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December 13 2018
University of Debrecen
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Source: http://www.doksinet 2nd seminar Antiepileptic drugs, Antipsychotics László Drimba M.D Department of Pharmacology and Pharmacotherapy University of Debrecen Source: http://www.doksinet history: „morbus sacer” most common neurology disorder accidental epileptiform seizures can be provoked in 5% of population epilepsy – 0,1% of population background: Epilepsy, seizures localized or generalized discharge of the cerebral neurons (seizures=somatic manifestations of the CNS discharge) definition epileptiform seizure (accidental, temporary) fever (neonates, children) hypoglycaemia drug/alcohol withdrawal hyperventillation hypoxia epilepsy (as disease) – regular intervals, repetitive idiopathic (genuine) symptomic trauma (CNS) neoplasma meningitis malformations in CNS Source: http://www.doksinet Patomechanism 1. 2. 3. 4. excitation – PDS – spontaneous depolarization propagation – depol. spreading into
diferrent CNS structures hypersynchronization seizures (somatic manifestation) Hypothesis: glutamate ↑ GABA ↓ BDRF ↑ Source: http://www.doksinet Patomechanism, targets VG-Ca++ (blocked by ethosuximide, lamotrigine, gabapentin, pregabalin) NMDA (blocked by felbamate, valproic acid) VG-Na+ (blocked by phenytoin, carbamazepine, lamotrigine) GABA transaminase, (blocked by vigabatrin) AMPA (blocked by PB, lamotrigine, topiramate) GAT-1 blocked by tiagabine BDZ receptors BDZ, barbiturates Targets: GABA↑ glutamate↓ Source: http://www.doksinet Seizure types Partial seizures (motoric, sensoric, vegetative) simple partial seizure complex partial seizures partial seizures (becoming generalized) Generalized seizures absence seizures GTCS (generalized tonic clonic seizures) myoclonic seizures atonic/akinetic seizures clinical forms! epileptic attack – (ictus epilepticus) repeated seizures status epilepticus – (continuous seizures) Source: http://www.doksinet
Antiseizure drugs Phenytoin, fosphenytoin, mephenytoin pharmacodynamic features pharmacokinetic features well absorbed PPB↑, CAVE: phenylbutazon, warfarin, sulfonamide enzyme induction!!! adverse effects (diphenylhidantoin) Epanutin®, Diphedan® the oldest antiseizure drug blocking VG Na+, (VG Ca++) channels (antiarrhythmic drugs) pro-arrhythmic hyperthyreosis-(increased affinity to THBG) diplopia, ataxia gingiva hyperplasia clinical use partial seizures GTCS 15-20 mg/kg Source: http://www.doksinet Antiseizure drugs Carbamazepine (Tegretol ®, Neurotop® ) tricyclic structure (see in antidepressants!) pharmacodynamic features pharmacokinetic features well absorbed PPB ≈ 70% microsomal enzyme induction (CAVE: OAC) adverse effects blocking VG Na+, channels glutamate↓ teratogenic diplopia, ataxia, drowsiness aplastic anaemia, agranulocytosis clinical use partial seizures GTCS
trigeminus neuralgia effective dose 600-800 mg/day Source: http://www.doksinet Antiseizure drugs Oxcarbazepine (Trileptal®) similar to carbamazepine lower extent in hepatic enzyme induction Phenobarbital pharmacodynamic features pharmacokinetic features well absorbed hepatic enzyme induction! adverse effects GABA R modulating effect - PDS↓ blocking VG Na+, channels, VG-Ca++ channels, glutamate↓ cardiovascular/respiratory depression clinical use partial seizures GTCS Source: http://www.doksinet Antiseizure drugs Primidone pharmacokinetic features metabolized to phenobarbital and phenyl-ethyl-malonamide (PEMA) Topiramate pharmacodynamic features blocking VG Na+, channels GABA R modulating effect (different from BDZ binding site) - PDS↓ pharmacokinetic features rapidly absorbed adverse effects fatique, cognitive slowing paraesthesias clinical use partial seizures West’s syndrome Lennox-Gastaut syndrome
