Epilepsy

Epilepsy

 Epilepsy: as recurrent episodes of abnormal cerebral neuronal

discharge; the resulting seizures are usually clinically obvious.

 Aetiology is wide: heredity, infection, trauma, infarction and

neoplasia.

 Seizures result in PAROXYSMAL neurological abnormalities.

 The clinical manifestations of seizures are related to the parts of

the brain that are involved.



Management



 The management of epilepsy involves:

 Supportive care during a seizure:

 Termination of seizures.

 Prophylaxis of seizures

 the choice of drug should be compatible with the likely

seizure type (see below)

 only one drug should be used at a time if possible

 the drug should be started at low dose, and doses should

be tailored to seizure frequency and adverse effects.



Management in pregnancy:

 Advising pregnant women with epilepsy can be difficult.

 Given the risk to both mother and fetus of discontinuation of

anti-epileptic drugs, most physicians advise their continuation.

 Several anti-epileptic drugs (inc. valproate and carbamazepine)

are associated with a substantially increased risk of congenital

abnormalities, and this must be discussed with the patient.

 Importance of folate supplements.



Common seizure types

Generalised seizure



 Absence (petit mal).

 Abrupt onset and cessation, with impaired consciousness, but

with normal posture often retained.

 EEG shows a typical ‘spike and wave’ pattern.

 First choice drugs: valproate, ethosuximide.

 Tonic/clonic (grand mal) this often starts as a focal seizure.

 May be preceded by an ‘aura’.

 Consciousness is impaired and patient usually falls to the

floor.

 Brief phase of muscle contraction (tonic phase) followed by

irregular muscle clonus (clonic phase) and followed by sleep.

Incontinence may occur.

 First choice drugs: carbamazepine, lamotrigine, valproate.

 Myoclonic.

 Consciousness is usually intact; jerking of single or multiple

muscle groups.

 First choice drugs: valproate, clonazepam.

 Atonic.

 Sudden loss of limb tone causes the patient to fall;

consciousness is usually intact.

 First choice drugs: valproate, clonazepam.



Partial seizures

 Simple partial seizures.

 Features are determined by the anatomical site (e.g. motor

seizures (Jacksonian)).

 Consciousness is usually unimpaired.

 First choice drugs: carbamazepine, lamotrigine, valproate.

 Complex partial seizures (temporal lobe epilepsy).

 Consciousness is impaired; seizure may involve complex,

often repetitive, actions; may be confused with psychosis.

 First choice drugs: carbamazepine, lamotrigine, valproate.

Carbamazepine

Clinical pharmacokinetics

 Absorption of carbamazepine is slowed by giving it with food.

 Carbamazepine is cleared largely by hepatic metabolism, and

one of its metabolites possesses anticonvulsant activity.

 The half-life is about 36 hours after the first dose but, because it

is a potent inducer of hepatic enzymes, with chronic dosing the

half-life can fall by up to 50%.



Therapeutic uses

 Partial seizures

 Tonic/clonic seizures: carbamazepine is not effective against

other generalised seizure types

 Chronic pain: including trigeminal neuralgia.



Adverse effects

 Acute, concentration-dependent CNS effects:

— diplopia

— nystagmus

— ataxia

— nausea and vomiting

— sedation (usually only at very high concentration)

 Other dose-related adverse effects include hyponatraemia

leading to water intoxication.

 Idiosyncratic responses to carbamazepine are uncommon.

 Carbamazepine carries a risk of causing spina bifida.



Contraindications

 Hypersensitivity

 Porphyria

Drug interactions

 Carbamazepine is a potent inducer of liver enzymes.

 Carbamazepine reduces the plasma levels of:

— oral contraceptive steroids

— warfarin

— phenytoin

 Carbamazepine levels have been reported to rise when it is

combined with:

— dextropropoxyphene

— sodium valproate.







Sodium valproate

Clinical pharmacokinetics

 Valproate is rapidly and extensively absorbed when given

orally.

 It is cleared by hepatic metabolism with a half-life of 10–20

hours.

 Therapeutic drug monitoring is not useful.



Therapeutic uses

 Absence seizures

 Myoclonic seizures

 Tonic/clonic seizures

 Partial seizures.



Adverse effects

 Symptomatic:

— indigestion, nausea and reflux

— weight gain

— alopecia

 Idiosyncratic:

— hepatotoxicity, particularly in children

— thrombocytopenia

 Teratogenicity:

— increased risk of spina bifida RISK IS HIGHER THAN

WITH OTHER COMMONLY USED DRUGS



Contraindications

 Liver disease.



Drug interactions

 Valproate can inhibit the metabolism of other anticonvulsants.

 Can also displace phenytoin from plasma protein binding.







Lamotrigine.

Clinical pharmacokinetics

 Actions are terminated by liver metabolism.

 Therapeutic drug monitoring is not useful.



Therapeutic uses

 Can be used as a monotherapy, or in combination.

 Tonic/clonic seizures

 Partial seizures.



Adverse effects

 Symptomatic:

— indigestion, nausea and reflux

— weight gain

— alopecia

 Idiosyncratic:

— serious rashes, particularly in children

— influenza-like syndromes

— thrombocytopenia

— hepatic dysfunction



Contraindications

 Liver disease.



Drug interactions

 Valproate can increase lamotrigine concentrations.







Phenytoin

Clinical pharmacokinetics

 well absorbed after oral administration, but this is very

dependent on formulation.

 extensively bound to plasma proteins.

