1. Antiepileptic Drugs Department of Pharmacology NEIGRIHMS, Shillong

2. SOME FAMOUS PEOPLE WHO WERE AFFLICTED

• • ALEXANDER THE GREAT

• • JULIUS CAESAR

• • NAPOLEON

3. What are Epilepsies?

Group of disorders of the CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizure) of loss of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena.

4. What are seizures?

A seizureis a transient alteration of behaviour due to the disordered, synchronous, and rythmic firing of populations of brain neurones. Seizure can be nonepileptic and can be evoked in normal brain

A seizureis a paroxysmal behavioral spell generally caused by an excessive disorderly discharge of cortical nerve cells.

5. What are Epilepsies Clinically?

Epilepsy is a syndrome of two or more unprovoked or recurrent seizureson more than one occasion.

Epilepticseizuresrange from clinically undetectable (electrographicseizure) to convulsions.

6. How many types?

Generalized:

Generalized tonic-Clonic Seizures

Absence Seizure

Atonic Seizures

Myoclonic Seizures

Infantile Spasms

7. Types of seizures contd.

2.Partial (focal) Seizures

• Simple Partial Seizures

• Complex Partial Seizures

8. 1. Generalized seizures

A. Generalized tonic-clonic

GTCS/major epilepsy/grand mal

Commonest of all

Lasts for 1-2 minutes

Aura-cry-unconsciousness-tonic phase-clonic phase

Usually occurs in both the hemispheres

Manifestations are determined by cortical site of seizure occurence

9.

Tonic phase:

- Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation.

EEG:Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials.

Generalized Seizures contd. 10.

Clonic phase:

- Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical.

EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.

Generalized Seizures contd. 11. Generalized Seizures contd. 12. Generalized Seizures contd. 13. Generalized Seizures contd.

B. Absence seizure:

Also called minor epilepsy/petit mal

Usually in Children and lasts for 1-2 minutes

Typical generalized spike-and-wave type discharges at 3 per second (3 Hz)

Momentary loss of consciousness, patient stares at one direction

No motor (muscular component)

No convulsions

Minor muscular twitching restricted to eyelids (eyelid flutter) and face.

No loss of postural control.

14. Generalized Seizures contd.

C. Atonic Seizures:

Unconsciousness with relaxation of all muscles

Patient falls down

Loss of postural tone, with sagging of the head or falling

D. Myoclonic Seizures:

Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG

Momentary contractions of muscles of limbs or whole body

No loss of postural control

15. Generalized Seizures contd.

E. Infantile spasm:

An epileptic syndrome.

Characterized by brief recurrent myoclonic jerks muscle spasm) of the body with sudden flexion or extension of the body and limbs.

Progressive mental deterioration

16. 2. Partial (focal) Seizures

A. Simple partial seizure

Lasts for 20 60 seconds

Confined to a group of muscles or localized sensory disturbances depending on area of cortex involved

For example if motor cortex of the left thumb then jerking movement of left thumb, and if it is sensory cortex then paresthesia of left thumb.

No alteration of consciousness

17. Partial (focal) Seizures contd.

B. Complex partial seizure (temporal lobe/psychomotor epilepsy)

Focus is located in temporal lobe

Confused behaviour and purposeless movements and emotional changes lasting for 30 seconds to 2minutes

An aura often present

Motor activity appears as non-reflex actions.

Automatisms (repetitive coordinated movements).

Wide variety of clinical manifestations

Consciousness is impaired

18. Complex partial seizure contd. Deja vu 19. Partial (focal) Seizures contd.

C. Secondarily generalized:

(Jacksonian)

Partial seizures initially

Followed by generalized tonic-clonic seizure

20. Secondarilygeneralized seizure 21. Partial (focal) Seizures contd. 22. Types of Seizure: Summery: 23. Status epilepticus

Continuous seizure activity for more than 30 minutes, or 2 or more seizures without recovery of consciousness.

Emergency:Recurrent tonic-clonic convulsions without recovery in between.

24. Causes of Epilepsy

• • ACUTE

• • CONGENITAL

25. Causes of Epilepsy contd.

• • ACUTE EPILEPSY

• • CORTICAL DAMAGE

• • TRAUMA

• • STROKE

• • NEOPLASM

• • AUTOIMMUNE EFFECTS

26. Causes of Epilepsy contd.

• • Congenital:

• • Hippocampus DYSGENESIS (FAILURE OF CORTEX TO GROW PROPERLY)

• • VASCULAR MALFORMATIONS

• • AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE ASSOCIATED WITH EPILEPSY motor cortex, somatosensory cortex, visual cortex, auditory cortex, temporal lobe cortex and olfactory.

