Anticonvulsant or Antiepileptic - JU Medicine · 2020. 7. 25. · Initially marketed for Trigeminal Neuralgia. (a type of headache might be confused with migraine headache which affects

Anticonvulsant or AntiepilepticDrugs

Munir Gharaibeh, MD, PhD, MHPE

School of Medicine, The University of Jordan

February, 2019

Note Done by : Raneen Hamdan

Corrected by :Haneen Khriesat

Anticonvulsant or Antiepileptic Drugsor antiseizure

Epilepsy: a disease characterized by recurrent attacks of convulsions and seizures.

Convulsion (Fit): the attack itself .(describes what happens to the patient)

Seizure: an abnormal electrical activity, not

necessarily to result in a convulsion.

-Epilepsy, convulsions and seizures can be used interchangeably as synonyms, but they are actually (scientifically) different.

- One incidence (fit) of the disease is called convulsion.

- A patient may have a convulsion once in his life, but he might not develop a disease (epilepsy) because epilepsy is defined as recurrentattacks of convulsions and seizures.

Neuronal Mechanisms involved in Seizures

Munir Gharaibeh, MD, PhD,MHPEFebruary194

Suppression of Inhibition---Onset

(brain has inhibitory and excitatory mechanisms and inhibition of

inhibition leads to over activity of excitatory mechanisms)

Post-tetanic Potentiation---Spread and

Maintenance (of abnormal electrical activity)

Reinstitution of Inhibition---Termination(the inhibitory mechanisms in the brain will take over again after

being disinhibited)

Pathophysiological Conditions Enhancingconvulsions


LowPO2(hypoxia)

HighpH(alkalosis)

Increased IntracranialPressure

LowCa++(hypocalcemia)

LowGlucose(hypoglycemia)

Overhydration

Fatigue

EmotionalState

Causes of Convulsions


Poisons(chemical and non chemical)

Trauma(to the head)

Infection(causes fever, which is one of the causes of

convulsion especially in children before age of 1 = infants)

Space Occupying Lesions(like a tumor, hemorrhage or

thrombosis)

Fever

Drugs

Idiopathic, Epilepsies (in most cases)


classifications vary between different sources and books .

/ localized

*Complex partial seizures might be confused with psychological and psychiatric problems

Classification of Epilepsies


Grand Mal or Major Epilepsy or Tonic-Clonic Epilepsy:

8

characterized by:

1-Aura(the patient feels that he will get an attack and that there is

something wrong with him and he might suffer from visual or auditory

hallucinations; just like schizophrenic patients)

*aura happens in migraine patients

2-Cry-Loss of consciousness(spasm of the vocal cords, followed by a

rush of air through these spastic vocal cords causing crying or loud

voice followed by loss of consciousness which might continue all

through the attack as well as afterward)3-Tonic Phase: Rigid violent muscle contraction with limbs fixed.

4-Clonic Phase: Repetitive muscle jerks (shaking)5-Post-ictal depression and incontinence(the patient goes into deep

sleep lasts for hours or very long period of time relative to the attack

itself, this is accompanied with loss of reflexes and urination)

February 19 Munir Gharaibeh, MD, PhD, MHPE 8

*Different phases of tonic-clonic type of epilepsy



Petit Mal or Minor Epilepsy or Absence States:

Psychomotor Epilepsy:(characterized by)

Clouded dreamy feeling

Automatic movements

Aggressiveness

A Condition characterized by absence state; you might see the patient with a brief loss of consciousness that happens many times a day, one episode may last for less than a minute or a few minutes . it happens in children and may retard the learning process ,usually these attacks are noticed and reported when the child goes to school by his teacher . It was proved that these absent states are triggered by TV or mobile light .

*Could be confused with conditions like schizophrenia or psychotic conditions.



Status Epilepticus (recurrent attacks during the day despite

the usual treatment, so the patient is taking his regular treatment

but the attacks come recurrently)

Parietal Lobe Epilepsy

Infantile Myospasm (benign attacks of epileptic convulsions

characterized by sudden movements or spasms of the upper and

lower limbs which usually occurs in infants less than 1 year of

age, sometimes they are called ”Salaam attacks”, the baby will

extend his hands as if he is greeting people )

etc…..

Regarding the table : *The electrical activity of the brain is recorded or detected by electroencephalogram (EEG ). *In absence seizures (petit) the recorded waves are small waves or spikes and they are presented all the time , in other conditions you might find abnormal EEG during the attacks but not in between.

