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PSYCHOPHARMACOLOGY דר' שאולי לב-רן מרכז לבריאות הנפש "שלוותה" Neurotransmitters Classical Neurotransmitters Acetylcholine Monoamines Dopamine NE Serotonin (5-HT) Amino acids GABA Glycine glutamate Neuropeptides Somatostatin Vasopressin Prolactin GH Oxytocin Groups of drugs Anti-psychotics Anti-cholinergic Anti-depressants Mood stabilizers Sedatives Classical/typical anti-psychotics • • • • Chlorpromazine – 1954 Dopamine hypothesis Dopamine receptor antagonists (DRD2) Also antagonize α-1, central & peripheral cholinergic receptors, H1 • High potency vs low potency High potency EPS Low potency peripheral / systemic AE Classical / typical anti-psychotics Phenotiazines Aliphatics (chlorpromazine, levomepromazine, clotiapine) Piperazines (perhpenazine, fluphenazine) Piperidines (thioridazine, pericyazine) Thioxanthines (flupenthixol, zuclopenthixol) Butyrophenones (haloperidol) Diphenylbutylpiperidine (pimozide, penfluridol) Benzamides (sulpiride) EPS = extrapyramidal syn. Medication induced movement disorder Parkinsonism Acute dystonia Acathisia Tardive dyskinesia NMS Treatment of NMS Discontinuation of dopamine antagonist Monitoring vital signs, electrolytes, renal output Symptomatic treatment of fever IV dantrolene/bromocriptine/amantadine After symptoms subside – switch to atypical anti-psychotic Non-EPS AE • Dopamine • endocrine effects: gallactorhea, impotence, amenorrhea, anorgasm • ACh • Dry mouth, mydriasis, blurred vision, constipation, urinary retention, central anticholinergic effect • α1 • Orthostatic hypotension • H1 • sedation Cardiac effects: QT, PR elongation, T wave changes, arrhythmias Hematological efffects: agranulocytosis Dermatological effects: allergic dermatitis, photosensitivity (chlorpromazine) Ophtalmological effects: retinal pigmentation (thioridazine – irreversible, chlorpromazine – benign) Hepatological effects: obstructive jaundice Neurologic : seizures Atypical anti-psychotics 5-HT2 > DRD2 Improve positive and negative symptoms Lower incidence of EPS Atypical anti-psychotics Risperidone (risperdal) Olanzapine (zyprexa) Clozapine (leponex) Quetiapine (seroquel) Ziprasidone (geodon) Dispulpride (solian) Adverse effects Metabolic Weight gain, glucose intolerance, hypercholesterolemia Hematological agranulocytosis (clozapine) weekly/monthly CBC Sialorrhea – clozapine Genitourinary – clozapine In addition: similar AE to typical anti-psychotics but to a lesser degree. Long acting anti-psychotics • Indicated mainly for patients with low compliance to treatment • IM: • • • • • Haloperidol - Halidol decanoas Fluphenazine – Modiket Zuclopenthixol – Clopixol depot Flupenthixol – Fluanxol depot Risperidone – Risperidal consta • PO: • Penfluridol – Semap Drug of choice… Depends on: Pharmacodynamics & pharmacokinetics Diganosis, major symptoms, past treatments Demographics – age, support group, substance abuse Medical issues Other – availability, price, personal experience Groups of drugs Anti-psychotics Anti-cholinergic Anti-depressants Mood stabilizers Sedatives Anticholinergics Used for treatment of medication-induced movement disorder Antimuscarinic Trihexyphenidyl (artane), Biperiden (dekinet), orphenadrine citrate (flexin) Risk of anticholinergic intoxication Treatment of medication-induced movement disorders Parkinsonism anticholinergics, amantadine Acute dystonia anticholinergics (IM) Akathisia beta-blockers, BZ Tardive dyskinesia clozapine, (vit E?) Groups of drugs Anti-psychotics Anti-cholinergic Anti-depressants Mood stabilizers Sedatives Causes of Disability by Illness Category United States and Canada 15-44 years old Mental Illness* Alcohol and drug use Injuries, including self-inflicted Respiratory disease Musculoskeletal disease Sense organ disease Cardiovascular disease Migraine Infectious disease, excluding HIV 0 5 10 15 20 25 30 35 WHO World Health Report 2002 40 Causes of Disability by Specific Illness United States and Canada 15-44 years old Unipolar depression Alcohol use Drug use Bipolar disorder