27. Experimental Models

Maximal electroshock seizures: tonic phase abolished by drugs effective in GTCS

PTZ clonic seizures (Pentylenetetrazole): Can be prevented by drugs effective in absence seizure

Chronic focal seizure: alumina cream in monkey

Kindled seizures: bursts of weak electrical impulses tonic-clonic seizure

28. Classification antiepileptic drugs

Hydantoins:phenytoin , phosphenytoin

Barbiturates:phenobarbitone

Iminostilbenes:carbamazepine , oxcarbazepine

Succinimides:ethosuximide

Aliphatic carboxylic acid:Valproic acid , divalproex

Benzodiazepines : clonazepam, diazepam, lorazepam

New compounds:gabapentin, lamotrigine , tiagabine, topiramate,vigabatrin , zonisamide,felbamate

29.

Most common ones:

Modification of ion conductance

• Prolongation of Na +channel inactivation

• Inhibition of `T` type Ca ++current

Increase inhibitory (GABAergic) transmission.

Glutamate receptor antagonism (NMDA, AMPA, or kainic acid)

Genetic mechanism

Mechanisms of seizure & antiseizure drugs: 30.

The Sodium Channel:

Resting State

Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.

Refractory State, Inactivation reduce the rate of recovery.

Na + Na + Na + Sustain channel in this conformation Anticonvulsant mechanism contd. 31. The Sodium Channel contd.

Drugs acting via this channel:

Phenytoin, Sodium Valproate, Carbamezepine, Lamotrigine, Topiramide and Zonisamide

32. Anticonvulsant mechanism contd.

T type Ca ++current inhibition:

T type current is responsible for 3 Hz spike-and-wave

Throughout the thalamus `T` current has large amplitudes

Bursts of action potential is by action of T current

In absence seizure

Drugs ethosuximide, valproate and trimethadione

33. Anticonvulsant mechanism contd.

The GABA mediated CL- channel opening

Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate

34. Individual Drugs 35. Phenobarbitone

First effective organic antiseizure agent

Mechanism:

• Mechanism of CNS depression like other barbiturates, but less effect on Ca++ channel and glutamate release less hypnotic effect

• GABA Areceptor mediated like other Barbiturates

• Continued use sedation effect lost but not anticonvulsant action

• Raises seizure threshold and limits spread

• Suppresses kindled seizures

Pharmcokinetics:

• Slowly absorbed and long t 1/2(80 120 hrs)

• Metabolized in liver and excreted unchanged in kidney

• Single dose after3 wks. steady state

36. Phenobarbitone contd. (Gardenal/Luminal)

Adverse effects:

• Sedation

• Behavioural abnormalities

• Hyperactivity in children

• Rashes, megaloblastic anaemia and osteomalacia

• Primidone:deoxybarbiturate

• Phenobarbitone andPEMAShort half life 6-14 hrs

Uses:

• Many consider them the drugs of choice for seizures only in infants

• GTC

• SP and CPS

Dose:

• 60 mg 1-3 times a day

Child: 3-6 mg/kg/day

• Available as tabs 30/60mg, syr. and inj.

37. Phenytoin (Dilantin/Epsolin/Eptoin)

Pharmacological actions:

• Not CNS depressant

• But muscular rigidity and excitement at toxic doses

• Abolish tonic phase of GTC seizure

• No effect on clonic phase

• Prevents spread of seizure activity

• Tonic-clonic phase is suppressed but no change in EEG andaura

• In CVS depresses ventricular automaticity, accelerates AV conduction

38. Phenytoin sodium contd.

Mechanism of action:

• Prevents repetitive detonation of normal brain cells during ` depolarization shift`

• Prolonging the inactivation of voltage sensitive Na+ channel

• No high frequency discharges

• Na+ channel recovers

• No interference with kindling only on high frequency firing

39. Phenytoin sodium contd.

Pharmacokinetics:

• Slow oral absorption

• 80-90% bound to plasma protein

• Metabolized in liver by hydroxylation and glucoronide conjugation

• Elimination varies with dose first order to zero order

• T1/2 life is 12 to 24 hrs

• Cannot metabolize by liver if plasma conc. Is above 10 mcg/ml

• Monitoring of plasma concentration

40. Phenytoin sodium contd.

Adverse effects:

Hirsutism, coarsening of facial features and acne

Gum hypertrophy and Gingival hyperplasia.

