Antianxiety Agents, Antianxiety Agents, Sedative-Hypnotics Sedative-Hypnotics and Antidepressants: and Antidepressants: Pharmacokinetics Pharmacokinetics Adverse Effects Adverse Effects Drug Interactions Drug Interactions BIJU SOMAN M.Sc, MBA BIJU SOMAN M.Sc, MBA ASSISTANT PROFESSOR ASSISTANT PROFESSOR MANIPAL UNIVERSITY MANIPAL UNIVERSITY
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BIJU SOMAN M.Sc, MBA ASSISTANT PROFESSOR MANIPAL UNIVERSITY
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Antianxiety Agents, Antianxiety Agents, Sedative-Hypnotics and Sedative-Hypnotics and
Generalized anxiety disorder (GAD)Generalized anxiety disorder (GAD) Phobic disordersPhobic disorders Anxiety disorder due to general medical conditionAnxiety disorder due to general medical condition
Onset of action:Onset of action: Lipid solubility Lipid solubility →→ faster onset faster onset
Duration of action:Duration of action: Single dose:Single dose: the greater the lipid solubility the greater the lipid solubility →→ faster redistribution to fat tissues faster redistribution to fat tissues →→ shorter shorter duration of actionduration of action
Chronic use:Chronic use: in equilibrium with fat tissues in equilibrium with fat tissues
Protein binding:Protein binding: HIGH for all agentsHIGH for all agents
Metabolism:Metabolism:
Elimination half life:Elimination half life:
Lorazepam, oxazepam, temazepam not Lorazepam, oxazepam, temazepam not metabolized by liver CYP 450metabolized by liver CYP 450
In part, determines duration of actionIn part, determines duration of action
Acute parenteral (IM)Acute parenteral (IM) Lorazepam – Lorazepam – drug of choicedrug of choice, rapid and reliable absorption, rapid and reliable absorption Chlordiazepoxide and diazepam – may precipitate locally Chlordiazepoxide and diazepam – may precipitate locally
and are poorly absorbed, painfuland are poorly absorbed, painful
Slow onset of actionSlow onset of action Weeks vs. daysWeeks vs. days
CYP 3A4 substrateCYP 3A4 substrate Inducers Inducers → ? Loss of efficacy→ ? Loss of efficacy Inhibitors → ? Toxicity or increased side effectsInhibitors → ? Toxicity or increased side effects
SedationSedation and impairment of performance and impairment of performance Psychomotor skillsPsychomotor skills
Driving; engaging in dangerous physical activities; using Driving; engaging in dangerous physical activities; using hazardous machineryhazardous machinery
Especially during initial phase of treatmentEspecially during initial phase of treatment MemoryMemory impairment impairment
Anterograde amnesia (desired before surgery, Anterograde amnesia (desired before surgery, other procedures)other procedures)
Dose-related, and tolerance may not developDose-related, and tolerance may not develop Most likely with triazolamMost likely with triazolam
DisinhibitionDisinhibition Possible risk factors: History of aggression, Possible risk factors: History of aggression,
impulsivity, borderline or antisocial personalityimpulsivity, borderline or antisocial personality
Abuse potentialAbuse potential decreases when properly prescribed and decreases when properly prescribed and supervised.supervised.
DependenceDependence may occur at usual doses taken beyond several may occur at usual doses taken beyond several weeks.weeks.
Withdrawal Withdrawal may occur even when discontinuation is not abrupt may occur even when discontinuation is not abrupt (e.g., by 10% every 3 days). Symptoms include: tachycardia, (e.g., by 10% every 3 days). Symptoms include: tachycardia, increased blood pressure, muscle cramps, anxiety, insomnia, increased blood pressure, muscle cramps, anxiety, insomnia, panic attacks, impairment of memory and concentration, panic attacks, impairment of memory and concentration, perceptual disturbances, derealization, hallucinations, perceptual disturbances, derealization, hallucinations, hyperpyrexia, seizures. May continue for months.hyperpyrexia, seizures. May continue for months.
Rebound anxietyRebound anxiety: : return of target symptoms, with increased return of target symptoms, with increased intensity.intensity.
AdvantagesAdvantages No sedation or impairment of performanceNo sedation or impairment of performance No cross-tolerance with BZDsNo cross-tolerance with BZDs No tolerance or withdrawalNo tolerance or withdrawal No abuse potentialNo abuse potential
BZD BZD withdrawalwithdrawal when other drugs that when other drugs that increase seizure risk are also takenincrease seizure risk are also taken
Diazepam may increase levels of Diazepam may increase levels of digoxin digoxin and phenytoinand phenytoin
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Drug Interactions: Drug Interactions: Anxiolytic/HypnoticsAnxiolytic/Hypnotics
Drugs that affect CYP 3A4Drugs that affect CYP 3A4 Inhibit BZD metabolismInhibit BZD metabolism
(e.g., fluoxetine/norfluoxetine via P450 3A3/4 (e.g., fluoxetine/norfluoxetine via P450 3A3/4 inhibits metabolism of triazolam)inhibits metabolism of triazolam)
Effect on zolpidem > zaleplonEffect on zolpidem > zaleplon May be clinically nonsignificantMay be clinically nonsignificant
Clinically relevant increased exposure for Clinically relevant increased exposure for eszopiclone and inhibitorseszopiclone and inhibitors
Other psychiatric Other psychiatric disorders (e.g., disorders (e.g., schizoaffective disorder, depressive type)schizoaffective disorder, depressive type)
Mood disorder Mood disorder due to a general medical due to a general medical condition condition (e.g., dementia with depression; (e.g., dementia with depression; Alzheimer’s type)Alzheimer’s type)
Substance-induced Substance-induced mood disorder (e.g., mood disorder (e.g., amphetamine or similarly acting amphetamine or similarly acting sympathomimetic intoxication or withdrawal)sympathomimetic intoxication or withdrawal)
aNot approved by the FDA for depression. bNot available in the United States. cSerzone no longer available. dTransdermal system approved for depression.
