Anti- Epileptic drugs
What is epilepsy
Epilepsy is a common condition that causes repeated seizures.The seizures are caused by bursts of electrical activity in the brain that are not normal.
Seizures may cause problems with muscle control, movement, speech, vision, or awareness.
They usually don't last very long, but they can be scary.
The good news is that treatment usually works to control and reduce seizures.
Epilepsy is not a type of mental illness or retardation. .It does not affect - think or learn.
Causes
Head injury,Brain tumor,
Brain infection,
Stroke
Symptoms
The main symptom of epilepsy is repeated seizures that happen without warning.Without treatment, seizures may continue and even become worse and more frequent over time.
There are different kinds of seizures. You may have only one type of seizure.
Some people have more than one type.
Depending on what kind of seizure you have:
- Your senses may not work right. Ex - you may notice strange smells or sounds.
- You may lose control of your muscles.
- You may fall down, and your body may jerk.
- You may stare off into space.
- You may lose consciousness.
- Autonomic hyperactivity
It is a common neurological abnormality affecting about 1% of the world population
It is a collective term applied for a group of convulsive disorders
Seizure – Abnormal discharge at high frequency, from an aggregate of neurons in cerebral cortex
Def- It is a condition characterized by recurrent episodes of seizures
The site of the origin of discharge is called epileptic focus. From the discharge spreads to the surrounding areas of the brain
Classification
1. Generalized seizures –
Involving the entire body widespread electrical discharge that involves both sides of
the brain at once.
Hereditary factors are important in many of these seizures.
Occupying 60%
A. Grand Mal or Tonic – Clonic epilepsy
B. Petit Mal or Absence of seizures
C. Myoclonic epilepsy
D. Atonic epilepsy
E. Clonic epilepsy
F. Tonic epilepsy
2.Partial seizures (Localized seizures )
Partial seizures begin with an electrical discharge in one limited area of the brain.
Some are related to head injury, brain infection, stroke, or tumor, but in most cases the cause is unknown.
Occupying 60% of the patients
The seizure activity is restricted to a discreet area belonging to one cerebral hemisphere only
A. Simple partial seizures
B. Complex partial seizures
Generalized Seizures (Produced by the entire brain) | Symptoms | Drugs |
1. "Grand Mal" or tonic- clonic | Unconsciousness, Convulsions, Muscle rigidity Muscle contraction & relaxation | Phenytoin, primidone, phenobarbitone, carbamazepine, Sodium valproate |
2. Absence or Petit mal epilepsy | Muscle - No movement, Staring Lack of awareness of surroundings Sudden halt in conscious activity Brief loss of consciousness | Ethosuximide, valproate, clonazepam |
3. Clonic (One in which the contractions are intermittent) | Jerking movements Clonic seizures consist of rhythmic jerking movements of the arms and legs, sometimes on both sides of the body. | |
4. Tonic (restore to normal) | Muscle stiffness, rigidity | |
5. Atonic | Loss of muscle tone | |
6. Myoclonic | Seizures are brief, shock-like jerks of a muscles "Myo" means muscle and "clonus" means rapidly alternating contraction and relaxation—jerking or twitching—of a muscle. | |
Partial Seizures (Produced by a small area of the brain) | Symptoms | Drugs |
1. Simple (awareness is retained) | Phenytoin, Primidone, Carbamazepine, Sodium valproate | |
A. Simple Motor | Jerking, Muscle rigidity, Spasms, Head-turning | |
B. Simple Sensory | Unusual sensations affecting either the vision, hearing, smell taste, or touch | |
C. Simple Psychological | Memory or emotional disturbances | |
2. Complex partial (Impairment of |
Grand mal epilepsy
Symptoms
- Loss of consciousness
- General muscle contraction and rigidity (tonic posture)
- Violent rhythmic muscle contraction and relaxation (clonic movement)
- Biting tongue, clenched teeth or jaw
- Incontinence (loss of urine or stool control)
- Stopped breathing or difficulty breathing during seizure
- Blue skin color
A petit mal seizure is most commonly called an "absence seizure."
It is a brief (usually less than 15 seconds) disturbance of brain function due to abnormal electrical activity in the brain.
Petit mal seizures occur most commonly in people under age 20, usually in children ages 6 to 12.
