Introduction to anticonvulsants.

Classification of epileptic seizures Classification of anticonvulsants agents; Hydantoins, lamotrigine

Dr Keli F Kenyatta University Medical School 2/5/2013

What are Seizures ?

A seizure is a transient alteration of behavior due to abnormal synchronous electrical activity in the brain

What is Epilepsy ?

Epilepsy is a condition where there are recurring, unprovoked seizures Diagnosis of epilepsy is based on clinical findings and EEG features Abnormal EEG is recognized by rythmicity or amplitude of waves and patterns

What is a convulsion ?

A medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure Not all epileptic seizures lead to convulsions, and not all convulsions are caused by epileptic seizures

EEG during a seizure

Focal onset with secondary generalization

Classification of Seizures

Partial Seizures (Focal Onset)

Simple Partial Complex Partial Partial with secondary generalization

Generalized (Bilateral Onset)

Absence seizure Myoclonic Tonic-clonic other types

Parial Seizures

Simple Partial : Diverse manifestations determined by region affected eg motor cortex representing the thumb clonic jerking of the thumb, if the somato sensory area is affected then paraesthezias of thumb Complex Partial: impaired consciousness lasting 30 sec to 2 min of purposeless movements eg hand writing

Partial Seizures

Partial with Secondarily generalised Tonic Clonic seizure; its a simple or complex seizure which develops into a tonic clonic seizure with loss of consciousness and sustained contraction with periods of relaxation lasting 1 to 2 min

Complex seizures

Absence Seizure: Abrupt onset of impaired consciousness associated with staring and cessation of ongoing activities < 30 secs Myoclonic seizure: brief shock like contraction of muscles may be restricted or generalized Tonic Clonic Seizure: its a generalized seizure contraction and relaxation of muscles Atonic seizures: Sudden loss of postural tone Consciousness may be lost

Antiepileptics-drug discovery
Traditional:

random screening of compounds in animal models Rational -based on presumed biochemical or molecular mechanisms.

Target Mechanisms for anticonvulsants

Inhibit repetitive activity of neurons blockade of voltage-gated sodium channels Increase inhibitory inputs GABA enhancers Reduce excitatory input glutamate antagonists

Enhanced Gaba Synaptic Transmission

Sodium channel and Seizure

Ca channel and seizure medication

Anticonvulsants

Selective CNS drugs (Depressants), used to treat epilepsy. These syndromes affect about 1% of the population. One would hope to have anticonvulsants that affect pathologically altered neurons of seizure foci, which would then prevent or reduce their excessive discharge.

Anticonvulsants

The way that anticonvulsants work is:

to reduce the spread of excitation from seizure foci and prevent detonation and disruption of function of the normal neurons. The underlying pathology is not affected.

Idiopathic epilepsy: No visible pathology of initiation and yet abnormal neuronal firing takes place and spreads throughout the brain. The pattern the extent of propagation determines the type and severity of the seizure.

Anticonvulsants A Plethora Of Drugs

Hydantoins Barbiturates Iminostilbenes Succinimides Benzodiazepines Valproic Acids

Partial seizure drugs

Hydantoins Barbiturates Iminostilbenes Vigabatrin new Lamotrigine a phenyltriazines Felbamate Gabapentin analogue of GABA many other uses Topiramate Tiagabine nipecotic acid derivative Zonisamide sulphonamide derivative Levetiracetam a piracetam

Drugs for partial and secondarily generalized seizures

Phenytoin

/ fosphenytoin (Hydantoins) Carbamazepine Barbiturates Valproic acid New and investigational agents

Generalized Seizure Drugs

Succinimides Valproic Acids Oxaline diones

The Hydantoins
Phenytoin (Dilantin) Fospenytoin Mephenytoin (Mesantoin) Ethotoin (Peganon) Phenacemide (Phenurone)

Phenytoin

Phenytoin (Dilantin) - Prototypic Drug

Made

in 1908 Used for seizure control in 1938 In therapeutic doses, no loss of consciousness

Phenytoin

useful for the treatment of

partial seizures generalized tonicclonic seizures

It does not treat primary generalized seizures such as absence seizures or myoclonic seizures

