Antiepileptics

Class

Drug

Specific mechanism

Pharmacokinetics

Side effects

Indicated

Dose

Benzodiazepam

Diazepam

Potentiates GABAa receptor
Inc. GABAA action → inc. frequency of Cl– channel opening

- Most have long half-lives and active metabolites (exceptions [ATOM]: Alprazolam, Triazolam, Oxazepam, and Midazolam are short acting → higher addictive potential)
- Lorazepam, Oxazepam, and Temazepam can be used for those with liver disease who drink a LOT due to minimal first-pass metabolism
- Treat overdose with flumazenil (competitive antagonist at GABA benzodiazepine receptor).

- Dependence, additive CNS depression effects with alcohol and barbiturates (all bind the GABAA receptor).
- Less risk of respiratory depression and coma than with barbiturates.
- Can precipitate seizures by causing acute benzodiazepine withdrawal.
- Anxiety, panic disorder, spasticity, eclampsia, medically supervised withdrawal (eg, alcohol/DTs;
long-acting chlordiazepoxide and diazepam are preferred), night terrors, sleepwalking, general anaesthetic (amnesia, muscle relaxation), hypnotic (insomnia).

Status epilepticus (lorazepam, diazepam, midazolam)

Epilepsy 2-10 mg BD or QDS
Status 10MG (PR) or IV

Clonazepam

Lennox-Gastaut, akinetic, myoclonic

lorazepam

Status

Status 2mg IV/24hrs then another 2mg if not improving

Barbiturates

Phenobarbital

Inc. GABAA action → inc. duration of Cl− channel opening

- CYP450 induction
- Overdose treatment is supportive (assist respiration and maintain BP).
- Contraindicated in porphyria

Respiratory and cardiovascular depression (can be fatal); CNS depression (can be exacerbated by alcohol use); dependence;

Status, GTC, partial Sz, febrile Sz, neonatal Sz

Status 10 mg/kg (max 1 g).

Pentobarbital

GABA analogues

Tiagabine

Inc. GABA by inhibiting reuptake

Adj – partial Sz

Vigabatrin

Irreversible GABA transaminase inhibitor

Visual field loss with maintained central field (can be asymptomatic for long time)
• That means the visual field loss can progress for some time before it is noticed. Symptomatic patients have complained of blurred vision, oscillopsia, tunnel vision, and difficulty in navigation.
• The prevalence of visual field loss is generally estimated to be 30-40%

Gabapentin

Primarily inhibits high-voltage activated Ca²⁺ channels;

Adj – partial Sz

300 mg OD slow increase (Max 3600mg/day divided dose)

Ethosuximide

Blocks thalamic T-type Ca²⁺ channels.
Thalamocortical neurons are hypothesized to be generators of the classic 3 Hz spike-and-wave discharges seen with absence seizures and rely heavily on low threshold T-type calcium channels to do so. Ethosuximide can lower the threshold of T-type calcium currents and disrupt the oscillatory activity of thalamocortical circuitry by blocking T-type calcium channels

Sedation, dizziness, vomiting
Gastrointestinal distress.

- 1st line absence seizures
- If pt cannot tolerate ethosuximide
- If pt not well controlled on Ethosuximide.
- If the absence seizures are associated with generalized tonic-clonic seizures

500mg BD (Max 2g/day)

Carbamazepine

Blocks Na⁺ channels

- Oral absorption is erratic, and smaller, more frequent doses are preferred.
- Oral suspension is absorbed more readily but cannot be given with other liquid medicines
- Bioavailability Oral ≈ 90%; IV ≈ 95%
- T1/2: Acute: 20-55hrs Chronic: 20hrs adults, 8 child
- Tpeak: 4-24 hrs
- Tss: 10 days
- TD/C: 4 wks
- Therapeutic range: 6-12mcg/ml
- Toxicity
- CYP450 induction

- Drowsiness and GI upset: minimized by slow dose escalation
- Relative leukopenia in many: usually does not require discontinuing drug
- Transient diplopia
- Ataxia
- Less effect on cognitive function than PHT
- Haematological toxicity: (Rare)
◦ Agranulocytosis & aplastic anaemia
◦ Check FBC before starting
◦ Check 1/52 for 3 months → 1/12 for 3 yrs
◦ Stop if
▪ WBC< 4K,
▪ RBC< 3 × 106,
▪ Hct < 32%,
▪ Platelets < 100K,
▪ Reticulocytes < 0.3%,
▪ Fe > 150 mcg%
- SJS/TEN
- DRESS
- SIADH
- Hepatitis (occasionally fatal)

- Partial seizures with or without secondary generalization.
- Trigeminal neuralgia.
- An IV form for use in e.g. status epilepticus is in development.