Hypersensitivity rashes, lymphadenopathy

Megaloblastic anaemia

Osteomalacia

Hyperglycaemia

Cognitive impairment

Exacerbates absence seizures

Fetal Hydantoin Syndrome

41. Phenytoin sodium contd.

Uses:It is the first lineantiepileptic for

• GTCS, no effect in absence seizure

• Status epilepticus

• Trigeminal neuralgia 2 ndto Carbamazepine

Availableas caps/tabs/inj

25 to 100 mg caps and tabs.

42. Phenytoin sodium contd.

Drug Interactions:

• Phenytoin and carbamazepine increases each others metabolism

• Induces microsomal enzyme steroids, digitoxin etc

• Phenytoin metabolism inhibition by warfarin, isoniazide etc.

• Sucralfate decreases phenytoin ebsorption

43. Phenytoin sodium contd. 44. Phenytoin sodium contd. Phenytoin Toxicities Fetal Hydantoin Syndrome 45. Images of Phenytoin preparations 46. Carbamazepine (Tegretol/Tegrital)

Chemically related to imipramine

Trigeminal neuralgia

Resembles phenytoin in pharmacological actions

Unlike phenytoin inhibits kindling, modifies electroshock seizures and raises threshold to PTZ and electroshock

47. Carbamazepine contd.

Pharmacokinetics:

• Poorly water soluble and oral absorption is low

• 75% bound to plasma protein

• Metabolized in liver: active 10-11 epoxy carbamazepine

• Substrate and inducer of CYP3A4

• Half life 20 to 40hrs. Decreases afterwards due to induction

48. Carbamazepine contd.

Adverse effects:

• Autoinduction of metabolism

• Nausea, vomiting, diarrhoea and visual disturbances

• Hypersensitivity rash, photosensitivity, hepatitis, granulocyte supression and aplastic anemia

• ADH action enhancement hyponatremia and water retention

• Teratogenicity

• Exacerbates absence seizures

49. Carbamazepine contd.

Uses:

• Complex partial seizure

• GTCS and SPS

• Trigeminal and related neuralgias

• Manic depressive illness and acute mania

Availableas tabs (100mg 200, 400 etc.) and syr.

Oxcarbamazepine

50. Carbamazepine contd.

Interactions:

• Enzyme inducer reduce efficacy of OCPs and others

• Metabolism is induced by phenobarbitone, phenytoin, valproate

• Inhibits its metabolism isoniazide and erythromycin

51. Ethosuximide

Drug of choice for absence seizures

Does not modify maximal electroshock seizure or inhibit kindling

High efficacy and safety

Not plasma protein or fat binding

Mechanism of action involves reducing lowthreshold Ca2+ channel current (T-type channel) in thalamus

At high concentrations:

Inhibits Na+/K+ ATPase

Depresses cerebral metabolic rate

Potentiates GABA

• • Phensuximide = less effective

• • Methsuximide = more toxic

52. Ethosuximide contd.

Toxicity:

• Gastric distress, including, pain, nausea and vomiting

• Lethargy and fatigue

• Headache

• Hiccups

• Euphoria

• Skin rashes

Doses:

• 20-30mg/kg/day

• Available as syr./caps.

53. Valproic acid (Encorate/Valparin)

Broad spectrum anticonvulsant

Effects on chronic experimental seizure and kindling

Potent blocker of PTZ seizure

Effective in partial, GTCS and absence seizures

Mechanism:

• Na+ channel inactivation

• Ca++ mediated `T` current attenuation

• Inhibition of GABA transaminase

Pharmacokinrtics: well absorbed orally, 90% bound to plasma protein and completely metabolized in liver and excreted in urine t 1/2is 10-15 hrs.

54. Valproic acid contd.

Adverse effects:

• Elevated liver enzymes including own rise in serum transaminase

• Nausea and vomiting

• Abdominal pain and heartburn

• Tremor, hair loss, weight gain

• Idiosyncratic hepatotoxicity

• In Girls polycystic ovarian disease and menstrual irregularities

• Negative interactions with other antiepileptics

• Teratogenicity:spina bifida

Availableas tabs. (200/300/500, syr. and inj.)