Provocative Procedures*experimental procedures have been done on animals, you can provoke epileptic attacks by giving drugs like:


Pentylene tetrazole "Metrazole"(which was used as a CNS stimulant to stimulate respiration in respiratory depressed patients/patients with hypoventilation but it's no longer used )

Hyperventilation(might result in respiratory alkalosis which can provoke or enhance convulsion attacks )

Photic stimulation - Flicker Fusion (important in absence state )

Principles of Epilepsy Treatment


* Seizures are self-limiting ( we don’t treat the seizure we treat the disease (epilepsy) so you have to leave the seizure and let it go by itself, but you have to protect the patient during the attack {protect him from falling down + breaking his body/head/limbs + biting his tongue}and you have to ensure a patent airways)

* Use one drug at a time( Monotherapy):

Lower incidence of adverse reactions.

Avoidance of drug interactions.

Improved patient compliance.

Lower medication cost.

* Start with a small dose.(start with a small dose, then you can increase it with time or keep it as it is )

* Monitor serum level.

Notes on the table :-SRF=sustained high frequency repetitive firing-GABA ( and its agonists ) activity in the brain is inhibitory- Calcium currents :1- T , IN THE BRAIN 2-M 3-N

Notes on the picture :- Sodium channels present in 3 phases :1- closed but capable of opening 2- open/activated3- closed and not capable of opening (inactivated)- So activity refers to opening of channels and allowing sodium current to enter as a result of the arrival of the action potential to a certain point in the membrane of neurons

Barbituratesthe long acting barbiturates are utilized in the treatment and prevention of epileptic attacks, especially when we talk about:


Phenobarbital

Mephobarbital

Methabarbital

Primidone

Barbiturates


Oldest but still used. ( since 1930s )

Relatively safe, but sedating.(cause excessive sedation, so children under the influence of this drug will not be able to learn in school normally compared to their peers )

Effective in Grand mal and partial seizures.

Might worsen patients with other types.

Bind to GABA receptor, to prolong opening of Cl- channels.

Also, at high doses, block Na+ and Ca++ channels (L and N

type).

Also block Glutamate receptors.

Barbiturates

Adverse Effects:


Drug Interactions (they are highly bound to plasma proteins so they can displace other drugs from their binding sites on proteins and cause drug interactions)

Enzyme Induction ----- Withdrawal!!(they can induce the metabolism of other drugs as well as their own, so this cause lowering of barbiturate blood levels and we will need to increase the dose to achieve the desired effect . Withdrawing the drug will lead to the recurrence of the epileptic attacks )

Sedation

Allergies

Anemia

Additive to CNS depressants.(like alcohol and benzodiazepine)

Phenytoin(1938)


(Diphenyl Hydantoin DPH- the old name)

Generalized tonic - clonic seizures

Partial seizures with complex symptomatology

Antipsychotic

Antiarrhythmic

Many others

Revolutionary

*good for digitalis induced cardiac arrhythmia

*used in healing skin ulcers as cream also in diabetic patients

* Almost all types of epilepsy can be treated with phenytoin

Phenytoin


Mechanism of Action:

Acts on several physiologic systems.

Major action is sodium channel blockade, arising from preferential

binding to and prolongation of the inactivated state of the Na +

channel.

Also, inhibits Ca++ influx, membrane potential, as well as, the

concentrations of amino acids, NE, ACh, and GABA .

Blocks sustained high-frequency repetitive firing of action

potentials(SRF).

*all will lead to suppression of epileptic activity in the brain

Phenytoin


Pharmacokinetics:

–Slow absorption(from GIT)

–90% bound to proteins.

–Metabolized:

Zero order in high doses used in epilepsy, so, no

SSL achieved.(SSL=steady state level>>it doesn’t follow first order kinetics in which you can achieve a steady state level if you give a

definitive dose every half life, but here if you give the drug at half life, it

will keep going up in zero order meaning that it depends on the timing

but first order depends on half life)

–Interactions:

Protein binding. (high binding capability so

it can replace other drugs for their binding site)

Enzyme induction.(induce metabolism of

other drugs)

Phenytoin


Adverse Effects: (not serious and tolerable by the patient; because it is very effective drug in the suppression of epileptic attacks )

Skin rashes, fever

Blood: megaloblastic anemia, agranulocytosis,lymphadenopathy.

Hirsutism

"Hydantoin Facies"(patients receiving the drug will have peculiar faces )

Peripheral neuropathy

Cerebellar degeneration(causes ataxia and dizziness)

Gingival hyperplasia (50%)

Teratogenic ------- Folate Deficiency(might cause congenital abnormalities)


Hirsutism

Hypertrophy of gums might need excision and it will

not be reduced by reducing the dose or after stopping

the drug(irreversible )

Cause skin allergic reaction

and hirsutism

Phenytoin


Overdose:(these are signs of cerebellar degeneration)

Nystagmus,

Ataxia,

Vertigo,

Diplopia

Loss of consciousness.

Carbamazepine


Partial seizures

Generalized tonic - clonic

Like phenytoin and barbiturates, it is not useful for petit mal

Initially marketed for Trigeminal Neuralgia.(a type of headache might be confused with migraine headache which affects the trigeminal nerve)

Bipolar mood disorders, it is a tricyclic compound.(very important in the treatment of depression and mood disturbances)

Peripheral Neuropathy (in diabetic patients)

Migraine ------------ etc

Carbamazepine


Mechanism of Action:

Like phenytoin, blocks Na+ channels.

