PES eT Peseta Dept.of Pharmacology & Therapeutics = Objectives: Able to - Define & classify neurochemical basis of schizophrenia State antipsychotic agents v Explain MOA &pharmacological effects of drugs v State pharmacokinetic of drugs State indications, A/E & C/l of drugs v Compare different agents _—==— Prevalence: According to WHO 1% population is suffering from schizophrenia... In UK 15-20% suffering from psychiatric illness Most occur in early adeloscent— Mal 26-30 years Female : 28-32years: ‘Types of psychiatric disorder: © Organic - acute(delerium) & chronic(demensia) © Functional- » schizophrenia, » affectivedisorder(mania depression, bipolar disorder.eating disorder,obscessive compulsive disorder...)& » dillusional disordererrr Aetiological factors of psychiatric illness: * exact cause is unknown * genetic factor: 6:7% chance to occur from 1* degree relatives,monozygotic twins © environmental factor - maternal viral infection hypertention + Others factor-stressfll life events,chro illness familial disharmonysocial instability poverty * smoking Major psychiatric illness schizophrenia Antipsychotic means drugs that used in schizophrenia It may be defined as a kind of psychosis characterized mainly by a clear sensorium but a marked thinking, disturbances Sypmtoms of schizophrenia Positive syptoms ‘Nagative symptoms © hallucinations «affective flattening © delusion © attention problem © thought disorder © apathy “ Neurochemical basis of psychosis or dopamine hypothesis: eral lit of evic ive lit mit ivi le in sis- + Many antipsychotic drugs strongly block post synaptic Dareceptors in CNS + Drugs that increased dopaminergic activity such as ~ livodopa,amphitamine,apomorphine,bromocriptine either aggravate or produce psychosis = Postmortem findings showed increased dopamine receptor density in the the brain of schizophrenic patient who have not treated with antipsychotic drugsCont... © Some schizophrenic patient's postmortem studies, revealed increased dopamine level and D2 receptor density(in neucleus accumbens,caudate &putamen © Image studies shows increased drug induced striated dopamine release,increased baseline occupency of striatal D2 receptor by extracellular dopamine and other measure consistent with increased striatal dopamine synthesis &release Serotonin hypothesis:(more acceptable)" 5-HT dysfunction involved in schizophrenia and many effective antipsychotiesact as 5-HT2A antagonist in addition to blocking dopamine receptor Glutamate hypothesis: Glutamate NMDA receptor —_ antagonist like....phencytamine,ketamine produce _ psychotic symptoms in human & reduced glutamate concentration & glutamate receptor density have been reported in postmortem of brain in schizophrenic patient Dopaminergic system: important pathway: 1.Mesolimbic-mesocortical pathway—related to behaviour 2.Niagrostratal pathway-~-involved in coordination of voluntary movement 3.Tuberoinfundibular system-—-inhibit prolactin secretion 4 Medullary-periventricular pathway-~involved in eating behaviour 5lncer to hypothalamic pathway-—function isnot exact known,Dopamine receptor ° Di-D5. » D1 & Ds-—stimulate adenyl cyclase enzyme © D2,D3&D4—inhibit adenyl cyclase enzyme Antipsychotic agents Before 1940 there was no specific drug... May be classified as-—- 1)Classical agents I1)Atypical agents 1)Classical agents are- A)Phenothiazine derivatives--- > Alephate dertaties Mchlopomaine Promazine > Pein esate Tatra Per + Pesprasine dete TiloperainPrphenasine = Cont... B)Thioxanthine derivatives-— > Thioxanthin > Flupenthixol ©) Butyrophenone derivatives Haloperidol > Benperidol Cont. I)Atypical agents: > Clozapine Olanzapine > Quetapine >>Molindone > Resperidond > Sertindoleaa Chlorpromazine Tsprototype drug.It blocks Da receptorin the mesolimbic - mesocortcal pathway and also block a, S-HT2A>D2>01 Pharmacological effects: 1.Psychological(anti psychotic effects due to blockade of D2 receptor in mesolimbic mesocortical pathway ): + decrease spontaneous motor activity decrease agitation decrease sty emotional quitening ‘modilyabaoemal behaviour Patent el sleep fecrease intelectual activity Sedation decrease attention ‘decrease emotion Tnerease pin threshold _ Cont... 2.Exrppyramidal symptoms (due to blockade of Dz receptor in ngrostital pathway dhstnia Ferkinsoian symptoms Shathsa 3.Endocrine effects (due to blockade of D2 receptor in tuberoinfundibular pathway): 1 pate penny ot } tent ee a Cont... 3.Antiemetic effect due to blockade of D2 receptor in CTZ and gut 4.Anticholinergic effect: dry mouth blurring of vision urinary retention constipation etc.= Cont..: 5.a1 adrenoceptor blocking effect: postural hypotention failure of ejaculation 6.Anti histaminic activity:(H1 blocking effect) 7.Cardiovascular effect: decrease peripheral resistance reduce mean arterial pressure increase hear rate decrease stroke volume ‘orthostatic hypotension Clinical use: Schizophrenia Mania in acute phase ‘Asantiemetie Persistant pruritus Incense hiceup Severe pain Senile dementia vertigo severe pain with analgesic sed in neuroleptic anaesthesia Adverse effects: (On CNS-Extrapyramidal symptom-? litre/hour biotransformation in liver,excreted through kidney;more than 90% bounds to pp.clemination half life is 10-24 hrs, Plasma half life: 35 hrs.so to get antipsychotic effect we require 2-3 wks. 2 mg Halloperidol is used for antipsychotic effect MOA: (came as chlorpromazine)Da>ai>D4>sHTa>Di>Hi Adverse effects: (same as chlorpromazine) Adverse effects of Atypical agents: granulocytosis, Leukopenia Olanzapine Sertindole may cause-cardiac arvhythmia How can you manage these adverse effects? > EPScan be managed by adding Procyclidine with Chlorpromazine_or, Benztropin or,Benzhexol » Endocrine effect can be minimized by lowering the dose oxby adding Bromocriptin. » Skin aned eye problem can't manage Limitations of classical agents: ‘EPS and other adverse effects * Effective in only 70% cases-rest remain registant to treatment * Ineffective in negative symptoms Advantage of atypical agents: + Better tolerated(EPS &Endocrine A/E less) = Compliance also good + Effective in negative symptoms * Some are effective in registant schizophrenia(clozapine) y Disadvantage of atypical agents: Expensive * Notavailable Comparison between Chlorpromazine and Halloperidol typical and atypical agents