migraine 200-600 mg/day Source: http://www.doksinet Antiseizure drugs Vigabatrine (Sabril®) pharmacodynamic features pharmacokinetic features well absorbed adverse effects irreversible inhibitor of GABA-T (GABA transaminase) drowsiness, dizziness, weight gain agitation, confusion intramyelinic oedema (infants) clinical use partial seizures West’s syndrome once a day 500 mg-2500 mg Source: http://www.doksinet Antiseizure drugs Tiagabine pharmacodynamic features pharmacokinetic features total absorption: 90-100% adverse effects inhibitor of GABA re-uptake mechanism blocking GAT-1> GAT-2> GAT-3e.c GABA↑ modulating VG-Ca++ channels (N-type)glutamate release↓ nervousness, dizziness, tremor somnolence, ataxia clinical use partial seizures GTCS 10-50mg/day Source: http://www.doksinet Antiseizure drugs Gabapentin, Pregabalin GABA analogs pharmacodynamic features pharmacokinetic
features not bound to PP adverse effects not agonise GABAA R (in spite of structural resemblence to GABA) modulating VG-Ca++ channels (N-type)glutamate release↓ sedation clinical use partial seizures GTCS pain syndromes 2400mg/day Source: http://www.doksinet Antiseizure drugs Felbamate (Taloxa®) pharmacodynamic features pharmacokinetic features well absorbed excreted in urine adverse effects blocking NMDA R modulating GABAA R hepatitis aplastic anaemia, agranulocytosis clinical use refractory cases Lennox-Gastaut epilepsy Source: http://www.doksinet Antiseizure drugs Ethosuximide pharmacodynamic features pharmacokinetic features rapidly absorbed half life: 40 hours adverse effects blocking T-type Ca++ channels (especially in thalamic neurons) gastric distress nausea, vomitus paraesthesias clinical use absence seizures Source: http://www.doksinet Antiseizure drugs Lamotrigine
(Lamictal®) pharmacodynamic features pharmacokinetic features rapidly absorbed half life: 24 hours adverse effects blocking N-type Ca++ channels headache, diplopia somnolence skin rash clinical use partial seizures 100-300mg/ day Source: http://www.doksinet Antiseizure drugs Valproic acid (Convulex®) pharmacodynamic features pharmacokinetic features well absorbed PPB≈90% adverse effects blocking NMDA R facilitating GAD (GABA synthesis) inhibiting GAT-1 inhibiting GABA-T (GABA transaminase) - at high concentrations nausea, vomitus valproic - embriopathy (spina bifida) clinical use absence seizures GTCS Source: http://www.doksinet Antiseizure drugs Benzodiazepines diazepam clonazepam clobazam pharmacodynamic features allosteric moduation on GABAAR clinical use continuous seizure activity repeated epileptiform attack status epilepticus Source: http://www.doksinet Therapeutic indications
simple/complex partial seizures carbamazepine phenytoin absence seizures valproic acid ethosuximide GTCS valproic acid carbamazepin phenytoin status epilepticus benzodiazepine diazepam (10-20 mg i.v), clonazepam (2 mg iv) O2, glucose i.v, tiamine phenytoin (15-20 mg/kg-EKG controll) phenobarbital (15-20 mg/kg, 100mg/min i.v) thiopental, muscle relaxation, resp. support Source: http://www.doksinet Dopaminergic neurotransmission Dopaminergic systems nigrostriatal pathway mesolimbic-mesocortical pathway hypothalamus-hypophysis endocrine functions dopamin=PIF, prolactin secretion↓ medullary-periventricular pathway mesencephalonlimbic system/cortex cognitive functions, self-reward system, perception, feelings N.B! – overstimulation! tuberoinfundibular pathway substantia nigracorpus striatum coordination of voluntary movement deficiency!Movement disorders of EPS beside the III.-IV ventricle eating behavior
