Section 2/ Drugs Acting on CNS 108 Oxcarbazepine is completely absorbed following oral administration and is extensively metabolised to its pharmacologically active 10-monohydroxy metabolite Adverse reactions include dizziness, diplopia, fatigue, nausea, vomiting, dyspepsia, ataxia, abnormal vision, tremor etc SUCCINIMIDES ETHOSUXIMIDE Ethosuximide is most commonly used antiepileptic agent in the treatment of petitmal epilepsy It acts on thalamocortical system by selectively suppressing T current without affecting other types of Ca2+ or Na+ currents It is completely absorbed from gastrointestinal tract and present in plasma in free form and approximately 20% is excreted unchanged in urine and remaining portion is metabolized in liver Adverse effects include anorexia, nausea, vomiting, drowsiness, dizziness, agitation, skin rashes and blood dyscrasias and rarely cause systemic lupus erythematosus METHSUXIMIDE It is similar to ethosuximide and used along with the other drugs in the treatment of temporal lobe epilepsy ALIPHATIC CARBOXYLIC ACID SODIUM VALPROATE (VALPROIC ACID) Sodium valproate increases the levels of GABA in the brain and increases the responses to GABA in the postsynaptic neurons Also sodium valproate affects potassium flow across the neurons The result of these effects is inhibition of initiation as well as spread of epileptic activity in the neurons Valproate has antiepileptic efficacy in different types of epilepsy It is therefore sometimes called the broad range antiepileptic drug It has no significant hypnosedative effects nor does it have respiratory depressant activity In addition it does not have undesirable effects on blood pressure, heart rate, kidney function and body temperature Absorption is rapid and complete Protein binding is between 80 to 95 percent and the elimination half life is to 22 hours It is metabolised in the liver and is excreted by the kidney There is no presystemic metabolism Adverse effects include anorexia, nausea, vomiting, diarrhoea and/or constipation, weight gain, skin rash; hair loss, neutropenia, tremors and ataxia are occasionally reported Valproic acid is contraindicated in liver disease, especially cirrhosis, pregnancy and hypersensitivity BENZODIAZEPINES CLONAZEPAM It is a benzodiazepine useful in the treatment of petitmal epilepsy, myoclonic seizures and infantile spasms It is used in the treatment of petitmal epilepsy not responding to ethosuximide and sodium valproate Clonazepam and diazepam act by increasing the effectiveness of the inhibitory neurotransmitter GABA, within the central nervous system Antiepileptic Agents Clonazepam is well absorbed orally and approximately 85 percent is bound with plasma proteins, completely metabolized in liver and excreted through kidney Adverse effects include sedation, lack of concentration, irritability, ataxia and behavioural abnormalities The detailed pharmacology of diazepam is discussed in chapter ‘Sedative and hypnotics’ CLOBAZAM It is 1, benzodiazepine with a chemical structure slightly different from that of diazepam and clonazepam This change in structure results in less sedative and psychomotor retardation Though introduced as an anxiolytic it has been found to be useful in treatment of patients with refractory epilepsy Its antiepileptic activity results from its binding to one or more specific GABA receptors increasing GABA mediated inhibition Adverse reactions include drowsiness, hangover effects, dizziness, weight gain, headache, dry mouth and orthostatic hypotension etc PHENYLTRIAZINE DERIVATIVE LAMOTRIGINE It is phenyltriazine compound, chemically unrelated to existing antiepileptic drugs It acts primarily via a dose dependent blockade of voltage sensitive sodium channels in their slow inactivated state, thus stabilizing the presynaptic neuronal membrane inhibiting release of excitatory neurotransmitters mainly glutamate 109 Lamotrigine is almost completely absorbed after oral administration and metabolized completely in liver The adverse effects include headache, rash, nausea, dizziness, somnolence and insomnia It is mainly used as adjunctive therapy in patients for simple partial seizures, complex partial seizures, secondary generalised tonic and clonic seizures NEWER COMPOUNDS TOPIRAMATE It is used as adjunctive treatment of seizures including refractory seizures, simple and complex partial seizures It acts by reducing epileptiform discharges generated by blocking the sensitive sodium channel and enhancing the activity of GABA receptors It is rapidly absorbed after oral administration and is unaffected by presence of food and excreted mainly through kidney Adverse effects include abdominal pain, anorexia, weight loss, impaired concentration, confusion, mood disorders, ataxia, dizziness, drowsiness, fatigue and psychotic symptoms GABAPENTIN It is a new anticonvulsant drug and is a structural analogue of GABA It increases the release of GABA by unknown mechanism It modifies maximal electroshock as well as inhibits pentylenetetrazol induced convulsions 110 After oral administration, it is rapidly absorbed and widely distributed into all