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Antipsychotics and Mood Stabilizers: Pharmacokinetics Adverse Effects Drug Interactions

Antipsychotics and Mood Stabilizers: Pharmacokinetics Adverse Effects Drug Interactions. Philip G. Janicak, MD Professor of Psychiatry Rush University Medical Center. Goals. Antipsychotics Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects

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Antipsychotics and Mood Stabilizers: Pharmacokinetics Adverse Effects Drug Interactions

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  1. Antipsychotics andMood Stabilizers:PharmacokineticsAdverse EffectsDrug Interactions Philip G. Janicak, MD Professor of Psychiatry Rush University Medical Center

  2. 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

  3. 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

  4. Negative symptoms: Affective flattening Alogia Avolition Anhedonia Social inattentiveness Positive symptoms: Delusions*Hallucinations*Disorganized speechCatatonia Cognitive symptoms: AttentionMemoryExecutive functions Moodsymptoms: DysphoriaSuicidalityHelplessness Impact of Schizophrenic Symptoms on Overall Functioning Occupational Social Work Interpersonal Self- care *Schneiderian First Rank Symptoms 4

  5. Pharmacokinetics of Antipsychotics • ADME profiles • All are readily absorbed • All are metabolized by the hepatic cytochrome P450 system • prone to drug interactions • T1/2 is generally 20 hours except: • ziprasidone, quetiapine, aripiprazole • Dosing adjustment in elderly renal and/or hepatic impairment 5

  6. Antipsychotic Agents © Janicak 6

  7. Antipsychotic Agents (con’t) © Janicak 7

  8. Antipsychotics:Adverse Effect Profiles *At appropriate doses; 0 = none; + = mild; ++ = moderate; +++ = substantial Adapted from Masand PS et al. Handbook of Psychiatry in Primary Care. 1998.

  9. ADVERSE EFFECTS OF ANTIPSYCHOTICS Acute EPS Maximum Minimum HIGH POTENCY RISPERIDONE OLANZAPINE CLOZAPINE FGAs PALIPERIDONE ZIPRASIDONE (DOSE-RELATED) QUETIAPINE ARIPIPRAZOLE* • Psuedoparkinsonism • Dystonia • Akathisia • Tardive Dyskinesia *Based on clinical trial data 9

  10. 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 Dementia Patients 10

  11. 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

  12. The Metabolic Syndrome • Insulin resistance • Hyperinsulinemia • Decreased beta cell function • Postprandial hyperglycemia 12

  13. SGAs and Metabolic Abnormalities Risk for Worsening Drug Weight Gain Diabetes Lipid Profile Clozapine +++ + + Olanzapine +++ + + Risperidone ++ D D Quetiapine ++ D D Aripiprazole* +/- - - Ziprasidone* +/- - - + = increase effect; - = no effect; D = discrepant results. *Newer drugs with limited long-term data. Diabetes Care. 2004. 13

  14. Baseline Monitoring • History (personal or family) of obesity, diabetes, dyslipidemia, hypertension, CVD • BMI • Waist circumference • Blood pressure • Fasting lipid profile • Fasting plasma glucose 14

  15. Anticholinergic Effects Most common with: • Clozapine • Olanzapine • Quetiapine • Low-potency FGAs © Janicak 15

  16. Hematological • Clozapine-induced agranulocytosis • Management Stop agent Reverse isolation; supportive measures GSCF (filgastrim) • Rechallenging strategies © Janicak 16

  17. Cardiovascular • Related to both alpha1 adrenergic and muscarinic effects • Hypotension • Tachycardia • Myocarditis • Arrhythmogenic potential possible with all antipsychotics 17

  18. Rarely Torsade de pointes arrhythmia (syncope) Rarely Ventricular fibrillation (sudden death) Potential Consequences of QTc Interval Prolongation QTc prolongation Royal College of Psychiatrists. 1997. 18

  19. Time between onset of depolarization and repolarization Affected by diet, alcohol intake, time of day, heart rate Usually corrected for heart rate = QTc QT interval 19

  20. Antipsychotics:Drug Interactions • Pharmacodynamic • Anticholinergic • Hypotension • Pharmacokinetic • P450 inhibition (quinidine) • P450 induction (carbamazepine) 20

  21. Mania Euphoria Grandiosity Pressured speech Impulsivity Excessive libido Recklessness Diminished need for sleep Depression Depression Anxiety Irritability Hostility Violence or suicide Bipolar Disorder:Symptom Domains Manic, depressed or mixed Episode • Cognition • Racing thoughts • Distractability • Poor insight • Disorganization • Inattentiveness • Confusion • Psychosis • Delusions • Hallucinations • Sensory hyperactivity 21

  22. Mood Disorders:Therapeutic Options Lithium* (A, M) First generation antipsychotics Second generation antipsychotics Clozapine Olanzapine* (A, M) Risperidone* (A) Quetiapine* (A) Ziprasidone* (A) Aripiprazole* (A) Anticonvulsants Valproate* (A) Lamotrigine* (M) Carbamazepine (A) Oxcarbazepine* Topiramate Gabapentin • Pharmacological/Somatic • Antidepressants; OLZ/FLU* (D) • Quetiapine* (D) • Electroconvulsive therapy • Possibly: • Bright light therapy • Transcranial magnetic stimulation • Vagal nerve stimulation • Sleep deprivation Psychotherapy Cognitive behavioral therapy Marital/family counseling Interpersonal therapy Group therapy * FDA approved © Janicak 22

  23. Mood Stabilizer Pharmacokinetics 23

  24. Narrow therapeutic index Slow onset of action Numerous adverse effects BIPOLAR DISORDER LITHIUM DISADVANTAGES © Janicak 24

  25. 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

  26. Lithium: Adverse Effects Neurological Cognitive; tremors 26

  27. BIPOLAR DISORDER Anticonvulsants for Mood Disorders • Valproate (VPA) • Lamotrigine (LTG) • Carbamazepine (CBZ) • Oxcarbazepine • Gabapentin (GBN) • Topiramate (TOP) • Others © Janicak 27

  28. Adverse effects Weight gain Tremors Hyperammonemia PCOS (?) BIPOLAR DISORDER VALPROATE DISADVANTAGES • Pancreatitis • Hepatotoxicity • Teratogenicity © Janicak 28

  29. Valproic Acid Pharmacokinetics • Usually inhibits hepatic metabolism • Occasionally induces hepatic metabolism 29

  30. CBZ Pharmacokinetics • Oxidation to CBZ-10,11-epoxide • Potent enzyme inducer • antidepressants, anticonvulsants, antipsychotics • Autoinduction • serum level should stabilize within 4 weeks 30

  31. Carbamazepine Metabolism Carbamazepine oxidation → Toxicity 10,11 epoxide metabolite Valproic acid X Further metabolism 31

  32. Slow titration to avoid rash Adverse effects Serious rashes SJS TEN BIPOLAR DISORDER LAMOTRIGINE DISADVANTAGES © Janicak 32

  33. 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

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