area postrema chemosensitive trigger zone antiemesis-antpsychotics Source: http://www.doksinet Dopaminergic neurotransmission Dopamine receptors: D1 like, D2 like D1:GsACcAMP↑ putamen, cortex, nucleus accumbens D2 :GicAMP↓, seen above D3 :GicAMP↓ frontal cortex, medulla, mesencephalon D4 :GicAMP↓ cortex D5 :GsACcAMP↑, hippocampus, hypothalamus Source: http://www.doksinet Schizophrenia psychiatric disease etiology: dopamine hypothesis serotonin hyperfunction of mesolimbic-mesocortical dopaminergic pathway primarily described (development of typical antipsychotics-D2R antagonism) D2 R blocking drugs reduce psychotic symptoms D2 R activating drugs (levodopa, bromocriptine) produce psychosis post-mortem study – increased D2 R density in midbrain (mesencephalon) increased dopamine levels in putamen, nucleus accumbens indole hallucinogenes (LSD), mescalin provoke psychotic symptoms 5HT2A R agonism – hallucinations
inverse agonists of 5HT2A R (AAP-clozapine, queitapine) reduce sch. sympt glutamate hypothesis hypofunction of NMDA R located on GABAerg neurons provoke schizphr. Source: http://www.doksinet Schizophrenia Symptoms: positive symptoms: illusions / delusions (irreal) auditory/visual hallucinations thinking disorders agitation, agressive behaviour negative symptoms: blunted effect and emotion poverty of speech (alogia) inability to experience pleasure (anhedonia) lack of motivation lack of social relationships apathia, agonia Source: http://www.doksinet Antipsychotics (neuroleptics) Classification (based on chemical structure) phenothiazine derivatives propyl-amines piperidine derivatives haloperidol droperidol tiaprid suliprid dibenzodiazepines thiothixene benzamide derivatives typical antipsychotics butyrophenon derivatives perphenazine thioxanthene derivatives thioridazine Classification
(based on receptor selectivity and side effect profile): piperazine derivatives chlorpromazine promethazine clozapine olanzapine quetiapine benzioxazol derivatives risperidon atypical antipsychotics Source: http://www.doksinet Antipsychotics Typical antipsychotics: D2 R antagonism anti-cholinerg effect (obstipation) anti adrenerg effect (orthostatic hypotension) reduction of the positive symptoms of schizophrenia (negatives?) broad side effect profile EPS (dopamine depletion of nigrostriatal pathway) acute achatisia (uncontrolled restlessness) acute dystonic reactions (spastic retrocollis/torticollis) chronic pseudo Parkinson syndrome perioral tremor tardive dyskinesia (choreo-athetoid movements) MNS (malign neuroleptic syndrome) - th.: bromocriptin, danthrolen endocrine effects (dopamine depletion of tuberoinfundibular pathway) hyperprolactinaemia, galactorrhea-amenorrhea gynecomastia, impotence Source: http://www.doksinet
Antipsychotics broad side effect profile antiemetic effects (D2R blocking in area postrema) promethazine cardiac toxicity thioridazine arrhythmias Source: http://www.doksinet Antipsychotics Atypical antipsychotics: expanded receptor profile reduction both of the positive and negative symptoms of schizophrenia reduced side effect profile clozapine blocking D4 R> D2R = 5HT2AR > D1R central adrenerg effect mesolimbic selectivity side effects obesity, insulin resistance agranulocytosis! myocarditis olanzapine (Zyprexa®) 5HT2AR > H1R > D4 R> D2R mesolimbic selectivity side effects obesity, insulin resistance Source: http://www.doksinet Antipsychotics Atypical antipsychotics: risperidone (Risperdal®) blocking D2R > 5HT2AR > H1R mesolimbic selectivity side effects EPS hyperprolactinaemia sedation, headache MNS (depot) sertindole (Serdolect®), ziprasidone D2R > 5HT2AR > α1
