Antiepileptic and anticonvulsive drugs

Antiepileptic Drugs

Before knowing anit-epileptic drugs, you must know What is epilepsy?

Epilepsy: Epilepsy is a neurological disorder characterized  by short, recurrent electrical malfunctions of the brain which leads to changes in muscle activity, sensation and consciousness. 

Factors:
Many factors may contribute to the onset of epilepsy

• Brain damage related to birth 
• Brain abnormalities present before birth 
• Brain infections 
• Brain tumors 
• Abnormalities in blood vessels of the brain 
• Head injuries 
• Drug or alcohol abuse 
• Lead poisoning 
• Family history of seizure disorders 
• Stroke 
• Low blood sugar 

Common seizure types of Epilepsy
1-Generalized seizures.

• Absence (petit mal).
• Tonic/clonic (grand mal). 

2-Partial seizures.

• Simple partial seizures.
• Complex partial seizures

NOTE: The type of epileptic seizure determines the drug selected for therapy.

Generalized seizures:
Absence (petit mal): 
These seizures have abrupt onset and cessation, with impaired consciousness, but with normal posture often retained. The EEG shows a typical ‘spike and wave’ pattern.
Tonic/clonic (grand mal): 
Consciousness is impaired and the patient usually falls to the  floor. A phase of muscle contraction (‘tonic’) is followed by irregular muscle clonus and then by sleep. Injury may occur.
Partial seizures:
Simple partial seizures: features depend on the part of the brain affected, result from discharge in the precentral gyrus. Consciousness is unimpaired.
Complex partial seizures (temporal lobe epilepsy):
Consciousness is impaired with complex, often repetitive action.

Pathogenesis:
The neuron in brain lesion depolarizes together suddenly, and then product high-frequency, out-break discharge.
The discharge can diffuse to surrounding normal tissue →extensive excitation →the brain function transient aberration.
Therapeutic principle:
Change the permeability of Na+
Ca2+and K+ in nerve cell membrane, degrade excitement stage, extend refractory phase.
Directly or indirectly increase CNS levels of GABA.

Classification of Antiepileptic Drugs
Hydantoins：Sodium Phenytoin
Barbiturates：Phenobarbital, Primidone
Succinimide：Ethosuximide
Benzodiazepine:  Diazepam, Nitrazepam
Others:  Sodium Valproate

Sodium Phenytoin
Phenytoin is the oldest nonsedative antiseizure drugs, introduced in 1938 following a systematic evaluation of compounds such as phenobarbital that altered electrically induced seizures in laboratory animals. It was known for decades as diphenylhydantoin.

Pharmacokinetics
Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption.
(1) Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 hours to 12 hours.
(2) Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended for phenytion. 
In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration.

The elimination of phenytoin is dose-dependent. 

1. At very low blood levels, phenytoin metabolism follows first-order kinetics.
2. As blood levels rise with in the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached.
3. Further increases in dose, even though relatively small, may pruduce very large changes in phenytoin concentrations.

The half-life of phenytoin varies from 12 hours to 36 hours,with an average of 24 hours for most patients, in the low to mid therapeutic range. 
At low blood levels, it takes 5-7 days to reach steady-state blood levels after every dosage change; at higher levels, it may be 4-6 days before blood levels are stable. 

Mechanism of action:

1. It can block sodium channels (voltage-, frequency-, and time dependent fashion ) and inhibit the generation of action potentials. It can also block L and N type Calcium channels.
2. It can increase the function of inhibitory transmitter GABA, inhibit nerve terminal to uptake GABA and induce the increasing of GABA receptor, thereby enhance GABA-mediated postsynaptic inhibition.

Clinical application

1. Anti-epileptic: It can be used for partial seizures and tonic/clonic seizures, but not for other generalized seizure types.
2. Peripheral neuralgia: ischiadic nerve and cranial nerve.
3. Arrhythmia: membrane-stabilizing action, especially for the cardiac glycoside poisoning, it is the first choice.

