5 Antidepressants Flashcards
DSM-V Criteria for Major Depression
A. Five or more of the following during a 2 week period:
- Depressed mood most the day, nearly EVERY DAY
- Markedly diminished interest or pleasure in all, or almost all activities
- Weight loss or weight gain, or decrease or increase in appetite nearly EVERY DAY
- Insomnia or hypersomnia nearly EVERY DAY
- Psychomotor agitation or retardation nearly EVERY DAY
- Fatigue or loss of energy nearly every day
- Feelings of worthlessness or inappropriate guilt nearly EVERY DAY
- Diminished ability to think or concentrate or indecisiveness
- Recurrent thoughts of death, thought or plans of suicide
B. Sx cause significant impairment in cognitive, social, and occupational function
C. Sx are not due to the physiological effects of a substance or medical condition
PET scans of patients with depression show…
Decreased overall brain activity
What is the neurotrophic hypothesis of depression?
Deficits in nerve growth factors (BDNF) —> structural changes and neuronal loss in the brain, especially the hippocampus and frontal cortex
What is the Neuroendocrine Hypothesis of depression?
Dysregulation of the HPA axis —> altered glucocorticoid function
What is the biogenic amine hypothesis of depression?
Abnormal neurtotransmission of dopamine, NE, and serotonin
Evidence for it: Treatment with reserpine depletes NE —> depression
All antidepressants increase…
Amine neurotransmission
Why do antidepressants take 2-3 weeks to be fully effective?
Due to neuronal plasticity - it takes time for you brain to adjust to the increased amount of neurotransmitters
What are the different antidepressant targets?
- TCAs inhibit the reuptake of NE and 5HT
- SSRIs selectively inhibit the reuptake of 5HT
- SNRIs inhibit the reuptake of NE and 5HT
- DA reuptake inhibitors (Bupropion)
- MAOIs inhibit the metabolism of NE, DA, and 5HT
How does normal reuptake of 5HT work?
5HT levels in the synapse are modulated by reuptake and presynaptic inhibition
What do uptake inhibitors do to 5HT levels?
5HT levels in synapse will increase BUT so does feedback inhibition, thus balancing synaptic amine levels
What is the long-term effect of reuptake inhibitors?
Antidepressants down-regulate auto-receptors, increasing the firing rate of 5HT neurons
MOA for Tricyclic Antidepressants
Inhibit the re-uptake of NE and 5HT
Also block alpha-adrenergic, histamine, and muscarinic receptors
No euphoria/low abuse potential
Take 2-4 weeks to have effect
How are TCAs used?
Depression
Chronic pain (TMJ), fibromyalgia
Enuresis
(Limited use due to toxicity and potential overdose)
Examples of TCAs
Amitriptyline (Elavil) and Imipramine (Tofranil)
• Tertiary amines
• Primarily inhibit 5HT reuptake
• Produce more seizures than secondary amines
• More sedating than secondary amines
Nortriptyline (Pamelor) and Desipramine (Norpramin)
• Secondary amines
• Primarily block NE reuptake
Tertiary amines primarily block ________ reuptake while Secondary amines primarily block _________ reuptake
Tertiary = 5HT
Secondary = NE
How are TCAs prescribed?
Generally started at a low dose then increased
All TCAs are equally effective at treating depression
Choice of TCA is based on adverse effects
All antidepressants should be tapered gradually if possible
TCA pharmacokinetics
Well-absorbed orally
Variable and long half-lives (10-90 hours)
They are generally given once a day at bedtime
Metabolized by CYP2D6 - drug interactions VERY common
Side effects of TCAs
Weight gain
Histamine receptor blockade - sedation/fatigue
Cholinergic blockade - blurred vision, tachy, constipation, urinary retention, dry mouth, palpitations, impairment of memory
Alpha receptor blockade - cardiac depression and arrhythmias, postural hypotension, dizziness, reflex tachycardia
Analgesia
SIADH —> water intoxication and hyponatremia
Sexual dysfunction
Decrease in seizure threshold
Tolerance develops to sedation, postural hypotension and anticholinergic effects
Can TCAs be used in pregnancy?