side effects QT prolongation Source: http://www.doksinet Develompent of obesity and insulin resistance during AAP treatment weight gain blocing H1R in hypothalamus (VMHN, PVN) TNF-α hypersecretion α2 adrenergic agonism decreased leptin levels, leptin resistance insulin resistance antagonism ↓response of pancreatic β cells M3R antagonism ↓response of pancreatic β cells inhibitory effect on GLUT transporters in skeletal muscle 5HT1AR
diferrent CNS structures hypersynchronization seizures (somatic manifestation) Hypothesis: glutamate ↑ GABA ↓ BDRF ↑ Source: http://www.doksinet Patomechanism, targets VG-Ca++ (blocked by ethosuximide, lamotrigine, gabapentin, pregabalin) NMDA (blocked by felbamate, valproic acid) VG-Na+ (blocked by phenytoin, carbamazepine, lamotrigine) GABA transaminase, (blocked by vigabatrin) AMPA (blocked by PB, lamotrigine, topiramate) GAT-1 blocked by tiagabine BDZ receptors BDZ, barbiturates Targets: GABA↑ glutamate↓ Source: http://www.doksinet Seizure types Partial seizures (motoric, sensoric, vegetative) simple partial seizure complex partial seizures partial seizures (becoming generalized) Generalized seizures absence seizures GTCS (generalized tonic clonic seizures) myoclonic seizures atonic/akinetic seizures clinical forms! epileptic attack – (ictus epilepticus) repeated seizures status epilepticus – (continuous seizures) Source: http://www.doksinet
Antiseizure drugs Phenytoin, fosphenytoin, mephenytoin pharmacodynamic features pharmacokinetic features well absorbed PPB↑, CAVE: phenylbutazon, warfarin, sulfonamide enzyme induction!!! adverse effects (diphenylhidantoin) Epanutin®, Diphedan® the oldest antiseizure drug blocking VG Na+, (VG Ca++) channels (antiarrhythmic drugs) pro-arrhythmic hyperthyreosis-(increased affinity to THBG) diplopia, ataxia gingiva hyperplasia clinical use partial seizures GTCS 15-20 mg/kg Source: http://www.doksinet Antiseizure drugs Carbamazepine (Tegretol ®, Neurotop® ) tricyclic structure (see in antidepressants!) pharmacodynamic features pharmacokinetic features well absorbed PPB ≈ 70% microsomal enzyme induction (CAVE: OAC) adverse effects blocking VG Na+, channels glutamate↓ teratogenic diplopia, ataxia, drowsiness aplastic anaemia, agranulocytosis clinical use partial seizures GTCS
trigeminus neuralgia effective dose 600-800 mg/day Source: http://www.doksinet Antiseizure drugs Oxcarbazepine (Trileptal®) similar to carbamazepine lower extent in hepatic enzyme induction Phenobarbital pharmacodynamic features pharmacokinetic features well absorbed hepatic enzyme induction! adverse effects GABA R modulating effect - PDS↓ blocking VG Na+, channels, VG-Ca++ channels, glutamate↓ cardiovascular/respiratory depression clinical use partial seizures GTCS Source: http://www.doksinet Antiseizure drugs Primidone pharmacokinetic features metabolized to phenobarbital and phenyl-ethyl-malonamide (PEMA) Topiramate pharmacodynamic features blocking VG Na+, channels GABA R modulating effect (different from BDZ binding site) - PDS↓ pharmacokinetic features rapidly absorbed adverse effects fatique, cognitive slowing paraesthesias clinical use partial seizures West’s syndrome Lennox-Gastaut syndrome