Phenytoin Mechanism of Action

Stabilizes neural membranes

At

therapeutic concentration the main action is : Blocks voltage-dependent Na+ channels sodium ion movement across the cell Sodium channels are altered making drug binding favorable May prolong the refractory period of excitable cells by delaying the influx of potassium ions

Sodium channel and Seizure

Other Mechanisms of Phenytoin

At high concetrations it
inhibits the release of serotonin and norepinephrine Promotes uptake of dopamine Inhibits mono amine oxidase

It induces Ca permeability and influx explaining phenytoins ability to inhibit Ca induced secretory process eg release of hormones and neurotransmitters

Pharmacokinetics Phenytoin

Absorp form the GI is nearly complete in most patients peak at 3 -12 hrs Half life averagely 24 hrs After IM use is unpredicatble this route not recomended

hepatic metabolism with saturation kineticsie at large serum levels maximum capacity of met is saturated further increase in dosage = toxicity druds half life incraeses induces metabolism of other drugs

Pharmacokinetics Phenytoin

Its highly protein bound levels decrease in uremia and hypoalbuminemia Plasma level conc = CSF conc At low blood levels steady states are reached in 5-7 days at high levels 4-6 weeks

Dosage phenytoin

Therapeutic plasma levels 10-20 ug/ml Initiating dose; 300mg/day no regard to wt It should be increased at 25-30 mg ad give time to achieve a steady state NEVER 300mg TO 400mg Children dose 5mg/kg/day adjust to achieve steady therapeutic levels Two formulations are available rapidly absorbed and slow release tabs

Phenytoin drug interactions

Are related to binding or metabolism May be displaced by drugs that are highly protien bound since phenytoin is 90% bound eg phenylbutazone, sulphonamides This results to an apparent plasma increase A decrease in proteins (hypo albuminemia) may cause a decrease in total concentration but not the free concentration Attempts to increase drug concentration to therapeutic range results toxicity

Phenytoin interactions and Interference

Phenytoins protein binding is decreased in patients with renal disease Phenytoin has an affinity for to thyroid binding globulins if a patient is taking phenytoin thyroid functions are measured by TSH It induces microsomal enzymes that met drugs Its steady state is reduced after microsomal induction by phenobarbital carbamazepine Isoniazid increases the drug level by inhibiting its met

Phenytoin Toxicity

Similar to other antiseizure meds Occular;Nystagmus early ,Loss of smooth etraoccullar pursuit gaze paralysis (early) CNS; Diplopia ataxia are dose related require dose adjustment, Sedation at high dose Teratogenic:; consists of craniofacial anomalies (broad nasal bridge, cleft lip and palate, microcephaly) and a mild form of mental retardation (Fetal hydratoin syndrome)

Toxicity

Oral; Gingivitis Dermatological Hirsutim, Coarsening of facial features (hypertrichosis), JSJ, TEN Peripheral neuropathy manifested by diminished deep reflexes Hematologic; Folate deficiency inhibits folic acid absorption Hormonal Long term use may result to interference with vit D met osteomalacia

hypertricosis

Gingivitis and corrected gingivitis

Gaze paralysis

Hirsutism

SJS steven johnson syndrome

TEN Toxic Epidermolysis Necrosis

Phenytoin
Idiosyncratic reactions Skin rash indicating hypersensitivity Lymphadenopathy which resembles that of malignancy studies shows there is a causal relationship with Hogkin s lymphoma Hematological: agranulocytosis with fever and rash

Not water soluble -for IV must be dissolved in propylene glycol

Mephenytoin

Mephenytoin: effective against partial seizures and generalized tonic clonic seiz Pharmacokinetics: saturable met Met to 5,5 ethyl-phenylhydantoin by demerthylation active met therapeutic levels 5-16 ug/ml Therapeutic level for nivarnol (metabolite of mephenytoin) is 20ug/ml Further met of mephenytoin and nivarnol ocuurs by hydroxylation and conjugation Toxicity :dermatitis, agranulocytosis, hepatitis is higher than that of phenytoin

Ethotoin

Ethotoin: Recommended for patients with phenytoin hypersensitivity Large doses required less effective than phenytoin Toxicity less severe Low efficacy pharmacokinetics: saturation met

