NEW ANTIEPLEPTICS & CENTRALLY ACTING MUSCLE RELAXANTS

Vigabatrin: Vigabatrin, the first 'designer drug' in the epilepsy field, is a vinyl-substituted analogue of GABA acts by inhibitng GABA transaminase effectve in patients unresponsive to conventional drugs main side-effects: drowsiness, behavioral and mood changes. Drug interaction: decreases phenytoin conc.

Lamotrigine acts by inhibiting sodium channels broad therapeutic profile main side-effects are hypersensitivity reactions (especially skin rashes

FELBAMATE is an analogue of an obsolete anxiolytic drug, meprobamate M.O.A . It has only a weak effect on sodium channels . little effect on GABA. block of the NMDA receptor channel .

FELBAMATE Acute side effects are mild, mainly nausea, irritability and insomnia, but it occasionally causes severe reactions resulting in aplastic anaemia or hepatitis. For this reason, its recommended use is limited to a form of intractable epilepsy in children (Lennox- Gastaut syndrome) that is unresponsive to other drugs. Its plasma half-life is about 24 hours, and it can enhance the plasma concentration of other AEDs given concomitantly.

Gabapentin action appears to be on T-type calcium channel function, by binding to a particular channel subunit (α2δ), and it inhibits the release of various neurotransmitters and modulators. The side effects of gabapentin (mainly sedation and ataxia) are less severe than with many antiepileptic drugs.

The absorption of gabapentin from the intestine depends on the amino acid carrier system and shows the property of saturability, which means that increasing the dose does not proportionately increase the amount absorbed. This makes gabapentin relatively safe and free of side effects associated with overdosing.

Its plasma half-life is about 6 hours, requiring dosing two to three times daily. It is excreted unchanged in the urine and is free of interactions with other drugs. It has limited efficacy when used on its own, so is used mainly as add-on therapy.

It is also used as an analgesic to treat neuropathic pain. A recently introduced follow-up drug, pregabalin , is more potent than gabapentin but otherwise very similar. These drugs are excreted unchanged in the urine, and so must be used with care in patients whose renal function is impaired.

Oxcarbazepine Carbamazepine derivative MOA Blocking of sodium channels Uses Partial seizure Tonic-clonic seizure Side effects Rashes Hyponatremia Headache & dizziness

Primidone MOA Converted into phenobarbital Na channels blocker Uses Partial seizure Tonic-clonic seizure Side effects Drowsiness Sedation

Tiagabine an analogue of GABA that is able to penetrate the blood-brain barrier, acts by inhibiting the reuptake of GABA by neurons and glia. It enhances the extracellular GABA concentration, as measured in microdialysis experiments, and also potentiates and prolongs GABA-mediated synaptic responses in the brain. It has a short plasma half-life, and its main side effects are drowsiness and confusion.

TIAGABINE MOA Blocks GABA reuptake Uses Partial seizure Side effects Drowsiness and confusion Tremors and difficulty to conc. Weakness of knees Agitation

TOPIRAMATE MOA Weak sodium channels blocker Enhances GABA action blocks AMPA-receptor channel Carbonic anhydrase inhibitor Uses Refractory cases of epilepsy

Side effects Teratogenic Dizziness Ataxia Nervousness Memory problems Drug interaction: increases valproate conc.

Zonisamide MOA Blocks voltage sensitive sodium channels Blocks voltage dependent calcium channels Suppresses neuronal hypersynchronization Carbonic anhydrase inhibitor Free radical scavenger Uses Partial seizure (adjunctive Tx)

Side effects Confusion Hyperthermia Ataxia Fatigue Dizziness Wt. gain N.B. long t1/2 (60 hrs.) Drug interactions: increases conc. of carbamazepine , its level is increased by enz. inducer

Levetiracetam MOA UNKNOWN Uses Generalized seizure Side effects Somnolence Ataxia Anxiety Agitation Decrease in RBC Advantages No drug interaction Can be used in hepatic and renal impairment

Clinical uses of antiepileptic drugs Tonic-clonic (grand mal) seizures: carbamazepine (preferred because of a relatively favourable effectiveness:risk ratio), phenytoin , valproate use of a single drug is preferred, when possible, to avoid pharmacokinetic interactions newer agents include vigabatrin, lamotrigine , felbamate , gabapentin . Partial (focal) seizures: carbamazepine , valproate; alternatives are clonazepam or phenytoin .

Absence seizures (petit mal): ethosuximide or valproate valproate is used when absence seizures coexist with tonic-clonic seizures, because most other drugs used for tonic-clonic seizures can worsen absence seizures. Myoclonic seizures: diazepam intravenously or (in absence of accessible veins) rectally. Neuropathic pain: for example carbamazepine , gabapentin To stabilise mood in mono- or bipolar affective disorder (as an alternative to lithium ): for example carbamazepine , valproate

Conclusion Newer AEDs have higher effectiveness, better PK profile, less drug interactions and lower side effects which made them quite popular. However, more clinical studies are needed to clarify the teratogenicity and drug interactions

CENTRALLY ACTING MUSCLE RELAXANTS

CENTRALLY ACTING MUSCLE RELAXANTS Skeletal muscle relaxants may be used for relief of spasticity in neuromuscular diseases, such as multiple sclerosis, as well as for spinal cord injury and stroke

Mephenesin MOA Inhibition of polysynaptic excitation of motor neurons Uses Acute muscle spasm resulting from injury

Baclofen MOA Selective agonist at presynaptic GABA-B receptors Uses Spasticity associated with multiple sclerosis or spinal injury

Side effects Drowsiness Motor incoordination Nausea Behavioral effects Caution Kidney diseases CV & respiratory diseases Peptic ulcer (CI)

Other central muscle relaxants Benzodiazepine (diazepam, clonazepam) Carisoprodol: acts on reticular formation Cyclobenzaprine Tizanidine: alpha-2 agonist botulinum toxin injected into a muscle, this neurotoxin causes long-lasting paralysis confined to the site of injection, and its use to treat local muscle spasm is increasing dantrolene

Conclusion Central skeletal muscle relaxants are used to reduce the rigidity of skeletal muscles in treatment of muscles spasticity. Different agents with different MOAs can be used in the treatment of diseases like multiple sclerosis