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Epilepsy

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					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

				
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posted:11/13/2011
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