100–200 mg OD or BD (Max 1600–2000g/day)

Oxcarbazepine

Very similar efficacy profile to carbamazepine

Difference vs carbamazepine
1. There is no autoinduction (C-P450 is not involved in metabolism) and therefore minimal drug-drug interactions
2. No blood testing is required since
◦ No liver toxicity
◦ No hematologic toxicity
◦ No need to check drug levels
3. Dosing is BID
4. Kinetics are linear
5. More expensive

300mg PO BD

Hydantoins

Phenytoin (PHT)

Blocks Na channels; 0 order kinetics

- [Low]: 1st order (elimination proportional to concentration)
- [Therapeutic]: Zero Order (elimination at a constant rate)
- 90% of total drug is protein bound.
- See image
- Bioavailability Oral ≈ 90%; IV ≈ 95%
- T1/2: 24hrs
- Tpeak: 3 hrs
- Tss: 7-21 days
- TD/C: 4 wks
- Therapeutic range: 10-20mcg/ml (1-2mcg/ml of unbound PHT)
- CYP450 induction
- Toxicity
◦ Nystagmus (may also occur at therapeutic levels),
◦ Diplopia
◦ Ataxia
◦ Asterixis
◦ Slurred speech
◦ Confusion
◦ CNS depression
- Interactions
◦ Fluoxetine: inc. Phenytoin levels
◦ PHT impairs the levels of corticosteroids, warfarin, digoxin, doxycycline, oestrogen, furosemide, oral contraceptive, quinidine, rifampicin, theophylline, vit D

- Interfere with platelet f(x) → inc. Bleed
- Dec. Cognitive function
- SLE like syndrome
- Megaloblastic anaemia
- Cerebellar degeneration
- Gingival hypertrophy
- SJS/TEN
- DRESS
- Osteomalacia and rickets-PHT antagonizes vitamin D
- Hypersensitivity occurs <2/12 of start
- Pregnancy
◦ Haemorrhage in newborn
- Foetus
◦ Teratogenic (foetal hydantoin syndrome)
- Elderly (if given IV infusion)
◦ Purple gloves syndrome
◦ Heart block need for cardiac monitoring
- Phenytoin
◦ Advantages
▪ Long experience
▪ Single daily dose regimen for good compliance
▪ No need for a taper-up schedule
▪ Relatively quick disappearance of the medication after stopping
◦ Disadvantages
  ▪ Neurotoxicity (cerebellar ataxia, nystagmus, tremor, dysarthria, drowsiness)
▪ Cosmetic (thickening of skin, acne, undesired hair growth, and gum swelling)

- GTC
- S/C-P
- Occasionally in ABS
- Sz during or after neurosurgery

3-4mg/Day

Fosphenytoin (FPHT)

IV phenytoin

- Converted to PHT by organ and blood phosphatases
- Advantages over PHT
◦ Less venous irritation (due to lower pH of 8.6–9 compared to 12 for phenytoin) resulting in less pain and IV extravasation
◦ FOS is water soluble and therefore may be infused with dextrose or saline. PHT will crystallize when mixed with dextrose
◦ Tolerated well by IM injection (however, the IM route should not be used for status epilepticus)
◦ Does not come combined with propylene glycol (which can cause cardiac arrhythmias and/or hypotension itself)
◦ The maximum administration rate is 3 × as fast

- For short term use (<5days)
- GTC, CP, Sz during or after neurosurgery

Phenyltriazenes

Lamotrigine

Blocks Na
Blocks Glutamate release

- Sedation, dizziness, rash, SJS/TEN, DRESS
- Relatively safer for pregnancy

Adj – partial Sz, adj – Lennox-Gastaut

25mg OD (Max 500mg)

Topiramate

Blocks Na+ channel
Potentiates GABAa receptor

Sedation, dizziness, mood disturbance (eg, depression), weight loss, paresthesia, Kidney stones, angle-closure glaucoma

Adj – partial Sz or primarily GTC

Valproic acid (Depakene®) and divalproex sodium (Depakote®)

Blocks Na⁺ channel
Blocks Ca²⁺ channel
Blocks GABA transaminase

- Severe GI upset and short half–life make valproic acid much less useful than Depakote®
- CYP450 inhibitor