Yep
Why do you get analgesia when taking TCAs?
Results from activation of descending noradrenergic pathways in the spinal cord (NE acts on alpha2 receptors to decrease glutamate input into pain pathway going to brain)
What happens to you if you overdose on TCAs?
Primarily CARDIO toxic
Torsade de pointes Prolonged QT interval Cardiac arrhythmias Severe hypotension Agitation, delirium Seizures, hyperpyrexia Coma, shock, metabolic acidosis Respiratory depression
How do you treat a TCA overdose?
Cardiac monitoring and supportive care
Gastric lavage and activated charcoal
Magnesium, isoproterenol, and cardiac pacing for Torsades de pointes
Lidocaine, propranolol, phenytoin to manage arrhythmias and/or prevent seizures
Sodium bicarb and potassium chloride to restore acid/base balance
Combining TCAs with MAOIs can…
Result in SEROTONIN SYNDROME
Severe CNS toxicity manifested by hyperpyrexia, convulsions, and coma
Should you combine TCAs and SSRIs?
No, you dummy
They compete for metabolism, thus combo can lead to toxic levels of TCAs
What happens if you combine TCAs and amphetamines?
May cause hypertension
TCAs can potentials the sedative actions of ….
Alcohol and CNS depressants
TCAs can potentials the effects of …
Anticholinergic drugs
What are the different SSRIs mentioned in this lecture?
Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Citalopram (Celexa) Escitalopram (Lexapro)
Uses for SSRIs
Depression Panic disorder OCD (***Paxil***) Social anxiety (***Paxil***) Bulimia Alcoholism Children and Teenagers
Which SSRI is most likely to have drug interactions?
Fluoxetine (Prozac)
Inhibits CYP450s
Also, it impairs blood glucose in diabetics
Long half life (2-3 days)
Which SSRI is least likely to interact with other drugs
Sertraline (Zoloft)
Preferred in the elderly
Half life of 26 hours and extensive first-pass elimination
Which SSRI is currently the DOC for depression?
Citalopram (Celexa) or Escitalopram (Lexapro)
Low incidence of pharmacokinetic interactions and side effects
MOA for SSRIs
Selectively inhibits 5HT reuptake
Take 2-3 weeks to be effective
Pharmacokinetics for SSRIs
Well absorbed by gut
Half-life = 24-72 hours
Metabolized by CYP2D6
Inhibits CYP450s - many drug interactions**
SSRI side effects
Mild - less autonomic side effects and risk of arrhythmia compared to TCAs
GI: nausea, loss of appetite, constipation
Weight loss or gain possible
CNS stimulation (anxiety/insomnia) with fluoxetine or sertraline
Sedation more likely with other drugs
Sexual disinterest/dysfunction
Photosensitivity
SSRIs + TCAs =
Inhibition of metabolism of TCAs —> increased toxicity
SSRIs + phenytoin and carbamazepine =
Increased levels and toxicity
SSRIs + MAOIs =
Serotonin Syndrome
SSRI + St. John’s Wort or amphetamines =
Serotonin syndrome
SSRIs + beta blockers =
May result in heart block and hypotension
SSRIs + Opioids
Codeine - fluoxetine inhibits conversion to the active compound
Meperidine - increases 5HT —> potential for serotonin syndrome
Tramadol - increased risk of seizures
What are SNRIs?
Serotonin-NE Reuptake Inhibitors
More side effects than SSRIs
How are SNRIs used?
Depression
Neuropathic pain
Post menopausal hot flashes
Venlafaxine (Effexor) is a _______ that may increase________.
SNRI
Increase BP
Duloxetine (Cymbalta) is an SNRI that may…
Cause hepatotoxicity
Cause bilateral acute angle-closure glaucoma
MOA for MAOIs
Irreversibly inhibit MAO (Monoamine Oxidase), which metabolize NE, DA, and 5HT
MAO-A metabolizes all three in both the CNS and periphery
MAO-B selectively metabolizes DA in the CNS but NOT in the GI tract
What should be know about Phenelzine (Nardil)?
