Drugs effective in the therapy of the epilepsies

General consideration

• The epilepsies are common and frequently devastating disorders, affecting approximately 2.5 million people in the USA alone. More than 40 distinct forms of epilepsy have been identified. Epileptic seizures often cause transient impairement of consciousness , leaving the individual at risk of bodily harm and often interfering with education and employment.

Terminology and epileptic seizure classification

• Seizure refers to a transient alteration of behavior due to the disordered, synchronous , and rhythmic firing of populations of brain neurons.

• Epilepsy refers to a disorder of brain function characterized by the periodic and unpredictable occurrence of seizure.

• Seizure can be nonepileptic when evoked in a normal brain by treatments such as electroshock or chemical convulsant when occurring without evident provocation.

• Pharmacological agents in current clinical use inhibit seizures, and thus will be referred to as antiseizure drugs.

Classification of epileptic seizure

• Partial seizure– Simple partial: diverse manifestation , determ

ined by the region of cortex activated by seizure , lasting approximating 20 to 60 seconds. key feature is preservation of consciousness. Conventional antiseizure drugs: carbamazepine, phenytoin , phenobarbital, primidone, lamotrigine,gabapentin.

– Complex partial: impaired consciousness lasting 30s to 2min, often associated with purposeless movements such as lip smacking or hand wringing .The drugs: the same as simple partial.

– Partial with secondarily generalized tonic-clonic seizure. Simple or complex partial seizure evolves into a tonic-clonic seizure with loss of consciousness and sustained contractions of muscles throughout the body followed by periods of muscle contraction alternating with periods of relaxation typically lasting 1 to 2min.The drugs :the same as simple partial.

• Generalized seizures– Absence seizure: abrupt o

utset of impaired consciousness associated with staring and cessation of ongoing activities typically lasting less than 30s. Drugs: clonazepam , ethosuximide, valproate, lamotrigine.

– Myoclonic seizure: a brief (perhaps 1s),shocklike contraction of muscles with may be restricted to part of one extremity or may be generalized. Drugs: valproate

– Tonic-clonic seizure: the same as partial with secondarily Parkinsonian disorders, generalized tonic-clonic seizure.

Mechanism of action

• One is to limit the sustained repetitive firing of a neuron , an effect mediated by promoting the inactivated state of voltage-activated Na+ channels. Inhibition of the high-frequency firing is thought to be mediated by reducing the ability of Na+ channels to recover from inactivation.

• TOP: Closed State. This state is favored at hyperpolarized potentials ( in this case just before the pulse). This is one of the 7 possible closed and non-inactivated states. MIDDLE: Open State. This state is favored by the depolarizing pulse to 10 mV. The current is negative because the driving force is directed inwardly. BOTTOM: Inactivated State. Even though the membrane is still depolarized and the gates are in the open position, the channel is not conducting because the inactivating particle is blocking the internal mouth of the pore.

– Because firing at a slow rate permits sufficient time for Na+ channels to recover from inactivation, inactivation has little or no effect on low-frequency firing. however, reducing the rate of recovery of Na+ channels from inactivation would limit the ability of a neuron to fire at high frequencies, an effect that likely underlies the effects of carbamazepine, lamotrigine, phentoin, and valproic acid against partial seizure.

• Insight into mechanisms of seizure suggest that enhancing GABA-mediated synaptic inhibition would reduce neuronal excitability and raise the seizure shreshold

• The principal postsynaptic receptor of synaptically released GABA is termed the GABAA receptor. Activation of the GABAA receptor effects inhibition of the postsynaptic cell by increasing the flow of Cl- ions into the cell, which tends to hyperpolarize the neuron.

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benzodiazepines

barbiturates

Clinically relevant concentrations of both benzodiazepines and barbiturates can enhance GABAA receptor –mediated inhibition through distinct actions on GABAA receptor . This mechanism probably underlies the effectiveness of the these compounds against partial and tonic-clonic seizure in human beings

• The EEG hallmark of an absence seizure is generalized spike and wave discharges at a frequency of 3 per second in both the thalamus and the cortex. one intrinsic property of thalamic neurons that is pivotally involved in the generation of the 3-per-second spike and wave is a particular form of the voltage –regulated Ca 2+ current, the low threshold (T) current.

