam, lamotrigine
Genetics associated with carbamazepine
HLAB1502
- Strong association between HLAb1502 and SJS after carbamazepine
- Han chinese, thai, indian
HLAA3101 and carbamazepine
- Hypersensitivity reaction in europeans
- Maculopapular exanthema and SJS=TEN
- If a rash is developed with carbamazepine, can increase risk of developing rash in other medications, eg: phentyoin, lamotrigine,
- Lamotrigine - rash is dose dependent
What is important in testing drug levels?
- Free drug is what matters
- What affects drug concentration include
Hypoalbuminaemia states
Endogenous displacing agents such as uremia
Drugs that compete for serum protein binding sites
Note: carbamazepine autoinduces itself, will overestimate drug level it taken too early.
What is the most effective anti-epileptic dual therapy?
Lamotrigine (NMDA inhibitor, sodium channel blocker)
Valproate (potentiation of GABA activity, calcium channel blocker)
When using dual therapy,
- Combinations of AEDs with different mechanisms are more effective
- Combinations of Na+ channel blockers are not effective
What are the effects of oestrogen and progesterone for epilepsy?
- Estrogen promotes neuroexcitatory properties
- Progesterone promotes neuroinhibitory properties
Anti-epileptics to avoid during pregnancy
- Valproate: neural tube defects, facial clefts, hypospadias, lead to lower IQ in children
- Phenytoin: hypospadias, cardiac defects
Phenytoin induces vitamin K metabolism, which can cause a relative vitamin K deficiency, creating the potential for hemorrhagic disease of the newborn. The most common sites of bleeding are the umbilicus, mucous membranes, gastrointestinal tract, and venepunctures. - Carbamazepine - neural tube defects
lamotrigine, phenobarbital contribute to the risk of cardiac defects
Sodium valproate, phenytoin, phenobarbital - reduce cognitive outcomes of children
Anti-epileptics that are tolerated in pregnancy
Lamotrigine
Carbamazepine (but should avoid as teratogenic)
Keppra
Note: polytherapy is much more worse than monotherapy - try to wean patients to monotherapy prior to pregnancy
- During pregnancy, lamotrigine (increase 200-300%) and levetiracetam undergo increased clearance and require increased dosing
- Carbamazepine remains stable
RF for Sudden Unexpected Death in Epilepsy
GTCS > 2 years
Nocturnal seizures
Treatment resistant seizures
Long duration of epilepsy and early age of onset
Dravet syndrome - sodium channel gene mutation
Tends to occur at night (80% unwitnessed)
What neuro transmitters are involved in epilepsy?
- Excitatory neurotransmitter: glutamate
- Inhibitory neurotransmitter: GABA
Anticonvulsants act to either reduce excitatory signals or amplify inhibitory signals.
Carbamazepine
- Indication
- MOA
- Side effects
Indication:
- First line for focal and generalised tonic/clonic seizures
- Trigeminal neuralgia
MOA: Sodium channel blocker
SE:
- Strong association between HLAb1502 and SJS after carbamazepine
- Diplopia
- Aplastic anaemia/agranulocytosis
- Hyponatremia
- Hepatotoxicity
what are the strong inducers of cytochrome p450?
Rifampicin and carbamazepine are some of the strongest inducers of cytochrome P450 enzymes and can thus interact with many drugs.
Which drugs are eliminated by zero order kinetics?
Zero order kinetics: elimination rate (green line) is independent of plasma drug concentration and, therefore, remains constant, resulting in a decreasing t½ (half-life) with decreasing drug concentration.
It takes zero PHEN-tAS-E (fantasy) to remember the drugs that are eliminated by zero-order kinetics: PHENytoin, ASpirin, Ethanol, Theophylline
Levetiracetam/Brivaracetam
- MOA
- Side effects
MOA:
- Inhibits presynaptic calcium channels reducing neurotransmitter release an and act as a neuromodulator
Modulation of SV2A mediated neurotransmitter release
SE:
- Sedation
- Dizziness
- Psychiatric symptoms: psychosis, depression
Which anti-epileptic agents are broad spectrum vs narrow spectrum
Broad Spectrum: lamotrigine, levetiracetam, topiramate, valproate - can treat generalised and focal seizures
Narrow Spectrum: carbamazepine, gabapentin, phenytoin
Phenytoin
MOA
SE
MOA:
Sodium channel blocker
SE (PHENYTOIN)
- cytochrome p450 interaction
- hirsutism
- enlarged gums (gingival hyperplasia)
- Nystagmus, ataxia, diplopia (dose related)
- Yellow browning of skin
- Teratogenic
- Osteomalacia
- Interacts with folate - megaloblastic anaemia (secondary to altered folate metabolism)
- Neuropathy
Intravenous phenytoin can cause hypotension and bradyarrhythmias. Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels. Phenytoin is also a class IB antiarrhythmic drugs which blocks sodium channels in the heart resulting in shortening of repolarization.
