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Philip G. Janicak, MD Professor of Psychiatry Rush University Medical Center

Antianxiety Agents, Sedative-Hypnotics and Antidepressants: Pharmacokinetics Adverse Effects Drug Interactions. Philip G. Janicak, MD Professor of Psychiatry Rush University Medical Center. Goals. Anxiolytic-Sedative-Hypnotics (ASHs) Diagnostic indications Classification of ASHs

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Philip G. Janicak, MD Professor of Psychiatry Rush University Medical Center

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  1. Antianxiety Agents, Sedative-Hypnotics and Antidepressants:PharmacokineticsAdverse EffectsDrug Interactions Philip G. Janicak, MD Professor of Psychiatry Rush University Medical Center

  2. Goals • Anxiolytic-Sedative-Hypnotics (ASHs) • Diagnostic indications • Classification of ASHs • Relevant Pharmacokinetics • Serious Adverse Effects • Drug Interactions • Antidepressants (ADs) • Diagnostic indications • Classification of ADs • Relevant Pharmacokinetics • Serious Adverse Effects • Drug Interactions

  3. Antianxiety/Sedative-Hypnotics:Diagnostic Indications • Generalized anxiety disorder (GAD) • Phobic disorders • Anxiety disorder due to general medical condition • Panic disorder • Obsessive-compulsive disorder (OCD) • Posttraumatic stress disorder (PTSD) • Sleep disorders (dyssomnias; parasomnias)

  4. Antianxiety Agents *Not approved by the FDA.

  5. Antianxiety Agents *Not approved by the FDA.

  6. Sedative-Hypnotics *Not approved by the FDA.

  7. Pharmacokinetics: Benzodiazepines

  8. Pharmacokinetics: Benzodiazepines • Dosing adjustments • Elderly • Hepatic impairment • Cytochrome P450 isoenzymes • Route of Administration • Oral route • Faster absorption = greater “rush” • Acute parenteral (IM) • Lorazepam – drug of choice, rapid and reliable absorption • Chlordiazepoxide and diazepam – may precipitate locally and are poorly absorbed, painful

  9. Pharmacokinetics: Buspirone • T½ – 2-3 hrs • Slow onset of action • Weeks vs. days • CYP 3A4 substrate • Inducers → ? Loss of efficacy • Inhibitors → ? Toxicity or increased side effects

  10. Pharmacokinetics:Nonbenzodiazepine Hypnotics

  11. Adverse Effects: Benzodiazepines • Sedation and impairment of performance • Psychomotor skills • Driving; engaging in dangerous physical activities; using hazardous machinery • Especially during initial phase of treatment • Memory impairment • Anterograde amnesia (desired before surgery, other procedures) • Dose-related, and tolerance may not develop • Most likely with triazolam • Disinhibition • Possible risk factors: History of aggression, impulsivity, borderline or antisocial personality

  12. Adverse Effects:Benzodiazepines • Abuse potentialdecreases when properly prescribed and supervised. • Dependencemay occur at usual doses taken beyond several weeks. • Withdrawal may occur even when discontinuation is not abrupt (e.g., by 10% every 3 days). Symptoms include: tachycardia, increased blood pressure, muscle cramps, anxiety, insomnia, panic attacks, impairment of memory and concentration, perceptual disturbances, derealization, hallucinations, hyperpyrexia, seizures. May continue for months. • Rebound anxiety: return of target symptoms, with increased intensity.

  13. Adverse Effects: Buspirone • Advantages • No sedation or impairment of performance • No cross-tolerance with BZDs • No tolerance or withdrawal • No abuse potential • Disadvantages • Nausea • Headache • Insomnia, nervousness • Restlessness • Dizziness, lightheadedness

  14. Drug Interactions: Benzodiazepines • Additive pharmacodynamic effects(e.g., alcohol) • BZD withdrawal when other drugs that increase seizure risk are also taken • Diazepam may increase levels of digoxin and phenytoin

  15. Drug Interactions: Anxiolytic/Hypnotics • Drugs that affect CYP 3A4 • Inhibit BZD metabolism(e.g., fluoxetine/norfluoxetine via P450 3A3/4 inhibits metabolism of triazolam) • Effect on zolpidem > zaleplon • May be clinically nonsignificant • Clinically relevant increased exposure for eszopiclone and inhibitors • Additive CNS depression • Alcohol, antipsychotics, mood stabilizers

  16. Antidepressants: Diagnostic Indications • Mood disorders • Major depressive disorder • Single or recurrent • With or without melancholia • Seasonal pattern • Bipolar disorder • Depressed • Mixed • Cyclothymic disorder • Dysthymic disorder

  17. Antidepressants: Diagnostic Indications • Other psychiatric disorders (e.g., schizoaffective disorder, depressive type) • Mood disorder due to a general medical condition (e.g., dementia with depression; Alzheimer’s type) • Substance-induced mood disorder (e.g., amphetamine or similarly acting sympathomimetic intoxication or withdrawal)

  18. Antidepressant Agents SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor. aNot approved by the FDA for depression. bNot available in the United States. cSerzone no longer available. dTransdermal system approved for depression.