 Phenytoin is cleared mainly by hepatic metabolism

 but this process can be saturated at concentrations readily

reached in clinical practice.

 The relevance of such zero-order pharmacokinetics is seen as

drug doses are increased: at lower doses, plasma phenytoin

concentration correlates well with dose, but at higher doses

small dose increments can produce large increases in plasma

concentration, leading to toxicity.

 The ‘half-life’ of phenytoin, at therapeutic concentrations, is

around 20 hours but is prolonged at high concentration.

 Phenytoin clearance is reduced in patients with liver disease.

 Because phenytoin’s therapeutic range is relatively narrow (40–

80 mmol/l), and its dose–response relationship is unpredictable,

therapeutic drug monitoring is essential.



Therapeutic uses

 Partial seizures

 Tonic/clonic seizures: phenytoin is not usually effective against

other generalised seizure types

 Status epilepticus: i.v. phenytoin is a second-choice drug after

diazepam; it is given as a slow injection while monitoring the

ECG and vital signs.



Adverse effects

 Acute, concentration-dependent effects:

— diplopia

— nystagmus

— ataxia

— nausea and vomiting

— sedation (usually only at very high concentration)

 Chronic effects:

— gingival hyperplasia, hirsutism and coarsening of facial

features (these are very common)

— peripheral neuropathy

— enhanced vitamin D metabolism causing osteomalacia

— folate malabsorption causing macrocytosis

 Idiosyncratic effects:

— fever

— rashes

— lymphadenopathy

 Teratogenic effects:

— associated with increased risk of congenital abnormalities

including cleft palate/lip and congenital heart disease.



Contraindications

 Porphyria.



Drug interactions

 Phenytoin enhances the elimination of:

— warfarin

— carbamazepine

— oral contraceptive steroids

— theophyllines

 Plasma concentrations of phenytoin may be increased by:

— sulphonamides

— some sulphonylureas

— ketoconazole

— cimetidine

 Plasma concentrations of phenytoin may be reduced by:

— carbamazepine

— antacids.







Phenobarbitone

Clinical pharmacokinetics

 Phenobarbitone may be given orally, i.m. or by slow i.v.

 The therapeutic range is 40–120 mmol/l, in the short term;

patients on long-term treatment develop tolerance.

 Most of a dose of phenobarbitone is excreted as

pharmacologically inactive metabolites, but about 40% is

excreted unchanged.



Therapeutic uses

 This is not a first-choice drug for epilepsy since phenobarbitone

is sedative; but very cheap.

 Indications remain:

• Partial seizures

• Tonic/clonic seizures



Adverse effects

 Sedation

 Respiratory depression.

Contraindications

 Porphyria.



Drug interactions

 Phenobarbitone is an inducer of liver enzymes.



Other antiepileptics



Vigabatrin.

 used in combination with other antiepileptic drugs as

supplementary therapy for refractory partial seizures —

particularly complex partial seizures.

 The main adverse effect is sedation.

Topiramate

 used alone, or in combination with other drugs, for refractory

partial and tonic-clonic seizures.

 The main adverse effect is mood change.





Anti Depressants

Depression is a disorder of mood associated with an alteration in

behaviour, energy, appetite, sleep and weight. Prevalence up to

20%.





Older

 Tricyclic antidepressants

 (Monoamine oxidase inhibitors)

 Lithium



Newer

 Selective Serotonin reuptake inhibitors (SSRI)

 Serotonin and Noradrenaline reuptake inhibitors (SNRI)

Tricyclic Antidepressants (TCA)

Pharmacokinetics:

 rapid absorption

 very lipid soluble, crosses the blood brain barrier

 binds to extravascular tissues

 large vol. of distribution hence no dialysis in overdose



Uses:

 depression – no improvement should be expected <2 weeks

 anxiety

 chronic pain

 nocturnal enuresis in children



Adverse Effects:

 Antimuscarinic i.e. atropine like

 Antiadrenergic e.g. postural hypotension, tachycardia

 Antihistamine e.g. sedation

 seizures

 idiosyncratic reaction- hepatotoxicity, agranulocytosis



Acute Toxicity

 CNS: delirium, convulsions, coma

 CVS: arrhythmia’s and death





Lithium

 used for bipolar illness

 mechanism of action is unknown

pharmacokinetics;

 well absorbed and widely distributed

 narrow therapeutic index

 eliminated in the urine.



Adverse effects;



At therapeutic levels

polyuria, polydypsia, dry mouth

reduction in urinary conc. Ability

weight gain

tremor

hypothyroidism and goitre

hypercalcaemia



At toxic levels

neurotoxicity; tremor, ataxia, dysarthria,

confusion, stupor, coma, death

cardiovascular

renal





Drug Interactions;

Diuretics -Na depletion reduces lithium excretion

NSAID’S - facilitate PCT reabsorption



Treatment of toxicity;

stop lithium and interacting drugs

rehydrate with normal saline

haemodialysis



Newer Antidepressants

SSRI; paroxetine, fluoxetine, citalopram

SNRI; venlafaxine



 All newer antidepressants are synthetic

 They are no more effective than traditional antidepressants

 Different side effect profile i.e. less effect on cardiovascular

function and minimal psychomotor impairment

 Perhaps safer in OD

 Suicide risk of SSRI in adolescents





Pharmacokinetics;

 small molecules with high lipid solubility

 high plasma protein binding

 variable half life determines frequency of dosing e.g.

fluoxetine t1/2 40hrs and venlafaxine t1/2 4hrs