L5-6 Antidepressants Flashcards
If a patient is on an antihypertensive drug already, which of the TCAs is the best to give?
Nortriptyline
would not contribute to an even lower BP (through alpha blockade)
What are the uses of TCAs?
Depression
Panic Disorder
Pain
Fibromyalgia
Enuresis-Imipramine
ADHD
Name the TCA tertiary amines.
What is significant about them?
Imipramine
Amitriptyline
Trimipramine
Doxepin
- more sedating than secondary amines
- more serotonin effect
Name the TCA secondary amines.
What is significant about them?
Desipramine
Nortriptyline
Protriptyline
- less sedating
- more NE effect
What are the two TCA drugs you would NOT want to give in patients with pre-existing cardiac problems?
Imipramine (tertiary) and desipramine (secondary)
What is the mechanism of action of the TCAs?
What are the three receptors do TCAs block?
TCAs inhibit the uptake of NE and serotonin.
Histamine blockade: drowsiness and sedation, tolerance develops in 1 wk
Muscarinic blockade (anti-cholinergic): impairment of memory and cognition
Alpha blockade: postural hypotension, dizziness, reflex tachycardia
What are the autonomic effects of the TCAs?
With with TCAs are these most likely to be seen?
Cholinergic blockade: blurred vision, tachycardia, palpitations, constipation, urinary retention, dry mouth, metallic taste, gastric distress
More common with the tertiary compounds.
Why do the TCAs cause analgesia?
Due to a direct action of descending noradrenergic pathways in the spinal cord, activating endorphin neurons in the dorsal horn. This, in turn, decreases release of Substance P.
What are the cardiac effects of the TCAs?
Most common: orthostatic hypotension and tachycardia due to **alpha blockade and anti-cholinergic effects. **Can potentiate effect of antihypertensives.
Cardiac depression (more severe in patients with conduction defects or on Class I anti-arrythmatics)
Increased irritability
Can lead to ventricular arrhythmias (Torsades de pointes), can see inverted or flattened T waves
What patients should never be given TCAs?
Previous MI
BBB
Use caution in: seizure patients (decrease seizure threshold), patients with cardiac problems or who are on antiarrythmatics
What are the CNS effects of TCAs?
Sedation, drowsiness (histamine blockade)
Weakness, fatigue
Worse with tertiary TCAs
Anti-cholinergic: delirium at toxic doses
What are some side effects of TCAs that are not autonomic, cardiac, or CNS related?
weight gain
decreases the seizure threshold
SIADH: water intoxication, hyponatremia
Sexual dysfunction
Some physical dependence: muscle aches and malaise if stopped abruptly
Can TCAs be used in pregnancy?
YES
What are some basic pharmacokinetic principles with the TCAs?
Well absorbed orally
Long half-lives
Significant protein binding
Metabolized in liver-interactions common
What are the effects of a TCA overdose?
Cardiac conduction defects and arrythmias-torsades de pointes
Severe hypotension
Agitation, delirium
Neuromuscular irritability and seizures
Hyperpyrexia
Coma, shock, metabolic acidosis
Respiratory depression
How do you treat a TCA overdose?
Cardiac monitoring, supportive care
Gastric lavage, charcoal
Magnesium, isoproterenol, cardiac pacing for torsades de pointes
Lidocaine, propranolol, phenytoin to manage arrythmias and seizure prevention
Sodium bicarb and potassium chloride to restore acid base balance
What is the big drug interaction with TCAs?
MAOIs = serotonin syndrome: CNS toxicity, hyperpyrexia, convulsions, coma
SSRIs= compete for metabolism-toxic levels
Clonidine: decrease effectiveness–>leads to hypertension
Amphetamines: hypertension
Potentiate effects of other CNS depressants and alcohol
What is Clomipramine?
A TCA approved for use in OCD. Works similarly to SSRIs.
What is the mechanism of action of MAOIs?
