|Aliphatic carboxylic acid||Valproic acid (sodium valproate)Divalproex|
|Benzodiazepines||Clonazepam Diazepam Lorazepam Clobazam|
|Cyclic GABA analogue||Gabapentin Pregabalin|
|Newer drugs||Topiramate Zonisamide Levetiracetam Vigabatrin Tiagabine Lacosamide|
- Enhancement of GABAA receptor medited synaptic inhibition appears to be most important mechanism
- Higher anticonvulsant: hypnotic ratio of phenobarbitone is due to minimal effect on Ca2+ channels and glutamate release.
- It has a wide spectrum of anticonvulsant property – it raises seizure threshold as well as limits spread and suppresses kindled seizures
- A mean intravenous or intramuscular loading dose of 15 mg/kg of phenobarbitone safely achieved therapeutic levels within 2 hours of injection and high therapeutic levels weremaintained with a dose of 6 mg/kg a day. (1)
- In infants with asphyxia, prophylactic phenobarbitol does not reduce the incidence of seizures, HIE and mortality. (2)
- Parenteral phenobarbitone is an integral part of the management of status epilepticus in resource poor counteries (RPC). It is highly effective at cntrolling seizures. Withdrawal of this drug is likely to have a devastating effect on the outcome of status epilepticus in RPCs. (3)
- Phenobarbitone potentiates the effect of ethyl alcohol in human behaviour. (4)
- Activated charcoal seems to be as efefctive as forced alkaline diuresis, hemodialysis and hemoperfusion for removal of phenobarbitone following overdosage. (5)
- Phenobarbital is more selective than pentobarbital in increasing motor cortical thresholds. (6)
- Phenobarbitoen is an alternative to beta -adrenoreceptor antagonists in treating essential tremor. (7)
- Phenobarbital is still the most cost effective pharmacological treatment for epilepsy. It helps to close the gap in low and middle income counteries during its second century of clinical use. (8)
- Phenobarbital is safe and effective as a large community based intervention for epilepsy care. (9)
- Phenobarbitone induce the metabolism of acetaminophen. (10)
- Phenobarbitone is efefctiv, well tolerated AED and donot have cognitive impairment. There is variable and distinct improvement in cognition and psychosocial functioning and is effective in seizure control. (11)
- Has slow oral absorption and a long plasma t ½ (80-120 hours).
- It is metabolized in liver and excreted unchanged in urine
- Steady state is reached after 2-3 weeks and single daily dose can be used for maintenance
- Side effects include:
- Megaloblastic anemia
- Mental confusion in older people
- Hyperactivity in children
- Impairment of learning and memory
- Dimunition of intelligence
- Behavioural abnormalities
- It induces drug reaction with eosinophillia and systemic symptoms (DRESS). (12)
- Generalized tonic clonic seizures (GTC)
- Simple partial seizures (SP)
- Complex partial seizures (CP)
- A deoxybarbiturate, converted by liver into phenobarbitone and phenylethyl malonamide (PEMA)
- T ½ of primidone is 6-14 hours
- Primidone is effective in reducing essential tremor in hand and head, its effective is comparable to that of propanolol. (13)
- Primidone is an effective agent in the treatment of essential tremor. (14)
- Primidone is a very effective drug in focal seizures and is the drug of choice for psychomotor seizures. It is relatively more effective on first and second day of the treatment while there is a sharp increase in the effectiveness of diphenylhydantoin on the fifth treatment day. (15)
- Primidone possesse independent anticonvulsant activity and is more potent than phenobarbital with respect to maximal electroshock. Primidone and phenobarbital are more effective anticonvulsant than phenylethylmelonamide. (16)
- Primidone kinetics is influenced by concurrent antiepileptic drugs and by the duration of primidone therapy. (17)
- Primidone is effective in suppressing ventricular arrhythmias and shortening of QT interval in patients with seizures, ventricular fibrillation and syncope. (18)
- About 1/3rd of primidone is excreted unchanged in urine
- Dose to dose, primidone is less potent, but anti epileptic efficacy is similar to phenobarbitone
- Adverse effects are:
- Adverse effect similar to phenobarbitone
- Psychotic reaction
- Lymph node enlargement
- GTCS generalized tonic clonic seizures
- Partial epilepsy
- Not a CNS depressant
- Toxic dose produces excitement and muscular rigidity
- Abolition of tonic phase of maximal electroshock seizures, with no effect on or prolongation of clonic phase
- It limits the spread of seizure activity
- Threshold for PTZ convulsions is not raised
- Tonic clonic epilepsy is suppressed but paroxysmal focal EEG discharge and aura persists
- Phenytoin is appropriate for the treatment of sone seizures seen in the ED, it is associated with significant adverse effects. Trials are ongoing regarding the use of other anticonvulsants in the treatment of status epilepticus. (19)
- On increasing the dose of phenytoin in chronic epileptics receiving phenytoin and either phenobarbitone or primidone, there was no effect on minor seizures but major seizures were abolished or reduced. Serum concentration of phenobarbitone also raised. (20)
- Phenytoin appears to be a useful topical agent in promoting healing of diabetic foot ulcers. (21)
- Marked phenytoin toxicity occurs in critically ill patients associated with hypoalbuminemia causing gradual decrease in the level of consciousness and cerebellar signs. It can be detected only by direct measurement of free phenytoin levels. (22)
- Phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials and improving clinical status in a model of neuroinflammation. (23)
- There is worsening of seizures following phenytoin discontinuation which reflects loss of therapeutic drug effect rather than a true abstinence phenomenon. (24)
- When taking phenytoin with food, product switches may result in either side effects or loss of seizure control. (25)
- Even though phanytoin is classified as both an anticonvulsant and an antiarrhythmic, its sodium channel kinetics and various studies have shown that phenytoin is unlikely to produce cardiac arrhythmias even in setting of severe toxicity. (26)
- Mechanism of action
- It has stabilizing influence on neuronal membrane – prevents repetitive detonation of normal brain cells during depolarization shift that occurs in epileptic patients
- It prolongs the inactivated state of voltage sensitive neuronal Na+ channel
- Higher toxic concentration cause reduction in Ca2+ influx, inhibition of glutamate and facilitation of GABA responses
- Absorption by oral route is slow
- It is widely distributed in the body and is 80-90% bound to plasma protein
- Phenytoin is metabolized in liver by hydroxylation involving CYP2C9 and 2C19 as well as glucoronide conjugation