55. Valproic acid contd.

Drug Interactions:

• Valproate and carbamazepine induce each others metabolism

• Inhibits phenobarbitone metabolism and increases its plasma level

• Displaces phenytoin from protein binding sites and thereby decreases its metabolism phenytoin toxicity

56. Benzodiazepines

Mainly used agents Clonazepam, Diazepam, Lorazepam and Clobazam

Antiseizure properties:

• Prevents PTZ induced seizures prominently and modifies electroshock seizure pattern

• Clonazepam has potent effect on PTZ induced seizures but almost nil action on ME seiures

• Suppress the spread of kindled seizures and generalized convulsions

• Do not abolish abnormal discharges at site of stimulation

57. Benzodiazepines contd.

Pharmacokinetic properties:

• Well absorbed orally (peak 1-4 hrs)

• IV administration redistribution

• Diazpam rapid redistribution (1 hr)

• Diazepam 99%, Clonazepam 85% bound to plasma protein

• N-desmethyldiazepam (metabolite) is less active than diazepam partial agonist

• Diazepam and NDD hydroxylated to active metabolite oxazepam t 1/2is 1 to 2 days

• Clonazepam reduction of nitro group to inactive 7-amino derivatives

• Lorazepam conjugation with glucoronic acid t 1/2is 14hrs

58. Benzodiazepines contd.

Adverse effects:

• Long term use of Clonazepam drowsiness and lethargy tolerance to antiseizure effects

• Muscular incoordination and ataxia

• Hypotonia, dysarthria and dizzziness

• Behavoiural abnormalities in children aggression, hyperactivity, irritability and difficulty in concentration

• Increased bronchial and salivary secretions

• Exacerbation of seizures

59. Benzodiazepines contd.

Therapeutic uses:

• Cloonazepam in absence seizure and myoclonic seizure in children (1 to 6 months)

• Dose initial 1.5mg/day, children 0.01 to 0.03mg/kg/day

• Status epilepticus Diazepam Lorazepam may be used as alternative

60. Benzodiazepines contd. 61. Gabapentin

GABA molecule covalently bound to a cyclohexane ring

Originally designed to be centrally active GABA agonist rapid transfer across BBB

Pharmaqcological Effects:

• Inhibits hindlimb extension in ME seizure

• Inhibits clonic seizures induced by PTZ

• Efficacy is equal to valproic acid but different from carbamazepine and phenytoin

62. Gabapentin contd.

Mechanism of action:

• Unknown

• Does not mimic GABA

• Probably, promotes nonvesicular release of GABA

• Binds a protein in cortical membrane similar to L type of voltage sensitive Ca++ channel

• But, do not alter Ca++ currents

• Does not reduce repetitive firing of action potentials

63. Gabapentin contd.

Pharmacokinetics:

• Absorbeed orally

• Not metabolized in humans

• Not bound to plasma proteins and excreted unchanged in urine

• Half life is 4 to 6 hrs.

• No known drug interaction

Uses:

• Partial seizures with or without secondary generalization in addition to other drugs

• 900-1800mg/day is equivalent to 300 mg/day of carbamazepine if used alone

• Usual starting dose is 300mg/day

Adverse effects:somnolence, dizziness, ataxia etc.

64. Lamotrigine

Phenyltriazine derivative

Originally, as antifolate agent

Pharmacological Effects and Mechanisms:

• Suppresses tonic hindlimb extension in ME seizure

• Partial and secondarily generalized in kindling

• No action on PTZ seizures

• Delays recovery from inactivation of Na+ channels carbamazepine and phenytoin

• Effective against partial and secondarily generalized seizures

• Broad spectrum activity action in areas other than Na+ channels

• Inhibition of glutamate release

65. Lamotrigine contd.

Pharmacokinetics:

• Completely absorbed from GIT and metabolized by glucoronidation

• Plasma half-life 15 to 30 hrs

• Phenobarbitone, carbamazepine and phenytoin reduces half life

• Valproate increases plasma concentration but its concentration reduces

• Together with Carbamazepine increase in 10,11-epoxide and toxicity

Uses:Monotherapy and add on therapy in simple partial and secondarily generalized seizures

66. Topiramate

Sulfamate substituted monosaccharide

Pharmacological effects and MOA:

• Broad spectrum antiseizure drug

• Carbonic anhydrase inhibitor

• Antiseizure activity against PTZ, ME seizure and partial and secondarily generalized tonic-clonic kindling

• Multiple actions Na+ channel, K+ channel, GABA A , AMPA-kainate subtypes of glutamate

Pharmacokinetics:

• Rapidly absorbed orally, 10-20% bound to plasma protein, excreted unchanged in urine

• Metabolized by hydroxylation, glucoronidation and hydrolysis

• Reduction in estradiol level

67. Major DrugInteractions

Phenytoin:

• With P.barbitone unpredictable overall reaction

• With Carbamazepine increases each other`s metabolism

• With Valproate displaces phenytoin from protein binding

• Mainly significant interactions are due to displacement of protein binding - sulfonamides

Carbamazepine:

• Increase in metabolism of other drugs like primidone, phenytoin, ethosuximide, valproic acid, and clonazepam

