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Antipsychotics and Mood Stabilizers: Pharmacokinetics Adverse Effects Drug Interactions Manipal 1 Goals Antipsychotics Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects Drug Interactions Mood Stabilizers Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects Drug Interactions 2 Antipsychotics: Diagnostic Indications Psychiatric Schizophrenia Schizoaffective disorder Mood disorders with psychosis Delusional disorder Nonpsychiatric Dementia/Delirium Psychosis secondary to a non-psychiatric medical disorder Developmental disability with psychosis and/or aggression Tourette’s disorder Nausea, vomiting 3 Impact of Schizophrenic Symptoms on Overall Functioning Positive symptoms: Delusions* Hallucinations* Disorganized speech Catatonia Negative symptoms: Social Cognitive symptoms: Work Attention Memory Executive functions Affective flattening Occupational Alogia Avolition Anhedonia Social inattentiveness Interpersonal Mood Selfcare *Schneiderian First Rank Symptoms symptoms: Dysphoria Suicidality Helplessness 4 Pharmacokinetics of Antipsychotics ADME profiles All are readily absorbed All are metabolized by the hepatic cytochrome P450 system T1/2 is generally 20 hours except: prone to drug interactions ziprasidone, quetiapine, aripiprazole Dosing adjustment in elderly renal and/or hepatic impairment 5 Antipsychotic Agents Class/Trade Name Generic Name Dosage (average range; PO, qd) Thorazine Chlorpromazine 100-1000 mg Sparine Vesprin Promazine Triflupromazine 25-1000 mg 20-150 mg Mellaril Serentil Quide Thioridazine Mesoridazine Piperacetazine 30-800 mg 20-200 mg 20-160 mg Stelazine Prolixin Trilafon Tindal Compazine Trifluoperazine Fluphenzine Perphenazine Acetophenazine Prochlorperazine 2-60 mg 5-40 mg 2-60 mg 40-80 mg 15-125 mg Navane Taractan Thiothixene Chlorprothixene 6-60 mg 10-600 mg Loxitane Loxapine 20-250 mg Haldol Inapsine Haloperidol Droperidol 3-50 mg 2.5-10 mg (IM) Moban Molindone 15-225 mg Phenothiazines Aliphatics Piperidines Piperazines Thioxanthenes Dibenzoxapines Butyrophenones Dihydroindolones © Janicak 6 Antipsychotic Agents (con’t) Class/Trade Name Generic Name Dosage (average range; PO, qd) Clozapine 100-900 mg Risperidone Paliperidone 2-10 mg 3-12 mg Olanzapine 5-20 mg Quetiapine 75-750 mg Ziprasidone 40-160 mg Aripiprazole 10-30 mg Penfluridol 100 mg/wk Pimozide 1-10 mg Dibenzodiazepines Clozaril Benzisoxazole Risperdal Invega Thienobenzodiazepines Zyprexa Dibenzothiazepines Seroquel Benzisothiazolyls Geodon Quinolinones Abilify Diphenytbutyrylpiperidines Semap Orap © Janicak 7 Antipsychotics: Adverse Effect Profiles EPS* HPDL CLOZ RISP OLZ QTP ZIP ARIP Neurological +++ 0 + 0/+ 0 0/+ 0/+ Weight gain/ Endocrine + +++ ++ +++ ++ 0/+ 0/+ ++ Anticholinergic 0 +++ 0/+ +/++ 0/+ 0/+ 0 0/+ Hematological 0 +++ 0 0 0 0 0 0 Cardiovascular + 0/+ + + + ++ 0 + Prolactin ++ 0/+ +++ 0/+ 0/+ 0/+ 0 +++ Sedation + +++ + +/++ ++ ++ + *At appropriate doses; 0 = none; + = mild; ++ = moderate; PALI + + +++ = substantial Adapted from Masand PS et al. Handbook of Psychiatry in Primary Care. 1998. 8 ADVERSE EFFECTS OF ANTIPSYCHOTICS Acute EPS Maximum HIGH POTENCY FGAs Minimum RISPERIDONE OLANZAPINE PALIPERIDONE (DOSE-RELATED) • Psuedoparkinsonism CLOZAPINE ZIPRASIDONE QUETIAPINE ARIPIPRAZOLE* • Dystonia • Akathisia • Tardive Dyskinesia *Based on clinical trial data 9 Dementia Patients Risks Mortality rate CVA in 4% vs 2% Risks may be higher for all APs Recommendations Avoid in those with vascular dementia Avoid with TIA, hypertension, Afib Use low doses Monitor for hypotension, sedation, EPS 10 Weight Gain: Overview General population Increased morbidity and mortality Stigmatization Major mental disorders This adverse effect is more common with some recent antipsychotics Recognized problem since chlorpromazine Polypharmacy may contribute Divalproex sodium Lithium Antidepressants Antipsychotics © Janicak 11 The Metabolic Syndrome Insulin resistance Hyperinsulinemia Decreased beta cell function Postprandial hyperglycemia 12 SGAs and Metabolic Abnormalities Weight Gain Risk for Diabetes Worsening Lipid Profile Clozapine +++ + + Olanzapine +++ + + Risperidone ++ D D Quetiapine ++ D D Aripiprazole* +/- - - Ziprasidone* +/- - - Drug + = increase effect; - = no effect; D = discrepant results. *Newer drugs with limited long-term data. Diabetes Care. 2004. 