- Kinetics of metabolism is capacity limited; changes from first order to zero order over the therapeutic range
- The t ½ (12-24 hours at therapeutic level), progressively increases (up to 60 hours) when plasma concentration rises above 10 mcg/ ml
- Adverse effects:
- At therapeutic levels
- Gum hypertrophy
- Hirsutism, coarsening of facial features, acne
- Hypersensitivity reaction – rashes, DLE, lymphadenopathy, neutropenia
- Megaloblastic anemia
- It can inhibit insulin release and cause hyperglycemia
- Used during pregnancy, causes fetal hydantoin syndrome: hypoplastic phalanges, cleft palate, hare lip, microcephaly
- At high plasma level:
- Cerebellar and vestibular manifestations: ataxia, vertigo, diplopia, nystagmus
- Drowsiness, behavioural alterations, mental confusion, hallucinations, disorientation and rigidity
- Epigastric pain, nausea and vomiting
- Local vascular injury
- Fall in BP and cardiac arrhythmias occur on iv injection
- Drug interactions
- Phenobarbitone inhibits phenytoin metabolism
- Carbamazepine and phenytoin induce each other’s metabolism
- Valproate displaces protein bound phenytoin and decreases its metabolism
- Valproic acid displace phenytoin from plasma binding sites, enhancing the systemic clearance of the drug and inhibit its metabolism thereby increasing the concentration of free drug in the serum. (27)
- Chloramphenicol, isoniazid, cimetidine and warfarin inhibit phenytoin metaboilism
- Phenytoin inhibit warfarin metabolism
- Phenytoin increases degradation of steroids
- A number of acidic drugs displace it from protein binding sites
- Generalized tonic clonic seizures, simple and complex partial seizures
- Status epilepticus
- Trigeminal neuralgia
- Water soluble prodrug of phenytoin.
- Administration of fosphenytoin iv ot im offers a tractical and convenient alternative to iv phenytoin. (28)
- fosphenytoin can be safely administered thrugh the im route and it also offers advantage over phenytoin for iv administration. The efficacy, safety and pharmacokinetics of fosphenytoin is similar in 5-18 year old children and in young adults. (29)
- Fosphenytoin is a valuable treatment option for the rapid treatment of status epilepticus. The risk of venous adverse events is lower than with pheytoin when administered at the recommended rate. (30)
- Administration of iv fosphenytoin causes prolongation of ST segment and the QT interval and merging of P and T waves. These changes may be attributed to inorganic phosphate induced hypocalcemia. (31)
- Both intravenous and intramuscular administration of fosphenytoin is well tolerated, with mild bruising, tenderness, swelling and/or erythema seen at infusion and injection sites in small number of patients. (32)
- A single intramuscular injection of fosphenytoin (20 phenytoin equivalents/kg) does not prevent seizures or neurologic dificts in childhood nontraumatic coma. (33)
- In a single institution, fosphenytoin administartion is inappropriate almost half the time. Oral phenytoin loading is less expensive and safe. (34)
- Intramuscular fosphenytoin is rapidly absorbed (therapeutic levels achieved as early as 5-20 min). It is well tolerated in most patients irrespective of injection volume. (35)
- Fosphenytoin sodium is considered to be useful substitute for phenytoin sodium with almost no associated injection site reactions. (36)
- In the body, it is rapidly metabolized to phenytoin
- On iv injection, only minor vascular complications occurs. It is less damaging to intima
- Fosphenytoin can be injected with both saline and glucose
- It is a first line antiepileptic drug
- Carbamazepine modifies maximal electroshock seizures as well as raises threshold to PTZ and electroshock convulsions
- It exerts a lithium like therapeutic effect in mania and bipolar mood disorder
- It also has antidiuretic action, by enhancing ADH action on renal tubules
- Carbamazepine is efficacious in the maintenance treatment of bipolar disorder in naturalistic clinical practice, either as monotherapy or in combination with other medicines. (37)
- Carbamazepine causes anticonvulsant drug hypersensitivity syndromes which can present with wide spectrum of symptoms like diarrhea, negative t wave, fever, skin rashes etc. (38)
- Lamotrigrine and carbamazepine has similar effeicacy against partial onset seizures and primary generalized tonic-clonic seizures in newly diagnosed epilepsy. (39)
- Crabamazepine suppresses methamphetamine induced Fos expression in a regionally specific manner. The nucleus accumbens and the Caudate/ Putamen brain region are involved in the antimanic effects of carbamazepine. (40)
- Haemodilysis is a simple, cheap and good therapeutic option in removing carbamazepine from the circulation in patients with severe carbamazepine overdose. (41)
- Oral absorption is slow and variable because of poor water solubility
- It is 75% bound to plasma proteins and metabolized in liver by oxidation to an active metabolite (10-11 epoxy carbamazepine) as well as hydroxylation and conjugation to inactive ones
- Plasma t ½ of 20-40 hours but decreases on chronic medication due to autoinduction of metabolism
- Multiple epoxides and a cyclic peroxide are involved in the invivo metabolism of carbamazepine in man. (42)
- Adverse effects:
- Dose related neurotoxicity- sedation, dizziness, vertigo, diplopia and ataxia
- Vomiting and diarrhea
- Acute intoxication causes coma, convulsions and cardiovascular collapse
- Hypersensitivity reactions: rashes, photosensitivity, hepatitis, lupus like syndrome, agranulocytosis and aplastic anemia
- Water retention and hyponatremia occurs in elderly as it enhances ADH action
- Carbamazepine is a potentially hepatotoxic drug. Vitamin C has a hepatoprotective activity against carbamazepine induced hepatotoxicity. (43)
- Carbamazepine can reduce efficacy of haloperidol, oral contraceptives, lamotrigine, valproate and topiramate
- Metabolism of carbamazepine is induced by phenobarbitone, phenytoinand vice versa
- Erythromycin, fluoxetine, isoniazid inhibit metabolism of carbamazepine
- Erythromycin induces carbamazepine toxicity which manifest as drowsiness, lethargy, ataxia, vomiting and nystagmus. More serious adverse effects are heart block and severe liver and kidney failure. (44)
- Simethicone and carbamzepine when taken together may be a cause of carbamazepine toxicity. (45)
- Complex partial seizures (CPS)
- GTCS (generalized tonic clonic seizures)
- SPS (simple partial seizures)
- Trigeminal and other neuralgia: carbamazepine is the drug of choice
- Manic depressive illnesses and acute mania
- Newer congener of carbamazepine that is rapidly converted to an active metabolite that is glucoronide conjugated but not oxidized
- Risk of hepatotoxicity is lower but that of hyponatremia is more
- Indications are same as that of carbamazepine, but it is better tolerated.
