1 / 54

ANTI-PSYCHOTIC DRUGS

ANTI-PSYCHOTIC DRUGS. DON D. CUA, MD Department of Pharmacology. TYPES OF PSYCHOSIS. SCHIZOPHRENIA AFFECTIVE DISORDERS (DEPRESSION/MANIA) ORGANIC PSYCHOSES (CAUSED BY HEAD INJURY, ALCOHOLISM, OTHERS). SCHIZOPHRENIA.

sonja
Télécharger la présentation

ANTI-PSYCHOTIC DRUGS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ANTI-PSYCHOTIC DRUGS DON D. CUA, MD Department of Pharmacology

  2. TYPES OF PSYCHOSIS • SCHIZOPHRENIA • AFFECTIVE DISORDERS (DEPRESSION/MANIA) • ORGANIC PSYCHOSES (CAUSED BY HEAD INJURY, ALCOHOLISM, OTHERS)

  3. SCHIZOPHRENIA A clinical syndrome characterized by profound disruption in cognition and emotion, affecting the most fundamental attributes: language, thought, perception, affect and sense of self. clear sensorium but marked thinking disturbance

  4. THE NATURE OF SCHIZOPHRENIA • 1% population, begins at an early age, with strong hereditary factor • SEX: Equally prevalent in men and women • AGE: MEN-between 15 and 25 WOMEN-between 25 and 35

  5. POSITIVE SYMPTOMS • Delusions Disorganized behavior • Hallucinations Disorganized speech/thinking • Thought disorder Catatonic behaviors NEGATIVE SYMPTOMS • Withdrawal from social contacts • Flattening of emotional responses • Alogia, Avolition-Apathy, Anhedonia-Asociality • Attention

  6. MAJOR AFFECTIVE /MANIC DEPRESSIVE DISORDERS • Abnormal emotion or mood • Disorders of affect & depression, dysphoria, elation or mania • Bipolar or non-bipolar • Can occur as a mild disorder or can be associated with other psychiatric or medical illnesses

  7. NEUROSES: • Less pervasive psychiatric disorders • Comprehend reality, suffering & disability are sometimes severe • Acute or transient, persistent or recurrent • Mood changes- anxiety , panic, depression • Limited abnormalities of thought- obsessions, irrational fears • Behavior – rituals, compulsions, hysterical conversions

  8. Diagnostic Criteria for SchizophreniaDSM IV A. Two or more of the following ( one-month period ) delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior and negative symptoms. B. Social/occupational dysfunction: one or major areas of functioning such as work, interpersonal relations, or self-care, are markedly below the level achieved prior to the onset. C. Continuous signs of the disturbance persist for at least SIX months.

  9. THE DOPAMINE HYPOTHESIS SCHIZOPHRENIA: WITH EXCESSIVE DOPAMINERGIC ACTIVITY; NORe and GABA • ANTI-PSYCHOTIC DRUGS BLOCK POSTSYNAPTIC D2 RECEPTORS IN CNS • DRUGS THAT INCREASE DOPA AGGRAVATE SCHIZOPHRENIA • DOPAMINE RECEPTOR DENSITY ↑ in schizos • POSITRON EMISSION TOMOGRAPHY (PETS) ↑ Dopamine Receptor Density • HOMAVANILLIC ACID (HAV) CHANGE IN AMOUNT

  10. CLASSIFICATION OF ANTIPSYCHOTIC DRUGS: • TYPICAL ANTIPSYCHOTICS: A. PHENOTHIAZENE DERIVATIVE • 3 ring structure, 2 benzene rings are linked by sulfur & nitrogen atom • N position 10 is replaced by carbon atom with a double bond to the side chain

  11. ALIPHATIC DERIVATIVE: • CHLORPROMAZINE • TRIFLUPROMAZINE PIPERIDINE DERIVATIVE: • THIORIDAZINE • MESORIDAZINE • PIPERACETAZINE • Decrease incidence of EPS side effects due to  antimuscarinic activity

  12. PIPERAZINE DERIVATIVE: • FLUPHENAZINE • PERPHENAZINE • TRIFLUOPERAZINE • Most potent phenothiazene & thioxanthene antipsychotic compound •  EPS but  tendency to produce sedation or autonomic side effects

  13. B. THIOXANTHENE DERIVATIVES: ALIPHATIC DERIVATIVE: • CHLORPROTHIXENE PIPERAZINE DERIVATIVE: • CHLOPENTHIXOL • FLUPENTIXOL • THIOTHIXENE

  14. C. BUTYROPHENONE: • HALOPERIDOL

  15. CLASSIFICATION OF ANTIPSYCHOTIC DRUGS 1. TYPICAL ANTI-PSYCHOTICS A. Phenothiazine Derivatives • Aliphatic Derivative: CHLORPROMAZINE • Piperidine Derivative: THIORIDAZINE • Piperazine Derivative: FLUPHENAZINE, PERPHENAZINE, TRIFLUOPERAZINE B. Thioxanthene Derivative: THIOTHIXENE C.Butyrophenone:HALOPERIDOL