Symptoms:
Muscle - No movement, Fluttering eyelids, Lip smacking, staring
Lack of awareness of surroundings
Sudden halt in conscious activity
Full recovery of consciousness, no confusion
Generalized Seizures
There are six types of generalized seizures.
The most common and dramatic, and therefore the most well known, is the generalized convulsion, also called the grand-mal seizure.
1.Gramd mal epilepsy
The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase).
During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.
2. Absence seizures
These cause a short loss of consciousness (just a few seconds) with few or no symptoms.
The patient, most often a child, typically interrupts an activity and stares blankly.
These seizures begin and end abruptly and may occur several times a day.
Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time."
3. Myoclonic seizures
It consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks.
When violent, these seizures may result in dropping or involuntarily throwing objects.
4. Clonic seizures
These are repetitive, rhythmic jerks that involve both sides of the body at the same time.
6. Tonic seizures
These are characterized by stiffening of the muscles.
6. Atonic seizures
It consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.
CLASSIFICATION
1. Hydantoins
Phenytoin
2. Barbiturates
Phenobarbitone
Primidone
3. Iminostilbbenes
Carbamazepine
4. Succinimides
Ethosuximide
5. Aliphatic carboxylic acid
Sodium valproate
6. Benzodiazepines
Clonazepam
Clobazam
Diazepam
7. Newer antiepileptic
Lamotrigine
8. Miscellaneous
Trimethadione
Acetazolamide
Generalized epilepsy |
Preferred drug Alternative drug
Tonic - clonic | |||||
Phenytoin Carbamazepine | |||||
Phenobarbitone Primidone | |||||
Petit mal | |||||
Ethosuximide | |||||
Valproic acid | |||||
Myoclonic | |||||
Valproic acid | |||||
Clonazepam | |||||
Status epilepsy | |||||
Phenytoin | |||||
Diazepam Lorazepam | |||||
Partial epilepsy | |||||
Simple partial | ||
Phenytoin Carbamazepine | ||
Phenobarbitone Primidone | ||
Simple partial | ||
Phenytoin Carbamazepine | ||
Phenobarbitone Primidone | ||
Simple Complex | ||
Phenytoin Carbamazepine | ||
Primidone | ||
Drugs for the treatment | Mechanism Of action | ADME | Adverse effects | Dose | Uses |
1. Phenytoin | Na channel Blockers Increases the refractory period | Oral Half life- 24 hrs Enzyme inducer | 25 – 100 mg | Tonic clonic Simple and complex partial epilepsy Status epilepsy | |
2. Carbamzepine | Na channel Blockers Increases the refractory period | Oral Enters brain due to high fat solubility Enzyme induce | 00 – 200 mg | Tonic clonic Simple and complex partial epilepsy | |
3. Valproic acid | Na channel Blockers Increases the refractory period | Broad spectrum Oral It inhibit the metabolism of number of epileptic drugs | 200 -500 mg | Tonic clonic Peitit mal, myoclonic | |
4. Ethosuximide | Inhibit the Ca in particularly in thalamus | Oral Not bound to plasma proteins | 750 -1000 mg | Petit mal | |
5. Primidone | Na channel Blockers Increases the refractory period | Oral Same ad phenobarbitone | 500 – 5000 mg | Tonic clonic epilepsy Simple and complex epilepsy | |
6. Barbiturtates | Na channel Blockers Increases the refractory period | Oral Penetrate into brain Enzyme inducer | 30 -60 mg | Simple partial epilepsy Tonic clonic Status epilepsy | |
7. Diazepam | GABA receptor Hyperpolarizaiton | acute | 5 mg/ml | Status epilepsy | |
8. Lorazepam | GABA receptor Hyperpolarizaiton | chronic | 5 mg/ml | Status epilepsy | |
9. Clonazepam | GABA receptor Hyperpolarizaiton | acutes | 5 – 15 mg | Petit mal Myoclonic |
1. Phenytoin
Phenytoin was synthesized in 1908, but its anticonvulsant property was discovered only in 1938
It is effective in suppressing tonic-clinic and partial seizures and is a drug of choice for initial therapy, particularly in treating adults
Mechanism of action
Antiepileptic drugs are believed to suppress the formation or spread of abnormal electrical discharges in the brain
There are different mechanisms
- Inhibition of t he sodium or calcium influx responsible for neuronal depolarization
- Augmentation of inhibitory GABA neurotransmission
- Inhibition of excitatory glutamate neurotransmission
1. Effect on ion channels
Under normal circumstances, voltage- sensitive ( voltage gated) sodium channels are rapidly opened when t he neuronal membrane potential (voltage) reaches its threshold