- Dose to dose, it is 1 ½ times less potent
- Oxcarbamzepine induces immunoglobulin deficiency. (46)
- Oxcarbamazepine has a potent antineuralgic properties in the absence of significant side effects and therfore may be useful in the management of intractable trigeminal neuralgia. (47)
- For patients with partial onset seizures, oxcarbamazepine is less likely to be withdrawn. It cannot be assessed whenther oxcarbamazepine is equivalent, superior or inferior to phenytoin in seizure control. (48)
- Oxcarbamazepine can be used in patients with autistic disorder and significant disruptibe behaviors. It has a favorable side effect profile and is available in liquid formulation which is more convenient for autistic patients. (49)
- Acute dyskinesia is a rare adverse efefct of oxcarbamazepine in epilepsy patient with neurobehavioral symptoms. (50)
- Oxcarbamazepine does not suppress cortical spreading depression and thus cannot be used for migraine prophylaxis. (51)
- Oxcarbamazepine is a useful adjunct in the treatment of gabapentin resistant complex regional pain syndrome type 1 in children. (52)
- Superior oblique myokymia is a rare form of nystagmus that causes oscillopsia and blurry vision. oxcarbamazepine can be used to successfully eliminate oscillopsia without serious adverse reaction. (53)
- Oxcarbamazepine can also induce Steven Johnson syndrome. (54)
- The most prominent action is antagonism of PTZ induced clonic seizures at doses which produces no discernable action
- It raises seizure threshold but does not modify maximal electroshock seizures or inhibit kindling
- Clinically effective only in absence seizures
- Primary action is exerted on thalamocortical system which is involved in generation of absence seizures
- It selectively suppresses T current without affecting other types of Ca2+ or Na+ currents
- It does not potentiate GABA at therapeutic concentrations
- Slowly but completely absorbed, not protein bound, evenly distributed in the body.
- It is metabolized in liver by hydroxylation and glucoronidation and excreted in urine – about ¼ in unchanged form
- Plasma t ½ averages 48 hours in adults and 32 hours in children
- Adverse effects:
- Gastrointestinal intolerance
- Mood changes
- Headache, drowsiness and inability to concentrate
- Hypersensitivity reaction like rashes, DLE and blood dyscrasias
- The only indication of ethosuximide is absence seizures
- Ethosuximide is used in the treatment of absence (petit mal) seizures. (55)
- There is ethosuximide induced conversion of of typical childhood absence seizures to rolandic spikes. (56)
- Ethosuximide compensate damage caused by seizure attacks and other neuronal loss disorders. (57)
- Granulopenia and thrombocytopenia occurs after ethosuximide. (58)
- In human adult and infant plasma, the monohydroxyethosuximides are present in larger quantities than the unchanged drug. Four monohydroxymetabolites of ethosuximide are identified in urine of man. (59)
- Ethosuximide may be useful pharmacological agent for alcohol withdrawal and treatment of resulting seizures. (60)
- Age does not alter the plasma level of ethosuximide. The plasma level increases more rapidly in females than males. Intake of methylphenobarbitone and not phenytoin, phenobarbitone, primidone and carbamazepine alter the relationship between plasma ethosuximide level and ethosuximide dose. (61)
- Ethosuximide and Gabapentin significantly attenuates nonconvulsive seizures in a dose related manner and may help to improve patient outcome from brain ischemia induced seizure activity. (62)
Valproic acid (Sodium Valproate)
- It is a branched chain aliphatic carboxylic acid with broad spectrum anticonvulsant action
- More potent in blocking PTZ seizures than in modifying maximal electroshock
- At anticonvulsant doses, valproate produce little sedation or other central effects
- It is effective in partial seizures and GTCS as well as absence seizures
- Valproate facilitates critical period learning in the adult human brain. (63)
- Sodium valproate is most efficacious in generalized seizure disorders, particularly absence seizures. Drowsiness and gastrointestinal symptoms are most common side effects which are usually minor and transient. (64)
- Maternal use of valproate during pregnancy is associated with significant increase risk of autism spectrum disorder and childhood autism in the offspring even after adjusting maternal epilepsy. (65)
- Intravenous sodium valproate is non-inferior to intravenous phenytoin as the first line treatment in status epilepticus with no significant cardiovascular compromises. (66)
- Sodium valproate or lithium is used as first line treatment in euphoric mania. Sodium valproate is the agent of choice in patients with mixed mania, rapid cycling, comorbid substance use or other associated neurological abnormalities. (67)
- Sodium valproate is a gamma-aminobutyric acid (GABA) transaminase inhibitor and it is suggested that it raises GABA levels in the hypothalamus and ir responsible for the reduction in ACTH secretion. (68)
- The use of valproic acid results in elevated plasma ammonia which may lead to hyperammonemic encephalopathy. (69)
- Intravenous sodium valproate is an effective alternative to diazepam infusion in controlling refractory satus epilepticus in children and is free of respiratory depression and hypotension. (70)
- In mitochondrial disorders, there is a high prevalance of valproate toxicity predicting genomic alterations. (71)
- The mood stabilizing effects of valproic acid may be mediated in part by alterations in corticotropin releasing factor neuronal activity. (72)
- Valprate protect beta-cells of pancreas from palmitate induced apoptosis and ER stress via GSK-3beta inhibition, independent of ATF4/CHOP pathway. (73)
- Multiple mechanisms:
- A phenytoin like frequency dependent prolongation of Na+ channel inactivation
- Weak accentuation of Ca2+ mediated T current (ethosuximide like)
- Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation (by GABA transaminase) and also increasing its synthesis from glutamic acid
- Oral absorption is good
- It is 90% bound to plasma proteins; completely metabolized in liver mainly by CYP2C9 and 2C19 and glucuronide conjugation and then excreted in urine
