Antidepressants Flashcards
SSRI
Antidepressant
First Line
SNRIs
Antidepressant
First Line
Bupropion
Antidepressant
First Line
Mirtazapine
Antidepressant
First Line
TCAs
Antidepressant
Second Line/Alternative Agent
MAOIs
Antidepressant
Second Line/Alternative Agent
Major Depressive Disorder
5+ for atleast 2 weeks
- DEPRESSED MOOD
- DIMINISHED INTEREST/PLEASURE (anhedonia)
- significant weight loss/gain
- insomnia or hypersomnia
- psychomotor agitation/retardation
- fatigue or loss of energy
- feelings of worthlessness or excessive guilt
- diminished ability to think or concentrate; indecisivenss
- recurrent thoughts of death; suicidal ideation or attempt
The Monoamine Hypothesis
- depressed mood results from decreased monoamine neurotransmission
- major classes of clinically useful drugs INCREASE monoamine neurotransmission by LIMITING THE REUPTAKE OF MONOAMINE NEUROTRANSMITTERS or by preventing their breakdown
Process of release/effect of NT
Neurotransmitters:
- synthesized from amino acid precursors in specific neurons
- packaged into vesicles
- released in response to stimulus
- bind postsynaptic receptors
- subject to reuptake by presynaptic transporters
Catecholamines from Tyrosine
Monoamine Neurotransmitters
- epinephrine
- dopamine
- norepinephrine
Tryptamines from Tryptophan
Monoamine Neurotransmitter
- serotonin
Reserpine
inhibits VMAT
SSRI Site of Action
- block reuptake of serotonin
- serotonin left in extracellular space left to interact with receptors for longer period of time
SNRI Site of Action
- block reuptake of serotonin and norepinephrine
- same as TCAs
- serotonin and norepi left in extracellular space left to interact with receptors for a longer period of time
- ** MORE SELECTIVE THAT TCAs***
TCAs Site of Action
- block reuptake of serotonin and norepinephrine
- same as SNRIs
- serotonin and norepi left in extracellular space left to interact with receptors for a longer period of time
- ** INTERACT WITH A WHOLE BUNCH OF OTHER RECEPTORS AS WELL ***
MAOIs Site of Action
- prevent breakdown of monoamines in presynaptic cell
- inhibit MAO; prevents breakdown of NT, increasing amount in extracellular space
- ACT INTRACELLULARLY
Bupropion Site of Action
- blocks reuptake of DOPAMINE and norepinephrine
- acts on dopaminergic neuron
Mirtazapine Site of Action
- blocks presynaptic a2 receptors and some 5-HT2/3 receptors
- antagonist of presynaptic a2 autoreceptor, which ENHANCES RELEASE OF NE and 5-HT
- block binding of NT to presynaptic recpetor
Limitations to Monoamine Hypothesis
- clinically useful antidepressants act rapidly at pharmacologic sites of action, yet clinical effects require 3+ weeks of therapy
- while reserpine rapidly depletes neurotransmitter, several weeks of treatment are required to induce depression
Major Antidepressant Site of Action Targets
Neurotransmitter reuptake transporters
* activity limited by reuptake rate*
Autoreceptors
- found on presynaptic cell
- respond to level of neurotransmitter
- when reuptake is blocked, elevated NT in synapse leads to down-regulation of synthesis and release of additional NT
- upon chronic use, autoreceptors may be down regulated, thereby relieving inhibition of NT synthesis and release, and enhancement of neurotransmission
- receptors constantly bound to ligand, receptor downregulated and removed from cell surface
- MAY ACCOUNT FOR LIMITATIONS OF HYPOTHESIS
SSRI uses
- MAJOR DEPRESSION
- anxiety disorder
- OCD
- PTSD
- PMDD
SNRI uses
- major depression
- anxiety disorder
- chronic pain
- fibromyalgia
Bupropion uses
- major depression*
- *first-line alternative to SSRI or SNRI when anxiety is not a prominent symptom
- smoking cessation
Mirtazapine uses
- major depression*
- * particularly useful in patients with insomnia or marked weight loss
TCAs uses
- alternative agent
- major depression (when unresponsive to other drugs)
MAOIs
- alternative agent
- major depression (when unresponsive to other drugs)
Anti-depressant Boxed Warning
SUICIDE RISK
Antidepressant Adverse Events (All)
- suicide risk
- mania (most often in patients with undiagnosed bipolar disorder)
SSRIs Adverse Events
- inhibit 5-HT reuptake SELECTIVELY compared to NE reuptake; side effects limited to effects on 5-HT mediated responses
Adverse Events:
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfunction
- seizures with gross overdose
SNRIs Adverse Events
- inhibit reuptake of both 5-HT and NE; side effects due to excess of both serotonin and norepi
Adverse Events: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ - nausea - headache - anxiety - agitation ........................... same as SSRIs - insomnia - sexual dysfunction seizures with gross overdose \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ - anticholinergic - sedation - hypertension (veniafaxine)
Bupropion Adverse Events
- inhibits reuptake transporters for NE and dopamine
- resembles amphetamine
- ** especially helpful in patients with impaired concentration ***
- ** alternative for patients with antidepressant-induced sexual dysfunction ***
Adverse Events:
- nausea
- headache
- anxiety
- irritability
- insomnia
- mild hypertension and tachycardia
- tremor
- appetite suppression
- dose related seizures (minimized with EXT release formulation)
Why Sexual Dysfunction with SSRIs and SNRIs but not Bupropion?
