Drugs for Epilepsy Asst Prof Dr Inam S. Arif - PowerPoint Presentation

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Drugs for Epilepsy

Asst Prof Dr Inam S. Arifisamalhaj@yahoo.compharm.dr.isamalhaj@uomustansiriyah.edu.iq

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Epilepsy is:

The third most common neurologic disorder after cerebrovascular and Alzheimer’s diseaseA collection of different seizure types and syndromes originating from several mechanisms It is a sudden, excessive, and synchronous discharge of cerebral neurons, which may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated

The site of origin of the abnormal neuronal firing determines the symptoms that are produced.

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if the motor cortex is involved, the patient may experience abnormal movements or a generalized

convulsion.Seizures originating in the parietal or occipital lobe may include visual, auditory, and olfactory hallucinationsIn general, seizures can be controlled with one medication in approximately 75% of patients

Patients may require more than one medication in order to optimize seizure control, and some patients may never obtain total seizure control

Overview (

cont.)

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Etiology of SeizureIn most cases, epilepsy has no identifiable cause

Focal areas , may be triggered into activity by changes in physiologic factors, e.g. alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deprivation, alcohol intake, and stressPrimary focusEpilepsy can be due to genetic, structural, or metabolic cause or an unknown cause

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Etiology (cont.)

A. Genetic epilepsyThese seizures result from an inherited abnormality in the central nervous system (CNS)B. Structural/metabolic epilepsyA number of causes, e.g. illicit drug use, tumor, head injury, hypoglycemia, meningeal infection, and the rapid withdrawal of alcohol from an alcoholic, can precipitate seizures

C. Unknown cause

When no specific anatomic cause for the seizure, e.g. trauma or neoplasm, is evident

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Classification of Seizures

Seizures have been categorized by site of origin, etiology, electrophysiologic correlation, and clinical presentation

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Classification of Seizures (cont.)

A. FocalFocal seizures involve only a portion of the brain/one lobe of one hemisphere. The symptoms of each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain. Focal seizures may progress to become generalized tonic–clonic

seizures.

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Classification of Seizures (cont.)

1. Simple partial: Electrical discharge does not spread, & no loss of consciousness or awareness. The patient shows abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance.

2. Complex partial:

Complex sensory hallucinations and mental distortion

Motor dysfunction may involve chewing movements, diarrhea, and/or urination,

Consciousness is altered

May spread to become generalized convulsion.

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Classification of Seizures (cont.)

B. Generalizedmay begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain. Primary generalized seizures may be convulsive or nonconvulsive

, and the patient usually has an immediate loss of consciousness

Tonic–

clonic

:

Loss of consciousness, followed by

tonic

(continuous contraction) &

clonic

(rapid contraction and relaxation) phases.

The seizure may be followed by a period of confusion due to the

depletion of glucose and energy stores.

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Classification of Seizures (cont.)

2. Absence: brief, abrupt, & self- limiting loss of consciousness Starts at 3 to 5 years of age and lasts until puberty or beyond.

The patient stares and exhibits rapid eye-blinking, for 3 to 5 seconds An absence seizure has a very distinct 3/sec spike and wave discharge seen EEG

3

. Myoclonic

:

consist of short episodes of muscle contractions that may recur for several minutes

generally occur after wakening and exhibit as brief jerks of the limbs

occur at any age but usually begin around puberty or early adulthood.

4.

Clonic

:

short episodes of M contractions resemble myoclonic seizures.

Consciousness is more impaired with

clonic

seizures as compared to myoclonic.

5. Tonic:

involve increased tone in the extension muscles & <60 seconds long.

6. Atonic:

known as drop attacks &characterized by a sudden loss of muscle tone.

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Antiepilepsy medication Benzodiazepines

GABA inhibitory receptors to reduce firing ratereserved for emergency or acute sei- zure treatment due to toleranceClonazepam &

Clobazam  adjunctive therapy for particular types of seizures

Diazepam/ rectal/ avoid or interrupt prolonged generalized tonic–

clonic

seizures or clusters when oral administration is not possible

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Carbamazepine

Blocks Na channelsEffective in focal seizures & generalized tonic–clonic seizures, trigeminal neuralgia, and bipolar disorderAbsorbed slowly & incomplete after oral administration Induces its own metabolism, resulting in lower total

carbamazepine blood concentrations at higher doses

inducer of the CYP1A2, CYP2C, and CYP3A

anglucuronosyltransferase

(UGT) enzymes, which increases the clearance of other drugs

Hyponatremia /elderly

Carbamazepine

CI in absence seizures because it may cause an increase in seizures.