Adverse effects
1-Digestive system
anorexia, nausea, vomiting and abdominal pain(recommend to take it after meal). 
2-Gingival hyperplasia
It common occurs in children and teenagers after long term use, the incidence rate is about 20%. Generally, this effect can resolve after drug withdraw 3 to 6 months.
3-Nervous system
diplopia, vertigo, ataxia(usually only at very high concentration). Severe patient occurs language disorder, mental confusion and cataphora
4-Hematological system
Because it can inhibit the absorption of folinic acid and accelerate its metabolism. 
5-Skeletal system
It can enhance vitamin D metabolism, so Phenytoin may increase the risk of hypocalcemia, rickets and osteomalacia  after long-term treatment (pretreat with vitamin D if necessary).
6-Allergic response
rash, thrombocytopenia, agranulocytosist can enhance vitamin D metabolism, so Phenytoin may increase the risk of hypocalcemia, rickets and osteomalacia  after long-term treatment (pretreat with vitamin D if necessary).and aplastic anemia.
7-Others
Rarely appear male barymastia, female hirsutism and lymphadenectasis

1-Phenobarbital
Aside from the bromides, phenobarbital is the oldest of the currently available antiseizure drugs. Although it has long been considered one of the safest of the antiseizure agents, the use of other medical with lesser sedative effects has been urged. 
Mechanism of action:

• Phenobarbital can inhibit the paradoxical discharge of epilepsy focus selectively, enhance stimulation of surrounding tissues and block discharge diffuse to normal tissues.
• Phenobarbital facilitate GABA-mediated inhibition of neuronal activity.

Clinical application

• Phenobarbital is an effective agent for generalized tonic-clonic and partial seizures. 
• However, its sedative effects and its tendency to disturb behavior in children have reduced its use as a primary agent.

Adverse effects

• Somnolence, depression
• Tolerance develops after long-term treatment.

2-Primidone
Primidone was first marketed in the early 1950s. It was later reported that Primidone was metabolized to phenobarbital and phenylethylmalonamide (PEMA), All three compounds are active anticonvulsants.

Pharmacokinetics

• Primidone is completely absorbed, usually reaching peak concentration about 3 hours after oral administration. 
• Primidone is metabolized by oxidation to phenobarbital, which accumulates very slowly, and by scission of the heterocyclic ring to form PEMA. Both Primidone and phenobarbital under go subsequent conjugation and excretion.
• Primidone has a larger clearance than most other antiseizure drugs(2L/kg/d), corresponding to a half-life of 6-8 hours. PEMA clearance is approximately half that of primidone, but phenobarbital has a very low clearance. The appearance of phenobarbital corresponds to the disappearance of Primidone. Phenobarbital therefore accumulates very slowly but eventually reaches therapeutic concentrations in most patients when therapeutic doses of primidone are administered.

Clinical application

• It can be used for all types of epilepsy except petit mal. It,s better to use this drug with sodium phenytoin. 
• With regard to grand mal, the effect of primidone is better than phenobarbital, this drug is useless to petit mal. 

Adverse effects

• Common: somnolence, vertigo, nausea and vomiting
• Rare: megaloblastic anemia, leucopenia and thrombocytopenia

3-Ethosuximide
Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures and was introduced as a “pure petit mal” drug. 

Pharmacokinetics
Absorption is complete following administration of the oral dosage forms. 
Peak levels are observed 3-7 hours after oral administration of the capsules. Animal studies indicate that chronic administration of the solution may prove irritating to the gastric mucosa.
Ethosuximide is completely metabolized, principally by hydroxylation, to inactive metablites. 

Half Life
The drug has a very low total body clearance(0.25/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.

Clinical application
Ethosuximide is effective against absence seizures but not tonic-clonic seizures.

Adverse effects

• Gastrointestinal tract: anorexia, nausea, vomiting
• CNS: headache, dizziness and somnolence
• Rarely appear agranulemia and aplastic anemia

4-Diazepam & Nitrazepam

Pharmacokinetics:

• The drug are well absorbed, widely distributed, and extensively metabolized, with many active metabolites.
• The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. 
• Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg.
• The onset of action is very rapid.
• Total body clearances of the parent drug and its metabolites are low, corresponding to half-life of 20-40 hours.

