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Psychopharmacs : antipsychotics prof. MUDr. Eva Češková, CSc. Dept. of Psychiatry, Dept. of Psychiatry, Masaryk University, Brno Masaryk University, Brno.

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Presentation on theme: "Psychopharmacs : antipsychotics prof. MUDr. Eva Češková, CSc. Dept. of Psychiatry, Dept. of Psychiatry, Masaryk University, Brno Masaryk University, Brno."— Presentation transcript:

1 Psychopharmacs : antipsychotics prof. MUDr. Eva Češková, CSc. Dept. of Psychiatry, Dept. of Psychiatry, Masaryk University, Brno Masaryk University, Brno

2 Psychopharmacs : antipsychotics §definition and history §classification according to chemistry §classification according to clinical efficacy §mechanism of action §pharmacokinetic §doses and duration of treatment §side effects §indication §literature

3 Definition, history Neuroleptics ( antipsychotics, AP ) are psychopharmacs influencing psychic integration in a positive way Antipsychotics are the cornerstone of treatment of schizophrenia. The first antipsychotic drugs was discovered by accident in the 1950s when a drug thought to be an antihistamine (chlorpromazine) was serendipitously observe to have unique antipsychotic effect

4 Classification according to chemistry §phenothiazines - 3 ring nucleus, drugs differ in the side chains(aliphatics, piperidines, piperazines) §thioxanthenes - differ from the phenothiazine by the substitution of a C instead of N in the middle ring §butyrophenones (haloperidol) §dephenylbutyrylpiperidines (penfluridol, pimozid) §dibenzodiazepines (clozapine) §benzisoxale (risperidone) §thienobenzodiazepine (olanzapine) §dibenzothiazepine (quetipine) §benzamide §others

5 Classification according to the clinical efficacy Conventional antipsychotics: §incizive (high potency):e.g., haloperidol, fluphenazine, perphenazine, trifluoperazine) §basale (low potency):e.g., chlorpromazine, thioridazine Atypical antipsychotics: aripiprazole, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, zotepine

6 Conventional antipsychotics Limitations of conventional antipsychotics: § insufficient efficacy with targeted symptoms (e.g., negative symptoms, cognitive deficits) § positive symptoms resistant to therapy in (15– 48% of patients) §motor side effects (irreversible tardive dyskinesia in 5–10% of patients with long-term treatment §affective side effects (dysphoria, anhedonia) §poor adherence (only 30% of patients during long-term treatment)

7 Classification of atypical antipsychotics §specific D2 and D3 antagonists -sulpiride, amisulpiride (f.o. Solian) §serotonin/dopamine antagonists SDA - risperidone (f.o.Risperdal), ziprasidone (f.o. Abifal) §multireceptor targeted antagonists (MARTA) clozapine (f.o. Leponex), olanzapine (f.o.Zyprexa), quetiapine (f.o. Seroquel), zotepine (f.o. Zoleptil)

8 Atypical antipsychotics (new APs, 2 nd generation APs ) Advantages of atypical antipsychotics Better efficacy: in treatment-resistant patients +(+) in negative symptoms ++ in neuropsychological deficits ++ no clinically relevant motor side effects +++ Fewer affective side effects +(+) Better adherence ++ Better subjective well-being and quality of life ++

9 Classification of atypical antipsychotics - receptor binding affinities

10 Depot antipsychotics Benefits of depot (long-acting) injections: §optimise treatment adherence (reduce relapse) §assure delivery, avoid first-pass metabolism §use lowest effective dose, predictable plasma levels §simple administration, regular contact with team Available depot APs: §fluphenazine decanoate/enanthate §flupenthixol decanoate, haloperidol decanoate §zuclopenthixol decanoate, oxyprothepin decanoate §available depot atypical APs -Risperdal Consta

11 §relapse rates are lower with continuous antipsychotic therapy ! §relapses with APs signif. lower than with placebo (circa 20% vs 50%) §poor adherence leads to relapse and high costs to individuals, families, carers and society §stopping medication is the most powerful predictor of relapse

12 Mechanism of action §all available clinically effective APs block D (dopamine) receptors, the potency to reduce psychotic symptoms is most closely correlated with the affinity to D2 receptor §others systems may play important role (glutamate, noradrenaline, serotonin, GABA, neuropeptides) §atypical APs differentially affect other systems (serotonin) - more specific pharmacological action generally safer, better tolerated §APs differ in their ability to block the various receptors - e.g. in their side effects profiles, but no in their therapeutic profiles

13 Mechanisms of action All the known APs share the common property of blocking DA receptor: §blockade of DA receptors in the nigrostriatal DA pathway - a drug-induced parkinsonism §blockade of DA receptors in the mesolimbic DA pathway - antipsychotic efficacy (especially positive symptoms) §blockade of DA receptors in the mesocortical DA pathway - blunting of emotions and cognitive side effects §blockade of DA receptor in tuberoinfundibular DA pathway - elevation of prolactin levels

14 Mechanism of action - dopaminergic pathways of the CNS Stahl SM.: Essential Psychopharmacology, 2000

15 Pharmacokinetics §most APs have high binding to plasma protein, volume of distribution, and lipid solubility §the most important clinical generalisation is that all the APs can be given in a one daily dose once patient is in a stable condition §APs are metabolised in the liver and reach steady plasma levels in 5-10 days.