- Interfere with platelet f(x) → inc. bleed
- Most teratogenic antiepileptic drug

Primary GTC. Also useful in ABS with GTC, juvenile myoclonic epilepsy, and partial seizures
Migrane prophylaxis

300mg BD (Max 2500mg/day)

Levetiracetam

May modulate GABA and glutamate release
Blocks Synaptic Vesicle protein 2A (SV2A)

- Sedation, dizziness, fatigue, Neuropsychiatric (eg, psychosis)
- Relatively safer for pregnancy

300mg BD (Max 2500mg/day)
25mg/kg IV (Max 2500mg/day)

MgSO₄
Magnesium sulphate

- Magnesium is excreted in the urine; thus, impaired renal function may affect serum levels.
 
- Narrow therapeutic index: toxicity
◦ Loss of deep tendon reflexes at blood levels of 8-12 mg/dL,
◦ Respiratory depression at concentrations of > 14 mg/dL,
◦ Muscular paralysis and respiratory arrest at levels > 15-17 mg/dL.
◦ Cardiac arrest can occur above 30 mg/dL.
Recommended treatment for toxicity includes calcium gluconate.

- Optimal treatment both to prevent seizures in women with hypertension at the time of admission for delivery (preeclampsia) and to treat seizures in established eclampsia.
- Shown to result in a reduction in recurrent seizures and in maternal morbidity and mortality compared with both diazepam and phenytoin.
In addition, the fetus should be delivered as quickly as possible, using cesarean section if necessary.
- Eclampsia is an example of the posterior leukoencephalopathy syndrome
◦ Was shown to result in a reduction in recurrent seizures and in maternal morbidity and mortality compared with both diazepam and phenytoin.
◦ In addition, the fetus should be delivered as quickly as possible, using caesarean section if necessary.
◦ Eclampsia is an example of the posterior leukoencephalopathy syndrome.

Dose is 4-5 g intravenously, followed by a 1 g/h intravenous infusion.
 
The goal serum concentration is considered to be 4-8 mg/dL (2.0-3.5 mol/L).

ACTH

West syndrome

Mechanism

Clearance / half‑life

Side effects

Voltage‑gated Na channel

Hepatic CYP450, 12–17 h

CYP450 induction, hyponatremia, neurotoxicity, leukopenia, aplastic anemia, Stevens–Johnson syndrome, hepatitis

Voltage‑dependent Na channels; increases GABA; T‑type Ca current

Hepatic, 9–12 h

Weight gain, insulin resistance, thrombocytopenia, hepatotoxicity, teratogenicity, pancreatitis, hyperammonemia

Voltage‑dependent Ca channel; GABA(B) receptor; reduces glutamate

Renal, 4–6 h

Weight gain, sedation

Voltage‑gated Ca channels; glutamate, norepinephrine, substance P modulation

Renal, 6 h

Euphoria, myoclonus, weight gain

Voltage‑gated Na channels; modulated CRMP‑2

13 h

Dizziness, ataxia, blurred vision

T‑type Ca current in thalamus

Hepatic, 30–60 h

Insomnia, pancytopenia, hyperactivity

Binds SV2A and inhibits presynaptic Ca channels

Renal, 6–12 h

Aggression, depression

GABA(A) receptor, NMDAR antagonist, weak carbonic anhydrase inhibitor

Renal, 20 h

Cognitive impairment, weight loss, mood disturbance, somnolence, metabolic acidosis, renal stones

Voltage‑dependent Na channels; synaptic transmission; Ca‑calmodulin phosphorylation

Hepatic amine oxidase, 7–40 h

Gingival hypertrophy, osteomalacia, teratogenicity, hirsutism, rash/SJS, lymphadenopathy

GABA(A) receptor → increased chloride current

Hepatic, 24–100 h

Lethargy, cognitive impairment, teratogenicity

AMPA receptor antagonist

Hepatic, 100 h

Dizziness, aggression, weight gain

Voltage‑dependent Na and T‑type Ca channels; carbonic anhydrase inhibitor

Hepatic/renal, 60 h

Renal stones, anorexia, rash/SJS, agranulocytosis

Na channel blocker

Liver glucuronidation; renal excretion; 10–60 h

Rash/SJS, angioedema, multiorgan failure/DIC, somnolence, drug interactions, myoclonus

GABA transaminase inhibitor

Renal, 6–8 h

Concentric visual field loss, weight gain, depression