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Eslicarbazepine

A prodrug that is converted to the active metabolite eslicarbazepine by hydrolysis S-

licarbazepine is the active metabolite of oxcarbazepine

Block voltage-gated Na channel & used for partial-onset seizures in adults

Linear pharmacokinetics and is eliminated via

glucuronidation

SE: dizziness, somnolence, diplopia, and headache, rash, psychiatric side effects, and hyponatremia occur rarely.

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Ethosuximide

Rreduces propagation of abnormal electrical activity in the brain, most likely by inhibiting T-type calcium channels It is only effective in treating absence seizures.

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Ezogabine

Open voltage-gated M-type K channels leading to stabilization of the resting membrane potentialExhibits linear pharmacokinetics and no drug interactions at lower dosesSE: urinary retention, QT interval prolongation, blue skin discoloration, and retinal abnormalities

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Felbamate

has a broad spectrum of anticonvulsant action with multiple proposed mechanisms Block voltage-dependent Na channelsCompeting with the glycine

coagonist binding site on the N

-methyl-D-aspartate (NMDA) glutamate receptor

Block calcium channels, and potentiating GABA action

It is an inhibitor of drugs metabolized by CYP2C19 and induces drugs metabolized by CYP3A4

Reserved for use in refractory epilepsies (particularly Lennox-

Gastaut

syndrome) because of the risk of aplastic anemia (about 1:4000) and hepatic failure.

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Gabapentin

Analog of GABA/ enhance GABA actions or convert to GABAPrecise mechanism of action is not knownApproved as adjunct therapy for focal seizures and treatment of postherpetic neuralgia

Nonlinear pharmacokinetics due to its uptake by a saturable transport system from the gut

Does not bind to plasma proteins & excreted unchanged by the kidneys.

Well tolerated by the elderly population with partial seizures due to its relatively mild adverse effects

It may also be a good choice for the older patient because there are few drug interactions.

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Lacosamide

Affects voltage-gated Na channels / stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firingBinds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in neuronal differentiation and control of axonal out- growth

The role of CRMP-2 binding in seizure control is unknownApproved for adjunctive treatment of focal seizures

SE: dizziness, headache, and fatigue

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Lamotrigine

Blocks Na channels & high voltage-dependent Ca channelsEffective in a wide variety of seizure types, including focal, generalized, absence seizures, & bipolar disorderMetabolized primarily to the 2-N-glucuronide metabolite through the UGT1A4 pathway General inducers increase clearance leading to lower concentrations, whereas divalproex

results in a significant decrease in lamotrigine

clearance (higher

lamotrigine

concentrations

Slow titration is necessary due to risk of rash, which may progress to a serious, life-threatening reaction.

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Levetiracetam

Approved for adjunct therapy of focal onset, myoclonic & primary generalized tonic–clonic seizures in adults and childrenMechanism of anticonvulsant action is unknownhigh affinity for a synaptic vesicle protein (SV2A)Well absorbed orally and excreted in urine mostly unchanged, resulting in few to no drug interactions

Cause mood alterations that may require a dose reduction or a change of medication.

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Oxcarbazepine

A prodrug, rapidly reduced to the 10-monohydroxy (MHD) metabolite responsible for its anticonvulsant activity MHD blocks N channels, preventing the spread of the abnormal dischargemodulate calcium channels/adults and children with partial-onset seizuresless potent inducer of CYP3A4 and UGT than

carbamazepineSE: hyponatremia limits its use in the elderly.

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 Perampanel

Selective α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid antagonist resulting in reduced excitatory activityPerampanel has a long half-life enabling once-daily dosing / adjunctive treatment of partial-onset seizures in patients 12 years or older

Perampanel is a newer antiepileptic agent

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Phenobarbital and primidone

Enhancement of the inhibitory effects of GABA-mediated neurons Metabolized to phenobarbital (major) and phenylethylmalonamide both with anticonvulsant activity

Phenobarbital is used primarily in the treatment of status epilepticus when other agents fail.

