1Antianxiety Agents,Sedative-Hypnotics andAntidepressants:PharmacokineticsAdverse EffectsDrug InteractionsPhilip G. Janicak, MDProfessor of PsychiatryRush University Medical Center2Goals4 Anxiolytic-Sedative-Hypnotics (ASHs)4 Diagnostic indications4 Classification of ASHs4 Relevant Pharmacokinetics4 Serious Adverse Effects4 Drug Interactions4 Antidepressants (ADs)4 Diagnostic indications4 Classification of ADs4 Relevant Pharmacokinetics4 Serious Adverse Effects4 Drug Interactions23Antianxiety/Sedative-Hypnotics:Diagnostic Indications4 Generalized anxiety disorder (GAD)4 Phobic disorders4 Anxiety disorder due to general medical condition4 Panic disorder4 Obsessive-compulsive disorder (OCD)4 Posttraumatic stress disorder (PTSD)4 Sleep disorders (dyssomnias; parasomnias)4Antianxiety Agents0.1-0.5Clonidine* Catapres30-120Propranolol* InderalNoradrenergic agents50-100Trazodone* Desyrel15-60Buspirone Buspar25-250SSRIs Sertraline, othersSerotonergic agents0.75-4Alprazolam Xanax60-160Halazepam Paxipam20-60Prazepam Centrax1-10Lorazepam Ativan15-60Chlorazepate Tranxene, others30-120Oxazepam Serax, others2-40Diazepam Valium, others10-100Chlordiazepoxide Librium, othersBZDsUsual Daily Dosage (mg/d)Generic NameClass/Trade Name*Not approved by the FDA.35Antianxiety AgentsPartial BZD agonists (e.g., abecarnil)*, Neurosteroids*,CRF antagonists*, Substance P antagonists*, NMDAreceptor antagonists*Investigational Treatments210-240 mg/kLKava KavatrolNatural Remedies250-2,000Valproate* Depakote, others4-16Tiagabine* Gabitril150-600Pregabalin* Lyrica300-5,000Gabapentin* NeurontinAnticonvulsants25-50Hydroxyzine* Atarax25-50Diphenhydramine* BenedrylAntihistamines20-60Duloxetine Cymbalta75-375Venlafaxine XR Effexor XRSerotonergic/noradrenergic agentsUsual Daily Dosage (mg/d)Generic NameClass/Trade Name*Not approved by the FDA.6Sedative-HypnoticsBenzodiazepines400-900Valerian* -0.3-2Melatonin* -Natural Remedies500-1,500Choral hydrate NotecBarbituate like agents25-100Trazodone DesyrelSedating antidepressants8-16Ramelteon RozeremMelatonin Receptor Agonists10-20Indiplon* -2-3Eszopiclone Lunesta5-20Zaleplon Sonata5-20Zolpidem AmbienNonbenzodiazepines0.125-0.25Triazolam Short acting: Halcion15-45Temazepam Restoril0.5-2Estazolam Intermediate acting: Prosom7.5-15Quazepam Doral15-45Flurazepam Long acting: DalmaneDaily Dosage (mg/d)Generic NameClass/Trade Name*Not approved by the FDA.47Pharmacokinetics: BenzodiazepinesHIGH for all agentsProtein binding:Lorazepam, oxazepam, temazepam notmetabolized by liver CYP 450In part, determines duration of actionMetabolism:Elimination half life:Chronic use: in equilibrium with fat tissuesSingle dose: the greater the lipid solubility →faster redistribution to fat tissues → shorterduration of actionDuration of action:Lipid solubility → faster onsetOnset of action:Variable speedAbsorption:8Pharmacokinetics: Benzodiazepines4 Dosing adjustments4 Elderly4 Hepatic impairment4 Cytochrome P450 isoenzymes4 Route of Administration4 Oral route4 Faster absorption = greater “rush”4 Acute parenteral (IM)4 Lorazepam – drug of choice, rapid and reliable absorption4 Chlordiazepoxide and diazepam – may precipitate locallyand are poorly absorbed, painful59Pharmacokinetics: Buspirone4 T½ – 2-3 hrs4 Slow onset of action4 Weeks vs. days4 CYP 3A4 substrate4 Inducers → ? Loss of efficacy4 Inhibitors → ? Toxicity or increased side effects10Pharmacokinetics:Nonbenzodiazepine Hypnotics(Selectively bind to the BZD1 receptors)* Prolonged in elderly; † prolonged in severe hepatic impairment6*†2.1*†1.04†T1/2 (Hr)11.41.4Tmax (Hr)CYP 3A4,2E1Various CYPisoenzymesAldehydeoxidase,CYP 3A4MetabolismEszopicloneZolpidemZaleplon611Adverse Effects:Benzodiazepines4 Sedation and impairment of performance4 Psychomotor skills4 Driving; engaging in dangerous physical activities; usinghazardous machinery4 Especially during initial phase of treatment4 Memory impairment4 Anterograde amnesia (desired before surgery,other procedures)4 Dose-related, and tolerance may not develop4 Most likely with triazolam4 Disinhibition4 Possible risk factors: History of aggression,impulsivity, borderline or antisocial personality12Adverse Effects:Benzodiazepines4 Abuse potential decreases when properly prescribed andsupervised.4 Dependence may occur at usual doses taken beyond severalweeks.4 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.4 Rebound anxiety: return of target symptoms, with increasedintensity.713Adverse Effects: Buspirone4 Advantages4 No sedation or impairment of performance4 No cross-tolerance with BZDs4 No tolerance or withdrawal4 No abuse potential4 Disadvantages4 Nausea4 Headache4 Insomnia, nervousness4 Restlessness4 Dizziness, lightheadedness14Drug Interactions:Benzodiazepines4 Additive pharmacodynamic effects(e.g., alcohol)4 BZD withdrawal when other drugs thatincrease seizure risk are also taken4 Diazepam may increase levels of digoxinand phenytoin815Drug Interactions:Anxiolytic/Hypnotics4 Drugs that affect CYP 3A44 Inhibit BZD metabolism(e.g., fluoxetine/norfluoxetine via P450 3A3/4inhibits metabolism of triazolam)4 Effect on zolpidem > zaleplon4 May be clinically nonsignificant4 Clinically relevant increased exposure foreszopiclone and inhibitors4 Additive CNS depression4 Alcohol, antipsychotics, mood stabilizers16Antidepressants:Diagnostic Indications4 Mood disorders4 Major depressive disorder4 Single or recurrent4 With or without melancholia4 Seasonal pattern4 Bipolar disorder4 Depressed4 Mixed4 Cyclothymic disorder4 Dysthymic disorder9174 Other psychiatric disorders (e.g.,schizoaffective disorder, depressive type)4 Mood disorder due to a general medicalcondition (e.g., dementia with depression;Alzheimer’s type)4 Substance-induced mood disorder (e.g.,amphetamine or similarly actingsympathomimetic intoxication or withdrawal)Antidepressants:Diagnostic Indications18Antidepressant Agents100-600Serzonec NefazodoneTriazolopyridine150-600Desyrel
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