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László Drimba - Antiepileptic drugs, Antipsychotics

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 2011 · 28 page(s)  (608 KB)    English    3    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 blocking NMDA R  modulating GABAA R   pharmacokinetic features well absorbed  excreted in urine   adverse effects hepatitis  aplastic anaemia, agranulocytosis   clinical use refractory cases  Lennox-Gastaut epilepsy  Source: http://www.doksinet Antiseizure drugs Ethosuximide  pharmacodynamic features   blocking T-type Ca++ channels (especially in thalamic neurons) pharmacokinetic features rapidly absorbed  half life: 40 hours   adverse effects 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 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   serotonin 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  5HT1AR antagonism ↓response of pancreatic β cells  M3R antagonism ↓response of pancreatic β cells  inhibitory effect on GLUT transporters in skeletal muscle