Epilepsy

Definition

Epilepsy is a sudden excessive, rapid depolarization of groups of cerebral neurons which may remain localized or which may spread to cause a generalized seizure

Primary: Unknown / Inherited, life-long Rx

Secondary:

Rx given until underlying cause is removed

Infections

(meningitis, encephalitis)

Brain tumors

Head injury

Metabolic disturbances

(hypocalcemia, hypoglycemia)

Excessive hydration (hyponatremia)

Sudden alcohol withdrawal

CNS stimulant drugs

(caffeine, methylphenidate)

Classification of Seizures

Focal:

• involve only a portion of one hemisphere

• may progress to become bilateral tonic-clonic seizures

• may lose consciousness or awareness

• begins with motor or non-motor activity

Generalized:

• begin locally and progress to include abnormal electrical discharges

• both hemispheres

• convulsive or non-convulsive

• immediate loss of consciousness

• Types:

  • Tonic-Clonic

  • Absence

  • Myoclonic

  • Clonic

  • Tonic

  • Atonic

Unnown

• epileptic spasms

Mechanism of Epilepsy

• ↓ed levels of GABA in brain → ↑ed excitability

• Glutamic acid decarboxylase (GAD):

  • Rate limiting enzyme in GABA synthesis

  • ↓ed GAD activity found in epilepsy

• BDZs & barbiturates act by ↑ing GABA

MECHANISMS OF ANTI-SEIZURE DRUGS

• Modulation of voltage-gated Na, Ca or K channels

• Enhancement of fast GABA-mediated synaptic inhibition

• Modification of synaptic release processes

• Diminution of fast glutamate-mediated excitation

• supress seizures but don’t cure or prevent them

MOA of Phenytoin

• Membrane Stabilizing Effect: Na channel blockade → reduces neuronal excitability and prevents repetitive firing

• Activation of Na / K ATPase → inc outflux of Na and inc influx of K → helps restore RMP + prevents after-discharge

• Delayed outward K Conductance → inc in refractory period of cells (red excitability)

• ↓ed post-tetanic potentiation (PTP)

  • by inhibiting Ca release by reducing noradrenaline lvls

  • helps supress seizure spread at synaptic levels

• ↑ed GABAergic transmission

PK of Phenytoin

• pKa value: 8.06-8.33

• PPC after 3-12 hrs

• PPB up to 90%

• CSF Conc. = unbound fraction in plasma

• exhibits saturable enzyme metabolism

• 1st order kinetics in low dose (t ½ = 24 hrs)

• Zero order kinetics at high dose (t ½ = 60 hrs)

• Enzyme inducer (CYP2C and CYP3A and UGT enzyme)

• Dose: 300-400 mg/d

T/U of Phenytoin

• All types of epilepsy, except absence seizures

• Neuralgias

• Digitalis induced arrhythmias

• status epilepticus

Adverse Effects of Phenytoin

• CVS: myocardial depression on IV admn.

• CNS: drowsiness, sedation, vertigo, diplopia, ataxia, nystagmus, hallucinations

• PNS: peripheral neuropathy, ↓ed reflexes

• GIT: nausea, vomiting, anorexia, discomfort

• Coarsening of facial features in children

• Gingival hyperplasia (gums grow over teeth)

• Hypocalcemia:

  • induces P450 enzyme → ↑ed metabolism of vitamin D → hypocalcemia

  • Rickets in children, Osteomalacia in adults

• Megaloblastic anemia:

  • Interferes with B12 metabolism

  • ↓ed folate levels → impairs DNA synthesis

• Hirsutism on prolonged admn.

• Hypersensitivity: skin rashes, urticaria, blood dyscrasias

• Endocrine: ↓ed ADH secretion, ↓ed insulin release → hyperglycemia

• Depuytren’s contracture − contraction of palmer aponeurosis → ring and little finger flexed (phenytoin alters CT metabolism)

• Fetal Hydantoin syndrome: cleft lip, cleft palate, cardiac abnormalities, mental changes, ↓ed growth of fetus

  • due to in utero exposure to phenytoin

  • causes free radical formation → oxidative stress → DNA damage of fetus

Drug Interactions of Phenytoin

• Enzyme inducer: can ↑ metabolism of other antiseizure drugs

• Can ↑ metabolism of anticoagulants, antibiotics, quinidine, levo-dopa

• Plasma conc. ↑es when admn. with enzyme inhibitors (cimetidine, isoniazid, sulfonamides)

Fosphenytoin

• Water soluble pro-drug

• Lower incidence of purple glove syndrome

• Given I/V in status epilepticus, to avoid cardiac toxicity by phenytoin

Carbamazepine

• Chemistry: Related to TCA, imipramine

• MOA: Similar to phenytoin (blocks Na Ch) → inhibits generation of repetitive AP in epileptic focus and preventing spread

• Active metabolite:

  • Carbamazepine-10,11-epoxide

• induces its own metabolism so lower total carbamazepine blood concentrations at higher doses

• PPC after 6-8 hrs

• CSF conc. = Plasma conc.

