SEIZURE PRECIPITANTS AND CONVULSANTSBy. Dr Lokesh Shetty

MPHARM (PHARMACOLOGY)

LECTURER- RCDPs.

SEIZURE PRECIPITANTS AND CONVULSANTS

Convulsion A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body.

Seizure Uncontrolled electrical activity in the brain, which may produce a physical convulsion, minor physical signs, thought disturbances, or a combination of symptoms.

Epilepsy epilepsy is a sudden, excessive and disorderly discharge of cerebral neurons. Sudden detonation of normal brain cell. This result in sudden abnormal movement of body.

Symptoms based on site of discharge produced 2 TYPEseizure with convulsion – if motor cortex involvedseizures with visual, auditory & olfactory hallucination – parietal or occipital cortex involved.

Causes : 2 TYPEPrimary no specific anatomic cause – trauma, neoplasm inherited abnormality in CNS.Secondary a number of reversible disturbances – tumour, head injury, hypoglycemia, meningeal infection

Types of epileptic seizure: Partial & GeneralizedPartial Begins focally ( focal origin) in cortical site.

These may or may not become generalized tonic clonic seizure. 2 types Simple & Complex partial.Simple partial A group of hyperactive neurons exhibiting abnormal electrical activity and are confined to single locus in the brain. Electrical discharge does not spread. Person does not become unconscious, only the region controlled by that part got effected

Complex Partial The seizure focus is located in temporal lobe (temporal lobe epilepsy) Characterised by complex sensory hallucination, mental distortion & loss of consciousness'.

Generalized Seizure: They begin locally but rapidly spread producing abnormal electrical discharge throughout both hemispheres of brain. GS is may convulsive or may not convulsive – but immediate loss of consciousness.

Types:Generalized Tonic – Clonic Loss of consciousness– Tonic – Clonic– Confusion & Exhaustion ( 1-2 min)Petitmal Seizure: common in children brief, abrupt & self limiting loss of consciousness.MyoclonicFebrilePatho: Reduction in Inhibitory / Increase in Excitatory / Alteration in voltage dependent ion channel.

HOW DO EXCITATORY AND INHIBITORY NEUROTRANSMITTERS DIFFER?

Neurotransmitters are classified as excitatory or inhibitory according to their effects on postsynaptic membranes.

A neurotransmitter is called excitatory if activation of the receptor causes depolarization of the membrane and promotes action potential generation.

A neurotransmitter is called inhibitory if the activation of the receptor causes hyper polarization and depresses action potential generation.

MAJOR EXCITATORY (AMINO ACID) & INHIBITORY NEUROTRANSMITTER

Excitatory:- Includes Glutamate, Aspartate etc Receptor subtypes NMDA, AMPA, KAINATE etc These are ionotropic receptors regulating cation

channel. Responsible for Ca+ ion influx, thus depolarization

& excitation.

Inhibitory:-o GABAo Binds on GABA A Receptoro Responsible for Cl - ion influx, thus

hyperpolarisation

CONVULSANT:

A convulsant is a drug which induces convulsions and/or seizures.

Most convulsants are antagonists (or inverse agonists) at either the GABAA or glycine receptors, or ionotropic glutamate receptor agonists.

Convulsants are also widely used in scientific research, for instance in the testing of new anticonvulsant drugs.

•Bemegride •Bicuculline •Cicutoxin •Cyclothiazide •DMCM •FG-7142 •Fipronil •Flumazenil •Flurothyl

•Gabazine •Oenanthotoxin •Pentetrazol •Picrotoxin •Sarmazenil •Securinine •Thujone

GABAA receptor antagonists,

Glycine receptor antagonists•Brucine •Colubrine •Diaboline •Gelsemine •Hyenandrine •Strychnine •Tutin

Ionotropic glutamate receptor agonists

•AMPA •Domoic acid •Kainic acid •NMDA •Quisqualic acid •Tetrazolylglycine

SEIZURE PRECIPITANTS

Seizure Precipitants are provokes the seizure, or decreases seizure threshold or precipitate or triggers seizures in epileptic patients.

2 Factors involved- Endogenous and exogenous factors.

Endogenous precipitants include emotional stress , fatigue, infections or Fever , menstrual cycle , and sleep deprivation etc.

Exogenous precipitants include alcohol use, caffeine use, fasting , flashing lights, heat, humidity or Medications etc.

MEDICINE AS SEIZURE PRECIPITANTS

Some of the medicines are seizure precipitants and thus are contraindicated in epileptic seizures.

Thus such drugs to be avoided in epileptic patients.

ISONIAZID

Isoniazid is commonly used in the treatment of Tuberculosis.

At higher doses it acts as Convulsant & triggers epilepsy.

At therapeutic dose acts as seizure precipitant thus to be avoided in epileptic patients.

