Antidepressants Flashcards
What are the physiologic factors in depression?
changes in receptor-neurotransmitter relationships in the limbic area
-serotonin, norepinephrine, dopamine
-decrease in functional balance of these NTs
What are the three mechanisms for alterations in the balance/function of neurotransmitters?
impaired synthesis of neurotransmitters
increased breakdown/metabolism of neurotransmitters
increased pump re-uptake of neurotransmitters
What are the classes of antidepressants?
SSRI
SNRI
TCA
MAOI
atypical antidepressants
What is the MOA of SSRIs?
inhibit SERT
Which two SSRIs must be known for the exam?
escitalopram
citalopram
What is the MOA of SNRIs?
inhibit SERT and NET
Which SNRI must be known for the exam?
venlafaxine
What is the MOA of TCAs?
inhibit SERT + NET + muscarinic receptors + a1 receptors + histamine receptors + Na+ channels
-also produce antiarrhythmic effects
Which TCA must be known for the exam?
amitriptyline
Which pump does desipramine prefer?
NET > SERT
What is the MOA of MAOIs?
inhibit MAO which breaks down NTs
Why are MAOIs last choice?
drug-drug interactions
drug-food interactions
-tyramine –> hypertensive crisis
Which MAOI must be known for the exam?
isocarboxazid
What is the feel good hormone?
dopamine
-released in cases of drug abuse or smoking
What is the atypical antidepressant?
bupropion
What is the MOA of bupropion?
inhibits DAT and NET
What is another use of bupropion besides depression?
smoking
What is bupropion toxicity associated with?
seizures and cardiac toxicity
-narrow therapeutic margin
-structurally similar to amphetamine
Which antidepressant class is the safest?
SSRI
-fewer significant adverse effects and less problematic in overdose than TCAs and MAOIs
-more fatalities reported with extremely larger doses or co-ingestants like benzos or ethanol
-fatality is rare
-SNRIs like venlafaxine = greater risk of mortality in overdose
Describe SSRI ADME.
absorption:
-tmax: 4-8h
distribution:
-PPB: 80-98%
-Vd: 10-40 L/kg
metabolism:
-CYP 2D6
elimination:
-t1/2: average of 15-35h
-numerous active metabolites
-mostly renally excreted
What is the PPB of escitalopram?
56%
Which SSRIs are potentially more toxic in overdose?
citalopram and escitalopram
-dose dependent QT prolongation
-structurally different from other SSRIs
What is serotonin syndrome?
excessive levels of serotonin
-diaphoresis, diarrhea, hyperthermia, mental status change, myoclonus
-occurs most frequently after use of combination of serotonergic xenobiotics or high doses of isolated serotonergic xenobiotics
Which labs should be taken if experiencing SSRI toxicity?
ECG if citalopram, escitalopram, SSRI + co-ingestant
neuromuscular finding labs (CK, myoglobin, SCr)
What is the management of SSRI toxicity?
symptomatic and supportive care
seizures: BZD
cardiac abnormalities: sodium bicarbonate
torsades de pointes: magnesium sulfate
serotonin syndrome: cyprohepatidine
What is the MOA of sodium bicarbonate in SSRI toxicity?
increases in serum pH and extracellular sodium = increased electrochemical gradient across cardiac cell membranes
What is the MOA of magnesium sulfate?
decreases acetylcholine in motor nerve terminals and acts on myocardium = slowed rate of SA node impulse formation = prolonged conduction time
What is the MOA of cyprohepatidine?
competitive binding to serotonin receptor = cooling and treatment of muscular rigidity
What is the role of decontamination in SSRI toxicity?
? SDAC
-most benefit within 1-2 h
-may use up to 4 h
no role for gastric lavage
What is the role of elimination in SSRI toxicity?
no role for MDAC
-no role due to rapid absorption
no role for hemodialysis
-ineffective due to high PPB, Vd
What is the key to successful management in TCA toxicity?
early identification
-hard to distinguish serious toxicity based on symptoms alone
-progression of clinical toxicity is unpredictable and may be rapid
-get an ECG!
Describe TCA absorption.
well absorbed
tmax up to 12h in overdose
anticholinergic effect on gastric emptying
=delay emptying
Describe TCA distribution.
highly lipophilic and widely distributed
-Vd = 10-50 L/kg
PPB: 85-98% (highly protein bound)
not a good candidate for hemodialysis
How are TCAs metabolized?
multiple CYPs
metabolism is highly variable
Why is TCA metabolism highly variable?
genetic polymorphisms in 2D6
influenced by concomitant ingestion of ethanol or coingestants that induce or inhibit 2D6
What is a poor predictor of outcome in TCA toxicity?
dose ingested and plasma concentration
What is essential with TCA toxicity?
early ECG
Which symptoms of TCA toxicity show rapid progression?
cardiotoxic symptoms
-onset often within 2 hours of ingestion
What is the main mechanism of TCA causing cardiotoxicity?
Na+ channel blocking = QRS prolongation
Which body systems are impacted by TCA toxicity?
cardio
respiratory
CNS
How is the severity of TCA toxicity best reflected?
by ECG, not serum levels
At what point does the QRS show risk of cardiotoxicity?
> 100 ms
What is the first line management for dysrhythmias caused by TCAs?
sodium bicarbonate
What is the MOA of sodium bicarbonate for dysrhythmias caused by TCAs?
sodium load: helps overcome Na+ channel blockade
alkalinization of arterial blood pH: inhibits binding of TCA to myocardial Na+ channel as drug is not ionised
benefit due to increased pH and increased sodium
What is the standard of care for TCA poisoning?
sodium bicarbonate
What is the treatment if dysrhythmias continue from TCA poisoning despite sodium bicarbonate?
lidocaine
-blocker of Na+ and K+ channels
hypertonic saline
magnesium sulfate
Which drugs should not be given during dysrhythmias from TCAs?
class IA or IC antiarrhythmics
beta blockers
physostigmine and type 3 anti-dysrhythmic agents
flumazenil
What is the management of seizures caused by TCA toxicity?
benzodiazepines
sodium bicarbonate may also help manage/prevent seizures if QRS complex is shortened
What is the role of decontamination in TCA toxicity?
?/maybe gastric lavage
-reasonable in adults with intentional OD
-risk of aspiration
SDAC
-binds
-risk of aspiration
What is the role of elimination in TCA toxicity?
maybe MDAC
no hemodialysis
-PPB, lipophilic, Vd
What is the antidote for TCA toxicity?
intravenous lipid emulsion
-hemodynamically unstable patients or those in cardiac arrest unresponsive to conventional therapy
-also in patients where bicarbonate is not effective