16 Doses (and dose equivalence of atypicals) 180120 – 180140 – 18080 – 160100 – 160 Ziprasidone 3015 – 2015 – 3010 – 20 Aripiprazole 950400 – 750500 – 800300 – 600350 – 700 Quetiapine 4012.5 – 22.515 – 2510 – 20 Olanzapine 850300 – 550400 – 600250 – 500300 – 500 Clozapine Atypicals Maintenance treat. (mg/day) Acute treat. (mg/day) Maintenance treat. (mg/day) Acute treat. (mg/day) Highest final acute dose (mg/day) Multi-episode patientFirst-episode patient Medication 10.53.5 – 5.54 – 6.52 – 4.52.5 – 5 Risperidone

17 115Partial response to treatment 63Little or no response to treatment Maximum number of weeks to wait Minimum number of weeks to wait Duration of treatment 104Partial response to treatment 63Little or no response to treatment Maximum number of weeks to wait Minimum number of weeks to wait Inadequate response to initial antipsychotic Inadequate response to second antipsychotic

18 Side effects Acute extrapyramidal side effects: §parkinsonian syndrome §acute dystonia §akathisia Tardive dyskinesia (new antipsychotics 0.6% vs haloperidol 5.3%) Neuroleptic malignant syndrome (NMS)

19 Side effects Autonomic side effects: §anticholinergic (blurred vision, dry mouth, constipation, urine retention) §hypersalivation Cardiovascular effects: §orthostatic hypotension §cardiac rhythm disturbances Dermatological and ocular effects Endocrine effects Hepatic effects Haematological effects

20 Side effects Metabolic side effects: §hyperprolactinemia §weight gain §diabetes §dyslipidemia QTc prolongation

21 Hyperprolactinemia Prolactin (PRL): Pituitary hormone involved in lactation, learning, body temperature, immune response, cortisole secretion §normal values: 5 - 25 ng/ml (or U/l) in men and non-pregnant and non-lactating women §prolactin-related side effect: galactorrhoea, amenorrhea, sexual dysfunction §PRL is elevated by: D2 blockers (antipsychotics) sleep, stress, exercise, sexual activity, food, pituitary lesions, seizure disorder, renal/hepatic disease, hypothyroidism

22 Side effects - hierarchy of antipsychotic weight gain (10 weeks) Mean change in body weight (kg) (Allison DB et al. Am J Psychiatry 1999;156:1686–96) 5 4 3 2 1 0 –1 Placebo Molindon e Ziprasidone Fluphenazine Haloperidol Non-pharm control Risperidone Chlorpromazine Sertindole Thioridazine Olanzapine Clozapine Hierarchy of weight gain but also differential rate (trajectory) and total gain (plateau)

23 Consensus development conference on antipsychotic drugs and obesity and diabetes (American diabetes association, APA, American Association of clinical endocrinologists, North American Association for the study of obesity).

24

25 -5 0 5 10 15 20 25 30 35 40 Zipr. 160 mg Risp. 16 mg Olan. 20 mg Seroq. 750 mg Thior. 300 mg Halo. 15 mg (n=24) (n=25) (n=27) (n=27) (n=31) (n=30) Adverse effects - QTc prolongation Mean change of QTc (msec) Pfizer Study 54

26 Indications §schizophrenia disorder §delusional disorder §mood disorders with psychotic symptoms §psychosis secondary to nonpsychiatric medical condition or substance-induced condition

27 References : §Allison DB, Mentore JL, Moonseong H.: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry, 156, 1999, pp. 1686-1696 §Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27, 2004, 2, pp. 596-601 §Janicak PG.: Handbook of psychopharmacology, Baltimore: Williams and Willkins, 1999 §Kaplan HI, Sadock BJ, Grebb JA.: Kaplan and Sadock´s synopsis of psychiatry, Baltimore : Williams and Wilkins, 1997 §Stahl, SM.: Psychopharmacology of antipsychotics, London: Martin Dunitz, 1999 §Stahl SM.: Essential Psychopharmacology, Cambridge: Cambridge University Press, 2000


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