• PPB: 70%

• Dose: 800-1200 mg/d

• t ½ : 36 hrs after initial single dose,

  • ↓ed to 8-12 hrs in cont. Rx

• ONLY ANTI-EPILEPTIC USED IN PREGNANCY

• Can be used in all types of epilepsy except absence seizures (it can cause an increase in seizures in absence)

• Preferred for (trigeminal) neuralgias (DOC)

• Rx of Bipolar depression/manic depressive illness

A/Es:

• diplopia, ataxia, unsteadiness,

• drowsiness, blood dyscrasias (more common than phenytoin), GIT upsets

• hyponatremia & water intoxication, hepatic dysfunction, teratogenic potential

• osteomalacia/rickets

• megaloblastic/aplastic anemia

Enzyme inducer of CYP1A2, CYP2C, CYP3A, UGT → can inc clearance of other antiseizure drugs

OXCARBAZEPINE: pro-drug, less potent, less toxic (less blood dyscriasis), less drug interactions

VALPROIC ACID (CARBOXYLIC ACID)

Mechanism of action

• Inhibits GABA degradation enzymes: GABA Transaminase + Succinic semialdehyede dehydrogenase → inc in GABA conc → red epilepsy

• Blocks Na Channels

• Blocks thalamic Ca-T Channels

PK:

• pKa value: 4.56

• BA: > 80%

• PPC: within 2 hrs

• PPB: 90%

• T ½: 9-18 hrs

• Enzyme inhibitor of CYP2C9, UGT and epoxide hydrolase

• divalproex Na → converted to valproate in GIT → improves GIT tolerance of valproic acid

Uses:

• DOC in myoclonic seizures

• Used in primary gen. tonic clonic, absence & mixed type

• Other uses: bipolar disorder & migraine prophylaxis

DIs: ↓es its own & other anti-seizures’ metabolism in low doses

Adverse Effects (imp)

• GIT: nausea, vomiting, heartburn

• CNS: sedation, fine tremor

• Allergic reactions: skin rashes, urticaria,

• Wt gain due to ↑ed appetite

• ↑ed BT due to thrombocytopenia & platelet aggregation inhibition

• Hair loss (reversible)

• Pancreatitis

• Idiosyncratic Hepatotoxicity

  • < 2 yrs : greatest risk

  • can lead to hepatic failure after 2-12 wks of adm

  • incidence is more when combined with other antiepileptics and inducers due to formation of metabolites

  • Rx:

    • careful monitoring of liver functions

    • oral or IV L-carnitine

    • withdrawal of drug

• Spina bifida if given during pregnancy

• avoid use in children under 2 and women

Barbiturates (Phenobarbitone)

• Derivative of barbituric acid

• Low dose: GABAergic effect → drug potentiates GABA → inc GABA lvls

• High dose: GABAmimetic effect → directly stimulate GABA receptors → inc duration of GABA mediated chloride conductance → hyperpolarization

• ↓ed release of glutamate

• Suppresses foci

• ↓es PTP → decreases spread of impulses

• ↑es seizure threshold

• t ½=100 hrs

  A/Es:

• drowsiness, ataxia, nystagmus, vertigo

• Paradoxical Symptoms: children & elderly

  • agitation, excitement, hyperactivity, confusion

  • due to depression of inhibitory interneurons in CNS → net inc in excitatory activity

• Allergic reactions: most important → bullous eruptions

• Enzyme inducer

• Hypoprothrombinemia → hemorrhage in fetus due to antivitK effect (Rx: give vit k during pregnancy)

• Avoided in children

Primidone: 2-desoxyphenobarbitone

• 2 active metabolites: phenobarbitone & phenyl ethyl melonamide (PEMA)

• Uses: primary gen. tonic clonic seizures, focal seizures, status epilepticus (phenobarbitone)

• A/Es: similar to phenobarbitone but less skin reactions

• DI: with phenytoin more conversion to phenobarbitone

ETHOSUXIMIDE

• Blocks hypothalamic Ca T channels → prevent generation of specific wave pattern of absence seizures

• PPC: 3-7 hrs after oral admn.