  16. CLASSIFICATION OF ANTI-PSYCHOTIC DRUGS 2. ATYPICAL ANTI-PSYCHOTICS • CLOZAPINE • LOXAPINE • RISPERIDONE • MOLINDONE • SERTINDOLE • ZIPRASIDONE • OLANZAPINE • QUETIAPINE • PIMOZIDE

  17. DOPAMINE RECEPTORSD1 like family • D1: CHROMOSOME 5; INCREASE cAMP…> activation of adenyl cyclase • D5 : CHROMOSOME 4; INCREASE cAMP D2 like family • D2: CHROMOSOMES 11: DECREASE cAMP …>blocks calcium channels ……> opens potassium channels • D3: CHROMOSOME 11: DECREASE cAMP • D4: DECREASE cAMP

  18. DIFFERENCES AMONG ANTI-PSYCHOTIC DRUGS CHLORPROMAZINE alpha1=5HT2 > D2 >D1 HALOPERIDOL D2>D1=D4>alpha1>5HT2 CLOZAPINE D4=alpha1>5HT>D2=D1 RISPERIDONE D2=5HT2 OLANZAPINE 5HT2> or= D1, D2, alpha2

  19. DOPAMINERGIC SYSTEM 1. MESOLIMBIC-MESOCORTICAL substancia nigra………>limbic system BEHAVIOR 2. NIGROSTRIATAL substancia nigra….>caudate & putamen VOLUNTARY MOVEMENTS 3. TUBEROINFUNDIBULAR arcuate nuclei & periventricular neurons,> hypothalamus & post pituitary INHIBITS PROLACTIN SECRETION

  20. DOPAMINERGIC SYSTEM 4. MEDULLARY-PERIVENTRICULAR motor nuclei of the vagus EATING BEHAVIOR 5. INCERTOHYPOTHALAMUS from the medial zona incerta to the hypothalamus and the amygdala REGULATE THE ANTICIPATORY MOTIVATIONAL PHASE OF COPULATORY BEHAVIOR IN RATS

  21. ANTI-PSYCHOTIC AGENTS • PSYCHOLOGICAL EFFECTS > sleepiness, restlessness, impaired performance & judgment • NEUROPHYSIOLOGIC EFFECTS > hypersyncrony focal /unilateral • ENDOCRINE EFFECTS > amenorrhea, galactorrhea, increase libido, false(-) pregnancy test >decrease libido in males, gynecomastia

  22. ANTI-PSYCHOTIC AGENTS • CARDIOVASCULAR EFFECTS • orthostatic hypotension • high resting pulse rate • increase PR, decrease stroke volume, decrease mean arterial pressure • decrease peripheral resistance

  23. PHARMACOKINETICS • READILY BUT INCOMPLETELY ABSORBED • FIRST PASS METABOLISM • HIGHLY LIPID SOLUBLE • LARGE VOLUME OF DISTRIBUTIION • PROTEIN BOUND • COMPLETELY METABOLIZED Except mesoridazine(major metabolites of thioridazine) • LITTLE EXCRETED UNCHANGED • T ½ is 10 -24 hours

  24. CLINICAL INDICATIONS A. PSYCHIATRY INDICATIONS • SCHIZOPHRENIA • SCHIZO-AFFECTIVE DISORDERS • MANIC EPISODES IN BIPOLAR DISORDERS • GILLES DE LA TOURETTE SYNDROME • SENILE DEMENTIA B. NON-PSYCHIATRIC INDICATIONS • ANTI-EMETIC EFFECT • ANTI-PRURITIC EFFECT • PRE-OPERATIVE ANESTHESIA • NEUROLEPTIC ANESTHESIA

  25. SIDE EFFECTTS OF NEUROLEPTIC DRUGS A. NEUROLOGIC EFFECTS 1. ACUTE DYSTONIA : spasm of muscles tongue, face, neck, back, may mimic seizures • During the first 1 -5 days of Rx • Mechanism unknown • Rx: anti-parkinson’s agents 2. AKATHISIA : motor restlessness • 5 -60 days • Mechanism unknown • Rx with diphenhydramine

  26. 3. PARKINSONISM • bradykinesia, rigidity, tremor, mask facies, shuffling gait seen in 5-30 days • Mechanism: antagonism of dopamine Rx: anti-parkinson’s agents 4. NEUROLEPTIC MALIGNANT SYNDROME • catatonia, stupor, fever, unstable BP, myoglobulinemia after weeks of treatment • Mechanism: antagonism of dopamine Rx: Stop neuroleptic immediately; dandrolene; bromocriptine, Anti-parkinsons- not effective