tissues It readily crosses blood brain barrier and is not bound to plasma proteins It is excreted unchanged in urine It is mainly used as adjunctive therapy in treatment of partial seizures with or without secondary generalization in adults Adverse effects include sedation, dizziness, diplopia, ataxia and fatigue Section 2/ Drugs Acting on CNS VIGABATRIN It is an inhibitor of GABA transaminase which degrades GABA It suppresses maximal electroshock and kindled seizures and is used in partial seizure with or without generalization It is well absorbed after oral administration and excreted unchanged in urine Adverse effects include drowsiness, dizziness, agitation and amnesia Muscle Relaxants r r e e t t p p a CChh 2.7 1.4 111 Muscle Pharmacodynamics Relaxants (Mode of Action of Drugs) D-TUBOCURARINE Chondrodendron tomentosum plant It initially produced motor weakness followed by flaccid paralysis after parenteral administration The paralysis occurs in following order e.g paralysis of fingers, toes, eyes, ears producing diplopia, speech slurring, difficulty in swallowing; the muscles of neck, limb, trunk, paralysis of diaphragm and death occur due to hypoxia It is an dextrorotatory quarternary ammonium alkaloid obtained from In higher doses, d-tubocurarine can produce blockade of autonomic ganglia It Skeletal muscle relaxants act peripherally at the neuromuscular junction or centrally in the cerebrospinal axis to reduce muscle tone Skeletal muscle relaxation can be achieved by following group of drugs as in table 2.7.1 NEUROMUSCULAR BLOCKERS Table 2.7.1: Classification of skeletal muscle relaxants I Neuromuscular blockers d-Tubocurarine Atracurium Pancuronium Vecuronium Succinylcholine Benzoquinonium Dantrolene 0.2-0.4 mg IV 10-15 mg IV 40-100 µg/kg IV 0.08-0.1 mg/Kg IV 30-50 mg IV 10-15 mg IV 25 to 100 mg/day II Centrally acting muscle relaxants Mephenesin Chlorzoxazone (MOBIZOX) Methocarbamol (FLEXINOL) Carisoprodol (CARISOMA) Orphenadrine (ORPHIPAL) Tizanidine (CITANZ) Baclofen (LIORESAL) Metaxalone (FLEXURA) 250 mg TDS 0.l5-1 g/day oral, 100-200 mg IM/IV 350 mg TDS 100-300 mg/day 2-6 mg/day 30-75 mg/day 400-800 mg TDS-QID 112 can also produce release of histamine and can cause bronchospasm and increase other body secretions d-Tubocurarine is not absorbed orally and after intravascular administration, it is widely distributed in tissue As it does not cross blood brain barrier it has no effect on CNS Section 2/ Drugs Acting on CNS cheal intubation, bronchoscopy, esophagoscopy, laryngoscopy etc) • Succinylcholine is used to avoid convulsion and coma from electroconvulsive therapy • In the treatment of tetanus and emergency of epilepsy (status epilepticus) • As a diagnostic tool for myasthenia gravis Adverse effects include hypoxia, respiratory paralysis, decreased blood pressure, bronchospasm etc CENTRALLY ACTING MUSCLE RELAXANTS d-Tubocurarine is not used now due to its prominent histamine releasing and ganglionic blocking effect These agents reduce skeletal muscle tone by a selective action on cerebrospinal axis without affecting consciousness PANCURONIUM Pancuronium is a synthetic steroidal compounds and approximately five times potent than d-tubocurarine Vecuronium is congener of pancuronium with short duration of action Atracurium is bisquarternary competitive blocker similar to pancuronium in properties and duration of action SUCCINYLCHOLINE It is a quarternary ammonium compound with a structure similar to acetylcholine (Details are discussed in chapter ‘Cholinergic agents’) Therapeutic uses • As a adjuvant to general anaesthesia (specially in major surgical procedures e.g abdominal and thoracic surgery, orthopaedic procedures, intubation etc) • Succinylcholine is used for surgical procedure of brief duration (endotra- Mephenesin was the first drug used as muscle relaxant but due to its serious side effects e.g haemolysis, hypotension and thrombophlebitis, it is not clinically used now CHLORZOXAZONE It is mephenesin related skeletal muscle relaxant After oral administration, it is rapidly and completely absorbed It is metabolized in liver and excreted in urine primarily as the glucuronide Adverse reactions include gastric irritation, nausea, lethargy, headache It is used in painful skeletal muscle spasm and is used in combination with paracetamol and diclofenac METHOCARBAMOL It causes skeletal muscle relaxation by preferential blockade of polysynaptic spinal reflexes It is rapidly absorbed from the GI tract, metabolised in the liver and excreted in ... sedation, lack of concentration, irritability, ataxia and behavioural abnormalities The detailed pharmacology of diazepam is discussed in chapter ‘Sedative and hypnotics’ CLOBAZAM It is 1, benzodiazepine... nausea, dizziness, somnolence and insomnia It is mainly used as adjunctive therapy in patients for simple partial seizures, complex partial seizures, secondary generalised tonic and clonic seizures... including refractory seizures, simple and complex partial seizures It acts by reducing epileptiform discharges generated by blocking the sensitive sodium channel and enhancing the activity of