Subject: Pharmacology Topic: Psychopharmacology 1 Lecturer: Maria Luisa D.

Delacruz, MD Date of Lecture: March 1, 2012 Transcriptionist: JE Rivera Editor: Melodicine Pages: 5

Psychopharmacology Antipsychotic drugs Drugs for Affective Disorders Antidepressants Antimanic Psychosedative/Antianxiety drugs Antipsychotic Drugs I. COMPONENTS OF PSYCHOTIC DISORDERS Positive Symptoms Negative Symptoms Hallucinations Affective Blunting Delusions Alogia Disorganized Thought Avolition Anhedonia

Mood Symptoms Insight Demoralization Suicide

Cognition New Learning Memory

II. DOPAMINE HYPOTHESIS There is a strong correlation between clinical antipsychotic potency and activity in blocking D 2-receptors Drugs that increase dopaminergic activity i.e sympathomimetics produce a psychotic-like state clinical efficacy of antipsychotic drugs is consistently achieved when D 2- receptor occupancy reaches about 80%.

Limitations to the Dopaminergic Overactivity Hypothesis does not account for negative symptoms, cognitive deficits and affective symptoms other neurotransmitters like serotonin, norepinephrine and glutamate interact with the dopaminergic pathways many effective antipsychotic drugs, in addition to blocking DA-receptor also act as 5-HT2 receptor antagonists atypical antipsychotic drugs antagonize 5HT2 receptors potently but antagonize D2 receptors less potently N-methyl d-aspartic acid (NMDA) receptor, a subtype of the ionotropic glutamate receptor, plays an important role in neurodevelopment and cognition psychotomimetic drug phencyclidine and the dissociative anesthetic, ketamine, both NMDAreceptor antagonists induce psychotic symptoms (positive and negative symptoms and cognitive deficits) D2 receptor blockade prevents the neurotoxicity produced by non-competitive NMDA-receptor antagonists

SY 2011-2012

III. CLASSIFICATIONS OF ANTIPSYCHOTIC DRUGS I. PHENOTHIAZINES 1. Aliphatic Chlorpromazine* Trifluopromazine 2. Piperidine Thioridazine Mesoridazine 3. Piperazines Fluphenazine Trifluoperazine II. THIOXANTHENES Thiothixene III. BUTYROPHENONES Haloperidol Droperidol IV. DIHYDROINDOLONES Molindone V. BENZEPINES Loxapine Quetiapine Clozapine* Olanzapine VII. BENZISOXAZOLE Risperidone VIII.BENZISOTHIAZOLPIPRAZINYLINDOLONE Ziprasidone IX. QUINOLINONE Aripiprazole **Pharmacologic Classification: 1. Typical or Neuroleptics Chlorpromazine Fluphenazine Haloperidol Thioridazine

2. Atypical Clozapine Olanzpine Quetiapine Risperidone Ziprasidone Aripiprazole

IV. GOALS OF PHARMACOTHERAPY 1. Reduce symptoms calming, less agitated more responsive and communicative diminished impulsive and aggressive behavior amelioration of hallucinations, delusions and disorganized or incoherent thinking 2. Improve cognitive function improvement of organization of thought processes reduction of social withdrawal 3. Abate mood disorders ameliorate depression or mania reduction of risk for suicidal behavior V. ACTIONS AND EFFECTS: Mechanism of Antipsychotic action: blockade of Dopamine (D2) receptors D2 receptor blockade in mesolimbic and mesocortical systems for antipsychotic effect D2 receptor blockade in nigrostriatal systems for EPS D2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia D2 receptor blockade in tuberoinfundibular for increase Prolactin secretion blockade of Serotonin (5HT2) receptors affect DA release prefrontal and basal ganglia, and midbrain noradrenergic outflow blockade of histaminergic, muscarinic and alpha1 receptors 1. Central nervous system Behavioral effects calming of psychomotor agitation decreased hostility decreased social isolation less interference from disorganized or delusional thought processes and hallucinations Sedation Lower seizure threshold Neuroleptic syndrome indifference to surroundings