  27. 5. PERIODIC TREMOR RABBIT SYNDROME • Peri-oral tremors after months or years of treatment • Mechanism : unknown • Rx: Anti-parkinson’s Drugs 6. TARDIVE DYSKINESIA Supersensivity of D receptors (cholinergic def) • oral-facial dyskinesia, choreoathetosis, dystonia • After months or years of RX • Worse on withdrawal • Mechanism: excess function of dopamine • Rx: prevention crucial • Rx: unsatisfactory

  28. ADVERSE EFFECTS B. BEHAVIORAL EFFECTS • Pseudo-depression; toxic confusional state C. AUTONOMIC NERVOUS SYSTEM EFFECTS • urinary retention, dry mouth, loss of accomodation, constipation (MUSCARINIC CHOLINERGIC BLOCKADE) • orthostatic hypotension, impotence, failure to ejaculate ( ALPHA ADRENORECEPTOR BLOCKADE)

  29. ADVERSE EFFECTS D. METABOLIC & ENDOCRINE EFFECTS • Weight gain, hyperglycemia, hyperprolactinemia, amenorrhea-galactorrhea syndrome, infertility, impotence in males E. TOXIC OR ALLERGIC REACTIONS • Agranulocytosis (clozapine) , cholestatic jaundice, skin eruptions F. CARDIAC TOXICITY • Ventricular arrythmias (thioridazine) G. OCULAR COMPLICATIONS: • “ browning of vision”

  30. ANTI-MANIC AGENTS • MANIA-- STATE OF ELEVATED MOOD & PSYCHOMOTOR ACCELERATION, WITH EXCESS CATHECHOLAMINES ACTIVITY TREATMENT: LITHIUM CARBONATE • CATHECOLAMINE RELEASE FROM ADRENERGIC NERVE TERMINALS

  31. LITHIUM INDICATIONS: BIPOLAR DISORDERS THYROTOXICOSIS INAPPROPRIATE ADH SECRETION

  32. LITHIUM PHARMACOKINETICS ABSORPTION : virtually complete within 6 -8 hrs; peak plasma levels in 30 min to 2 hrs DISTRIBUTION: in total body water; slow entry into intracellular compartment. No protein binding METABOLISM: None EXCRETION: virtually entirely in urine; plasma half life is about 20 hours

  33. LITHIUM PHARMACODYNAMICS • EFFECTS ON ELECTROLYTES & IONSTRANSPORT: • Substitute for sodium in generating action potentials • EFFECTS ON NEUROTRANSMITTERS • Enhance effects of serotonin? • Decrease norepinephrine & dopamine turnover • Block dopamine receptor supersensitivity • Augment synthesis of acetylcholine? • EFFECTS ON SECOND MESSENGERS • effect on Inositol 1,4,5 triphospate (IP3 )/ Diacylglycerol (DAG)-needed in alpha a andmuscarinic transmission

  34. Lithium inhibits several important enzymes in the normal recycling of membrane phosphoinositides. (-) IP2----IP1 (-) IP1----inositol It will lead to a depletion of PIP2(phosphotidylinositol-4,5-bis-phosphate) which is the membrane precursor of IP3 and DAG LITHIUM could cause a selective depression of the overactive circuits.

  35. LITHIUM ADVERSE EFFECTS • CNS EFFECTS: dizziness, mild ataxia • NEUROMUSCULAR EFECTS: fine tremors • CVS EFFECTS: ventricular arrythmias • GIT EFFECTS: nausea, vomiting, diarrhea • GUT EFFECTS: polyuria • ENDOCRINE EFFECTS: hypothyroidism • ALLERGIC REACTION: pruritus, rash • OVERDOSE TOXICITY: vomiting, drowsiness, decrease consciousness and seizures Rx: dialysis

  36. The TWO most common side effects UNCOUPLING OF THE VASOPRESSIN and TSH RECEPTORS FROM THEIR G PROTEINS

  37. LITHIUM CONTRAINDICATIONS A. MARKED DEHYDRATION OR SODIUM DEPLETION B. SIGNIFICANT RENAL OR CARDIAC DISEASES C. PREGNANCY D. RENAL CONCENTRATION ABILITY • Nephrogenic diabetes insipidus with polyuria

  38. LITHIUM DRUG INTERACTIONS • THIAZIDE DIURETICS: DECREASE RENAL CLEARANCE OF LITHIUM • NSAID: DECREASE LITHIUM CLEARANCE • ANTIPYSCHOTIC AGENTS: INCREASE NEUROTOXICITY

  39. DEPRESSION I. REACTIVE OR SECONDARY DEPRESSION Core Depression Syndrome: depression, anxiety, tension, bodily complaints, guilt (> 60%) II. ENDOGENOUS DEPRESSION Core Depression Syndrome plus ABNORMAL vital signs rhythm of sleep, motor activity, libido, decrease appetite ( 25%) III. DEPRESSION ASSOCIATED WITH BIPOLAR AFFECTIVE DISORDER (10-15%)