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Antidepressant AgentsAntidepressant AgentsClass/Generic NameClass/Generic Name Trade NameTrade Name Usual Daily Dosage (mg/d)Usual Daily Dosage (mg/d)
aNot approved by the FDA for depression. bNot available in the United States. cSerzone no longer available. dTransdermal system approved for depression.
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Pharmacokinetics: ADsPharmacokinetics: ADsDrugDrug AbsorptionAbsorption DistributionDistribution MetabolismMetabolism Elimin tElimin t
1/21/2
SSRIsSSRIs complete High PB hepaticfluoxetineactive met.
24 hoursfluox. days
VenlafaxineVenlafaxine complete widelyLow PB
hepaticactive metabolites
5 hours
NefazodoneNefazodone complete1st pass effect
loose PB hepatic active metabolites
2-4 hours
MirtazapineMirtazapine complete high PB hepatic active metabolites
Dose range (mg/d)Dose range (mg/d) 20-6020-60 20-8020-80 50-20050-200 10-5010-50 50-30050-300
Absorption altered Absorption altered by fast or fed statusby fast or fed status
NoNo NoNo YesYes NoNo NoNo
Linear Linear pharmacokineticspharmacokinetics
YesYes NoNo YesYes NoNo NoNo
GI absorption (%)GI absorption (%) ~100~100 8080 4444 6464 9494
Van Harten. Van Harten. Clin PharmacokinetClin Pharmacokinet, 1993. Preskorn. , 1993. Preskorn. Clin PharmacokinetClin Pharmacokinet. 1997. Data on file. Forest Laboratories, Inc. Preskorn. . 1997. Data on file. Forest Laboratories, Inc. Preskorn. J Clin PsychiatryJ Clin Psychiatry. 1993.. 1993.
DisadvantagesDisadvantages Sexual dysfunctionSexual dysfunction Increased risk of suicide (?)Increased risk of suicide (?) Drug interactionsDrug interactions
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.
Adverse Effects of AntidepressantsAdverse 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.
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Antidepressants: Antidepressants: Drug Interactions Drug Interactions
Antidepressants and mood stabilizers may be Antidepressants and mood stabilizers may be inhibitors, inducers, or substratesinhibitors, inducers, or substrates of one or more of one or more cytochrome P450 isoenzymescytochrome P450 isoenzymes
Knowledge of their Knowledge of their P450 profileP450 profile is useful in is useful in predicting drug-drug interactionspredicting drug-drug interactions
When some isoenzymes are absent or inhibited, When some isoenzymes are absent or inhibited, others may offer a others may offer a secondary metabolic pathwaysecondary metabolic pathway
P450 P450 1A2, 2C (subfamily), 2D6, and 3A41A2, 2C (subfamily), 2D6, and 3A4 are are especially important to antidepressant metabolism especially important to antidepressant metabolism and drug-drug interactionsand drug-drug interactions
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Minimizing the Risk of Drug Minimizing the Risk of Drug Interactions Associated with Interactions Associated with
AntidepressantsAntidepressants When adding an antidepressant with a potential
for pharmacokinetic interaction to another drug, clinicians could: Reduce the dose Reduce the dose of the current drug Begin with a low dose Begin with a low dose of the antidepressant Use therapeutic drug monitoring therapeutic drug monitoring where
appropriate MonitorMonitor therapeutic and adverse effects Choose an antidepressantChoose an antidepressant with a favorable profile
for that interaction
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Indications forIndications forTherapeutic Drug MonitoringTherapeutic Drug Monitoring
Nonresponders Nonresponders for dosage adjustmentfor dosage adjustment
Suspicion of Suspicion of noncompliancenoncompliance
To avoid To avoid toxicitytoxicity (especially in the elderly) (especially in the elderly)
OverdoseOverdose
If If adverse effects adverse effects limit further dosage increaseslimit further dosage increases
Patients with Patients with absorption abnormalitiesabsorption abnormalities
DocumentDocument response response
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GoalsGoals
Anxiolytic-Sedative-Hypnotics (ASHs)Anxiolytic-Sedative-Hypnotics (ASHs) Diagnostic indicationsDiagnostic indications Classification of ASHsClassification of ASHs Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions
Antidepressants (ADs)Antidepressants (ADs) Diagnostic indicationsDiagnostic indications Classification of ADsClassification of ADs Relevant PharmacokineticsRelevant Pharmacokinetics Serious Adverse EffectsSerious Adverse Effects Drug InteractionsDrug Interactions