- sexual dysfunction associated with SSRIs and SNRIs due to stimulation of 5-HT receptor subtypes in the brain and spinal cord
Mirtazapine Adverse Events
- antagonist of a2 autoreceptor; enhances release of NE and 5-HT
- antagonist at 5-HT 2/3 receptors
- ** particularly useful in patients with INSOMNIA or marked WEIGHT LOSS***
- ** helpful in patients who experience nausea with SSRIs, SNRIs, or bupropion ***
Adverse Events:
- sedation
- weight gain
- dizziness
- dry mouth
- constipation
When beneficial for Bupropion Use?
- patients with impaired concentration
- alternative for patients with antidepressant-induced sexual dysfunction
When beneficial for Mirtazapine Use?
- patients with insomnia or marked weight loss
- helpful in patients who experience nausea with SSRIs, SNRIs, or bupropion
Tricyclic Antidepressants Site of Action
- inhibit reuptake transporters for BOTH NE and 5-HT (like SNRIs)
- * tend to interact with a variety of OTHER receptors, therefore have a broader range of side effects than SNRIs*
Tricyclic Antidepressant Adverse Events
Those for SNRIs
- nausea
- headache
- anxiety
- agitation
- insomnia
- sexual dysfunction
- extrapyramidal effects (early in treatment)
- seizures with gross overdose
- serotonin syndrome with MAOI
- anticholinergic
- sedation
PLUS
- orthostatic hypotention
- weight gain
- arrhythmias
**********
Reuptake Blockers SNRI & TCAs
venlafaxine (SNRI)
imipramine (TCA)
amitriptyline (TCA)
SNRI & TCAs 5-HT ++ NE +
SAME mechanism of action; same effect on 5-HT and NE differ in spectrum of side effects
IMIPRAMINE AND AMITRIPTYLINE ACTIVATE MANY OTHER RECEPTORS which are why they are problematic to take
Reuptake Blockers SSRIs
fluoxetine
paroxetine
sertraline
ALL: 5-HT +++
fluoxetine: NE 0
paroxetine: NE +
sertraline: NE 0
MAOIs site of action
phenelzine
tranylcypromine
- inhibit Monoamine Oxidase (MAO)
- phenelzine combines IRREVERSIBLY with MAO to provide long-lasting inhibition
- tranylcypromine does not bind irreversibly, but still has prolonged effect
MAOIs Adverse Events
- hypertensive reactions in response to INDIRECTLY ACTING SYMPATHOMIMETICS (otherwise typically lower blood pressure)
- hypertensive crisis with tyramine containing foods
- hyperthermia
- CNS stimulation leading to agitation and convulsions
- seizures with overdose
- serotonin syndrome with SSRIs/SNRIs
Pharmacokinetics of Antidepressant Agents
In general most: - have rapid oral absorption - reach peak plasma concentration in 2-3 hours - have t1/2 of .5-1 day are tightly bound to plasma proteins - metabolized by liver - eliminated by kidney
Pharmacokinetics of specific drugs may influence choice of agent: SSRIs; escitalopram and citalopram
- several SSRIs are moderate to strong inhibitors of CYP2D6
- escitalopram and citalopram exhibit age-dependent decrease in CYP2C19 metabolism (use with care in elderly)
Fluoxetine half life
7-10 days much longer than most
avg .5-1 day
Drug Interactions
SNRIs, TCAs, Mirtazapine, Trazodone
- additive with other sedatives, particularly alcohol and benzodiazepines
SSRIs Drug Interactions
- additive effects on QT interval and torsade de pointes with other QT-interval prolonging drugs
SSRIs and SNRIs Drug Interactions
- increased risk of bleeding with antiplatelet or anticoagulant drug (SSRIs and SNRIs)
- risk of serotonin syndrome with MAOIs
Serotonin Syndrome
- can be caused by all serotonergic drugs; rare but potentially life-threatening triad of abnormalities consisting of cognitive, autonomic and somatic effects due to excess serotonin
- can progress toward coma and death
Management: sedation (benzodiazepines), paralysis, intubation and ventilation
Overdoses TCAs
- extremely dangerous; prescribed on “no refill basis”, small quantities
Overdoses MAOIs
- intoxication rare, requires supportive treatment
Overdoses SSRIs
- OD fatalities rare
- intoxication requires supportive treatment
Overdoses Bupropion
- seizures
Overdoses Mirtazapine
- disorientation, tachycardia
Overdoses of Antidepressants Newer Agents
- often involves other drugs, including alcohol