- Plasma t ½ is 10-15 hours, but anticonvulsant effects are longer lasting
- Adverse effects:
- Vomiting, loose motions
- Heart burn
- Drowsiness, ataxia and tremor
- Cognitive and behavioural effects are not prominent
- Alopecia, curling of hair
- Weight gain
- Bleeding tendency
- Asymptomatic rise in serum transaminase
- Fulminant hepatitis
- Used during pregnancy, it causes spina bifida and other neural tube defects
- Valpraote increases plasma levels of phenobarbitone and lamotrigine
- It displaces phenytoin from protein binding site and decreases its metabolism – phenytoin toxicity
- It inhibits hydrolysis of active epoxide metabolite of carbamazepine
- Concurrent use of clonazepam and valproate is contraindicated because absence status may be precipitated
- Fetal abnormalities are more common if valproate and carbamazepine are given concurrently
- Valproate is drug of choice for absence seizures
- It is an alternate/ adjuvant drug for GTCS, SPS and CPS
- Myoclonic and atonic seizures
- Mania and bipolar illness
- Also used in panic attacks
- Prophylactic efficacy in migraine
Divalproex (Semisodium Valproate)
- It is coordination compound of valproic acid with sodium valproate
- Oral absorption is slower, but bioavailability is same
- Gastric tolerance may be better
- Extended release divalproex sodium can be used in the treatment of bipolar disorders. (74)
- Divalproex treatment is associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. (75)
- Divalproex is an effective prophylactic drug for patients with migraine headache and is generally well tolerated. (76)
- Divalproex sodium is effective and generally well tolerated prophylactic treatment option as monotherapy or in polytherapy for migraine and cluster headache. (77)
- It is a BZD with prominent anticonvulsant properties; block PTZ at doses which produce mild sedation
- Efficacy in modifyomng maximal electroshock seizure is low
- It is singularly ineffective in GTCS
- Production of generalized seizures by kindling is suppressed, but local after-discharges persist
- BZD potentiate GABA induced Cl– influx to produce sedation.
- At large doses, high frequency discharges are inhibited akin to phenytoin
- Clonazepam is particularly valuable in epilepsy with associated myoclonus and in photosensitive epilepsy. (78)
- Clonazepam use is associated with pancytopenia, thus patient should be regularly monitored with complete blood count. (79)
- The sleep related painful erection in elderly men can be successfully treated with clonazepam. (80)
- Clonazepam can be used as agonist substitution treatment for benzodiazepine dependence and leads to improvement in clinical situation including cessation of craving, absence of withdrawal symptoms, reduced anxiety, improvements in social functioning and a better cognition level. (81)
- Clonazepam is used in the treatment of absence seizures with automatisms. (82)
- Clonazepam can be used as prophylactic treatment in busulfan related myoclonic epilepsy in autografted acute leukemia patients. (83)
- Adjuvant use of lansoprazole, clonazepam and dimenhydrinate is effective to treat intractable hiccups in patients with gastritis and reflux esophagitis complicated with myocardial infarction. (85)
- The combined paroxetine and clonazepam treatment resulted in more rapid response than with paroxetine monotherapy for panic disorder but there was no differential benefit beyond the initial few weeks of therapy. (86)
- Clonazepam is efficacious as an intermittent therapy for febrile seizures if parents are informed of its side effects like lethargy and ataxia. (87)
- Clonazepam is effective in the treatment of panic disorders. (88)
- Oral absorption is good
- It is 85% bound to plasma proteins, completely metabolized in liver and excreted in urine
- T ½ averages 24 hours
- It does not produce any active metabolite
- There is a steady-state concentration of clonazepam in serum after chronic oral administration. (84)
- Adverse effects
- Sedation and dullness
- Lack of concentration, irritability, temper and other behavioral abnormalities
- Motor disturbances and ataxia is dose related
- Salivation and increased respiratory secretions
- Absence seizures
- Used as an adjuvant in myoclonic and akinetic epilepsy
- Infantile spasms
- Also used to suppress acute mania
- Used partial, secondarily generalized tonic clonic as well as absence and atonic seizures, including some refractory cases
- Sedation and psychomotor retardation are less prominent, side effects is similar to other BZDs
- It appears to act by facilitating GABA action
- Oral bioavailability of clobazam is 90% and elimination t ½ is 18 hours, but an active metabolite is produced which has longer t ½ (> 35 hrs)
- Generally used as an adjuvant to other antiepileptic drugs like phenytoin, carbamazepine or valproate in refractory epilepsy
- Clobazam is effective as an intermittent therapy in febrile seizures. (89)
- Clobazam is effective in catamenial epilepsy. (90)
- Stable dosage of clobazam for Lennox-Gestaut syndrome is associated with sustained drop-seizure and total-seizure improvements over 3 years. (91)
- High and medium dosage clobazam is more efficacious than other epileptic therapies in Lennox Gestaut syndrome. (92)
- Clobazam is a 1,5-benzodiazepine. It diplays a wide seperation of psychosedative or tranquillizing properties from impairment of motor coordination. It is effective anxiolytic agent when given in daily doses of 20-30 mg and produces minimal effects on psychomotor performance. It has a long elimination half life of 18 h; the main metabolite is N-desmethylclobazam. (93)
- Clobazam can be used for the treatment of refractory epilepsy and chronic drug resistant complex partial seizures. (94)
- Clobazam can be used in the treatment of partial status epilepticus. (95)
- Clobazam is safe and effective in the treatment of focal epilepsy in childhood and should be considered in patients with refractory seizures. (96)
- Anticonvulsant activity in variety of seizures
- Prominent sedation action and rapid development of tolerance to the anti epileptic effect
- 1st line drug for emergency control of convulsions, eg status epilepticus, tetanus, eclampsia, convulant drug poisoning etc.