MOA: Blockade of Dopamine (D2) receptors

**Six Neurologic syndromes (attributed to D2 blocking effects) Acute dystonic reactions - occurs within first 24-48 hrs of treatment - potentially fatal Akathisia - strong subjective feelings of anxious distress or a discomfort - compelling need to be in constant movement may be mistaken for agitation in psychotic patients Parkinsonian syndrome

 paucity of thought psychomotor slowing emotional quiet lack initiative hyperthermia lowers seizure threshold Clozapine has higher dose dependent seizure risk 3-5% incidence per year Antiemetic block D2 receptors in the CTZ

- can not be distinguished from idiopathic PD - bradykinesia or akinesia - masked facies reduced arm movements during walking Neuroleptic malignant syndrome - Signs of autonomic instability: hyperthermia labile pulse, blood pressure and respiration - elevation of serum creatinine kinase myoglobinemia with potential nephrotoxicity the syndrome begins with marked muscle rigidity. fluctuating levels of consciousness >10% mortality Tardive dyskinesia - late appearing neurological syndrome / syndromes - greater risk in older patients and those with mood disorders - 15% to 25% prevalence in young adults - 3-5% annual incidence - late appearing neurological syndrome / syndromes - greater risk in older patients and those with mood disorders - 15% to 25% prevalence in young adults - 3-5% annual incidence - Facial signs of TD: smacking, licking of lips, chewing movements, rolling or protrusion of tongue - Spastic facial distortions, tics Perioral tremor or Rabbit syndrome - also appear late in chronic treatment

2. Cardiovascular system

3. Autonomic nervous system 4. Gastrointestinal 5. Metabolic effects

6.Hyperprolactinemia

7. Hematologic

8. Dermatologic 8. Ophthalmic 9. Tolerance and physical dependence

Ventricular arrhythmia Quinidine-like effects on the heart prolongation of Q-T and P-R intervals (-) inotropic effect very high doses increase risk of life-threatening myocardial depression Sudden cardiac death orthostatic hypotension anticholinergic effects constipation cholestatic jaundice impairs glucose control weight gain increase apettite dyslipidemia hypertriglyceridemia breast engorgement, galactorrhea amenorrhea gynecomastia impotence or infertility in males Agranulocytosis (Clozapine) ANC count <500/cumm overall agranulocytosis incidence is less than 1% highest risk during the initial 6 months of treatment peaks at 2-3 months Immune-mediated mechanism Cutaneous allergic reaction Photosensitivity ocular opacities (Chlorpromazine) Retinitis pigmentosa (Thioridazine) generally non-addicting abrupt drug withdrawal after prolonged use may produce malaise and insomnia Tolerance to sedative effects occur

VI. CLINICAL INDICATIONS Short Term 1. Conditions with Psychotic Features Delirium and dementia low doses only AP drug with less anticholinergic effects Mania mostly adjunctive benefits High daily doses required Major depressive disorder lower than average dose requirement Combined with antidepressants 2. Substance-induced psychoses substance abuse (metamphetamine, amphetamine, cocaine) parkinsons disease treatment 3. Brief psychotic disorder

Long term 1. Schizophrenia avoid AP with greater metabolic adverse effects 2-fold higher prevalence of metabolic syndrome and type 2 diabetes mellitus (DM) 2-fold greater cardiovascular (CV) related mortality rates than the general population 2. Delusional disorder 3. Schizoaffective disorder

Other Clinical Indications: 1. Anxiety disorder Obsessive compulsive disorder (OCD) Post-traumatic stress disorder (PTSD) 2. Tourettes disorder 3. Huntingtons disease 4. Autism (Risperidone) associated with explosive behavioral outbursts and aggressive or self-injurious behaviors 5. Nausea and vomiting 6. Intractable hiccough (Chlorpromazine)

