Antianxiety Agents Sedative Hypnotics and Antidepressants Pharmacokinetics Adverse Effects Drug Interactions Philip G Janicak MD Professor of Psychiatry Rush University Medical Center Goals 4 Anxiolytic Sedative Hypnotics ASHs 4 Diagnostic indications 4 Classification of ASHs 4 Relevant Pharmacokinetics 4 Serious Adverse Effects 4 Drug Interactions 4 Antidepressants ADs 4 Diagnostic indications 4 Classification of ADs 4 Relevant Pharmacokinetics 4 Serious Adverse Effects 4 Drug Interactions 2 1 Antianxiety Sedative Hypnotics Diagnostic Indications 4 Generalized anxiety disorder GAD 4 Phobic disorders 4 Anxiety disorder due to general medical condition 4 Panic disorder 4 Obsessive compulsive disorder OCD 4 Posttraumatic stress disorder PTSD 4 Sleep disorders dyssomnias parasomnias 3 Antianxiety Agents Class Trade Name Generic Name Usual Daily Dosage mg d Librium others Chlordiazepoxide 10 100 Valium others Diazepam 2 40 Serax others Oxazepam 30 120 Tranxene others Chlorazepate 15 60 Ativan Lorazepam 1 10 Centrax Prazepam 20 60 Paxipam Halazepam 60 160 Xanax Alprazolam 0 75 4 Sertraline others SSRIs 25 250 Buspar Buspirone 15 60 Desyrel Trazodone 50 100 Inderal Propranolol 30 120 Catapres Clonidine 0 1 0 5 BZDs Serotonergic agents Noradrenergic agents Not approved by the FDA 4 2 Antianxiety Agents Class Trade Name Generic Name Usual Daily Dosage mg d Effexor XR Venlafaxine XR 75 375 Cymbalta Duloxetine 20 60 Benedryl Diphenhydramine 25 50 Atarax Hydroxyzine 25 50 Neurontin Gabapentin 300 5 000 Lyrica Pregabalin 150 600 Gabitril Tiagabine 4 16 Depakote others Valproate 250 2 000 Kava 210 240 mg kL Serotonergic noradrenergic agents Antihistamines Anticonvulsants Natural Remedies Kavatrol Investigational Treatments Partial BZD agonists e g abecarnil Neurosteroids CRF antagonists Substance P antagonists NMDA receptor antagonists Not approved by the FDA 5 Sedative Hypnotics Class Trade Name Generic Name Daily Dosage mg d Dalmane Flurazepam 15 45 Doral Quazepam 7 5 15 Estazolam 0 5 2 Restoril Temazepam 15 45 Halcion Triazolam 0 125 0 25 Ambien Zolpidem 5 20 Sonata Zaleplon 5 20 Lunesta Eszopiclone 2 3 Indiplon 10 20 Ramelteon 8 16 Trazodone 25 100 Choral hydrate 500 1 500 Melatonin 0 3 2 Valerian 400 900 Benzodiazepines Long acting Intermediate acting Prosom Short acting Nonbenzodiazepines Melatonin Receptor Agonists Rozerem Sedating antidepressants Desyrel Barbituate like agents Notec Natural Remedies Not approved by the FDA 6 3 Pharmacokinetics Benzodiazepines Absorption Variable speed Onset of action Lipid solubility faster onset Duration of action Single dose the greater the lipid solubility faster redistribution to fat tissues shorter duration of action Chronic use in equilibrium with fat tissues Protein binding HIGH for all agents Metabolism Lorazepam oxazepam temazepam not metabolized by liver CYP 450 Elimination half life In part determines duration of action 7 Pharmacokinetics Benzodiazepines 4 Dosing adjustments 4 Elderly 4 Hepatic impairment 4 Cytochrome P450 isoenzymes 4 Route of Administration 4 Oral route 4 Faster absorption greater rush 4 Acute parenteral IM 4 Lorazepam drug of choice rapid and reliable absorption 4 Chlordiazepoxide and diazepam may precipitate locally and are poorly absorbed painful 8 4 Pharmacokinetics Buspirone 4 T 2 3 hrs 4 Slow onset of action 4 Weeks vs days 4 CYP 3A4 substrate 4 Inducers Loss of efficacy 4 Inhibitors Toxicity or increased side effects 9 Pharmacokinetics Nonbenzodiazepine Hypnotics Selectively bind to the BZD1 receptors Metabolism Tmax Hr T1 2 Hr Zaleplon Zolpidem Eszopiclone Aldehyde oxidase CYP 3A4 Various CYP isoenzymes CYP 3A4 2E1 1 4 1 4 1 1 04 2 1 6 Prolonged in elderly prolonged in severe hepatic impairment 10 5 Adverse Effects Benzodiazepines 4 Sedation and impairment of performance 4 Psychomotor skills 4 Driving engaging in dangerous physical activities using hazardous machinery 4 Especially during initial phase of treatment 4 Memory impairment 4 Anterograde amnesia desired before surgery other procedures 4 Dose related and tolerance may not develop 4 Most likely with triazolam 4 Disinhibition 4 Possible risk factors History of aggression impulsivity borderline or antisocial personality 11 Adverse Effects Benzodiazepines 4 Abuse potential decreases when properly prescribed and supervised 4 Dependence may occur at usual doses taken beyond several weeks 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 increased intensity 12 6 Adverse Effects Buspirone 4 Advantages 4 No sedation or impairment of performance 4 No cross tolerance with BZDs 4 No tolerance or withdrawal 4 No abuse potential 4 Disadvantages 4 Nausea 4 Headache 4 Insomnia nervousness 4 Restlessness 4 Dizziness lightheadedness 13 Drug Interactions Benzodiazepines 4 Additive pharmacodynamic effects e g alcohol 4 BZD withdrawal when other drugs that increase seizure risk are also taken 4 Diazepam may increase levels of digoxin and phenytoin 14 7 Drug Interactions Anxiolytic Hypnotics 4 Drugs that affect CYP 3A4 4 Inhibit BZD metabolism e g fluoxetine norfluoxetine via P450 3A3 4 inhibits metabolism of triazolam 4 Effect on zolpidem zaleplon 4 May be clinically nonsignificant 4 Clinically relevant increased exposure for eszopiclone and inhibitors 4 Additive CNS depression 4 Alcohol antipsychotics mood stabilizers 15 Antidepressants Diagnostic Indications 4 Mood disorders 4 Major depressive disorder 4 Single or recurrent 4 With or without melancholia 4 Seasonal pattern 4 Bipolar disorder 4 Depressed 4 Mixed 4 Cyclothymic disorder 4 Dysthymic disorder 16 8 Antidepressants Diagnostic Indications 4 Other psychiatric disorders e g schizoaffective disorder depressive type 4 Mood disorder due to a general medical condition e g dementia with depression Alzheimer s type 4 Substance induced mood disorder e g amphetamine or similarly acting sympathomimetic intoxication or withdrawal 17 Antidepressant Agents Class Generic Name Trade Name Usual Daily Dosage mg d Citalopram Celexa 20 40 Escitalopram Lexapro 1 20 Fluoxetine Prozac 10 60 Fluvoxaminea Luvox 100 300 Paroxetine Paxil 10 50 Sertraline Zoloft 50 200 Strattera 60 120 Cymbalta 30 60 SSRI SNRI Atomoxetinea
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