Schizophrenia Hearing loss Migraine Iron deficient anemia Diabetes mellitus 0 5 10 15 20 25 30 WHO World Health Report 2002 Anti-depressants 5HT Serotonin and NorepinephrineNE in the brain Limbic System Prefrontal Cortex Raphe Nuclei (5-HT source) Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996. Locus Ceruleus (NE Source) Functional domains of Serotonin and Norepinephrine1-4 Serotonin (5-HT) Sex Depressed Mood Anxiety Norepinephrine (NE) Concentration Appetite Vague Aches and pain Interest Aggression Irritability Motivation Thought process References: 1. Adapted from: Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications: 2nd ed. Cambridge University Press 2000. 2. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43. 3. Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35. 4. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114. TCAs (Tricyclic anti-depressants) Inhibit reuptake of NE + serotonin Antagonist to muscarinic, H1, H2, adrenergic receptors AE: anticholinergic, sedation, weight gain, orthostatic hypotension, cardiac TCAs Imipramine (tofranil) Clomipramine (anafranil) Amitriptyline (elatrol) Doxepin (gilex) Nortryptyline (nortylin) Maprotiline (melodil) MAO-I Inhibit degradation of biogenic amines Risk of tyramine (hypertensive) crisis Treated with α-adrenergic antagonist, diuretic, beta-blocker SSRIs (Serotonin Specific Reuptake Inhibitors) Low side effect profile AE: Sexual, GI, weight gain, headaches, insomnia/sedation, EPS, agitation Sexual AE are the most common AE of SSRIs (50-80-%) SSRIs Fluoxetine (prozac) Paroxetine (seroxate) Fluvoxamine (favoxil) Sertraline (lustral) Citalopram (cipramil) Escitalopram (cipralex) Serotonin Syndrome May occur when administrating an SSRI concurrent with a MAO-I, L-tryptophan or lithium Includes: Diarrhea Restlessness Extreme agitation, hyperreflexia, autonomic instability Myoclonus, seizures, hyperthermia, rigidity Delirium, coma, status epilepticus, CV collapse, death Treatment includes removing the offending agent + intensive supportive care additional anti-depressants Venlafaxine (SNRI) Mirtazapine (α-2 antagonist, H1 antagonist, 5-HT2,3 antagonist) Trazodone (relative serotonin specific, α-1 antagonist) ECT (electroconvulsive therapy) Phototherapy TMS (transcranial magnetic stimulation) VNS (vagus nerve stimulation) Groups of drugs Anti-psychotics Anti-cholinergic Anti-depressants Mood stabilizers Sedatives Mood Stabilizers Lithium Lithium Uncertain therapeutic mechanism AE: GI: gastric distress, weight gain Neurological: tremor, cognitive Renal: polyuria, secondary polydipsia Hypothyroidism Cardiac Dermatological Risk of lithium toxicity Blood level of lithium is available Contraindicated in 1st trimester (ebstein’s anomaly) Anticonvulsants Valproate Carbamazepine Blood level is attainable Contraindicated in pregnancy (neural tube defects) Anticonvulsants cont. Lamotrigine Increasing data regarding effects on bipolar depression May carry lower risk during pregnancy compared to other anticonvulsants (further studies needed) Risk of dermatologic AE (including life threatening Stevens-Johnson syndrome Slow titration to avoid side effects) Groups of drugs Anti-psychotics Anti-cholinergic Anti-depressants Mood stabilizers Sedatives SEDATIVES BZ (benzodiazepines) Sedative, muscle relaxant, anticonvulsant BZ Diazepam (valium) Lorazepam (lorivan) Clonazepam (clonex) Alprazolam (xanax) Brotizolam (bondormin) Dangers Dependance Overdose (treat with flumazenil) Accidents (i.e. while driving, falls common among elderly) Antihistamines H1 antagonists Also carry some antimuscarinic activity Used as: Sedative Treatment for medication induced movement disorder Common in practice: Promethazine (phenergan) Buspirone 5-HT1A agonist Takes 2-3 weeks for full effect Most commonly used for General Anxiety Disorder (GAD) A word for the wise… Classify the drug according to the major groups Knowledge of the Mechanism of action / receptor activity facilitates remembering both disorder hypotheses, drug activity and adverse effects.