anti-epilepsy agents class 2

8/6/2019 Anti-Epilepsy Agents CLASS 2

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Anti-epilepsy Agents


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Action Potential


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Synapse Activity


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Basis of Pharmacological RxMost anti-epileptic agents act either by blockade

of depolarisation channels (Na+ and Ca++)

OR

Enhancing the activity of GABA

(neurotransmission inhibition)


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5 Categories of Anti-epileptic Drugs All classifications are based upon chemistry:

Hydantoins

Succinimides

Benzodiazepines

Barbiturates

Miscellaneous


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Hydantoins - Phenytoin Phenytoin (diphenylhydantoin, phenytoin sodium)

blocking of Na+ channels to reduce excitability

blocking of Ca++ channels

Metabolism: Hepatic;

Distribution: Crosses placenta; enters breast milk

Excretion: Urine


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Phenytoin

Indications

Control of grand mal (tonic-clonic) seizures

Prevention and treatment of seizures occurring during or following

neurosurgery Control of status epilepticus (parenteral administration of fosphenytoin)

antiarrhythmic, particularly in digitalis-induced arrhythmias (IV

preparations);


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Contraindications and cautions

sinus bradycardia,

Sinoatrial block,

Stokes-Adams syndrome,

pregnancy ( incidence of birth defects; however, do not discontinue antiepileptictherapy in pregnant women who are receiving such therapy to prevent major

seizures; this is likely to precipitate status epilepticus, with attendant

hypoxia and risk to both mother and fetus),

lactation.

Use cautiously with hypotension, severe myocardial insufficiency, diabetes

mellitus, hyperglycemia.


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Available forms

Phenytoin is usually given twice a day: once in the morning and once in the

evening. Ideally, these times are 1012 hours apart.

Chewable tablets--50 mg;

oral suspension--125mg/5 mL;

capsules--30, 100 mg;

ER capsules--200, 300 mg;

injection--50 mg/mL (fosphenytion)


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Adverse effects:

Nausea & Vomiting

Impaired brainstem & cerebellar function (dizziness,tremor, nervousness, blurred vision)

Chronic congestive tissue defects (gum hyperplasia)

Folic acid (megaloblastic anaemia)

and Osteomalacia (due to Vit. D deficiency resulting

from increased metabolism)


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Sodium Valproate Use in all forms of epilepsy, as it suppresses

the initial seizure discharge and its spread.

Clinical actions are:

Antagonism of Na+ and Ca++ channels

Potentiation of GABA

Can be fast acting due to Na+ MoA, althoughthe full Rx effect usually takes weeks.


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Adverse effects: GI upset (Nausea, vomiting, anorexia, abdominal pain and diarrhoea)

Weight gain (appetite stimulation)

Transient hair loss Tremor

Thrombocyptopenia (platelets)

Severe hepatotoxicity (liver damage)


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Carbamazepine (Tegretol) Used in most epilepsy types.

MoA not fully understood but believed to be

related to: Antagonist action of Na+ channels to inhibit

repetitive neuronal firing

Decreasing the production (or release) of

glutamate (excitatory chemical)


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Pharmacokinetics:

Slow and incomplete absorption

Metabolised in the liver creates an expoxide metabolitethat can have a weak therapeutic effect

Relatively long half-life (1-2 days)

Potency decreases overtime therefore need to increase

dose to ensure adequate control of seizures

Plasma and salivary concentrations correlate well to

clinical effectiveness


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Adverse effects:

Nausea & vomiting (especially early Rx),

constipation, diarrhoea and anorexia Skin irritation

CNS toxcity dizzy, drowsy, confusion

Bone marrow depression (rare)

Drug-drug reactions (contraception, warfarin)


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Succinimides Ethosuximide Use for pts with Absence seizures

Acts by antagonising Ca++ channels in the

neurons => prevention of synchronised

neuronal firing => raising Action Potential

threshold


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Adverse effects:

Nausea, vomiting and anorexia

Cerebellar disturbance (drowsiness, dizziness,photophobia, headache, depression)

Contraindications:pregnancy (teratogencity)


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Bensodiazepines Clonazepam,

Diazepam Act by potentiating the actions of GABA

causing neurotransmission inhibition

(primarily in the CNS)

Can be used to induce sleep (high dose),

anticonvulsant therapy and reduction inmuscle tone.


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Pharmacokinetics:

Well absorbed from the gut

Lipid soluble to ensure ready prentration of theblood brain barrier

Metabolised in the liver to create active agents

(prolonged therapeutic action)

Slow elimination from body


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Adverse effects:

Drowsiness, lightheadness, confusion

Impaired memory

Muscle weakness

Tolerance (very common)

Dependence withdrawal effects could last up to3 weeks


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Barbiturates Phenobarbital Used for tonic-clonic seziures.

Act by increasing the duration of Cl- ion channelopening by activating neuronal GABAa receptors

Causing hyperpolarisation of the AP, making it less

likely to fire again

Essentially, acts like GABA and can even potentiate

the effects of GABA when present.


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Pharmacokinetics:

Almost complete absorption

Elimination is by heptic and renal (25% excretedunchanged)

Biotransformed in the liver into 2 activemetabolites

Plasma concentrations relate poorly to seizurecontrol, use only for monitoring of patientcompliance.


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Adverse effects: CNS effects (sedation and fatigue)

Restlessness/Hyperactivity

Folate deficiency Tolerance

Dependence with physical withdrawal reactions

Adverse drug-drug reactions (contraception and warfarin).

Contraindications: Do not use with patients with respiratorydepression, children or elderly.

NOTE: low therapeutic index means more toxic andoverdose can have serious consequences


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Thank you !!!!!!

AnyQuestions?


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Textbook References Lippincott Williams & Wilkins

Katzung : PHARMACOLOGY

anti-epilepsy agents class 2

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