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Phenytoin and fosphenytoin

Blocks voltage-gated Na channels Effective in focal and generalized tonic– clonic seizures & status epilepticusInduces drugs metabolized by the CYP2C and CYP3A families and the UGT enzyme systemExhibits saturable enzyme metabolism resulting in nonlinear pharmacokinetic properties Depression of the CNS occurs particularly in the cerebellum & vestibular system/nystagmus and ataxia/ elderly

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Gingival hyperplasia may cause the gums to grow over the teeth Long-term use may lead to development of peripheral neuropathies and osteoporosis/serious toxicity and adverse effects.

Fosphenytoin a prodrug, rapidly converted to phenytoin in the blood within minutes/IMdrug of choice and standard of care for IV and IM

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Pregabalin

Binds to the α2-δ site, an auxiliary subunit of voltage-gated Ca channels in the CNS, inhibiting excitatory neurotransmitter release. Used in focal seizures, diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia More than 90% of pregabalin

is eliminated by kidneysWeight gain and peripheral edema have been reported.

When the hepatic hydroxylation system becomes saturated, small increases in the dose of phenytoin cause a large increase in the plasma concentration of the drug.

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Rufinamide

Acts at Na channelsapproved for the adjunctive treatment of seizures associated with Lennox- Gastaut syndrome in children >4 yrs & adultsA weak

inhibitor of CYP2E1 and a weak

inducer

of CYP3A4 enzymes

Food increases absorption and peak serum concentrations

Serum concentrations affected by other

antiepilepsy

medications

Induced by

carbamazepine

and

phenytoin

and inhibited when given with

valproate

SE: potential for shortened QT intervals, patients with familial short QT syndrome should not be treated with

rufinamide

.

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Topiramate

blocks voltage-dependent Na channels, reduces high-voltage Ca currents (L type)A carbonic anhydrase inhibitor & may act at glutamate (NMDA) sitesEffective in partial and primary generalized epilepsy & also approved for prevention of migraineinhibits CYP2C19 & induced by phenytoin and

carbamazepineSE: include somnolence, weight loss, and

paresthesias

, renal stones, glaucoma,

oligohidrosis

(decreased sweating), & hyperthermia have also been reported.

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Valproic acid and divalproex

Na channel blockade, blockade of GABA transaminase & action at the T-type Ca channelsEffective in focal and primary generalized epilepsiesDivalproex sodium is a combination of Na valproate & valproic acid that is converted to valproate when it reaches the gastrointestinal tractCommercial products are available in multiple-salt dosage forms and extended-release formulations Valproate inhibits metabolism of the CYP2C9, UGT, and epoxide hydrolase systems

Rare hepatotoxicity may cause a rise in liver enzymes, which should be monitored frequentlyTeratogenicity is also of great concern.

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Vigabatrin

Irreversible inhibitor of GABA transaminase (GABA-T)/enhance GABAergic activity SE: visual field loss ranging from mild to severe in 30% or more of patient.

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Zonisamide

Sulfonamide deriv. / broad spectrum of action/ approved for focal epilepsyHas multiple effects, including blockade of both voltage-gated Na channels and T-type Ca currentsHas a limited amount of carbonic anhydrase activity Metabolized by the CYP3A4 isozyme and may, to a lesser extent, be affected by CYP3A5 and CYP2C19SE: CNS adverse effects, kidney stones & oligohidrosis has been reportedCI in patients with sulfonamide or carbonic anhydrase inhibitor hypersensitivity.

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Status EpilepticusTwo or more seizures occur without recovery of full consciousness in between episodes may be focal or primary generalized, convulsive or nonconvulsive

A life threatening, requires emergency treatment Administration of a fast-acting medication e.g. benzodiazepine, followed by a slower-acting medication such as phenytoin

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Women’s Health & EpilepsyWomen of childbearing potential with epilepsy require assessment of their antiepilepsy medications in regard to contraception and pregnancy planning.

Several antiepilepsy medications increase the metabolism of hormonal contraceptives, potentially rendering them ineffective. (phenytoin, phenobarbital,

carbamazepine,

topiramate

,

oxcarbazepine

,

rufinamide

, &

clobazam

)

Pregnancy planning is vital, as many antiepilepsy medications have the potential to affect fetal development and cause birth defects/(1-5 mg) of folic acid prior to conception

Divalproex

and barbiturates should be avoided

The pharmacokinetics of antiepilepsy medications and the frequency and severity of seizures may change during pregnancy.

Regular monitoring by both an obstetrician and a neurologist is important

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ReferencesLippincott Illustrated Reviews “Pharmacology” 7

th editionBasic & Clinical Pharmacology 14th edition