Block 4 Lecture 7 -- Antidepressants Flashcards
What is the MoA of MAOIs?
irreversibly blocks MAOa and MAOb
Where is MAOa located and what does it metabolize?
brain, liver, GI
NE, 5-HT
Where is MAOb located and what does it metabolize?
brain, platelets
DA
What are the MAOIs?
1) phenlzine
2) tranylcypromine
3) selegiline
What are the ADRs of MAOIs?
1) hepatotoxic
2) stimulation, insomnia, agitation
3) HTN
4) toxicity/od
What are symptoms of toxicity/od? How is it treated?
1) anxiety
2) HA
3) sweating, fever
4) seizures
5) sleepiness
treat sxs
– hospitalize x 1 week to rebuild normal [MAO]
What are the interactions for MAOIs?
1) sympathomimetic amines
- - inhaled b-agonists
- - stimulants (adderall)
2) PD drugs
3) tyramine
Where is tyramine found?
– found in fermented foods (beer, red wine, cheese, aged things)
ok in small amounts:
– yogurt, chocoalte, caffeine, ripe fruits ok in small amounts
What are the additional indications of MAOIs?
1) phenelzine
- - anxiety disorders, PTSD
2) tranylcypromine
- - anxiety disorders
3) selegiline
- - PD
PK data for phenelzine:
t1/2 = 12 hours
liver metabolized
PK data for tranylcypromine:
t1/2 = 2.5 hours
CYP2A6, C19, 2D6, MAOa, MAOb
PK data for selegiline:
t1/2 = 10 hours
liver metabolized
What is the MoA for selegiline?
MAOI
– selective for MAOb
What is the MoA of TCAs?
SERT, NET, a1 antagonists
What are the TCA agents?
1) amitriptyline
2) amoxapine
3) clomipramine
4) desipramine
5) imipramine
6) maprotiline
What are the TCA effects in normal people?
- no mood-elevating effect
- - sleepiness, lightheadedness (used for insomnia)
What are the on-target effects of TCAs in depressed patients?
– elevation in mood after 2-3 weeks
not used on PRN basis
What are the causes/categories of ADRs of TCAs?
1) H1 antagonism
2) mAChR (M1) antagonism
3) a1 antagonism
4) Na-channel antagonism
5) sexual dysfunction
6) CNS ADRs
What does H1 antagonism by TCAs cause?
1) weight gain
2) drowsiness
3) sedation
What does M1 antagonism by TCAs cause?
anti-sludge
- drowsiness
- glaucoma
What does Na-channel antagonism by TCAs cause?
1) QT prolongation
2) palpitations
3) arrhythmias (hi-dose)
4) cardiac arrest
5) seizures (lowered threshold)
What are the sexual dysfunction sxs caused by TCAs?
1) ED
2) anorgasmia
What are the CNS side effects of TCAs?
confusion memory impairment hallucinations disorientation restlessness agitation insomnia nightmares -- black box: suicide younger than 25 yo
What are drug-drug interactions of TCAs?
1) central depressants
2) dirty drugs
3) drugs that increase presynaptic NTs
- - St. Johns wort
4) 5-HT precursors
- - 5-HTP
- - Trp
What TCAs have alternate indications? What are they?
1) amitriptyline
- - anxiety, psychosis, ADHD, bipolar
2) clomipramine
- - anxiety, OCD, pain
3) desipramine
- - ADHD
4) maprotiline
- - panic disorder
PK data for amitriptyline:
t1/2 = 22-24 h
CYP2D6
PK data for amoxapine:
t1/2 = 8-10 h (active met 30h)
PK data for clomipramine:
t1/2 = 32 hours (active met = 70 hours)
CYP2D6
PK data for desipramine:
t1/2 = 24-36 hrs
PK data for imipramine:
t1/2 = 20 hours
CYP1A2, 2C19, 2D6
PK data for maprotiline:
t1/2 = 27-48 h
PK data for nortriptyline:
t1/2 = 16-90 h
Which TCAs are secondary vs. tertiary amines?
all secondary except:
- imipramine
- clomipramine
- amitriptyline
ADRs of amitriptyline:
severe QT prolongation
ADRs of amoxapine:
- tachycardia, seizures
- hypomania
- agranulocytosis
- NMS
- tardive dyskinesia
ADRs of imipramine
agranulocytosis
What are the SSRI agents?