- Diazepam can be used in the treatment of seizures. (97)
- Diazepam is relatively more discriminable than buspirone. (98)
- The regular use of diazepam does not increase the risk of breast cancer. (99)
- Pretreatment with diazepam exhibits anti-inflammtory property in cerulein induced acute pancreatitis possibly through peripheral benzodiazepine receptors. (100)
- Diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioids effects. (101)
- Diazepam can be used in suppressing gammahydroxybutyrate (GHB) dependence and realted withdrawal symptoms. (102)
- Diazepam is a valuable drug in case of acute myocardial infarction. It causes a lower stress reaction, which is beneficial in diminishing the incidence of malignant arrhythmias and preventing the existing myocardial injury from spreading. (103)
- Low dose diazepam can be combined with kava to reduce harmful effects and is recommended for clinical use in patients chronically treated with this anticonvulsant drug. (104)
- Adverse effects:
- Thrombophlebitis in injected vein
- Marked fall in BP
- Respiratory depression
- Rectal instillation of diazepam is preferred therapy for febrile convulsions in children
- 0.1 mg/ kg injected iv at a rate not exceeding 2 mg/ min is better suited than diazepam in status epilepticus or for emergency control of convulsions of other etiology
- Lesser thrombophlebitic complications and more sustained action than that of diazepam
- Lorazepam impairs highway driving performance more than heavy alcohol consumption. (105)
- Care should always be exercised when prescribing lorazepam in older patients. (106)
- Lorazepam is safe and feasible to prevent complications associated with alcohol withdrawal in patients with acute myocardial infarction. (107)
- High dose intravenous lorazepam may be an effective alternative to pentobarbital for the treatment of severe status epilepticus. (108)
- Absorption kinetics for both oral and intramuscular lorazepam is dose dependent. Plasma t1/2 for intact lorazepam is independent of dose and administration route. (109)
- Lorazepam is more effective than chlordiazepoxide in alcohol withdrawal in both a faster rate in the drop of withdrawal severity and lessening the total duration of withdrawal. (110)
- Propofol combined with lorazepam can be used for severe poly substance misuse and withdrawal states in intensive care unit. Lorazepam alone is ineffective in such cases. (111)
- Carbamazepine like action profile: modifies electroshock and decreases electrically evoked as well as photic after discharge duration
- Prolongation of Na+ channel inactivation and suppression of high frequency firing
- It may directly block voltage sensitive Na+ channels, thus stabilizing the presynaptic membrane and preventing release of excitatory neurotransmitters, mainly glutamate and aspartate
- It does not antagonize PTZ seizures or block NMDA type of glutamate receptors
- Used as add on therapy in refractory cases of partial seizures and GTCS
- Also effective in absence and myoclonic or akinetic seizures
- Lamotrigine is well absorbed orally and metabolized completely in liver
- Its t ½ is 24 hours, but is reduced to 16 hr in patient receiving phenytoin, carbamazepine or phenobarbitone
- Valproate doubled the blood level of lamotrigine but lamotrigine reduce the valproate level
- Women on lamotrigine are more likely to develop drug induced rashes. (112)
- Lamotrigine is used in the management of bipolar disorders. (113)
- Lamotrigine has a beneficial effect on the depressive symptoms in the depressed phase of bipolar disorder. (114)
- Aseptic meningitis is a rare complication of lamotrigine. (115)
- Lamotrigine is used in treating bipolar disorders particularly as maintenance therapy. It is used for treating bipolar depression and rapid cycling. It is generally well tolerated, but it can cause dose dependent CNS side effects and benign allergic rash. Drug interaction occurs with valproate (an inhibitor) and several enzyme inducers. (116)
- Lamotrigine and carbamazepine have similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, is better tolerated. (117)
- Combined lamotrigine and valproate are effective in controlling seizures in refractory epilepsy in children and adolescents. (118)
- Leucopenia can be seen in patients treated with lamotrigine. Thus a close haematological monitoring of patients should be done during first few weeks of treatment. (119)
- Lamotrigine is safe and effective treatment option for adult attention deficit hyperactivity disorder comorbid with bipolar and recurrent depression. (120)
- Side effects:
- Sleepiness, dizziness
- Ataxia and vomiting
- Rashes are seen in children requiring withdrawal
- GABA derivative which cross to the brain and enhances GABA release
- It modifies maximal electroshock as well as inhibits PTZ induced clonic seizures
- Modulate voltage sensitive Ca2+ channels. Decrease entry of Ca2+ entry into these channels reduce glutamate release, lowers the neuronal excitability
- Added to a first line drug, it reduced seizure frequency in refractory partial seizures with or without generalization
- Effective in SPS and CPS
- 1st line drug in neuralgic pain due to diabetic neuropathy and post herpetic neuralgia
- The treatment of refractory chronic cough with gabapentin is both effective and wel tolerated. (121)
- Gabapentin improves the analgesic efficacy of opioids both at rest and with movement, reduces analgesic consumption and opioid-related adverse effects, but is associated with an increased incidence of sedation and dizziness. (122)
- Gabapentin (Particularly 1800 mg dosage) is effective in treating alcohol dependence and relapse related symptoms of insomnia, dysphoria and craving with favourable safety profile. (123)
- Gabapentin improves sensory and motor symptoms in restless leg syndrome and also improves sleep architecture and periodic leg movements during sleep (PLMS). (124)
- Gabapentin induces cholestatic jaundice. (125)
- Duloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had inadequate pain response to gabapentin. (126)
- The treatment of pain associated with diabetic peripheral neuropathy and post herpetic neuralgia with pregabalin is a cost effective intervention compared to gabapentin. (127)