13 Baseline Monitoring History (personal or family) of obesity, diabetes, dyslipidemia, hypertension, CVD BMI Waist circumference Blood pressure Fasting lipid profile Fasting plasma glucose 14 Anticholinergic Effects Most common with: Clozapine Olanzapine Quetiapine Low-potency FGAs © Janicak 15 Hematological Clozapine-induced agranulocytosis Management Stop agent Reverse isolation; supportive measures GSCF (filgastrim) Rechallenging strategies © Janicak 16 Cardiovascular Related to both alpha1 adrenergic and muscarinic effects Hypotension Tachycardia Myocarditis Arrhythmogenic potential possible with all antipsychotics 17 Potential Consequences of QTc Interval Prolongation QTc prolongation Rarely Torsade de pointes arrhythmia (syncope) Rarely Ventricular fibrillation (sudden death) Royal College of Psychiatrists. 1997. 18 QT interval Time between onset of depolarization and repolarization Affected by diet, alcohol intake, time of day, heart rate Usually corrected for heart rate = QTc 19 Antipsychotics: Drug Interactions Pharmacodynamic Anticholinergic Hypotension Pharmacokinetic P450 inhibition (quinidine) P450 induction (carbamazepine) 20 Bipolar Disorder: Symptom Domains Mania Euphoria Grandiosity Pressured speech Impulsivity Excessive libido Recklessness Diminished need for sleep Psychosis •Delusions •Hallucinations •Sensory hyperactivity Manic, depressed or mixed Depression Depression Anxiety Irritability Hostility Violence or suicide Cognition •Racing thoughts •Distractability •Poor insight •Disorganization •Inattentiveness •Confusion 21 Mood Disorders: Therapeutic Options Lithium* (A, M) First generation antipsychotics Anticonvulsants Pharmacological/Somatic Valproate* (A) Antidepressants; OLZ/FLU* (D) Lamotrigine* (M) Quetiapine* (D) Carbamazepine (A) Electroconvulsive therapy Second generation antipsychotics Oxcarbazepine* Possibly: Clozapine Topiramate » » » » Gabapentin Bright light therapy Transcranial magnetic stimulation Vagal nerve stimulation Sleep deprivation Psychotherapy Cognitive behavioral therapy Marital/family counseling Interpersonal therapy Group therapy © Janicak Olanzapine* (A, M) Risperidone* (A) Quetiapine* (A) Ziprasidone* (A) Aripiprazole* (A) * FDA approved 22 Mood Stabilizer Pharmacokinetics Drug Desired Cp Distributio n Metabolis m Eliminatio n Lithium 0.6-1.0 mEq/L No PB kidneys, thyroid None Renally, 18-20 hours CBZ 6-12 mcg/ml Complete Hepatic, 15-28 hours autoinduc er 10,11 epoxide VPA 50-120 mcg/ml Rapid in CNS Hepatic, Inhibitor or 8-17 hours 23 BIPOLAR DISORDER LITHIUM DISADVANTAGES Narrow therapeutic index Slow onset of action Numerous adverse effects © Janicak 24 Factors Affecting Lithium Cp Impaired Renal Function Pregnancy Sodium balance Medications Diuretics → Na depletion → Li reabsorption Caffeine ↓ lithium levels ACE Inhibitors → ↓ GFR → increase Li concentration 25 Lithium: Adverse Effects Organ System Clinical Presentation Comments Cardiovascular ECG changes T wave suppression, delayed or irregular rhythm, increase in PVCs Sick sinus node syndrome (SSNS) Myocarditis Dermatologic Acne Psoriasis Rashes Worsens Treatment-refractory worsening Maculopapular and follicular Endocrine Hypothyroid state About 5% goiter; about 4% clinically significant hypothyroidism Hyperparathyroid state Clinically nonsignificant Fetus (teratogenic) Tricuspid valve malformation Atrial septal defect Ebstein’s anomaly Gastrointestinal Anorexia Nausea (10-30%) Vomiting Diarrhea (5-20%) Usually early in treatment and usually transient; may be early sign of toxicity Slow release preparations may help Hematological Granulocytosis Neurological Cognitive; tremors May be useful in disorders such as Felty’s syndrome, iatrogenic neutropenia. May counter CBZ-induced leukopenia Renal Polyuria-polydipsia (Nephrogenic diabetes insipidus) May be an indication of morphologic changes Requires adequate hydration 26 BIPOLAR DISORDER Anticonvulsants for Mood Disorders Valproate (VPA) Lamotrigine (LTG) Carbamazepine (CBZ) Oxcarbazepine Gabapentin (GBN) Topiramate (TOP) Others © Janicak 27 BIPOLAR DISORDER VALPROATE DISADVANTAGES Pancreatitis Adverse effects Weight gain Tremors Hyperammonemia PCOS (?) Hepatotoxicity Teratogenicity © Janicak 28 Valproic Acid Pharmacokinetics Usually inhibits hepatic metabolism Occasionally induces hepatic metabolism 29 CBZ Pharmacokinetics Oxidation to CBZ-10,11-epoxide Potent enzyme inducer antidepressants, anticonvulsants, antipsychotics Autoinduction serum level should stabilize within 4 weeks 30 Carbamazepine Metabolism Carbamazepine oxidation 10,11 epoxide metabolite Valproic acid → Toxicity X Further metabolism 31 BIPOLAR DISORDER LAMOTRIGINE DISADVANTAGES Slow titration to avoid rash Adverse effects Serious rashes SJS TEN © Janicak 32 Goals Antipsychotics Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects Drug Interactions Mood Stabilizers Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects Drug Interactions 33