Inhibits both MAO-A and MAO-B
Increases NE and 5HT (and DA)
Actions persist longer than serum levels
Also a substrate for MAOs
Used for depression that hasn’t responded to other drugs
(DRUG OF LAST CHOICE)
Drug of last choice for depression
Phenelzine (Nardil) - MAOI
What do we need to know about Selegiline (Deprenyl)?
Selectively inhibits MAO-B —> increased DA
Used in Parkinson’s
Fewer side effects
How are MAOIs used?
For depression which doesn’t respond to other drugs
What are the pharmacokinetics of MAOIs?
Long half life
Effects persist after discontinuing drug
Side effects of MAOIs
Hypertensive crisis (Phenelzine) - AVOID tyramine
Tremors, sedation or excitation and insomnia
Orthostatic hypotension
Weight gain (common)
Anticholinergic effects - blurred vision, dry mouth etc
What dietary advice should you give to you patient when prescribing an MAOI?
Avoid foods with tyramine (red wine, beer, aged cheese)
Tyramine causes release of amines and with limited metabolism by MAO-A, can lead to severe hypertension
What happens when you mix MAOIs with OTC cold and cough meds
If they contain sympathomimetic amines (phenylephrine, ephedrine, amphetamines) can lead to severe hypertension
Mixing what drugs with MAOIs will get you some sweat serotonin syndrome?
Meperidine
Dextromethorphan
TCAs
SSRIs
All can lead to hyperpyrexia
Because MAOIs can also inhibit CYP450s, they can…
Affect metabolism of SSRIs, Ca2+ blockers, etc
What is the MOA for Bupropion (Wellbutrin)?
Inhibits DA, and to a minimal extent, NE and 5HT reuptake
May work where others haven’t. Sometimes combined with SSRIs
Used in ADHD, alcoholism (decreases craving)
What is the extended release form of Bupropion?
Zyban - used for smoking cessation
What are the pharmacokinetics of Bupropion?
Extensive first-pass metabolism and high protein binding
Active metabolites
Side effects of Bupropion (Wellbutrin)
Seizures - contraindicated in patients with a history of seizures
CNS effects - anxiety, insomnia, restlessness, tremor, psychosis
Cardiac - tachycardia
Sexual dysfunction side effects are rare
MOA for Mirtazapine (Remeron)
Blocks presynaptic alpha2 receptors which inhibit release of NE and 5HT —> increased release of NE and 5HT
Blocks 5HT-2a and 5HT-3 receptors
Eliminates side effects associated with SSRIs - anxiety, insomnia, nausea, sexual dysfunction
May be an advantage in depressed patients with insomnia and anxiety
Side effects of Mirtazapine (Remeron)
Blocks histamine receptors —> drowsiness as a predominant side effect
What is the first non-stimulant treatment for ADHD?
Atomoxetine (Strattera)
Selective inhibitor of NE reuptake
Does not cause euphoria so good choice for addicts
May increase memory and attention
Side effects - most common are GI distress and insomnia
Liver damage rare but possible
What is Trazodone (Desyrel)
5HT-2a receptor antagonist
Short half life and high first pass metabolism
SEDATING - not good antidepressant, more often used as a sleep aid or for pain management
Side effects - sedation, dizziness, hypotension, nausea and priapism
Dude walks into the ER with a boner that’s lasted all day. He says he just started taking a new med for going to sleepy time. What do you think he was taking?
Trazodone (Desyrel) - it can cause priapism
How does St. John’s Wort (Hypericin) work?
May be effective in mild depression
Mechanism uncertain - may block reuptake or inhibit MAO
Causes photosensitivity
DO NOT combine with other antidepressants - can cause serotonin syndrome
May prolong the effects of general anesthetics
Efficacy of oral BC, digoxin, protease inhibitors and warfarin reduced due to increased metabolism