Phenacemide

A straight chain analogue of phenytoin Toxic Last resort refractory partial seizures

Fosphenytoin (Cerebyx) a prodrug

Fosphenytoin phenytoin

fosphenytoin is rapidly metabolized to phenytoin fosphenytoin is water soluble; allows IMadministration, and eliminates toxicity of propyleneglycol vehicle required for phenytoin 1200 mg phenytoin = $1.50; fosphenytoin = $119.00

Medical uses of anticonvulsants

Tegretol
Trigeminal

neuralgia Glossopharyngeal neuralgia

New and investigational anticonvulsants

Felbamate Gabapentin Lamotrigine Topiramate

Tiagabin Leviracetam Zonisamide

All of these released since 1994

None are currently FDA approved for monotherapy

New and investigational anticonvulsants

Topiramate (Topamax) - Mechanism is still unclear. Affects GABA Cl- flux similar to BDZs, but is not inhibited by Fumazenil. Not like barbiturates either. Antagonizes nonNMDA glutamate receptors. Tiagabine (Gabitril) - GABA reuptake inhibitor. Interesting SAR -vinyl GABA (vigabatrin), (Sabril). Inhibits GABA transaminase

Lamotrigine (lamictal)

Developed while studying antifolate effects of drugs phenytoin MOA; like phenytoin suppresses sustained rapid firing of neurons via Na+ channels. Similar to phenytoin and carbamazepine May have action on Ca2+ channels Clinical use ; add on therapy for partial seizures some studies indicate use as monotherapy May be active against absence and myoclonic seizures in children Toxicity ;Dizziness, headache, diplopia, nausea somnolence, skin rash life threatening dermatitis

Gabapentin

Analogue of GABA Originally planned as a spasmolytic MOA; similar structure to GABA but no effect on GABA receptors may alter GABA met, nonsynaptic release , re uptake by GABA transporters. Also binds onto Ca2+ channels Clinical use; adjunct in partial seizures and generalized tonic clonic seizures, post herpetic neuralgia Side effects ataxia, somnolence, dizziness, headache,tremor

Zonisamide (Zonegran)

A SULPHONAMIDE (HIV dermatitis and sulphonamides) MOA; At Na+ channels or Ca+2 channels. Clinical use; partial seiz, generalised tonic clonic seiz, INFANTILE SPASMS, some myoclonic seiz Dose 4-12 mg/d child Adults 100-600mg AE drowsiness cognitive impairment, PONTETIALLY serious skin rash No drug interactions

Principles for the management of epilepsy

Have a good seizure plan in the clinic Train personnel to appropriately respond to the seizure event Classify, localize and define etiology Not every seizure needs to be treated Monotherapy preferred Treat the patient, not the numbers 80% of patients can achieve control with 1 agent, 90% with multiple agents Consider surgical approaches

Clinical Considerations
Is the patient taking their medications regularly ???? Are there any external triggers which could set off the seizure ??? (light, sound, fatigue, odors) Are the patients changing medications or changing the dose ???

Clinical Considerations
Are the patients under unusual stress - divorce, family deaths, etc. Know the side effects of the medications

Pregnancy and anticonvulsants

All presently available anticonvulsants may have teratogenic effects Uncontrolled seizures also have an adverse effect on the fetus First 12 weeks is critical Fewest drugs and lowest doses are best Avoid valproic acid if possible (neural tube defects) Abrupt discontinuation of any anticonvulsant is not a good idea

Management of Status Epilepticus

Definition and identification Status epilepticus (SE) is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary Traditionally it is defined as one continuous, unremitting seizure lasting longer than 5 minutes,[1] or recurrent seizures without regaining consciousness between seizures for greater than 5 minute

Mx Status Epilepticus
Goal is control of seizures with 60 minutes ABCs: Airway, Breathing, Circulation IV access, initial labs, history and exam Thiamin (100mg IV), glucose (50g IV) Lorazepam, 1-2 mg IV Q3-5 min to 10 mg total OR Fosphenytoin, 15-20 mg/kg IV or IM OR Phenobarbital, initial dose 5-10 mg/kg IV OR For refractory status; ICU care and use General anaesthetic agents Propofol, Lidocaine, Ketamine