Inhibits MAO-A and MAO-B
Monoamine oxidase enzymes breaks down circulating catecholamines and compounds ingested from food (tyramine)
MAO-A breaks down NE and serotonin
MAO-B breaks down DA
Name the two MAOIs.
What are they used to treat typically?
Phenelzine and tranylcypromine both irreversibly inhibit borth MAO-A and MAO-B
Useful in aytpical depression that hasn’t responded to other drugs
Drug of last choice due to serious side effects
What are the pharmacokinetics of the MAOIs?
metabolized in liver
effects persist for 1-3 weeks after discontinuing the drug due to long half-lives and irreversible inhibition of MAO
What is the big dangerous side effect of the MAOIs?
HYPERTENSIVE CRISIS!
Irreversible inhibition of MAO in the GI tract allows accumulation of tyramine ingested in food
Tyramine causes release of catecholamines from nerve endings and adrenal medulla
Ingestion of foods containing tyramine can lead to severe hypertensive crisis which can produce fatal intracranial bleeding
Can also occur if MAOIs are taken with sympathomimetic drugs
Treated with alpha receptor blocker: phentolamine
What are some drug interactions with the MAOIs?
OTC cold and cough meds: anything containing sympathomimetic amines such as phenyleprine, ephedrine, or amphetamines–>severe hypertension
TCAS or SSRIs–>serotonin syndrome
Meperidine, tramadol, dextromethorphan–>serotonin syndrome
Buspirone–>hypertension
USE CAUTION WITH ALL MEDICATIONS
What does a MAOI overdose look like?
agitation, hallucinations, hyperreflexia, hyperpyrexia, convulsions, hypo or hypertension
Name the SSRIs.
fluoxetine
sertraline
paroxetine
citalopram
escitalopram
fluvoxamine
vortioxetine
vilazodone
Name the SNRIs
How do they work?
Venlafaxine (effexor)
desvelafaxine
duloxetine (cymbalta)
milnacipran
levomilnacipran
Inhibit 5-HT and NE reuptake
What is the mechanism of action of SSRIs?
Inhibit re-uptake of serotonin into the synaptic terminal
Alter expression of 5-HT receptors in long term
DOC for depression
Mild profile of side effects
How is fluoxetine different in its pharmacokinetics than the other SSRIs?
Extensively bound to plasma protein
Half life of 2-3 days, then converted to active form that has half life of 7-9 days
Paroxetine is the next longest half live (21 hours)
How does fluoxetine and paroxetine affect liver enzymes?
Fluoxetine and Paroxetine significantly inhibit CYP2D6
Inhibits metabolism or activation of many other drugs: other antidepressants, benzos, antipsychotics
Decreases activation of some opiods so they can be less effective in pain management
Decreases activation of tamoxifen, tx of breast cancer
Other SSRIs have fewer effects on hepatic enzymes and shorter half-lives
What are the uses for the SSRIs?
Depression: DOC
Panic Disorder: DOC
OCD: fluoxetine, paroxetine, sertraline, clomipramine, and fluvoxamine
Social anxiety: paroxetine and sertraline
Bulimia: fluoxetine
Alcoholism
What are the side effects of SSRIs?
GI: nausea, diarrhea, constipation, loss of appetite
Weight loss and weight gain
CNS stimulation: anxiety, insomina (fluoxetine, sertraline), sedation (paroxetine)
Sexual dysfunction: decreased libido
SIADH
Photosensitivity
What are the drug interactions with the SSRIs?