• Not protein-bound

• CSF conc. = Plasma conc.

• t ½ = 40 hrs

• most commonly used succinimide but replaced by valproate

A/Es:

• gastric distress, nausea, vomiting, transient, lethargy / fatigue,

• headache, dizziness, hiccup & euphoria

• prolonged administration: parkinson’s symptoms, photophobia, allergic reactions

Benzodiazepines

Mainly act on 3 parts of brain: cerebral cortex, thalamus, limbic area

MOA:

Bind BDZ receptor: supra-molecular complex post-synaptically

Activation of BDZ receptor → displaces GABAmodulin (which normally prevents binding of GABA with receptor)→ ↑ed GABA binding → ↑ed frequency of opening of Cl channels → hyperpolarization (reduces firing rate) → inhibitory effect

↑ed K conductance in high doses

↑ed Adenosine (Inhibitory NT)

PK

PPC after 1-4 hrs

PPB: 80-95%

Redistribution (longer DOA)

Uses

reserved for emergency or acute seizure treatment due to tolerance

Clonazepam: absence seizures (2nd line), myoclonic seizures, focal seizures

Diazepam: I/V for status epilepticus

A/Es:

sedation, hypotonia, dysarthria, anorexia /hyperphagia, ↑ed bronchial secretions, status

epilepticus on abrupt withdrawal, floppy baby syndrome in pregnancy

DIs:

potentiate effects of other sedative / hypnotics & alcohols

ACETAZOLAMIDE (DIURETIC)

Produces mild acidosis in brain

Used in absence seizures

SULTHIAME: sulfonamide derivative

Weak antiepileptic effect

Inhibits metabolism of other anti-seizure drugs,

causing their levels to rise

Newer Agents (2nd line)

• Given as 2nd line drugs

• Used in combination with other drugs

• Wide range of spectrum

• Minimal PPB

• No enzyme induction / inhibition

• Less drug interactions

VIGABATRIN

• Irreversible inhibitor of GABA aminotransferase(GABA-T)

• Also inhibits vesicular GABA transporter

• Used in focal seizures & infantile spasms

• Causes irreversible visual field defects (30-50 %)

• T ½ = 6-8 hrs

LAMOTRIGINE

• Blocks Na channels

• Blocks N & P/Q type Ca channels

• ↓es synaptic release of glutamate

• T ½ = 24 hrs

• Rx of bipolar disorder

• Severe rash in children

• Dose: 100-300 mg

GABAPENTIN

• Amino acid-like analog of GABA

• Doesn’t act thru GABA mechanisms

• Binds to α2δ subunit of N-type Ca channels

• ↓es synaptic release of glutamate

• T ½ = 5-8 hrs

• Used in focal seizures & infantile spasms

• Used in neuropathic pains & neuralgias

• A/Es: somnolence, dizziness, ataxia

TOPIRAMATE

• Blocks Na channels

• Blocks L type Ca channels

• Potentiates inhibitory effect of GABA by acting at a site different from BDZ or barbiturate sites

• Depresses neuro-excitatory activation of glutamate receptors by amino acid kainate

• T ½ = 20-30 hrs

• Rx of migraine headaches

• ↑ed incidence of urolithiasis

  • Rx: ↑ed water intake

• Dose: 200-400 mg/d

TIAGABINE

• Inhibits GABA uptake by GAT-1 in forebrain & hippocampus

• ↑es GABA conc. in synapses

• T ½ = 5-8 hrs

• A/Es: depression, dizziness, nervousness

• Dose: 16-56 mg/d

ZONISAMIDE (SULFONAMIDE)

• Blocks Na channels

• Blocks Ca T channels

• T ½ = 1-3 days

• Serious skin rashes

• Dose: 200-400 mg/d

LEVETIRACETAM

• Binds selectively to SV2A, which functions as a +ve effector of synaptic vesicle exocytosis

• Binding to SV2A in the vesicle ↓es release of glutamate

• T ½ = 6-8 hrs

• A/Es: somnolence, asthenia, ataxia, infection (colds) & dizziness

• Dose: 500-1000 mg/d