This causes rapid depolarization of the membrane and the conduction of an action potential along the neuronal axon
When action potential reaches the nerve terminal . it evokes the release of a neurotransmitter
After the neuronal membrane is depolarized, the sodium channels is inactivated by closure of the channels inactivation gate
The inactivation gate must be opened before the next action potential can occur
Many antiepileptic drugs , including carbamazepine, lamotrigine, phenytoin and topiramate prologs the time that the sodium channels inactivation gate remains closed and this delays the formation of the next action potential
These drugs bind to the channel when it is opened a greater percentage of the time than are slowly firing neurons, the drugs exhibit use dependent blockade
For this reason , the drugs suppress abnormal repetitive depolarization in a seizure focus more than they suppress normal activity
By these action, carbamazepine and other drugs prevent the spread of abnormal discharges in a seizure focus to other neurons
A few drugs ( Ex – ethosuximide and valproate) block T- type ( low- threshold ) calcium channels that are located in thalamic neurons and participate in the initiation of generalized absence seizures
2. GABA ergic systems
Antiepileptic drugs facilitate GABA neurotransmission by various means
Benzodiazepines (eg- clonazepam ) and barbiturates ( eg – Phenobarbital ) enhance GABA activation of the GABA A , receptor- chloride ion channel
Topiramate is believed to enhance activation of the GANA A receptor, Ganapentin increases GABA release , whereas valproate inhibits GABA degradation
Drugs that augment GANA may serve to counteract the excessive excitatory neurotransmission responsible for initiation and spreading abnormal electrical discharges
3. Effects on glutaminergic systems
A few antiepileptic drugs, including felbamate, topiramate and valproate , inhibit glutamate neurotransmission and other drugs that work via this mechanism are under development
This is an attractive mechanism of action because it may affect the formation of a seizure focus and thereby terminate a seizure at an early stage of its development
Seizure is caused by the synchronous discharge of a group of neurons in the cortex
Activation of N- methyl-D- aspartate (NMDA) receptors increases calcium influx and nitric oxides synthesis
NO then diffuses to presynpatic neuron and increases the release of glutamate via formation of cyclic guanosine monophosphate
Increased excitatory glutamate neurotransmission leads to long term potentiation
Long term potentiation is believed to facilitate a depolarization shift , characterized by prolonged depolarization s with spikelets
The depolarization shift can cause adjacent neurons to discharge synchronously and thereby precipitate a seizure
Pharmacological action
Phenytoin exerts antiseizure activity without causing general depression of the CNS
It is one of the most effective drugs against generalized tonic-clonic seizures and partial seizures
Phenytoin reduces the propagation of abnormal impulses in the brain
Phenytoin prevents the spread of seizures more than that of barbiturates
The drug has membrane stabilizing effects on all neuronal membranes including the peripheral nerve membrane as well as on all non- excitable and excitable membranes
The conversant action produced by drugs like strychnine , picrotixin and pentylenetetrazole are not blocked by phenytoin and the maximal electro shock seizures are effectively controlled by phebytoin
Besides , antiepileptic effects, phenytoin also produces antiarrhythmic effects and is useful in digitalis induced arrhythmias
Pharmacokinetics
Phenytoin is slowly and variably absorbed from the GIT and the peak plasma concentration occurs 3- 12 hrs after ingestion
In plasma it is 70- 95% bound to protein, mainly Albumin
It is metabolized in liver
Phenytoin is enzyme inducer
The inactive metabolite is excreted from the bile, subsequently in urine as a glucronide
Preparation and dose
Phenytoin Sodium I.P
Available as 50 mg and 100 mg Tablets I,V
Preparation containing 50 mg /ml is also available
Normal dose - 3- 4 mg/kg/day
Adverse effects
Toxicity depends upon dose , duration and route of administration
Phenytoin inhibits insulin release and produces hyperglycemia
Decreases the release of ADH
