Def- It is a collective term applied for a group of convulsive disorders
The common features of epilepsy are
Loss or disturbance of consciousnesses
Characteristic body movements (usually, but not always)
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
Gbapentine
8. Miscellaneous
Trimethadione
Acetazolamide
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
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. Primdone
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
It suppresses seizure spread from the epileptogenic focus and is effective in absence and myoclonic seizures , but tolerance develops
Clonazepate
Clorazepate is effective in partitial seizures when used in conjunction with other drugs
Diazepam
It is effective against
Pedestal epilepsy
Mylclonic seizures
Status epilepsy
It is drug of choice for status epilepticus
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 situations
Anti - parkinsonism
It was described b James Parkinson in 1817 and is therefore named after him
Parkinsonism is a chronic , progressive, motor disorder
Characterized by
Akinesia
Muscular rigidity
Tremors
Other symptoms
Excessive salivation
Abnormalities of posture and gait
Seborrhea
Mood changes
The incidence is about 1% of population above 65 years of age
It is usually idiopathic in origin but can also be drug induced
In idiopathic parkinsonism, there is degeneration of nigrostriatal neurons in the basal ganglia resulting in dopamine deficiency
The balance between inhibitory dopaminergic neurons and excitatory cholinergic neurons is disturbed
Antiparkinsonian drugs
It can only help to alleviate the symptoms and improve the quality of life
The two strategies in the treatment are
1. To enhance dopamine activity
2. To depress cholinergic over- activity
Classification of Anti parkinsonism drugs
1. Drugs that increase dopamine levels
A. Dopamine precursor
Levodo[a
B. Drugs that release the dopamine
Amantidine
C. Dopaminergic agonists
Bromocryptine
Lisuride
D. Inhibit dopamine metabolism
MAO inhibitors - Selegiline
11. Drug influencing cholinergic system
A. Central anticholinergics
Bintropine
Benzhexol
Biperidine
B. Antihistamines
Diphenhydramine
Promethazine
Etiology and pathogenesis
The causes of neuron degeneration in parkinsonism diseases remain largely unknown
According to oxidative stress theory oxidation of dopamine in the basal ganglia yields highly reactive free radicals that are toxic to dopaminergic neuron and lead to their degeneration
The basal ganglia are a group of interconnected sub cortical nuclei the it include the striatum (caudate and putamen), substantial nigra, globus pallidus and sub thalamus
In healthy individuals, the basal ganglia receive input from the entire cerebral cortex, process this information and send feedback to the motor area of the cortex in a way that leads to the smooth coordination of body movements
Even simple movements such as walking ,involve a complex sequence of motor acts whose smooth execution requires the continuous interplay of the cortex and basal ganglia
In patients with parkinsonism disease , neuron degeneration interrupts this interplay
The basal ganglia function via a series of reciprocal innervations among themselves and the cortex
The striatum receives input from the cerebral cortex and substantial nigra and then sends output to the thalamus via the globus pallidus
The thalamus then feeds information aback to the motor area of the cortex
Two pathways connect the striatum and the thalamus , a direct pathway , which is excitatory and an indirect pathway, which is inhibitory
In patients with parkinsonism disease, t eh degeneration of dopaminergic neuron results in decreased activity in the direct pathway and increased activity in the indirect pathway
As a result, feedback to the cortex is reduced and patients exhibit bradykinesia and rigidity
Excitory cholinergic neurons also participate in the interconnections between structures in the basal ganglia
In parkinsonism disease the degeneration of inhibitory dopaminergic neurons leads to a relative excess of cholinergic activity in these pathways
For this reason, patients with parkinsonism disease can be treated effectively with drugs the inhibit cholinergic activity in the basal ganglia or with drugs that increase dopamine levels and doaminergic activity in the basal ganglia
Levodopa
Acetylcholine and dopamine are excitatory and inhibitory neurotransmitters in the corpus striatum
The dopaminergic system is impaired in parkinsonism, so the balance is disturbed
