* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download CATECHOLAMINES - Drexel University College of Medicine
Polysubstance dependence wikipedia , lookup
Discovery and development of beta-blockers wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of TRPV1 antagonists wikipedia , lookup
Serotonin syndrome wikipedia , lookup
Toxicodynamics wikipedia , lookup
NMDA receptor wikipedia , lookup
CCR5 receptor antagonist wikipedia , lookup
5-HT2C receptor agonist wikipedia , lookup
Nicotinic agonist wikipedia , lookup
Discovery and development of antiandrogens wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
5-HT3 antagonist wikipedia , lookup
Chlorpromazine wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Antipsychotic wikipedia , lookup
Atypical antipsychotic wikipedia , lookup
Antipsychotics John A. Harvey, Ph.D. Department of Pharmacology and Physiology Neurobiology of Schizophrenia Schizophrenia represents a major mental illness, or possibly a group of Illnesses, manifested chiefly by disordered thought processes including disturbances in attention and associations. This leads to difficulties in communication, interpersonal relationships and reality testing. Studies Indicate that schizophrenia occurs 4-times more frequently among biological relatives than in the general population. Positive Symptoms Negative Symptoms Development of Abnormal Functions Reduction or Loss of Normal Functions 1. Delusions 2. Hallucinations 3. Disorganized Speech 4. Catatonic Behavior 1. Affective Flattening 2. Avolition 3. Attentional Deficits Psychiatric Uses Of Antipsychotic Drugs 1. Schizophrenia: Acute and Chronic Maintenance 2. Psychotic Depression (With Antidepressants) 3. Acute Mania (With Lithium) 4. Autism (For Control of Aggressive Behaviors) 5. Gilles de la Tourette’s Syndrome – Chronic Tics 6. Severe Agitation In Mentally Retarded and In Alzheimer’s Patients Pharmacological Actions of Antipsychotics At CNS Receptors • Dopamine: Antagonists at D2 or Partial Agonist at D2 (aripiprazole) • Serotonin: Antagonists at 5-HT2A • Histamine: Antagonists at H1 • Cholinergic: Antagonists at muscarinic M1-4 • Noradrenergic: Antagonists at α1 Therapeutic Targets of Antipsychotics • Dopamine: Antagonists at D2 • Serotonin: Antagonists at 5-HT2A Signal Transduction via Dopamine Receptors D2 D3 D4 D1 D5 Gs/q E Gi Second Messengers Trophic Actions: Neuronal Morphology Synaptic Plasticity Gene Expression Physiological Responses 5-HT2 Receptor Signaling Ligands 2A 2C ? PLA2 Phospholipids AA q/11ß PLC IP + DG PIP2 Rauwolfia Price:2.75/pkt Order Here Online Scientific Name: Rauwolfia serpentina Common Name: Rauwolfia Other Common Names: Plant Type: Perennial Where To Plant: Full Sun to Partly Shady Soil Types: Average Zones (See US Zone map): 11+ or Greenhouse Germination: Hard Number of Seeds Per Pack: 15 Uses: Medicinal Notes: Famous tranquilizer plant of India. Powerful hypnotic and sedative properties. Slow to germinate needs bottom heat 75 degree F. RAUWOLFIA SERPENTINA. Famous tranquilizer plant of India, where for 3000 years it has been used to treat mental illness. Long ignored by the West, until the 1950s, but now its active constituent, reserpine, is prescribed for its powerful hypnotic and sedative properties. Slow to germinate; bottom heat Typical Antipsychotics Have Antagonist Actions That Are Greater for the Dopamine D2 Than the 5-HT2A Receptor Phenothiazines & Derivatives Chlorpromazine Thioridazine Fluphenazine Perphenazine Butyrophenones Haloperidol A Newer Antipsychotic Is a Partial Agonist at the Dopamine D2 Receptor And A Serotonin 5-HT2A Receptor Antagonist Aripiprazole Atypical Antipsychotics Have Antagonist Actions that are Greater for 5-HT2A than D2 Risperidone Olanzapine Quetiapine Clozapine Ziprasidone A Newer Antipsychotic Is a Partial Agonist at the Dopamine D2 Receptor And A Serotonin 5-HT2A Receptor Antagonist Aripiprazole Dopamine Agonist DA Large Effect Large Effect DA Antagonist No Effect DA Partial Agonist Aripiprazole Small Effect Dopamine Hypothesis Of Schizophrenia: An Increase in Dopaminergic Activity in CNS 1. All Antipsychotics are DA Receptor Antagonists 2. Therapeutic effects correlated with D2 affinity 3. Dopamine Agonists (e.g., Amphetamines) Exacerbate Schizophrenic Symptoms at Low Doses 4. Higher Doses of Amphetamines Induce Paranoid Psychotic Reactions in Normal Individuals 5. Evidence of Changes in Dopamine Receptors in Schizophrenia is Still Controversial Decreasing affinity The therapeutic dose of antipsychotics is related to dopamine D2 receptor antagonism Increasing dose of drug Cognitive deficits can be due to too little as well as too much receptor activation 2D Graph 1 Y Data Level of Cognitive Functioning 100 Normal 80 Psychosis 60 40 20 0 0 2 4 6 8 X Data Activation DA Receptor Col 1 vs Col 2 10 Dopamine Projection Pathways 1. Neostriatal – Caudate/Putamen – Regulates Motor Function 2. Mesolimbic – Nucleus Accumbens and Amygdala – Regulates Emotions 3. Mesocortical – Limbic Cortex – Regulates Attention/Cognition 4. Tuberohypophysial – Arcuate Nucleus – Regulates Prolactin Release Blockade of Dopamine D2 Receptors • Emotion - Reduces expression of emotion • Cognitive functions – Decreases cognitive processes in prefrontal cortex • Motor functions – Produces akinesia and symptoms of Parkinsonism • Endocrine function – Produces increased release of prolactin The New England Journal of Medicine Established in 1812 September 22, 2005, Vol. 353 no. 12 Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E. Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., and John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators* Conclusions • The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. • Olanzapine was the most effective in terms of the rates of discontinuation, however it was associated with greater weight gain and increases in measures of glucose and lipid metabolism. • The efficacy of the typical antipsychotic agent perphenazine appeared similar to that of the atypical antipsychotics, quetiapine, risperidone, and ziprasidone. • Although atypical antipsychotics tended to have less extrapyramidal effects they were not free of them. Typical Antipsychotics Have Antagonist Actions That Are Greater for the Dopamine D2 Than the 5-HT2A Receptor Phenothiazines & Derivatives Chlorpromazine: First drug Thioridazine: Fluphenazine Perphenazine: Equally Effective with Atypicals Butyrophenones Haloperidol: Still Widely Used Atypical Antipsychotics Have Antagonist Actions that are Equal or Greater for 5-HT2A than D2 Risperidone: Widely Used Olanzapine: Well tolerated but greater weight gain Quetiapine Clozapine: Agranulocytosis in 2% of patients Drug Weight Gain Risk for Worsening Diabetes Lipid Profile Clozapine +++ + + Olanzapine +++ + + Risperidone ++ ± ± Quetiapine ++ ± ± Aripiprazole ± - - Ziprasidone ± - - Absorption and Distribution • Readily but incompletely absorbed • Significant first-pass metabolism • Highly lipid soluble and protein bound • Large volume of distribution • Long clinical duration (e.g., 6 weeks or more to full relapse) Metqbolism • Cytochrome P450 Enzymes CYP 3A4: Inhibitors are erythromycin, fluvoxamine Inducers are carbamazepine, phenytoin, phenobarbital CYP 2D6: Inhibitors are buproprion, fluoxetine, paroxetine, quinidine CYP 1A2: Inhibitors are fluvoxamine, omeprazole Metabolism Thioridazine metabolized to more potent compound – mesoridazine Aripiprazole metabolized to active compound dehydroaripiprazole with a half-life of 96 hours Clozapine metabolized to active compound N-desmethylclozapine Excretion Little excreted unchanged Adverse Effects of Antipsychotics At CNS Receptors • Dopamine: Antagonists at D2 • Serotonin: Antagonists at 5-HT2A • Histamine: Antagonists at H1 • Cholinergic: Antagonists at muscarinic M1 • Noradrenergic: Antagonists at α1 Adverse Pharmacologic Effects of Antipsychotic Drugs Type Manifestations Mechanism Autonomic nervous system Loss of accommodation, dry mouth, difficulty urinating, constipation Orthostatic hypotension, failure to ejaculate Hypotension, arrhythmia Muscarinic blockade Central nervous system Parkinson’s syndrome, acute akathisia(motor restlessness), acute dystonia (spasm of tongue, face, neck) Tardive dyskinesia, tardive dystonia (choreoathetoid movements or dystonia) Toxic-confusional state Sedation Dopamine receptor blockade (Early Onset) Endocrine system Amenorrhea-galactorrhea, infertility, impotence Dopamine receptor blockade resulting in hyperprolactinemia Miscellaneo us Neuroleptic malignant syndrome Not known Alpha1adrenoreceptor blockade Antiadrenergic Supersensitivity of dopamine receptors (Late Onset) Muscarinic blockade Antihistaminergic Sites of production of extra pyramidal signs by antipsychotic drugs and 1. DA receptor blockade by antipsychotics and actions of D2 agonist bromocriptine and D1/D2 agonist pergolide 2. Antimuscarinic effect of benztropine Glu = glutamate Ach = acetylcholine GABA = γ-aminobutyric acid DA = dopamine + = excitatory synapse ▬ = inhibitory synapse Circuitry for Extrapyramidal Control of Movement Side Effects Drug Chemical Class CPZ Equi v DA2 Affinity Ch-M Affinity Adr1 Affinity Low potency Chlorpromazine Thorazine Aliphatic phenothiazine 100 + +++ +++ Thioridazine Mellaril Piperidine phenothiazine 100 + +++ +++ Midpotency Perphenazine Trilafon Piperazine Phenothiazine 8 ++ ++ ++ 10 ++ ++ ++ 2 +++ - + Loxapine Loxitane Dibenzoxazepine Extrapyramidal I n c r e a s i n g S e v e r it y Anticholinergic Sedation Hypotension I n c r e a s i n g S e v e r it y Different Antipsychotics Ranked by Functional Class High potency Haloperidol Haldol Butyrophenone Fluphenazine Prolixin Piperazine phenothiazine 2 +++ - + Dibenzodiazepine 80 + +++ ++ Very Low High 2 ++ - ++ Low Low Atypical Clozapine Clozaril Risperidone Risperdal Benzisoxazole THE END