Osteomalacia , hypocalcaemia due to altered metabolism of vitamin D and inhibition of intestinal absorption of Ca
Chronic oral medical effects is dose related and causes change in behavioral effects , increased frequency of seizure , gastric irritation accompanied by nausea and vomiting
If large amounts are administered intravenously for cardiac arrhythmia or status epileptics the most important toxic symptoms are cardiovascular collapse or central nervous system depression
Gingival Hyperplasia - Hyperpalasia and hypertrophy of the gums with edema and bleeding occur.. It is common in children’s
Hypersensitivity - Rashes , hepatic necrosis , and neutropenia
Megaloblastic anemia – Phenytoin decreases absorption and increases excretion of folates
Teratogenicity
When taken by the pregnant lady, phenytion produces fetal hydantion syndrome characterized by hypo plastic phalanges, cleft palate, and harelip
Hirsutism - Coarsening of facial features ( troublesome in young girls ) , acne
Drug interactions
Phenytoin is an enzyme inducer
Ethanol inactivates phebytoin
Phenytoin given with phenobarbitone , both increases each other metabolism
Phenytoin and carbamazepine enhance each others metabolism
Valproate displaces protein bound phenytoin
Cimetidine and chloramphenicol inhibit the metabolism of phenytioin resulting in toxicity
Antacids decreases the absorption of phenytoin
Sucralfate binds phebytoin in GIT and decreases its absorption
Therapeutic uses
It is used in all types of epilepsy except petit mal
Phenytoin is highly effective for all partial seizures ( simple and complex), for tonic-chronic seizures and in the treatment of status epileptics
It is specifically useful in grand mal, psychomotor and focal cortical epilepsies
It is also used in cardiac arrhythmias - Dose - 300 – 400 mg/day
Phenytoin is not effective for absence seizures, which often may worsen if treated with this drug
11. Phenobarbitone
Phenobartitone was the first effective antiepileptic drug to be introduced in 1912. It still remains one of the widely used drugs
It has antiepileptic activity and raises the seizure threshold
Mechanism of action
Barbiturates enhances the inhibitory neurotransmission in the CNS by enhancing the activation of GABA receptors and facilitating the GABA mediated opening of chloride ion channels
Pharmacokinetics
It is well absorbed orally
The drug freely penetrates the brain
Approximately 75 % of the drug is inactivated by the hepatic mocrosomal system, whereas the examining drug is excreted unchanged by the kidney
It is a potent inducer of the cytochrome P450 system and when given chronically, it enhances the metabolism of their agents
Half life – 4-5 days
Dose
60 – 180 mg in divided doses
Adverse effects
Sedation, ataxia, vertigo , nausea and vomiting
Agitation and confusion occur at high doses
Rebound seizures can occur on discontinuance of Phenobarbital
Therapeutic uses
\
It provides favorable response for simple partial seizures, but it is not very effective for complex partial seizures
The drug had been regarded as the first choice in treating recurrent seizures in children, including febrile seizures
It also used to treat recurrent tonic-clonic seizures, especially in patients who donot respond to diazepam plus phenytoin
It also used as a mild sedative to relieve anxiety, nervous tension and insomnia
111. Prim done
It structurally related to Phenobarbital and it resembles Phenobarbital in its anticonvulsant activity
It is an alternative choice in partial seizures and tonic – clonic seizures
It has more efficacy due to the its metabolites Phenobarbital and phenyl-ethyl-malonamide which have longer half- lives than the parent drug
It is effective against tonic-clinic and simple partial seizures and phenyl-ethy-lmalonamide is effective against complex partial seizures
Primidone is often used with carbamazepine and phenytoin
It is well absorbed orally
It exhibits poor protein binding
These drug has the same adverse effects as those seen with Phenobarbital
Dose
500 mg – 5000 mg /day
1V. Carbamaepines
Actions
It reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potential in the epileptic focus and preventing their spread
ADME
It is absorbed slowly following oral administration
It enters the brain rapidly because of its high lipid solubility
It induces the drug metabolizing enzymes in the liver