- Gabapentin is efefctive in treating refractory insomnia in children. (128)
- Gabapentin is a safe alternative for the management of recurrent, refractory idiopathic priapism. (129)
- 3000 mg gabapentin extended release taken once daily is effective and well tolerated for the treatment of diabetic peripheral neuropathy pain. (130)
- Monotherapy or adjuvant therapy with venlafaxine is comparable to gabapentin for neuropathic pain management. (131)
- Single preoperative or repeated doses of gabapentin continued up to few days after surgery decrease acute postoperative pain and/ or need of postoperative opioids. It also decrease chronic pain several weeks after surgery. (132)
- A single low dose of 600 mg gabapentin administered 1 hour prior to surgery produce effective and significant postoperative analgesia after total mastectomy and axillary dissection without significant side effects. (133)
- Perioperative administration of gabapentin significantly decreases the incidence of post operative nausea and vomiting and the requirement for postoperative antiemetic treatment following laparoscopic cholecystectomy. (134)
- Gabapentin has an analgesic and opioid sparing effect in acute post operative pain management when used in conjunction with opioids. (135)
- Prophylactic effect in migraine and is an alternate drug in phobic states
- Gabapentin is well absorbed orally and excreted unchanged in urine with t ½ of 6 hours
- Adverse effects:
- Mild sedation
- Pharmacodynamic and pharmacokinetic properties similar to gabapentin
- Used for neuropathic pain such as diabetic neuropathy, postherpetic neuralgia, complec regional pain syndrome (CRPS) and certain other types of chronic pain
- Pregabalin is associated with a significant, dose related improvement in pain in patients with diabetic peripheral neuropathy. (136)
- Pregabalin is safe and effective for the short treatment of generalised anxiety disorder. (137)
- In patients with diabetic peripheral neuropathy, pregabalin demonstrated early and sustained improvement in pain and a beneficial effect on sleep. It is well tolerated at all doses. (138)
- Combination of the standard doses of duloxetine and pregabalin is not superior to the maximum dose of either drug in patients with painful diabetic neuropathy. (139)
- All antineuropathic drugs are effective in relieving cancer related neuropathic pain. There is a statistically and clinically significant morphine sparing effect of pregabalin in relieving neuropathic cancer pain and neuropathic symptoms as compared to other antineuropathic drugs. (140)
- Pregabalin provides a significantly improved treatment outcomes in patients with restless leg syndrom. The augmentation rates are significantly lower with pregabalin than with 0.5 mg of pramipexole. (141)
- Pregabalin provides some pain relief in patients with fibromyalgia but does not cure the disease. (142)
- Pregabalin treatment may be associated with rhabdomylysis. (143)
- Perioperative pregabalin administration reduces opioid consumption and opioid related adverse efefcts after surgery. (144)
- Pregabalin is an effective adjuvant therapy for pain in patients with chronic pancreatitis. (145)
- Preoperative pregabalin (300 mg) and gabapentin (900 mg) administered 1 hour before surgery leds to significant reduction in preoperative anxiety and improves sedation without producing significant side effects. (146)
- Pre-emptive administration of 300 mg pregabalin reduces postoperative pain and morphine consumption. (147)
- Pregabalin reduces pain and improves sleep and health related quality of life in fibromyalgia syndrome patients. While indicated dosing is 300-450 mg divided twice daily, initial dosing of 25-50 mg at night is recommended owing to side effects including somnolence, dizziness and cognitive dysfunction. It can be safely combined with other medications and can be used in patients with renal failure when the dose is appropriate. It can worsen sedation when combined with CNS depressants. It should be discontinued gradually. (148)
- Insomnia is a common component of the clinical presentation of generalized anxiety disorder and pregabalin appears to be an efficacious treatment for this chronic an ddisbling symptom. (149)
- Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. (150)
- Pregabalin, in doses of 150-600 mg/day is safe and effective treatment of generalised anxiety disorder in patients 65 years and older. It has an early onset and significantly improves both psychic and somatic symptoms of anxiety. (151)
- In post herpetic neuralgia patients, 600 mg/day dose of pregabalin demonstrates increased pain relief compared to 300 mg/day. BID and TID regimens demonstrates similar efficacy. (152)
- In patients with diabetic peripheral neuropathic pain inadequately treated with gabapentin without concomitant use of antidepressants, switching to duloxetine insted of pregabalin provides better pain reduction. Conversely, in nonresponders to gabapentin who are concomitantly using an antidepressant, switching to duloxetine or pregabalin may provide similar pain reductions. (153)
- Side effects:
- Poor concentration
- Allergic reactions
- Weak carbonic anhydrase inhibitor with broad spectrum anticonvulsant activity in maximal electroshock, PTZ induced clonic seizures and in kindling model
- Mechanism of action
- Prolongation of Na+ channel inactivation
- GABA potentiation by post synaotic effect
- Antagonism of certain glutamate receptor
- Neuronal hyperpolarization through certain K+ channels
- Topiramate is used as monotherapy as well as supplementing other antiepileptic drugs in refractory SPS, CPS and GTCS
- Also used in myoclonic epilepsy
- It is readily absorbed orally and mainly excreted unchanged in urine with an average t ½ of 24 hours
- Topiramate is a valuable alterntive to existing mood stabilizers, either as an ajunct or monotherapy in patients with bipolar disorder or schizoaffective disorder. (154)
- Topiramate lacks efficacy in the treatment of acute mania. It has potential implications in reversing increased body weight, normalisation of glycemic control and blood pressure. (155)