  40. Pathogenesis of Major Depression DECREASED FUNCTIONAL AMINE-DEPENDENT SYNAPTIC TRANSMISSION

  41. ANTI-DEPRESSANTS A.TRICYCLIC ANTI-DEPRESSANTS(TCA) THREE-RING NUCLEUS- (anti-muscarinic, anti-H and @(-)adrenergic) IMIPRAMINE. AMITRYPTYLINE (mixedNorE and serotonin uptake inhibitors) DOXAPIN, NORTRIPTYLINE , DESIPRAMINE, CLOMIPRAMINE , PROTRIPTYLINE, TRIMIPRAMINE Note: toxicity due alpha adrenergic blocking activity B. HETEROCYCLIC: SECOND & THIRDGENERATIONS 1. SECOND GENERATIONS AMOXAPINE (dopamine receptor antagonist) MAPROTILINE TRAZODON, BUPROPION 2. THIRD GENERATIONS MIRTAZAPINE, VENLAFAZINE,NEFAZODONE

  42. ANTI-DEPRESSANTS C. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI) • FLUOXETINE • PAROXETINE • SERTRALINE, CITALOPRAM, FLUVOXAMINE D. MONOAMINE OXIDASE INHIBITORS (MAOI) • PHENELZINE, TRANYLCYPROMINE • MOCLOBEMIDE ,SELEGILINE • NOTE: MAO-A—amine oxidase responsible for NORe, serotonin and tyramine MAO-B---selective for dopamine(SELEGILINE)

  43. ANTI-DEPRESSANTS PHARMACODYNAMICS • ACTION OF ANTIDEPRESSANTS ON BIOGENIC AMINE NEUROTRANSMITTERS TCA(-) NorE and serotonin reuptake pump “OFF-SWITCHES” of the amine transmission MAO inhibitors (-) major degradation pathway resulting to accumulation of amines in presynaptic stores for the amino neurotransmitters and increase release Trazodone,Nefazodone and Mirtazepine(-) 5HT2a or 5HT2c Mirtazepine (-) alpha 2 NorE receptors (Increase therapeutic effects)

  44. B. RECEPTOR & POSTRECEPTOR EFFECTS Increase in neurotransmitter in the synapse acting on postsynaptic receptor giving ultimate effect. by decreasing cAMP rather than increase. and decreasing postsynaptic B adrenoreceptors as clinical improvement is seen. C. EFFECTS OF SPECIFIC ANTIDEPRESSANTS

  45. PHARMACOKINETICS • A. TRICYCLICS • Incompletely reabsorbed • First pass metabolism • Large volume of distribution • Metabolized due to transformation of tricyclic nucleus and alteration of the aliphatic side chain ( hydroxylation and conjugation and demethylation) • B. HETEROCYCLICS • Variable bioavailability • High protein binding • Variable and large volume of distribution • Active metabolites

  46. PHARMACOKINETICS • C. SSRI : FLUOXETINE • Well absorbed • PPC: 4 – 8 hrs • Inhibits drug metabolizing enzymes • D. MAOI • Readily absorbed

  47. CLINICAL INDICATIONS • DEPRESSION • PANIC DISORDER (Imipramine) • OBSESSIVE COMPULSIVE(SSRI-Fluoxetine) • ENURESIS (TCA) • CHRONIC PAIN (TCA,Phenothiazine) • OTHERS: Eating Disorder (Bulemia)(SSRI) Cataplexy associated with narcolepsy, school phobia, attention deficit syndrome NOTE: Serotonin Syndrome-hyperthermia,muscle rigidity and myoclonus

  48. ADVERSE EFFECTS • TRICYCLICS Sedation: sleepiness Sympathomimetic: tremors, insomnia Anti-muscarinic: blurred vision, constipation confusion, urinary incontinence Psychiatric: psychoses aggravated CVS: orthostatic hypotension Neurologic: Seizures Metabolic-Endocrine: weight gain, sexual disturbance

  49. Foods that interact with MAOI • High in tyramine content : • BEER • BROAD BEANS, LAVA BEANS • CHEESE • CHICKEN LIVER • SAUSAGES • RED WINE • YEAST

  50. MAO INHIBITORS • headache, drowsiness, dry mouth, weight gain, postural hypotension, sexual disturbance • AMOXAPIN • Tricyclic & anti-psychotic effects • MAPROTILINE • Tricyclic effects • TRAZODONE & NEFAZODONE: drowsiness, dizziness, insomnia, nausea and agitation • BUPROPION • dizziness, dry mouth, tremor • FLUOXETINE • Anxiety, insomnia, tremors, decrease libido, GIT effects

More Related