The enhanced hepatic cytochrome p450 system activity also increases the metabolism of many drugs including other antiepileptic drugs
It is an inducer of the cytochromep450 isozyme cyp3a4, which decrease the effects of drugs that are metabolized by his enzyme
Adverse effects
Chronic administration of carbamazepine can cause stupor, coma and respiratory depression
It also produces drowsiness, vertigo, ataxia, and blurred vision
The drug is irritating to the stomach and nausea and vomiting may occur
Drug interaction
The hepatic metabolism of carbamazepine is inhibited by several drugs
Toxic symptoms may arise if the dose is not adjusted
Therapeutic uses
It is effective in Temporal lobe epilepsy
Trigeminal neuralgia
Used in post hepatic pain
Dose
It available as 200 mg tab Initial dose 100 mg thrice daily gradually increased to 600 mg – 1200 mg /day
V. Ethosuximide
It reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting t- type calcium channels in a manner similar to the action of phenytoin on sodium channels
It is the first choice in absence seizures
It is well absorbed orally and is not bound to plasma proteins
About 25% of the drug is excreted unchanged in the urine and 75% is converted to inactive metabolites in the liver by the microsomal cytochrome P450 system
It does not induce P450 enzyme synthesis
The drug is irritating to the stomach and nausea and vomiting may occur on chronic administration
Adverse effects
Drowsiness, lethargy, dizziness , restlessness , agitation , anxiety and the inability to concentrate are often observed
Dose
It is available as 250 mg capsules and as a syrup (250 mg / 5 ml) , initial dose 250 mg, Maximum dose – 750 – 1000 mg
V1. Valproic Acid
It is a broad spectrum anticonvulsant
It has multiple actions , including sodium channel blockade and enhancement of GABAnergic transmission
It is the most effective agent available for treatment of myoclinec seizures
It also diminishes absence seizures, but because of its hepatotixic potential, it is a second choice
It also reduces the incidence and severity of tonic-clonic seizures
The drug is effective orally and is rapidly absorbed
About 90% is bound to the plasma proteins ,only 3% of the drug is excreted unchanged, the rest is converted into active metabolites by the liver
It is metabolized by cytochrome P450 enzymes. Metabolites are excreted by kidney
Adverse effects
It can cause nausea, vomiting ,sedation, ataxia and tremor are common
It inhibits the metabolism of a number of antiepileptic drugs , including Phenobarbital, carbamazepine and ethosuximide
Dose
It is available as capsules containing the equivalent of if 250 mg of valproic acid.
Normally dose 15 mg / kg to be given in divided doses , maximum dose is 60 mg / kg /day
V11. Benzodiazepines
Several of the benzodiazepines show antiepileptic activity
Diazepam and lorazepam are the drugs of choice in the acute treatment whereas
Clonazepam and clorazepate and clorazepate are used for chronic treatment of status epilepticus
Clonazepam
Well observed orally
Maximum concentration is achieved with 2-4 hrs
Protein binding is 85%
Half life is 1 day
The drug is excreted in 1-2 days
It suppresses seizure spread from the epileptogenic focus and is effective in absence and myoclonic seizures , but tolerance develops
Dose
Tab- 0.5 – 2 mg
Diazepam
Well observed orally
Maximum concentration is achieved with 2-4 hrs
Protein binding is 85%
Half life is 1 day
The drug is excreted in 1-2 days
It is metabolized into nordazepam oxzepam. Half life is1-2 days
Use
It is effective against
Status epilepsy
Dose
10 mg/2 ml
Lorazepam
Lorazepam and diazepam are both effective in interrupting the repetitive seizures of status epilepticus.
Lorazepam has a longer duration of action and is preferred by some clinicians
All of the antiepileptics, the benzodiazepines are the safest and most free from severe side effects
All benzodiazepines have sedative properties
Side effects
Drowsiness, Somnolence, Fatigue, Ataxia, Dizziness and behavioral changes Respiratory depression and cardiac depression may occur when given intravenously in acute situationssBarbiturates
These induce sleep
It has 2 components- REM(30%) & NREM (70%)
Dreams occur in REM
Mechanism
- Enhancement of GABA
- Inhibition of Na channelfunction
- Ca channel blockers
- Glutamate receptor blockers
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