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– Indeed burst of action potentials in thalamic neurons are mediated by activation of the T current. The T current plays an amplifying role in thalamic oscillation , on oscillation being the 3-per –second spike and wave of the absence seizure. Importantly, the principal mechanism by which most anti-absence seizure drugs( trimethadone, athosuximide, valproic acid) are thought to act is by inhibition of the T current.

Phenytoin

• Pharmacological effects– Antiepileptic effect

• Phenytion acts by stabilizing cellular membranes by decreasing Na+ conductance during high-frequency repetitive firing.

• Phenytoin exerts its dampening effect only when neuronal activity is abnormally high. It allows the normal conduction of AP, but halts seizure activity.

• Anti-peripheral neuralgia

The causes of neuralgias are varied. Chemicals can cause nerve irritation. Inflammation, trauma (including surgery), compression by adjacent structures (tumors or inflamed tissues), and infections can all lead to neuralgias. In many cases, however, the cause is unknown or unidentifiable. Neuralgias are most common in elderly persons, but they can occur at any age.

• Antiarrhythmia

• Clinical uses– Epilepsy : phenytoin is effective against all typ

es of partial and tonic-clonic seizure but not absence seizure.

– Peripheroneural pain. Trigeminal neuralgia, glossopharyngeal neuralgia.

– Arrhythmia

• Adverse reaction– Gastrointestinal irritation: it should be taken

with meal.– CNS depression: confusion, dullness, drawnsi

ness, etc.– Blood dyscrasias: neutropenia, leukopenia, ag

ranulocytosis, thrombocytopenia, aplastic anemia.

– Cardiovascular collapse: cardiac arrhythmias, hypotension.

– Gingival hyperplasia:• Gingival hyperplasia oc

curs in about 20% of all patients during chronic therapy and is probably the most common manifestation of phenytoin toxicity in children and young adolescents. The overgrowth of tissue appears to involve altered collagen metabolism. It can be minimized by good oral hygiene.

– Hepatitis– Allergic reaction.– Hirsutism– Megaloblastic an

aemia– Osteomalacia– Hyperglycaemia– Foetal hydantoin

syndrome

Barbiturates

• Phenobarbital is frequently used for epilepsy in barbiturates.

• Barbiturates have a narrow margin of safety, but most barbiturates have anti-seizure properties

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

• Adverse reaction: sedation , physical and psychological dependence.

Carbamazepine• The actions and mechanism of antiepile

ptic effect of carbamazepine are similar to those of phenytoin.

• Carbamazepine is useful in patients with generalized tonic-clonic and both simple and complex partial seizure.

• Acute intoxication with carbamazepine can result in coma, hyperirritability, convulsions, and respiratory depression. During long term therapy, the more frequent untoward effects of the drug include drowsiness, vertigo, blurred vision, serious hematological toxicity.

Ethosuximide• Ethosuximide is more effective against a

bsence seizure.• Ethosuximide reduces low-threshold Ca

2+ currents( T current) in thalamic neurous.

• Gastrointestinal complains and CNS effects, systemic lupus erythematosus, leukopenia, etc.

Valproic acid• To treat absence seizures, partial and generali

zed seizure.• Augmentation of release of inhibitory neurotra

nsmitters GABA and increasing its synthesis from glutamic acid.

• Spina bifida and NTDs.• Hepatic toxicity

Alopecia,rashes and thrombocytopenia

Benzodiazepines

Anticonvulsant drugs

• Convulsion is a symptom with the clinical manifestation of the involuntary contraction of skeletal muscles in the body caused by overexcitement of CNS and seen in high fever in infant, tetanus, puerperal convulsion, grand mal epilepsy and intoxication of central stimulants.

• Anticonvulsant drugs often used in clinic are barbiturates, diazepam, and magnesium sulfate injection.

Magnesium sulfate

• Pharmacological effects– Oral administration

• Catharsis• Promote excretion of bile

– Injection administration • Anticonvulsant effect: Mag

nesium sulfate inhibits episode of convulsion via inhibiting CNS by Mg2+ ,and relaxation of skeletal muscle by antiagonism of Ca 2+ and inhibiting release of Ach from end of motor nerve by Mg 2+

• Hypotensive effect: Magnesium sulfate reduce BP by direct vasodilation.

• Clinical uses:– Convulsion and hypertensive emergencies by

injection administration• Adverse reaction

– The overdose of magnesium sulfate causes breath inhibition and hypotension, even death. Calcium chloride or calcium gluconate should be administered.