Valproate
MOA
SE
MOA: potentiation of GABA activity, inactivate sodium channels
SE
- Teratogenic
- Tremor
- Alopecia
- Pancreatitis/hepatic failure
- sedation
- Weight gain
- Hypercholesteroema
- PCOS
Ethosuximide
Indication
MOA
SE
Indication: first line for absence seizures
MOA: inhibition of voltage gated calcium channels
SE: It SUCKS that STEVEN'S FATher has given everyone a HEADACHE with his ABsurd ALLEGorizations - Steven johnsons syndrome - Fatigue - Headache - Abdominal upset - Allergies, eg: urticaria
MOA and important side effect of vigabatrin
GABA potentiator
SE: irreversible vision loss
Topiramate
Indication
MOA
SE
Indication
- Focal and generalised tonic clonic seizure
- Migraine prophylaxis
- Idiopathic intracranial hypertension
MOA: sodium channel blocker, glutamate (NMDA) blocker, AMPA blocker (antagonism of glutamate)
SE
- Speech impairment
- Weight loss
- Cognitive impairment
- Sedation
- Kidney stones
- rare but important: acute myopia and secondary angle-closure glaucoma
It leaves you SPEECHless how LIGHTLY the COG RAILWAY travels through SEDiments and STONES to the TOP
Topiramate commonly causes nausea, lethargy, diarrhoea, mood change and weight loss. It is importantly associated with risk of glaucoma, renal stones, metabolic acidosis and reduced sweating. It should be avoided in acute porphyrias.
Topiramate: risk of oral cleft, low birth weight, hypospadias
Examples of
- Sodium channel blockers
- Calcium channel blockers
- Glutamate (NMDA) blockers
- Potentiation of GABA activity
- Modulation of SV21 mediated neurotransmitter release
- Sodium channel blockers: Carbamazepine Lamotrigine Phenytoin Topiramate
- Calcium channel blockers
Ethosuximide
Lamotrigine - Glutamate (NMDA) blockers
Lamotrigine
Topiramate - Potentiation of GABA activity
Barbiturates
Topiramate
Valproate - Modulation of SV21 mediated neurotransmitter release: levetiracetam
What the most common types of focal epilepsy?
Most common is temporal lobe epilepsy and then frontal lobe epilepsy.
Lamotrigine
MOA
SE
MOA: Glutamate (GABA) inhibitor, sodium and calcium channel blocker
mall prescribed in women of childbearing age, good option for older patients or those who have depression or other mood disorders.
SE
- Insomnia
- Headache, acne, double vision
- SJS
Effect of estrogen on lamotrigine
Estrogen containing contraceptive can reduce lamotrigine levels and lead to more seizures if lamotrigine dosage is not increased.
Epilepsy Syndromes
- Genetic (Idiopathic) Generalised Epilepsies
- Childhood and Juvenile Absence Epilepsies
- Juvenile Myoclonic Epilepsy - Focal Epilepsy
- Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
- Juvenile Absence Epilepsy
- Seizure onset at 8-12yo in children with normal development
- Occasional GTCS
- Seizures cease in late teens in over 80% of pts
- Tx: valproate
- good prognosis - 90-95% become seizure free in adolescence - Juvenile Myoclonic Epilepsy
- Seizure onset at 8-12yo in children with normal development
- Myoclonus in early waking states
- Worse with sleep deprivation + Alcohol
- EEG: 3HZ SPIKE/POLYSPIKE WAVE DISCHARGE - increased with hyperventilation and photic stimulation
- Tx: Valproate (1st line), Lamotrigine (child bearing) - Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis
- RF prolonged febrile convulsions and CNS infections (eg: meningitis)
- Typical auras, focal seizures with impaired awareness
- Dreamy states with perceived unreality or deja vu or jamis vu
- Can evolve to bilateral tonic clonic seizures
- Unilateral or rarely bilaterally hippocampal atrophy and T2 signal increase
- Medically refractory in 60-90% patients –> surgery