migraine 200-600 mg/day Source: http://www.doksinet Antiseizure drugs Vigabatrine (Sabril®) pharmacodynamic features pharmacokinetic features well absorbed adverse effects irreversible inhibitor of GABA-T (GABA transaminase) drowsiness, dizziness, weight gain agitation, confusion intramyelinic oedema (infants) clinical use partial seizures West’s syndrome once a day 500 mg-2500 mg Source: http://www.doksinet Antiseizure drugs Tiagabine pharmacodynamic features pharmacokinetic features total absorption: 90-100% adverse effects inhibitor of GABA re-uptake mechanism blocking GAT-1> GAT-2> GAT-3e.c GABA↑ modulating VG-Ca++ channels (N-type)glutamate release↓ nervousness, dizziness, tremor somnolence, ataxia clinical use partial seizures GTCS 10-50mg/day Source: http://www.doksinet Antiseizure drugs Gabapentin, Pregabalin GABA analogs pharmacodynamic features pharmacokinetic
features not bound to PP adverse effects not agonise GABAA R (in spite of structural resemblence to GABA) modulating VG-Ca++ channels (N-type)glutamate release↓ sedation clinical use partial seizures GTCS pain syndromes 2400mg/day Source: http://www.doksinet Antiseizure drugs Felbamate (Taloxa®) pharmacodynamic features pharmacokinetic features well absorbed excreted in urine adverse effects blocking NMDA R modulating GABAA R hepatitis aplastic anaemia, agranulocytosis clinical use refractory cases Lennox-Gastaut epilepsy Source: http://www.doksinet Antiseizure drugs Ethosuximide pharmacodynamic features pharmacokinetic features rapidly absorbed half life: 40 hours adverse effects blocking T-type Ca++ channels (especially in thalamic neurons) gastric distress nausea, vomitus paraesthesias clinical use absence seizures Source: http://www.doksinet Antiseizure drugs Lamotrigine
(Lamictal®) pharmacodynamic features pharmacokinetic features rapidly absorbed half life: 24 hours adverse effects blocking N-type Ca++ channels headache, diplopia somnolence skin rash clinical use partial seizures 100-300mg/ day Source: http://www.doksinet Antiseizure drugs Valproic acid (Convulex®) pharmacodynamic features pharmacokinetic features well absorbed PPB≈90% adverse effects blocking NMDA R facilitating GAD (GABA synthesis) inhibiting GAT-1 inhibiting GABA-T (GABA transaminase) - at high concentrations nausea, vomitus valproic - embriopathy (spina bifida) clinical use absence seizures GTCS Source: http://www.doksinet Antiseizure drugs Benzodiazepines diazepam clonazepam clobazam pharmacodynamic features allosteric moduation on GABAAR clinical use continuous seizure activity repeated epileptiform attack status epilepticus Source: http://www.doksinet Therapeutic indications
simple/complex partial seizures carbamazepine phenytoin absence seizures valproic acid ethosuximide GTCS valproic acid carbamazepin phenytoin status epilepticus benzodiazepine diazepam (10-20 mg i.v), clonazepam (2 mg iv) O2, glucose i.v, tiamine phenytoin (15-20 mg/kg-EKG controll) phenobarbital (15-20 mg/kg, 100mg/min i.v) thiopental, muscle relaxation, resp. support Source: http://www.doksinet Dopaminergic neurotransmission Dopaminergic systems nigrostriatal pathway mesolimbic-mesocortical pathway hypothalamus-hypophysis endocrine functions dopamin=PIF, prolactin secretion↓ medullary-periventricular pathway mesencephalonlimbic system/cortex cognitive functions, self-reward system, perception, feelings N.B! – overstimulation! tuberoinfundibular pathway substantia nigracorpus striatum coordination of voluntary movement deficiency!Movement disorders of EPS beside the III.-IV ventricle eating behavior
