antidepressants

Thursday, October 14, 2010

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

Petit mal epilepsy
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
  1. Inhibition of t he sodium or calcium influx responsible for neuronal depolarization
  2. Augmentation of inhibitory GABA neurotransmission
  3. 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

  1. Enhancement of GABA
  2. Inhibition of Na channelfunction
  3. Ca channel blockers
  4. Glutamate receptor blockers

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