Levodopa acts by getting converted to dopamine and restoring the balance
Parkinsonism is due to dopamine deficiency
Levodopa improves all the manifestations of parkinsonism
But it is not effective in drug induced parkinsonism
Decarboxylase inhibitors like carbidopa are administered with levodopa
They decrease the peripheral decarboxylation of levodopa
Dopamine is of no therapeutic value because it dies not cross the blood- brain barrier
Levodopa is a prodrug which is converted to dopamine in the body
It crosses the Blood- Brain-Barrier and is taken up by the surviving nigrostriatal neurons
Decarboxylase
Levodopa ------------------------------------------- Dopamine
Actions
On administration of levodopa, there is an overall improvement in the patient as all the symptoms subside
Other actions
CTZ - Dopamine stimulates CTZ to induce vomiting
CVS - Large amounts of levodopa converted to dopamine in the periphery causes
postural hypotension and tachycardia. Dopamine is a catecholamine
Endocrine -- Dopamine suppresses prolactin secretion
Pharmacokinetics
Levodopa is rapidly absorbed from the small intestine
The presence o food delays absorption
Some amino acids in the food compete with levodopa for the absorption and transport to the brain
It undergoes first pass metabolism in the gut and the liver
Its half life is 1-2 hours
Adverse reactions
Large amounts of levodopa is converted to dopamine is the periphery, several adverse effects are expected
Nausea, vomiting, postural hypotension ,palpitation and occasionally arrhythmia can occur
Tolerance develops to these effects after some time
Behavioral effects like anxiety, depression , hallucinations and sometimes psychosis can occur
Use
Levodopa is the most effective drug in idiopathic parkinsonism but is not useful in drug induced parkinsonism
Drug interactions
Pyridoxine enhances peripheral decarboxylation of levodopa and reduces its availability to the CNS
Phenothiazines, metoclopramide and reserine are DA antagonists.
They reverse the effects of levodopa
Carbidopa and benserazide
These Are Peripheral Dopa Decarboxylase Inhibitors
When carbidopa or bensrazide are given with levodopa, they prevent the formation of dopamine in the periphery
They do not cross the BBB and hence allow levodopa to reach the CNS
The combination is synergistic and therefore levodopa is always given with carbidopa or benserazide
Advantages of combination
Dose of levodopa can be reduced by 75%
Response to levodopa appears earlier
Side effects like vomiting and tachycardia are largely reduced
Pyridoxine does not interfere with treatment
Amantadine
It is an antiviral drug
It enhances the release of dopamine in the brain and diminishes the re-uptake of DA
The response starts early and its adverse effects are minor
Large doses produce insomnia, dizziness, vomiting , postural hypotension , hallucinations and ankle edema
Amantadine id used in mild cases of parkinsonism
It can also be used along wit h levodopa as an adjunct
Bromocriptine
It is an ergot derivative having dopamine agonistic activity at D2 receptors
It is used as
An adjunct to levodopa in the management of on- off phenomenon
An alternative inn patients unable to tolerate levodopa
Adverse effects
It include vomiting , postural hypotension, hallucinations, skin eruptions and first dose phenomenon - sudden cardiovascular collapse
Lisuride and pergolide are similar to bromocriptine
Seleglline
It is a selective MAO- B inhibitor
MAO- B is present in DA containing regions of the CNS
Selegilline prolongs the action of levodopa by preventing its degradation
Selegiline may delay the progression of parkinsonism
Uses - Mild cases of parkinsonism are started on selegiline. ’It is also used as an adjunct to levodopa
Anti- cholinergic
The cholinergic over activity is overcome by anticholinergics
Tremors, seborrhea and sialorrhiea are reduced more than rigidity
Atropine derivatives like benzhexol, benztropine, trihexyphenidyl are used
Antihistamines owe their beneficial effects in parkinsonism to their anticholinergic properties
Atropine like side effects such as dry mouth , constipation, blurred vision may be encountered
Uses
Anticholinergics are used as
Adjunct to levodopa
Drugs of choice in drug induced parkinsonism
Drug induced parkinsonism
Drugs like reserpine., metoclopramide and phenothiazines can induce parkinsonism
Reserpine depletes catecholamine stores, metoclopramide and phenothiazines are dopamine antagonists
Treatment withdrawal of the drug usually reverses the symptoms
When drugs are needed, one of the anticholinergics are effective