Diazepam: given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epileptics. 
The drug is occasionally given orally on a chronic basis, although it is not considered very effective in this application, probably because of the rapid development of tolerance. 
Nitrazepam: is not marketed in the USA but is used in many other countries, especially for infantile spasms and myoclonic seizures. It is less potent than clonazepam, and its clinical advantages over that drug have not been documented.
It’s highly effective in controlling petit mal and myoclonus epilepsy.

5-Sodium Valproate
Sodium Valproate, was found to have antiseizure properties when it was used as a solvent in the search for other drugs effective against seizures. 

Pharmacokinetics

• Valproate is well absorbed following an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours.
• Food may delay absorption, and decreased toxicity may result if the drug is given after meals.

Clearance for valproate is low; its half-time varies from 9 hours to 18 hours. At very high blood levels, the clearance of valproate is dose-dependent. There appear to be offsetting changes in the intrinsic clearance and protein binding at higher doses. Approximately 20% of the drug is excreted as a direct conjugate of valproate.

Clinical application

• Valproate is very effective against absence seizures. 
• Valproate is unique in its ability to control certain types of myoclonic seizures; in some cases the effect is very dramatic. The drugs is effective in generalized tonic-clonic seizures, especially those which are primarily generalized.

5-Carbamazepine
Closely related to imipramine and other antidepressants, carbamazepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well.

Pharmacokinetics

• The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all.
• Peak levels are usually achieved 6-8 hours after administration .

Distribution is slow, and the volume of distribution is rough 1 L/kg.
Carbamazepine has a very systemic clearance of approximately 1 L/kg/d at the start of therapy.

Mechanism of action
 Carbamazepine can block sodium channel, inhibit paradoxical discharge and discharge diffusion. It may relate to the postsynaptic inhibition of GABA.

Clinical application

• Carbamazepine is considered the drug of choice for generalized tonic-clonic seizures. It can be used with phenytoin in many patients who are different to control.
• The drug is also very effective in some patients with trigeminal neuralgia.
• Carbamazepine is also useful in some patients with mania.

Adverse effects

• CNS: somnolence
• Gastrointestinal tract: nausea, vomiting and anorexia
• Rash, thrombocytopenia, aplastic anemia and hepatic lesion.

Principle of Medication 
Grand pit (first choice): Sodium phenytoin or phenobarbital, carbamzepine, Primidone.
Petit mal (first choice): Ethosuximide, clonazepam and sodium valproate.
Status epilepticus: Diazepam or sodium phenytoin (IV), phenobarbital, diazepam, clonazepam.
Psychomotor: Sodium phenytoin or combine with  carbamazepine.

Principle of Medication (I)
The dose can be gradually increased from a low starting dose until reach the best effect.
In the initial stage, the patients should only be treated with a single antiepileptic drug, if the drug is useless, then it can be changed. When drug changing is necessary, it should be gradually withdrawn after the effect of new drug occurs. 
After the symptom is fully controlled, the patients should continuing be treated for 2 or 3 years. Sudden withdrawal of drugs are likely to precipitate relapse. 

Principle of Medication (II)
Enhance therapeutic effect: dosing individually, monitoring drug plasma concentration, examining regularly.  
Evaluating efficacy and safety.
Adjusting drug dosage: the therapeutic index of antiepileptic drug is low→easy to be poisoning Therapeutic dose is get close to toxic dose. 

Anticonvulsant Drugs

• Convulsions are involuntary skeletal muscular contractions. Convulsions can arise from pathological processes within or outside the brain, toxins, drug overdose, or withdrawal from drug dependence. 
• Commonly used anticonvulsant drugs are sedative and hypnotic drugs. Magnesium Sulfate is also used on this disease.

Pharmacological Effects
1 If used orally, it will have cathartic effect. 
2 It induces bile secretion as choleretic
3 Effect on neuromuscular system: reduce muscle contraction