MAOIs, St. John’s Wort, amphetamines: serotonin syndrome
TCAs: inhibition of metabolism increases TCA concentration and toxicity
Warfarin: inhibition of metabolism, increased risk of bleeding
Phenytoin or carbamazepine: increased anticonvulsant levels
Beta-blockers: inhibition of metabolism so increased in concentrations can result in heart block and hypotension
Opiods: less effective in treating pain, inhibits conversion of opiods to active compound by CYP2D6
Tramadol: seizures, serotonin syndrome
Tamoxifen: decreases metabolism of pro-drug to active compound
Fluoxetine (Prozac)
SSRI
very long duration of effect
need to wait 5 weeks after discontinuing to switch to MAOl
being tried for chronic pain because it has effects on NE re-uptake as well
taken in morning-may cause insomnia, restlessness
Sertraline (Zoloft)
SSRI
more selective for serotonin than fluoxetine
approved for use in OCD and social anxiety as well as depression
shorter duration of action and less inhibition of hepatic enzymes than fluoxetine
Paroxetine (Paxil)
more selective for serotonin
duration of action shorter
used in elderly
approved for OCD and social anxiety
More likely to cause sedation
more likely to cause anorexia and insomnia
Contraindicated in pregnancy
Citalopram and Escitalopram
Escitalopram is S-enantionmer of citalopram
Escitalopram may have a faster onset of action (1-2 weeks)
Little effect on CYP2D6-fewer pharmacokinetic drug interactions
Vortioxetine
SSRI
inhibits serotonin transporters
5-HT 3a and 7 antagonist, 5-HT 1b partial agonist, 5-HT 1a agonist
increases serotonegic activity
Side effects-nauesea, diarrhea, dry mouth, abnormal dreams, sexual dysfunction
Vilazodone
SSRI and partial 5-HT 1a agonist
lower incidence of sexual dysfunction
Venlafaxine and Desvenlafaxine
SNRI
Inhibits re-uptake of both serotonin and NE
long duration of action
Desvenlafaxine now available for tx of depression, being tested for hot flashes and neuropathic pain
What are the adverse effects of Venlafaxine and Desvenlafaxine?
Increased BP
SIADH
Duloxetine (Cymbalta)
SNRI
Inhibits re-uptake of serotonin and NE
Effective in improving physical symptoms
moderate inhibition of CYP2D6
What are the adverse effects of Duloxetine (Cymbalta)?
anorexia, drowsiness, headache, insomnia, nausea/vomiting, dry mouth
sinus tachycardia, constipation, diahrrea, dizziness
May be hepatotoxic-do not give in liver disease
Contraindicated in third trimester of pregnancy
Milnacipran and Levomilnacipran
SNRI
Milnacipran: approved for fibromyalgia
Levomilnacipran: approved for major depressive disorder
Side effects: GI upset, increase BP
Bupropion (Wellbutrin)
inhibits re-uptake of dopamine and NE
often works in patients who have not responded well to other antidepressants
can be combined with SSRIs to increase effectiveness and decrease incidence of sexual dysfunction
ADHD in children
appears to reduce cravings
What are the side effects of Bupropion?
CNS stimulation: anxiety, insomnia, restlessness, tremor
can induce psychosis (increased DA)
weight loss
headache, nausea
contraindicated in patients with hx seizures or head trauma
do not give in patients that are taking drugs that lower seizure threshold
Mirtazapine (Remeron)
antidepressant that blocks alpha2 receptors that normally inhibit release of NE and serotonin
increases release of NE and 5-HT from nerve terminals
Blocks 5-HT 2a and 3 which eliminates the normal side effects of SSRIs-anxietiy, insomnia, nausea, sexual dysfunction
Blocks histamine receptors–>drowsiness and sedation, increased appetite and weight gain
Atomoxetine
selective inhibitor of NE re-uptake
First non-stimulant for treatment ADHD: increase memory and attention by increasing NE levels
GI distress and insomnia
liver damage is possible but rare
Amoxapine
some antipsychotic effect, may be useful in depression with schizophrenia
DA receptor antagonism can cause Parkinson’s like symptoms, amenorrhea, galactorrhea, tardive dyskinesia
Trazodone
partial agonist at 5-HT 1a, block 5-HT 2a
fairly sedating, not very good antidepressant
pain management and sleep aid
Side effects: sedation, dizziness, hypotension, nausea, priapism