Mechanism: The mechanism of Isoniazid triggered

convulsion involves pyridoxine (Vit B6) metabolism, Isoniazid depletes systemic pyridoxine levels.

Three mechanisms responsible for interfering with the function and supply of pyridoxine1. Isoniazid binds directly with pyridoxine to formIsonicotinyl hydrazide.

2. Isoniazid is dehydrised to its hydrazones; which blockpyridoxine phosphokinase, thus preventing conversion of pyridoxine to its active from, pyridoxal 5’ phosphate.

3. Isoniazid hydrazides inactivate pyridoxal 5'phosphate, which is essential for the formation ofgamma amino-butyric acid from glutamic acid.

Lack of GABA formation, and the accumulation of glutamic acid leads to CNS excitation and seizures.

CAFFEINE Caffeine (1,3,7-trimethylxanthine) is the

most widely consumed stimulant drug in the world.

It is present in a variety of forms: medications, coffee, tea, soft drinks, and chocolate

caffeine is present in concentrated forms in over-the-counter (OTC) products, such as alertness-promoting medications (eg, NoDoz, Vivarin), menstrual aids (eg, Midol), analgesics (eg, Excedrin, Anacin, BC Powder), and diet aids (eg, Dexatrim).

Caffeine is also a component of prescription medications (eg, Fioricet, Cafergot), energy drinks, and herbal preparations.

Caffeine is contraindicated in epileptic patients.

Mechanism

o It is a adenosine receptor antagonist.o (Binding of adenosine to adenosine

receptor results in inhibition of release of excitatory transmitter in CNS)

o Inhibition of adenosine receptor results in activation of excitatory neurotransmitter thus convulsion.

THEOPHYLLINE

It is a CNS stimulant & bronchodilator.

Adenosine 5'-nucleotidase inhibitor.

Prevents formation of Adenosine.

Thereby predominance excitatory neuritransmitter.

Precipitation of Excitation.

MONOAMINE OXIDASE INHIBITORS Decrease the metabolism of monoamines,

increase the brain monoamine levels, and decrease the threshold for seizures.

Eg: 5HT, Nor Adr etc Drugs reported to have an epileptic potential in

increasing order are desipramine, nortriptyline, trimipramine, imipramine, clomipramine, amitriptyline.

Tricyclic antidepressants are associated with a higher incidence of seizures than selective serotonin reuptake blockers.

PSYCHOMOTOR STIMULANTS Psychomotor stimulants are another class of CNS

stimulants. Includes amphetamine, methamphetamine

etc considered as convulsants at larger doses, seizure

precipitant at therapeutic dose- contraindicated in epileptic patients.

They act by 1. Releasing monoamines at synapses in

the brain and spinal cord / may inhibit MAO 2. Inhibits neuronal uptake of monoamines 3. Direct agonist of dopamine and 5- HT

receptors 4. Antagonist at certain adrenoreceptors.

ANTIPSYCHOTICS

Phenothiazines. inhibition of GABAergic neural transmission.

Zotepine. This drug has a high affinity for the 5-HT1 binding sites in the cerebral cortex. This property is considered to induce seizures.

Other drugs:- Clozapine, Olanazapine.

BETA- LACTAM ANTIBIOTICS.

These antibiotics are known to have potent convulsant activity in humans.

Penicillin produces focal seizures in epileptic patients.

A possible mechanism of epileptogenic effect is via the blocking of GABA's effect when the beta-lactam ring binds to GABA receptors.

Cephalosporins and carbapenems might also induce convulsions through the inhibition of GABA receptor binding when they accumulate in the central nervous system.

CYTOKINES (IMMUNOMODULATING AGENTS)

Several cytokines are used as therapeutic agents.

Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis

ASPIRIN

The CONVULSANT effect of aspirin are almost entirely mediated by the salicylic acid that is formed by hydrolysis of the drug.

THYROXIN

Thyroid hormones lower the seizure threshold in humans and cause seizures in patients with Graves disease.

Thyroxin can exacerbate absence seizures in juvenile myoclonic epilepsy.

NICOTINE Nicotine, a powerful stimulant at lower doses, produce clonic convulsions at higher doses, reported to contraindicated in epileptics due to its seizure precipitant property at subconvulsant doses.

LITHIUM & PILOCARPINE TOGETHER

Induce Status Epilepticus. The combined treatment with Lithium and

Pilocarpine results in an accumulation of inositol monophosphate and reduction in cortical inositol results in convulsion.

LITIUM = INHIBITOR OF INOSITOL MONOPHOSPHATASE THUS INHIBIT FORMATION OF INOSITOL FROM IP3 == RELEAE CALCIUM = THUS EXCITATION.

PILOCARPINE = ACTIVATE MUSCARINIC CHOINERGIC RECEPTOR. = EXCITATION