Transcript Antianxiety Agents, Sedative-Hypnotics, and Antidepressants:

Antianxiety Agents,
Sedative-Hypnotics and
Antidepressants:
Pharmacokinetics
Adverse Effects
Drug Interactions
BIJU SOMAN M.Sc, MBA
ASSISTANT PROFESSOR
MANIPAL UNIVERSITY
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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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)
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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.
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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.
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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.
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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
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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
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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
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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
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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
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Adverse Effects:
Benzodiazepines
 Abuse potential decreases when properly prescribed and
supervised.
 Dependence may 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.
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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
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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
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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
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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
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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)
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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
DSNRI
Duloxetine
Milnacipranb
Venlafaxine
100-200
Effexor
75-375
Wellbutrin
150-450
Nefazodone
Serzonec
100-600
Trazodone
Desyrel
150-600
Aminoketone
Bupropion
Triazolopyridine
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.
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Antidepressant Agents
Class/Generic Name
Trade Name
Usual Daily Dosage (mg/d)
Amoxapine
Ascendin
200-600
Maprotiline
Ludiomil
75-225
Mirtazapine
Remeron
15-45
Amitriptyline
Elavil
75-300
Clomipramine
Anafranil
100-250
Desipramine
Norpramine
75-300
Doxepin
Sinequan
75-300
Imipramine
Tofranil
75-300
Nortriptyline
Pamelor
75-300
Protriptyline
Vivactil
20-60
Trimipramine
Surmontil
75-300
Isocarboxazid
Marplan
40-60
Phenelzine
Nardil
30-90
Tranylcypromine
Parnate
30-60
Selegilined
Emsam
20mg/20 cm2 patch
Tetracyclic
TCA
MAOI
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.
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Pharmacokinetics: ADs
Drug
Absorption
Distribution
Metabolism
Elimin t1/2
SSRIs
complete
High PB
hepatic
fluoxetine
active met.
 24 hours
fluox. days
Venlafaxine
complete
widely
Low PB
hepatic
active
metabolites
5 hours
Nefazodone
complete
1st pass
effect
loose PB
hepatic
active
metabolites
2-4 hours
Mirtazapine
complete
high PB
hepatic
active
metabolites
20-40 hours
> in women
TCAs
complete
1st pass
effect
High PB
hepatic
CYP 2D6
 24 hours
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Pharmacokinetics: SSRIs
Citalopram
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
% protein-bound
80
94
99
95
77
Peak plasma level
(hour)
3-4
6-8
6-8
2-8
2-8
Half-life (hours)
35
24-72
25
20
15
20-60
20-80
50-200
10-50
50-300
Absorption altered
by fast or fed status
No
No
Yes
No
No
Linear
pharmacokinetics
Yes
No
Yes
No
No
GI absorption (%)
~100
80
44
64
94
Dose range (mg/d)
Van Harten. Clin Pharmacokinet, 1993. Preskorn. Clin Pharmacokinet. 1997. Data on file. Forest Laboratories, Inc. Preskorn. J Clin Psychiatry. 1993.
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Adverse Effects: Antidepressants
Central Nervous System
Cardiac
Orthostasis,
hypertension,
heart block,
tachycardia
Dizziness, cognitive impairment,
sedation, light-headedness,
somnolence, nervousness,
insomnia, headache, tremor,
changes in satiety and appetite
Gastrointestinal
Urogenital
Erectile dysfunction,
ejaculation disorder,
anorgasmia, priapism
Nausea, constipation,
vomiting, dyspepsia,
diarrhea
Autonomic Nervous System
Dry mouth, urinary retention,
blurred vision, sweating
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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)
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Adverse Effects of Antidepressants
Drugs
Sedation
Anticholinergics
Orthostatic Hypotension
Cardiac Effects
Citalopram
Low
None
None
None
Escitalopram
Low
None
None
None
Fluoxetine
Low
None
None
None
Fluvoxamine
Low
None
None
None
Paroxetine
Low
Low
None
None
Sertraline
Low
None
None
None
Low
Low
Low
Low
Duloxetine
Low
Low
Low
Low
Milnacipran
Low
Low
Low
Low
Venlafaxine
Low
Low
Low
Low
Low
Very low
Very low - none
Low
Nefazodone
Low
Low
Low
Low
Trazodone
High
Low
Moderate
Low
SSRIs
SNRIs
Atomoxetine*
DSNRIs
Aminoketones
Bupropion
Triazolopyridines
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, 1995:493494. 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.
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Adverse Effects of Antidepressants
Drugs
Sedation
Anticholinergics
Orthostatic Hypotension
Cardiac Effects
Amoxapinea
Low
Moderate
Low
None
Maprotiline
Moderate
Moderate
Low
Moderate
Mirtazapine
Moderate
Low
Low
Low
Amitriptyline
High
High
Moderate
High
Clomipramine
High
High
Low
Moderate
Desipramine
Low
Low
Low
Moderate
Doxepin
High
Moderate
Moderate
Moderate
Imipramine
Moderate
Moderate
High
High
Nortriptyline
Moderate
Moderate
Low
Moderate
Protriptyline
Low
Moderate
Low
Moderate
Trimipramine
High
High
Moderate
High
Isocarboxazid
Low
None
High
None
Phenelzine
Low
Low
High
None
Tranylcypromine
High
Very low
Very low
None
Selegiline TS
Low
Low
High
High (high doses)
Tetracyclics
TCAs
MAOIs
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, 1995:493494. 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:
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
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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
 Use therapeutic drug monitoring where
appropriate
 Monitor therapeutic and adverse effects
 Choose an antidepressant with a favorable profile
for that interaction
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Indications for
Therapeutic 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
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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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