1) citalopram
2) fluoxetine
3) fluvoaxime
4) paroxetine
5) sertraline
All SSRIs are approved for:
depressive disorder
panic disorder
– exception: fluvoxamine doesn’t have panic disorder
What are the other indications of the SSRIs?
all except citalopram -- + OCD fluvoxamine: -- + anxiety fluoxetine: -- + PMDD, bulimia nervosa paroxetine: -- + anxiety, PMDD, hot flashes, PTSD
MoA of SSRIs:
inhibit SERT
What are the ADRs of serotonergic syndrome
central and peripheral
1) diarrhea
2) euphoria, dizziness, loss of consciousness
3) REM, mydriasis, hyperreflexia
4) shivering, high body temp, seizures
5) irregular heart beat, death
What are the ADRs of SSRIs?
1) nausea, diarrhea
2) weight gain
3) stimulation
- - anxiety, nervousness, insomnia
4) sex dysfunction
- - delayed ejaculation, anorgasmia
5) black box
What is the use-limiting ADR for SSRIs?
stimulation
– 1/3 to 1/2 of patients are limited
Which SSRI is FDA-approved for OCD?
fluvoxamine
PK data for citalopram:
t1/2 = 24-36 h
CYP2C19, 3A4, 2D6
PK data for fluoxetine:
t1/2 = 24-96 hours
PK data for fluvoxamine:
t1/2 = 6-26 hours
CYP1A2, 2C19
PK data for paroxetine:
t1/2 = 18-24 hours
PK data for sertraline:
t1/2 = 24-36 hours
CYP2D6, 2B6
ADRs of celexa:
QT prolongation
– FDA recommends less than 40 mg/day
What are the ADRs of fluoxetine?
– urticaria, rash, itchiness
What are the ADRs of paroxetine?
mania
caution withdrawal reaction
What are the ADRs of sertraline?
stimulation
agitation
What are the DDIs for sertraline?
pimozide (increased AUC, QT prolongation)
disulfiram (sertraline concentrate has EtOH)
What are the SNRI agents?
venlafaxine
duloxetine
What is the MoA of SNRIs?
inhibit SERT and NET
What are ADRs of SNRIs?
same as SSRIs
– add constipation
PK data for venlafaxine:
t1/2 = 5 hours (active met = 11 hours)
CYP2C19, 3A4, 2D6
PK data for duloxetine:
t1/2 = 12 hours
CYP2D6, 1A2
What are the indications for SNRIs?
depressive disorders and anxiety disorders
for duloxetine
– + neuropathic pain
What are the C/Is of duloxetine?
hepatic insufficiency
renal disease
What are the NRIs?
bupropion
What is bupropion indicated for?
depressive disorder
smoking cessation
PK data for bupropion:
t1/2 = 14-21 hr (active mets = 37h)
CYP1A2, 2A6, 2C9, 3A4, 2E1, 2C19
What are ADRs of bupropion?
stimulation
- agitation
- anorexia
- insomnia
What are the monoamine receptor antagonists?
1) mirtazipine
2) trazodone
MoA of mirtazipine:
a2 antagonist 5-HT 2c antagonist 5-HT 3 antagonist -- increases 5-HT release -- increases NE release
MoA of trazodone:
5-HT 2A antagonist
5-HT 2C antagonist
H1 antagonist
weak SERT-inhibitor
PK data for mirtazipine:
t1/2 = 20-40 hours
CYP1A2, 2D6, 3A4
PK data for trazodone:
t1/2 = 6-12 hours
ADRs of mirtazipine:
sedation!
dry mouth
weight gain
ADRs of trazodone:
cardiac arrhythmia
hepatotoxicity
What are the indications of the monoamine receptor antagonists?
depressive disorders
+ trazodone: anxiety
What are the phases of pharmacotherapy of depression? How long does each last?