  19. Antidepressant Agents SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor. aNot approved by the FDA for depression. bNot available in the United States. cSerzone no longer available. dTransdermal system approved for depression.

  20. Pharmacokinetics: ADs

  21. Pharmacokinetics: SSRIs Van Harten. Clin Pharmacokinet, 1993. Preskorn. Clin Pharmacokinet. 1997. Data on file. Forest Laboratories, Inc. Preskorn. J Clin Psychiatry. 1993.

  22. Adverse Effects: Antidepressants Central Nervous System Dizziness, cognitive impairment, sedation, light-headedness, somnolence, nervousness, insomnia, headache, tremor,changes in satiety and appetite Cardiac Orthostasis, hypertension, heart block,tachycardia Gastrointestinal Nausea, constipation, vomiting, dyspepsia, diarrhea Urogenital Erectile dysfunction, ejaculation disorder, anorgasmia, priapism Autonomic Nervous System Dry mouth, urinary retention, blurred vision, sweating

  23. Adverse Effects: SSRIs • Advantages • Improved safety and tolerability (e.g., cardiac toxicity) • Better long-term compliance (?) • Disadvantages • Sexual dysfunction • Increased risk of suicide (?) • Drug interactions • Pharmacodynamic (serotonin syndrome) • Pharmacokinetic (CYP 450 inhibition)

  24. Adverse Effects of Antidepressants SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor. Adapted from Ward M. Appendix B. In: Flaherty J, Davis JM, Janicak PG, eds. Psychiatry: Diagnosis and Therapy. 2nd ed. Norwalk, Conn: Appleton & Lange, 1995:493-494. aAmoxapine is the only antidepressant with a clinically meaningful potency for blocking D2 receptors with the potential to cause acute and tardive extrapyramidal effects. * Not FDA approved for depression.

  25. Adverse Effects of Antidepressants SSRI, Selective serotonin reputake inhibitor; SSRI, selective norepinephrine, DSNI, dual norepinphrine reputae inhibitor; TCA, Tricyclic antidepressant; MAOI, monoamine oxidase inhibitor. Adapted from Ward M. Appendix B. In: Flaherty J, Davis JM, Janicak PG, eds. Psychiatry: Diagnosis and Therapy. 2nd ed. Norwalk, Conn: Appleton & Lange, 1995:493-494. aAmoxapine is the only antidepressant with a clinically meaningful potency for blocking D2 receptors with the potential to cause acute and tardive extrapyramidal effects.

  26. Antidepressants: Drug Interactions • Antidepressants and mood stabilizers may be inhibitors, inducers, or substrates of one or more cytochrome P450 isoenzymes • Knowledge of their P450 profile is useful in predicting drug-drug interactions • When some isoenzymes are absent or inhibited, others may offer a secondary metabolic pathway • P450 1A2, 2C (subfamily), 2D6, and 3A4 are especially important to antidepressant metabolism and drug-drug interactions

  27. CYP 450 Inhibitors

  28. Minimizing the Risk of Drug Interactions Associated with Antidepressants • When adding an antidepressant with a potential for pharmacokinetic interaction to another drug, clinicians could: • Reduce the dose of the current drug • Begin with a low dose of the antidepressant • Usetherapeutic drug monitoring where appropriate • Monitortherapeutic and adverse effects • Choose an antidepressantwith a favorable profile for that interaction

  29. Indications forTherapeutic Drug Monitoring • Nonresponders for dosage adjustment • Suspicion of noncompliance • To avoid toxicity (especially in the elderly) • Overdose • If adverse effects limit further dosage increases • Patients with absorption abnormalities • Document response

  30. Goals • Anxiolytic-Sedative-Hypnotics (ASHs) • Diagnostic indications • Classification of ASHs • Relevant Pharmacokinetics • Serious Adverse Effects • Drug Interactions • Antidepressants (ADs) • Diagnostic indications • Classification of ADs • Relevant Pharmacokinetics • Serious Adverse Effects • Drug Interactions

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