- The rate of oral clefts observed is 11 times the background rate when topiramate is used in pregnancy. (156)
- The combination of phentermine and topiramate might be a valuable treatment for obesity that can be provided by family doctors. (157)
- Topiramate has a negative impact on cognition. It causes a decline in verbal intelelct. (158)
- Topiramate is used in the treatment of alcohol use disorders. (159)
- Topiramate might serve as a therapeutic option for inflammatory bowel disease in humans. (160)
- Topiramate use is associated with secondary angle closure glaucoma. (161)
- Topiramate is used in the prophylaxis of pediatric migraine. Weight loss, decreased concentration in school, sedation and parasthesias are important side effects. (162)
- Topiramate can induce acute transient myopia. (163)
- Due to its anticraving effect, topiramate can be used as a useful adjuvant in the treatment of diabetes. (164)
- Topiramate is a useful and well tolerated addition to the treatment of refractory epilepsy, but it should be titrated slowly in order to avoid adverse effects. (165)
- Topirmate is effective in the prevention of migraine in pediatric patients. It is safe and well tolerated. (166)
- Topiramate can be used for smoking cessation. (167)
- Adverse effects:
- Impairment of attention
- Word finding difficulties
- Poor memory
- Weight loss
- Renal stones
- Also used in prophylaxis of migraine
- Anticonvulsant with weak carbonic anhydrase inhibitor action that modifies maximal electroshock seizures and inhibit kindled seizures
- It does not antagonize PTZ
- Prolongation of Na+ channel inactivation resulting in suppression of repetitive neuronal firing
- Also found to suppress T type of Ca2+ current in certain neurons
- It is well absorbed orally and mainly excreted unchanged in urine with t ½ > 60 hours
- A small fraction is oxidized and conjugated with glucuronic acid
- It is used as add on drug in refractory partial seizures
- Zonisamide is used in the treatment of partial seizures in pediatric and adult patients. It has a favorable linear pharmacokinetic profile, long half life and low incidence of protein binding interactions with other AEDs. It is metabolized in liver through cytochrome P450 pathway. (168)
- Zinosamide has a good efficacy and tolerability profile and can be used as an adjunctive therapy for epileptic patients. (169)
- Zonisamide is reasonably effective and generally well tolerated in children with poorly controlled epilepsy and provides another treatment option for children with refractory seizures. (170)
- Zonisamide is non inferior to controlled relaease carbamazepine – according to International league against epilepsy guidelines- could be useful as an initial monotherapy for patients newly diagnosed with partial epilepsy. (171)
- Zonisamide is used in the treatment of refractory partial-onset seizures. (172)
- Zonisamide attenuates α -synuclein-induced toxicity in a manner independent of the formation and maturation of α-synuclein aggregates in an in vivo model of familial Parkinson’ disease. Zonisamide may protect nigrostriatal dopamine neurons by modulating cellular damage or a cell death pathway commonly caused by neurotoxins and α-synuclein. (173)
- Adjunctive zonisamide is well tolerated and efficacious over a period of at least 1 year in children with partial epilepsy, with no unexpected safety concerns and no consistent detrimental effects on growth and development. (174)
- Zonisamide reduces obstructive sleep apnea independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. (175)
- Zonisamide exerts beneficial effects on the motor symptoms of Parkinson’s Disease and can be used as an adjunctive treatment. (176)
- Zonisamide induces crystalluria without alkalinization of the urine. Crystalluria should be carefully monitored in patients treated with zonisamide to prevent urolithiasis. (177)
- Zonisamide is useful for treating overweight in binge eating disorder and bulimia nervosa patients and may be an option for controlling impulsive behaviours in patients with eating disorders. (178)
- In short term, open label priliminary trial, combination treatment of zonisamide and bupropion resulted in more weight loss than treatment with zonisamide alone. (179)
- Zonisamide is non inferior to carbamazepine for newly diagnosed epilepsy. (180)
- Side effects:
- Headache, irritability
- Metabolic acidosis
- Renal stones
- It is effective in kindled seizures but is ineffective against maximal electroshock or PTZ
- Clinically effective as adjuvant medication as well as monotherapy in refractory partial seizures with or without generalization
- It is completely absorbed orally, party hydrolyzed but mainly excreted unchanged in urine with t ½ of 6-8 hours
- Levetiracetam is effective as adjunctive therapy for refractory partial onset seizures, primary generalized tonic clonic seizures and myoclonic seizures of juvenile myoclonic epilepsy. It is equivalent to controlled release carbamazepine as a first line therapy for partial onset seizures. Its main adverse efefcts are somnolence, asthenia, infection and dizziness. (181)
- Levetiracetam is efefctive for treating idiopathic generalised epilepsy. (182)
- Levetiracetam does not produce clinically significant increase in blleding time in healthy male volunteers. (183)
- Levetiracetam and controlled release carbamazepine produces equivalent seizure freedom rates in newly diagnosed epilepsy at optimal dosing in a setting mimicking clinical practice. (184)
- Levetiracetam suppresses acute seizures induced by perinatal hypoxia and diminishes later life seizure susceptibility and seizure induced neuronal injury. Thus, It may be effective in neonatal seizures. (185)
- Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in Alzhemier’s disease model. (186)
- Hallucination can be seen in seizure patients using levetiracetam. (187)
- Cautious usage and concerns of levetiracetam associated potential alkaline phosphatase elevation should be considered when levetiracetam is prescribed to epilepsy patients, especially pediatric patients. (188)
- There is insufficient evidence to recommend the use of levetiracetam instead of phenytoin for seizure prophylaxis in setting of severe traumatic brain injury. (189)