1) acute phase (6-16 weeks)
2) continuation phase (4-9 mos after initial sxs reside)
3) maintenance phase (9-24 mos)
4) discontinuation phase
What are the GoTs of the continuation vs. maintenance phases?
continuation:
- - eliminate residual symptoms, prevent relapse
maintenance:
- - prevent recurrence of sxs
How long until peak antidepressant effect?
2-4 weeks
What drugs besides lithium are used for bipolar disorder?
1) ASDs
- - carbamazepine, valproate, lamotrigine
2) antipsychotics
- - olanzapine, risperidone, quetiapine
3) other drugs
- - BZDs, memantine, amantadine, ketamine
4) antidepressants
What is the MoA of lithium carbonate?
inhibits inositol monophosphatase
– disrupts a-adrenergic signaling
PK data for lithium:
t1/2 = 24 hours
- good GI absorption
- steady state CNS in 6-10 days
- 95% renal excretion
- 70-80% reabsorbed (Na+ transporter)
What is the therapeutic blood concentration for lithium?
0.6-1.2 mmol/L
- mania: 0.6-1.0 mmol/L
- maintenance: 0.6-0.8 mmol/L
- depression: 0.4-0.8 mmol/L
Lithium toxicity occurs at what blood range?
acute: 1.3-1.4 mmol/L
chronic: any range
Relapse/recurrence of bipolar sxs while on lithium treatment is associated with what blood concentration?
less than 0.6 mmol/L
What are the indications for lithium?
bipolar
What are the ADRs of lithium?
1) fatigue, sedation
2) dry mouth
- - excessive thirst and urination
3) weight gain, acne
4) slurred speech, ataxia, fine hand tremor, muscle weakness
To what ADRs of lithium does tolerance develop?
after 4 weeks, all sxs except:
- tremor
- urination/thirst
How are the ADRs of lithium managed?
beta-blocker for tremor
H2O intake regulated for urination/thirst
What are the sxs of acute toxicity of lithium?
mainly CNS – coma
- muscle rigidity, hyperreflexia, tremor, muscle twitching
- kidney failure
How is lithium toxicity treated?
symptomatic treatment
dialysis if severe poisoning
What are the interactions of lithium?
Na deficiency -- thiazides (Na-depleting) NSAIDs, TCNs -- decrease Li clearance excess sweating -- contributes to Li toxicity
When is lithium conraindicated?
pregnancy
– increases risk for congenital malformation
What are the categories of bipolar sxs and when do they usually appear?
late adolescence/early adulthood (depression first)
- manic mood
- depressive mood
- psychotic symptoms
- cognitive symptoms
What are the manic sxs of bipolar disorder?
1) amplified mood, energy
2) rapid speech, thoughts
3) hypersexuality
4) recklessness
5) decreased need for sleep
What are the depressive sxs of bipolar disorder?
1) depression
2) anxiety, irritability
3) hostility, violence
4) suicide
What are the psychotic symptoms of bipolar disorder?
delusions
hallucinations
formal thought disorder
What are the cognitive symptoms of bipolar disorder?
1) racing thoughts
2) distractibility
3) disorganization
4) inattentiveness
What is thought to be the cause of bipolar disorder?
imbalance of monoamines and other NTs
When is bipolar disease diagnosed?
only in manic phase!
– need neuropsychiatric history
What is the prevalence of bipolar disease (and suicide in patients)?
4% of adults, 1% of kids
– 20-25% attempt suicide
How was lithium historically used?
gout
salt sub in CVD
7-up
– tried for mania in humans after sedation was noticed in guinea pigs
How is lithium supplied for bipolar disorder treatment?
lithium carbonate (lithobid)
What black box is on all antidepressants?
may increase risk of suicide in patients under the age of 25