Chlorpromazine an aliphatic phenothiazine prominent D2 receptor activity low potency but high efficacy highly sedating latency to beneficial effects 4-6 weeks delay 70-80% of patients respond but 30-40% show only partial response relapse, recurrence of symptoms in 50% in two years non-compliance is common 30% of patients remain psychotic EPS and TD in 20%-50% of patients minimal improvement in negative symptoms failure to improve cognitive symptoms limited effect on depression and suicidality minimal improvement in over-all function Pharmacokinetics: readily absorbed from the gastrointestinal tract variable bioavailability due to first pass hepatic metabolism onset of action: IM administration: 15-30 minutes Oral administration: 30-60 minutes >90% bound to plasma proteins, principally albumin widely distributed; crosses the blood brain barrier, placenta; distributed in breast milk metabolized extensively by CYP 2D6 to at least 12 known metabolites elimination half-life is approximately 30 hrs excreted in the urine; less than 1% in unchanged form

Clozapine occupies 40-50% D2 receptors and 70-90% of 5-HT2A more active in cortical and limbic than in striatal dopaminergic receptor significant a adrenergic antagonist effects moderate anticholinergic effects histamine antagonist effect efficacy in treatment-resistant patients ability to decrease or totally eliminate psychotic symptoms in approximately 60% of patients improves cognitive function in psychotic patients choice for Levodopa-induced psychotic symptoms in patients with PD

Pharmacokinetics well absorbed from the GIT about 40% of an oral dose is metabolized before reaching the systemic circulation peak plasma concentration in approximatelly 2.5 hrs food does not affect systemic bioavailability metabolized by CYPs 1A2 (30%), 2C19 (24%), 3A4 (22%), 2C9 (12%) and 2D6 (6%) to inactive metabolites mean elimination half-life 12 hrs (4-66) approximately 50% of administered dose is excreted in the urine 30% excreted in the feces usually as inactive metabolites more metabolic effects (weight gain, impaired glucose tolerance, dyslipidemia) less risk for extrapyramidal adverse effects more likely to produce orthostatic hypotension lowers seizure threshold Special Indications: 1. Treatment Resistant Schizophrenia severely ill patients with Schizophrenia who fail to show acceptable response to adequate courses of standard antipsychotic drug 2. Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders

Comparative Affinity of Antipsychotics on Receptors D2 5HT2 Muscarinic Typical Chlorpromazine Haloperidol Atypical Clozapine Risperidone +++ +++ + ++ + + +++ +++ ++ ++ -

1 ++ + +++ +++

H1 +++ + +++ ++

Chlorpromazine Haloperidol Clozapine Risperidone

Comparative Pharmacologic Effects of Prototype Antipsychotics Sedation EPS Anticholinergic +++ ++ +++ + +++ + +++ + +++ ++ ++ 0 Comparative Metabolic Effects of Prototype Antipsychotics Dyslipidemia Hyperglycemia Weight gain

Hypotension +++ + +++ +++

Hyperprolactinemia ++ ++ 0 ++

Chlorpromazine Haloperidol Clozapine Risperidone

+++ +++ +/-

++ +++ +/-

+++ +/++++ +

Receptor D2 5HT2 H1 M1 alpha 1

Adverse Effects of Antipsychotics based on Receptor Occupancy Effects Extrapyramidal symptoms, tardive dyskinesia, prolactin secretion, sexual dsyfunction Extrapyramidal symptoms, increase appetite/weight gain Sedation, weight gain, extrapyramidal symptoms Memory, cognition, extrapyramidal symptoms, urinary retention, constipation Postural hypotension, dizziness, syncope

VII. ADVANTAGES OF ATYPICAL ANTIPSYCHOTICS 1. Reduced risk of extrapyramidal symptoms 2. Reduced risk of hyperprolactinemia 3. Cognitive enhancement 4. Improve adherence 5. Better efficacy against negative symptoms

___________________________________END OF TRANSCRIPTION____________________________________ Evening and morning and at noon I will pray, and cry aloud, and He shall hear my voice Psalm 55:17