• Phenobarbitone and Phenytoin increases its metabolism

• Significant interactions are due to enzyme induction

68. Major Drug Interactions contd.

Valproate:

• Due to Protein binding and inhibition of metabolism

• Phenytoin is displaced from binding

• Inhibits metabolism of phenobarbitone, phenytoin and carbamazepine

Ethosuximide:

• Valproate inhibits metabolism and clearance

69. Other uses of AEDs:

Gabapentin, carbamazepine neuropathic pain

Lamotrogine, carbamazepine bipolar disorder

Valproate, topirimate, gabapentin migraine

Diazepam Tetanus, eeclampsia and convulsant drug poisoning

70. Treatment of Epilepsies

Aim of the treatment:

• Control and prevent all seizure activity (seizure - freedom and improvement in quality of life!)

• To search the cause of epilepsy

• Attempts to remove the causes

• Symptomatic treatment with antiepileptic drugs

• To consider status epilepticus as medical emergency and treat efficiently and promptly

Choice of Drugs:According to the seizure types.

71. Treatment of Epilepsies Drug choices - Diazepam rectal 0.5mg/kg Febrile convulsions Phenytoin IV Phosphenytoin IV Diazepam Lorazepam Status epilepticus Lamotrigine Topiramate Valproate Myoclonic Gabapentin Lamotrigine Phenytoin, Carbamazepine and Valproate Complex partial seizure with or without generalization Ethosuximide Valproate Absence seizure Phenobarbitone and Valproate Carbamazepine, Phenytoin and Valproic acid Generalized tonic-clonic or simple partial seizure 2 nd choice 1 stchoice Seizure types 72. Treatment of Epilepsies contd.

3. Initiation of treatment:

• Initiate therapy even if it is isolated tonic-clonic seizure with family history of seizure, abnormal neurological examination, abnormal EEG and an abnormal MRI

• Treat with monotherapy

• Substitute another drug if fails

• Combination therapy only when all monotherapy fail

• Therapeutic monitoring of drugs dose adjustments

73. Treatment of Epilepsies contd.

4. Seizure diary

Withdrawal of drugs:

• Gradual withdrawal

• Prolong therapy life long/3yrs after last seizure

• Withdrawal childhood epilepsy, absence of family history, primarily generalized tonic-clonic seizure and normal EEG

74. Treatment of Epilepsies contd.

Antiepileptics and pregnancy

• Drugs should not be stopped if conceive status epilepticus

• Fits during pregnancy birth defects, mental retardation etc.

• Folic acid and vit.K supplementation

Care during attacks:tonic-clonic seizures

Surgical removal

75. Generalized Onset Seizures

Tonic-clonic, myoclonic, and absence seizures:1st line drug is usuallyvalproate

Generalized seizures:Phenytoin and carbamazepine are effective on tonic-clonic seizures but not other types of seizures

Absence seizures:Valproate and ethosuximide are equally effective in children, but only valproate protects against the tonic-clonic seizures that sometimes develop.

Risk of hepatoxicity with valproateshould not be used in children under 2

76. Partial Onset Seizures

Without generalization

• Phenytoin and carbamazepine may be slightly more effective

With secondary generalization

• First-line drugs are carbamazepine and phenytoin (equally effective)

• Valproate, phenobarbital, and primidone are also usually effective

Phenytoin and carbamazepinecan be used together (but both are enzyme inducers)

77.

Adjunctive (add-on) therapy: newer drugs felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide

Phenytoin and carbamazepine failure:Lamotrigine, oxcarbazepine, felbamate approved for monotherapy

Refractory partial seizures: Topirimate can be effective.

Partial Onset SeizuresNew Drugs 78. Status Epilepticus

Defn.:Continuous seizure activity for more than 30 minutes, or 2 or more seizures without recovery of consciousness. Recurrent tonic-clonic convulsions without recovery in between

Goal of therapy:rapid termination of seizure activity more difficult to control permanent brain damage

Prompt treatment with effective Drugs

Attentionto hypoventilation and hypotension

Treatment is IV only

79. Status Epilepticus contd.

Diazepam 10mg IV bolus injection (2mg/min)

• Fractional dose at every 10 min. or titrated dose by slow infusion

• Lorazepam: 0.1mg/kg

Followed by Phenobarbitone IM/IV (100-200mg) or Phenytoin slow IV in saline (25-50mg/min)

Resistant cases (refractory): IV anaesthetics

General supportive measures

80. Attentions

Selection of an appropriate antiseizure agent

Use of single drug

Withdrawal

Toxicity

Fetal malformations

81. Thank You