Discuss in detail the mechanism of action of named antiepileptic agents with reference to the relative clinical success of a particular mechanism in the treatment of epilepsy
Carbamazepine is a Sodium channel Blocker. It is the major first line antiepileptic drug. It is used for the treatment of partial seizures and generalized tonic-clonic seizures. Carbamazepine blocks sodium channels during rapid, sustained neuronal firing. It also prevents post-tetanic potentiation.
Phenytoin is also another first-line drug for the treatment of partial and secondary generalized seizures. Its mechanism of action is to block the movement of ions through the sodium channels during the propagation of action potential. This leads to blockage and prevention of post-tetanic potentiation. This leads to reduction in seizure activity and reduction in the spread of seizures. It also inhibits calcium channels and the sequestration of calcium ions in nerve terminals. By doing this, it inhibits voltage-dependent neurotransmission at the synapse.
Fusophenytoin is a prodrug that is metabolized to phenytoin after administration of the drug. It is used in treating status epilepticus. Its mechanism of action is the same as that of phenytoin.
Lamotrigine is a triazine compound. It blocks the conductance of sodium-channels. It inhibits depolarization of the glutaminergic presynaptic membrane thereby inhibiting the release of glutamate. It is used to treat secondarily generalized tonic-clonic seizures, primary generalized seizures, atypical absence seizures, tonic seizures and atonic seizures.
Zonisamide acts by reducing the neuronal repetitive firing by blocking sodium channels and preventing the release of neurotransmitter. It acts on the T-type calcium channels and it prevents the influx of calcium.
Clonazepam is a 1, 4 substituted benzodiazepine. It is one of the first benzodiazepines to be used in treating epilepsy. Clonazepam has an affinity for GammaAminoButyricAcid GABA-A receptors that do not bind to other benzodiazepines. It is unclear if Clonazepam also has some effect on sodium-channel conductance. It is used to treat myoclonic seizures and sub cortical seizures. It is also effective in treating generalize convulsions and partial epilepsy. Withdrawal may induce status epilepticus or an exacerbation of the seizures.
Phenobarbital. It acts directly on GABA-A receptors by binding to the barbiturate-binding site. This action prolongs the duration of chloride channel opening. It also reduces the conductance of sodium and potassium and calcium influx. It depresses glutamate excitability. Phenobarbital is a broad-spectrum anticonvulsant that can be used to treat a wide variety of seizure types.
Tiagabine is a derivative of nipectoic acid, which is a GABA uptake inhibitor. Its action is by inhibiting the GABA transporter-1 (GAT-1). This inhibition is a reversible one. It is used to treat refractory epilepsy. It may also cause status epilepticus.
Vigabatrin is an inhibitory neurotransmitter in the central nervous system. It is an analogue of GABA. It binds to the GABA-T receptor-binding site.
Review the current classification and anatomical location of voltage gated soidum channels. Discuss the role of voltage gated sodium channels as drug targets with an emphasis on cerebral ischaemic, pain and multiple sclerosis
Sodium channels are integral membrane protein ion channels that conduct sodium ions through the plasma membrane of cells. The channel are made up of a-subunits that associate with other proteins, b-subunit.
Nav1.1 is found in the central nervous system neurons, peripheral neurons and cardiac myocytes. Nav1.2 is also found in the central neurons and peripheral neurons. Nav1.3 is found in Central, peripheral neurons and cardiac myocytes. Nav1.5 is found in cardiac myocytes, uninnervated skeletal muscle and central nervous system neurons; Nav1.6 is found in central nervous system neurons, dorsal root ganglia, peripheral neurons, the heart and the glia cells. Nav1.7 is found in dorsal root ganglia, sympathetic neurons, Schwann cells and neuroendocrine cells; Nav1.8 is found in dorsal root ganglia.
The b-subunit also has four subtypes. Navb1 is found in central neurons, peripheral neurons, skeletal muscle, heart and glia cells. Navb2 is found in central neurons, peripheral neurons, the heart and glia cells. Navb3 is also found in central nervous system cells, the adrenal gland, the kidney and peripheral neurons. Navb4 is found in the heart, skeletal muscle, central and peripheral neurons.
Voltage gates Sodium channels play important roles in both physiological and pathological processes of the central nervous system. The heterogeneity displayed by voltage gated sodium channels offers the possibility of developing pharmaceutical agents that selectively block voltage-gated sodium channels involved in multiple sclerosis. This offers the possibility of symptomatic treatment of multiple sclerosis. Sodium channels provide a route for persistent influx of sodium into neurons. This could in turn lead to a trigger of calcium ion influx into axons, leading to axonal injury. Sodium channel blockers can potentially prevent this. Also in cerebral ischemia, influx of sodium into cerebral neuronal cells could lead to the cells swelling up, leading to cerebral edema. However, sodium channel blockers that selectively act on the central nervous system cells would go a long way in preventing this.
Voltage gated sodium channels play a role in controlling cellular excitability in pathological processes, as stated earlier. In the treatment of neuropathic pain, there is a role for sodium channel blockers as they could block the excitation of axons that serve as pain receptors, thereby reducing the experience of pain sensation.