area postrema chemosensitive trigger zone antiemesis-antpsychotics Source: http://www.doksinet Dopaminergic neurotransmission Dopamine receptors: D1 like, D2 like D1:GsACcAMP↑ putamen, cortex, nucleus accumbens D2 :GicAMP↓, seen above D3 :GicAMP↓ frontal cortex, medulla, mesencephalon D4 :GicAMP↓ cortex D5 :GsACcAMP↑, hippocampus, hypothalamus Source: http://www.doksinet Schizophrenia psychiatric disease etiology: dopamine hypothesis serotonin hyperfunction of mesolimbic-mesocortical dopaminergic pathway primarily described (development of typical antipsychotics-D2R antagonism) D2 R blocking drugs reduce psychotic symptoms D2 R activating drugs (levodopa, bromocriptine) produce psychosis post-mortem study – increased D2 R density in midbrain (mesencephalon) increased dopamine levels in putamen, nucleus accumbens indole hallucinogenes (LSD), mescalin provoke psychotic symptoms 5HT2A R agonism – hallucinations
inverse agonists of 5HT2A R (AAP-clozapine, queitapine) reduce sch. sympt glutamate hypothesis hypofunction of NMDA R located on GABAerg neurons provoke schizphr. Source: http://www.doksinet Schizophrenia Symptoms: positive symptoms: illusions / delusions (irreal) auditory/visual hallucinations thinking disorders agitation, agressive behaviour negative symptoms: blunted effect and emotion poverty of speech (alogia) inability to experience pleasure (anhedonia) lack of motivation lack of social relationships apathia, agonia Source: http://www.doksinet Antipsychotics (neuroleptics) Classification (based on chemical structure) phenothiazine derivatives propyl-amines piperidine derivatives haloperidol droperidol tiaprid suliprid dibenzodiazepines thiothixene benzamide derivatives typical antipsychotics butyrophenon derivatives perphenazine thioxanthene derivatives thioridazine Classification
(based on receptor selectivity and side effect profile): piperazine derivatives chlorpromazine promethazine clozapine olanzapine quetiapine benzioxazol derivatives risperidon atypical antipsychotics Source: http://www.doksinet Antipsychotics Typical antipsychotics: D2 R antagonism anti-cholinerg effect (obstipation) anti adrenerg effect (orthostatic hypotension) reduction of the positive symptoms of schizophrenia (negatives?) broad side effect profile EPS (dopamine depletion of nigrostriatal pathway) acute achatisia (uncontrolled restlessness) acute dystonic reactions (spastic retrocollis/torticollis) chronic pseudo Parkinson syndrome perioral tremor tardive dyskinesia (choreo-athetoid movements) MNS (malign neuroleptic syndrome) - th.: bromocriptin, danthrolen endocrine effects (dopamine depletion of tuberoinfundibular pathway) hyperprolactinaemia, galactorrhea-amenorrhea gynecomastia, impotence Source: http://www.doksinet
Antipsychotics broad side effect profile antiemetic effects (D2R blocking in area postrema) promethazine cardiac toxicity thioridazine arrhythmias Source: http://www.doksinet Antipsychotics Atypical antipsychotics: expanded receptor profile reduction both of the positive and negative symptoms of schizophrenia reduced side effect profile clozapine blocking D4 R> D2R = 5HT2AR > D1R central adrenerg effect mesolimbic selectivity side effects obesity, insulin resistance agranulocytosis! myocarditis olanzapine (Zyprexa®) 5HT2AR > H1R > D4 R> D2R mesolimbic selectivity side effects obesity, insulin resistance Source: http://www.doksinet Antipsychotics Atypical antipsychotics: risperidone (Risperdal®) blocking D2R > 5HT2AR > H1R mesolimbic selectivity side effects EPS hyperprolactinaemia sedation, headache MNS (depot) sertindole (Serdolect®), ziprasidone D2R > 5HT2AR > α1
side effects QT prolongation Source: http://www.doksinet Develompent of obesity and insulin resistance during AAP treatment weight gain blocing H1R in hypothalamus (VMHN, PVN) TNF-α hypersecretion α2 adrenergic agonism decreased leptin levels, leptin resistance insulin resistance antagonism ↓response of pancreatic β cells M3R antagonism ↓response of pancreatic β cells inhibitory effect on GLUT transporters in skeletal muscle 5HT1AR
