Antidepressant Drugs Flashcards
What is the biogenic amine hypothesis of mood disorders?
depression = too little CNS NE and/or 5HT amounts/activity (found when reserpine side effects produced depression and realized that reserpine depletes amines)
How to antidepressant drugs work in general
either by blocking reuptake of NE and 5HT or by increasing activity of NE and 5HT
Why does the pharmacological effect take place within minutes/hrs but clinical improvement isn’t seen for wks/months?
maybe it’s due to receptor re-regulation (possible downregulation of receptors) or changes in neurotrophic factors (brain derived neurotrophic factor)
What’s up with the placebo effect?
most docs agree that meds are beneficial over placebo in patients with very severe depression (jury’s out on less severe cases)
What are the major classes of antidepressant medications?
MAOIs, Tricyclics, SSRIs, SNRIs, “Atypicals”, Lithium salts for bipolar, etc etc
How do MAO-A and MAO-B typically act in nerve mitochondria? Which MAO is inhibited to treat depression?
MAO-A: oxidizes to NE, 5HT, tyramine
MAO-B: oxidizes to DA, phenethylamine
MAOIs irreversibly inhibit BOTH MAO-A and MAO-B
What are the two MAOIs used to treat depression and what are their less serious side effects?
Tranylcypromine and Phenelzine
Side effects: anticholinergic, orthostatic hypotension, sexual dysfunction, weight gain, sedation
What are some potentially life threatening side effects to using MAOIs?
1) Hypertensive crisis (liver MAO inhibited so there is loss of first pass metabolism with tyramine rich foods ie fermented foods–>major increase in tyramine)
2) Serotonin syndrome when taking an MAOI+SSRI (meperidine, dextromethorphan, etc)
What are two salient features of all of the amine reuptake inhibitors (tricyclics, SSRIs, “Atypicals)?
1) widely varying potencies/variable SELECTIVITY SPECTRUM in terms of inhib NE or 5HT or both
2) presence of active metabolites which are much longer acting in the body
What are the four tricyclics used to treat depression?
Desipramine, Imipramine, Amitriptyline, Nortriptyline
Why are the tricyclics considered to be “dirty drugs”
because they don’t just block reuptake of NE and 5HT but also variably block muscarinic, alpha adrenergic, dopamine and histamine receptor uptake. Thus these drugs have many variably side effects
Tricyclics: high or low lipid solubility? what kind of metabolism?
High lipid solubility (very large Vd); metabolism: N-demethylation + P450 oxidation+ glucuronide conjugation
What active metabolites do imipramine and amitriptyline form?
Imipramine–>Desipramine
Amitriptyline–>Nortriptyline
What are the side effects taking tricyclics?
**CARDIAC ARRYTHMIAS (conduction defects esp at overdose), seizures, sympathomimetic (tremor + insomnia), antimuscarinic (blurred vision, constipation), a-antagonist (orthostatic hypotension), histamine antag (sedation)
What are the names of the SSRIs used to tx depression?
Fluoxetine, Paroxetine, Sertraline, Escitalopram, Citalopram
What are the names of the SNRIs used to tr depression?
Duloxetine, Venlafaxine
What are the main differences between tricyclics and SSRIs?
1) longer duration of action
2) inhibition of P450 enzymes
3) much safer in overdose quantities (no seizures or cardiac arrhythmias)
4) less side effects
5) more nausea/complaints of decreased sexual function
Which of the SSRIs are potent inhibitors of P450 enzymes?
Fluoxetine and Paroxetine (inhibit CYP2D6 especially)
Which of the SSRIs form active metabolites?
Fluoxetine—>Norfluoxetine
What is the “serotonin syndrome”?
drug interaction between SSRI/MAOi–>increased 5HT stores+inhibited reuptake–>major increase in serotonin–>hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status and vital signs…could be lethal
What is unique about the drug Bupropion?
1) only agent to block dopamine uptake (in addition to NE)
2) can lower seizure threshold (bad)
3) can improve nicotine abstinence in people trying to quit smoking
Why is ketamine used to treat depression?
used for treatment resistant depressed patients. it’s an NMDA receptor antagonist that claims to produce rapid antidepressant response within hours (by increasing synaptogenesis?)
What are the general uses of antidepressant medications in addition to treating depression?
anxiety disorders, PTSD, chronic pain, enuresis (incontinence), bulimia, pre-menstrual dystrophic disorder (fluoxetine specifically), alcoholism, etc.
Why are SSRIs used more often than TCAs even though they are probably less effective?
much better tolerated, far less serious side effects and thus better compliance
What are the drugs used to treat bipolar disorder?
Lithium (anti-manic/mood stabilizing), Carbamazepine and Valproate (anticonvulsants), antidepressants (usually an MAOi), severe cases: benzodiazepines and antipsychotic drugs
What is the MOA of lithium?
relatively unclear; but known to act on second messenger systems by: depleting IP3 and DAG which are important in both a-adrenergic and muscarinic-cholinergic transmission
What are some side effects to taking lithium?
drowsiness, weight gain, tremor, polydipsia, polyuria; LOW SAFETY MARGIN–>neurotoxity, cardiac toxicity, renal dysfunction (early signs of OD are N/V)