Carbamazepine


Slow and erratic absorption (absorbed from GIT)

T½ 12-60 hr.(wide range , vary between patients)

Induces liver enzymes = Autoinduction.(induce the metabolism of its own)

Interactions.

Blood monitoring is necessary.

Carbamazepine


Adverse Effects:

Vertigo , Ataxia , Diplopia appear early.

Drowsiness , nausea , headache, dizziness.

Tolerance develops to the above effects.

Skin rashes , fever , hepatosplenomegaly , lymphadenopathy.

Blood dyscrasias: leukopenia, aplastic anemia, and

agranulocytosis.

Oxacarbazepine.


*it's a derivative of carbamazepine

Less capacity to induce enzymes.

T½1-2hr.

May be safer than carbamazepine

Vigabatrin


GABA-Transaminase irreversible inhibitor, which

breaks down GABA in the brain. (increasing the level of GABA in the brain )

Renal elimination. ( won't affect liver enzymes activity)

Partial seizure

Not for absence or myoclonic

Well tolerated: drowsiness, dizziness, weight gain,

visual field defects.

Lamotrigine


Inhibits Na+ and Ca++ channels, also decreases release of

glutamate. (glutamate is an excitatory neurotransmitter in the brain so if you decrease glutamate and inhibit sodium and calcium channels this will enhance the inhibitory activity of the brain)

Partial and generalized seizures

Completely absorbed

Glucoronidated, so will not induce or inhibit

enzymes(glucoronation (conjugation with glucuronic acid ) in liver, so it is not metabolized by microsomal liver enzymes and not fully metabolized by oxidizing liver enzymes)

Side Effects:

Similar to carbamazepine.

Skin rashes

Cerebellovestibular symptoms.

Gabapentin and Pregabalin


GABA analogs, but work indirectly to increase GABA levels in

the brain.

Partial Seizures.

Good PK Properties.(PK= pharmacokinetics)

Effective when combined with others.

Safe: somnolence, dizziness, ataxia.

Benzodiazepines


GABA mechanism, and Na+ channel inhibition in doses used in

status epilepticus.

*classified as sedative hypnotic agents and have antiepileptic activity

* They intensify chloride entrance through GABA receptors {GABA receptor permits cl- as inhibitory ion inside the cell while barbiturate prolong entrance of cl-}

Benzodiazepines

•Diazepam ----------- Status epilepticus){10mg IV}

•Lorazepam ---------- Longer acting(one injection compared to multiple injections of diazepam )

•Clonazepam --------- Petit mal, but causes


Nitrazepam

sedation and drooling

-------- Infantile Spasms

Infantile spasm might not need treatment, they usually disappear after the first year of life, but if the attacks are very frequent and parents required treatment, then this is the drug of choice.

Valproic Acid(old new drug-was used as an organic solvent in laboratory)


Increases GABA levels by enhancing synthesis and inhibiting

transaminase. (which breakdown GABA)

Also, blocks NMDA receptors(glutamate receptor), Na+ channels and

T-Ca++ channels.

90% bound to plasma proteins.

Valproic Acid (1969)


Petit mal and myoclonic epilepsy

Mixed seizures.

Bipolar disorder and migraine prophylaxis.

Valproic Acid


Toxicity:

Hepatotoxic

Neural tube defects(in pregnant women)

Thrombocytopenia.

Alopecia

GI.

Inhibits metabolism of many drugs.

Ethosuximide (1960s)


Blocks transient Ca++ currents.

Petit mal, still first choice.

Safe.

Acetazolamide


Diuretic, works by inhibiting Carbonic Anhydrase

Enzyme, so decreases intracellular pH, causing mild acidosis.

*carbonic anhydrase enzyme responsible for the conversion of H2CO3 into HCO3 and H+

*it is a weak diuretic and it is used in the treatment of glaucoma

*alkalosis is one of the conditions that enhance convulsions so by reducing PH we can

indirectly control seizures.

Helpful in all types of seizures.

Used as an adjunct to others in refractory seizures.

Tolerance develops.

Special role for seizures at the time of menses( alone or in

combination with other drugs )

Regarding the table :

*Blood levels are very important in control and follow up of epileptic patients, we have to make sure the drug level is within the acceptable range ( above the rangeside effects appear and below the range appearance of epileptic attacks) *you have to distinguish between most serious and most frequent adverse effects*the numbers in the boxes are the only ones mentioned by the doctor

Documents

Anticonvulsant or Antiepileptic - JU Medicine · 2020. 7. 25. · Initially marketed for Trigeminal Neuralgia. (a type of headache might be confused with migraine headache which affects