- The spinal myoclonus is markedly ameliorated by levetiracetam. (190)
- Levetiracetam is well tolerated and commonly used broad spectrum antiepileptic in both partial and generalised seizures. Levetiracetam induces psychosis may occur in children. (191)
- Levetiracetam is found to be safe in pregnancy. (192)
- Levetiracetam appears to be a promising therapy for the treatment of hot flashes. (193)
- Side effects:
- Behavioral changes
- In CPS, GTCS and myoclonic epilepsy
- Newer anticonvulsant potentiates GABA mediated neuronal inhibition by depressing GABA transporter GAT-1 which removes synaptically released GABA into neurons and glial cells
- Maximal electroshock and kindled seizures are suppressed
- Used as add on therapy in partial seizures with or without secondary generalization
- In newly diagnosed patients with partial epilepsy, tiagabine monotherapy is as effective as carbamazepine. The side effects include dizziness/ lightheadedness, asthenia/ lack of energy and somnolence, Induction of nonconvulsive status epilepticus. (194)
- There is increased risk of seizure activity with off label use of tiagabine. Off label use of tiagabine should be discouraged. (195)
- Chronic tiagabine administration decrese the aggressive behaviour in individuals with a history of substance abuse and antisocial behaviour. (196)
- Tiagabine in excess dosing scenarios has been rarely documented to cause status epilepticus. (197)
- Tiagabine can induce typical absence status epilepticus in a pateint with primary generalized epilepsy. (198)
- Tiagabine may be used as an add-on drug for drug resistant partial epilepsy. (199)
- Tiagabine is efficacious and well tolerated as adjunctive therapy in complex partial seizures. There is a clear dose-response relationship. (200)
- Tiagabine has a slow wave sleep enhancement effect which reduces selective aspects of the behavioural, psychological and physiologic impact of sleep restriction. (201)
- Side effects:
- Mild sedation
- Abdominal pain
Vigabatrin (gamma vinyl GABA)
- It is an inhibitor of GABA transaminase
- Anticonvulsant action may be due to increase in synaptic GABA concentration
- Effective in patients with refractory epilepsy, especially CPS with or without generalization
- Vigabatrin may be used for the treatment of refractory partial epilepsy. (202)
- Treatment with vigabatrin is associated with high prevalence of peripheral visual field defects. This is due to its toxic effect on the retina and persists even if the drug is withdrawn. (203)
- Vigabatrin is highly effective in eliminating infantile spasms caused by tuberous sclerosis complex but is less effective in patients with focal seizures. (204)
- Improvement in stiff man syndrome is seen with vigabatrin. (205)
- Light is a significant enhancer of vigabatrin toxicity and a portion of this is mediated, directly or indirectly, by phototransduction signalling in rod and cone photoreceptors. (206)
- Vigabatrin exert anxiolytic effects in CCK-4-induced panic in healthy volunteers. Vigabatrin might be useful in ameliorating panic symptoms in patients with panic disorders. (207)
- Vigabatrin can induce life threatening encephalopathy. (208)
- Vigabatrin therapy is efficacious at preventing CNS oxygen toxicity in swine and a single dose is not acutely associated with retinotoxicity. (209)
- The use of vigabatrin for complex partial seizures should be limited to those patients with seizures refractory to other treatments. Patients must have a baseline and follow up monitoring of visual fields, early assessment of its efficacy, and ongoing evaluation of the benefits and risks of vigabatrin therapy. (210)
- Vigabatrin is an effective treatment in infantile spasms. The most serious side efefct is retinal toxicity characterized by irreversible bilateral concentric constriction of the visual fields (BCCVF). Every effort should be made to evaluate the retinal function. (211)
- Adverse effects:
- Visual field contraction
- Behavioural changes
- Recently approved anti seizure drug indicated in adults only for add on therapy of partial seizures with or without generalization
- It acts by enhancing Na+ channel inactivation and suppressing repetitive firing of neurons
- It is metabolized by CYP2C19 and excreted in urine.
- Lacosamide as adjunctive therapy in patients with partial onset seizures increases the 50% responder rate but with significantly more adverse events. (212)
- Lacosamide is an effective therapy for most seizure types and is particularly effective for partial onset seizures. It is effective in Lennox-Gastaut syndrome. (213)
- Lacosamide is effective in seizure reduction as adjunctive theray in patients with uncontrolled partial onset seizures. It is generally well tolerated. The most frequent adverse events are dizziness, headache, nausea and diplopia. (214)
- Intravenous loading dose of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide is well tolerated in lacosamide-naive patients. The 400 mg loading dose is less well tolerated due to higher frequency of treatment emergent adverse events. (215)
- Lacosamide may be effective in the treatment of juvenile myoclonic epilepsy. (216)
- Lacosamide in combination with levetiracetam is effective in the treatment of Epilepsia Partialis Continua. (217)
- Lacosamide reduces neuropathic pain and is well tolerated in patients with painful diabetic neuropathy. (218)
- Acute liver failure is reported in patientswith levetiracetam and lacosamide combination treatment for unspecified epileptic disorder. (219)
- Lacosamide can induce acute pancreatitis. (220)
- Adverse effects:
- Cardiac arrhythmia
Plasma half life and toxic plasma concentration range of antiepileptic drugs
Half life (hr)
Plasma concentration (mcg/ml)
> 35 severe
Choice of antiseizure drugs
Type of seizure
First choice drug
Second choice drug
Alternative/ add on drugs
Generalized tonic clonic/ simple partial with or without generalization
Lamotrigine, Gabapentin, Topiramate, Primidone, Levetiracetam
Complex partial with or without generalization
Carbamazepine, Valproate, Phenytoin
Gabapentin, Lamotrigine, Levetiracetam
Clobazam, Zonisamide, Topiramate
Phenobarbitone (iv, im)
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