Pharm: Pharmacology of Antidepressants Flashcards
Biogenic amine hypothesis of mood disorders
- Depression = too little NE and/or 5HT in the CNS
- Therefore most antidepressants block reuptake/increase activity of NE and/or 5HT
What is a spooky mystery about how antidepressants work?
- The pharmacological effects of antidepressants happen within minutes to hours…but clinical improvement does not occur for WEEKS or MONTHS whoaaaaaa
- maybe d/t re-regulation of receptors in compensatory response
Neurotrophic hypothesis
Depression is a/w a drop in BDNF, and effective antidepressant therapy increases BDNF gene transcription and neurogenesis
What is the controversy over the serotonin hypothesis over depression?
Some people say that it’s been overused by the pharm industry to promote a simplistic biological model of depression to market SSRIs…
BUT studies have shown that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients, so who the fuck knows
What is the controversy over the placebo effect?
There’s a fuck ton of it
Studies have shown that there is very little evidence of true drug effect vs placebo in mild to moderate depression
BUT most agree that meds are beneficial over placebo in patients with very severe depression
HDRS
mild: 8-13
Moderate: 14-18
Severe: 19-22
Very severe: 23+
What are the older drug classes?
MAOIS: monoamine oxidase inhibitors, eg. tranylcypromine
Tricyclics: inhibitors of both NE & 5HT reuptake, eg. imipramine, amitryptyline
What are the newer drug classes?
SSRIS: selective serotonin reuptake inhibitors, eg. fluoxetine, citalopram
SNRIs: Serotonin-Norepinephrine reuptake inhibitors, eg. duloxetine, venlafaxine
Atypicals: inhibit 5HT uptake transporter, Da reuptake inhibition, agonist or antagonist at various serotonin receptor types, NE reuptake inhibition, antipsychotics, etc. eg, bupropion, mirtazapine
MAO types
MAOa: oxidizes mainly NE, 5HT, tyramine
MAOb: oxidizes mainly DA, phenyethylamine
What do MAOIs do? + 2 examples
Irreversibly inhibit both MAOa and MAOb
Tranylcypromine, Phenelzine
MAO side effects
Some anticholinergic, pronounced orthostatic hypotension, sexual dysfunction, weight gain, sedation
LIFE THREATENING SIDE EFFECTS of MAOI
Liver MAO is also inhibited, so there is loss of first-pass metabolism that protects against tyramine in foods (fermented foods, cheese, pepperoni, pickled herring)
Allows significant accumulation of tyramine –> hypertensive crisis. So don’t eat those foods when you’re on MAOI
Serotonin syndrome
when u combine MAOIs and SSRIs. potentially lethal increases of serotonin in synapse
- hyperthermia, muscle rigidity, myoclonus, rapid mental status changes, changes in vitals…
Tricyclics, SSRIs, atypicals features
- varying potencies and selectivities to inhibit reuptake transporter for NE, 5HT, or both
- Many have active metabolites that are longer acting than parent compound
Tricyclic drugs (4)
Desipramine, Imipramine, Amitriptyline, Nortriptyline
Tricyclic factoids
- “dirty drugs” that produce varying degrees of block at other NT receptors –> side effects
- high protein binding, high lipid solubility –> large Vd
- mechanism of reuptake inhibition: N-demethylation followed by p450 oxidation followed by glucuronide conjugation
Tricyclics that form active metabolics
imipramine > desipramine
amitriptyline > nortriptyline
Tricyclic adverse effects
Antimuscarinic: blurred vision, constipation, confusion
a- antagonist: orthostatic hypotension
Antihistamine; sedation, addictive sedative w/ alcohol
Sympathomimetic: tremor, insomnia
CARDIAC ARRYTHMIAS + CONDUCTION DEFECTS
seizures!!
SSRI drugs (5)
Fluoxetine, Paroxetine, Sertraline, Escitalopram, Citalopram
SNRI drugs (2)
Duloxetine, venlafaxine
SSRI differences from tricyclics
- SSRIs have longer duration
- some SSRIs inhibit P450 enzymes (esp CYP2C, 2D, 3A) so might interfere w/ metabolism of other drugs
- safer in OD than tricyclics: no seizures/heart probs
- less side effects
- BUT more nausea and decreased sexual function
SSRI drug-drug interactions
- some SSRIS esp. fluoxetine and paroxetine are potent p450 inhibitors…other drugs cleared by p450 may reach high levels (eg. desipramine, flecainide, tricyclics, dxtromethorphan, diazepam, cisapride, phenytoin)
Atypical antidepressant types
- Tetracyclics + Unicyclics, eg. Bupropion and mirtazapine
- 5HT2a agonists (also inhibit serotonin reuptake), eg. nefazodone, trazodone
How is bupropion unique
- Only agent w/ notable selectivity for the DA uptake transporter
- Lowers seizure threshold
- Useful in improving nicotine abstinence in smokers
Ketamine
- NMDA receptor antagonist
- produces a rapid antidepressant response (within hours) and is effective in treatment-resistant depressed patients
What are antidepressants used for?
Obvi depression, but also: anxiety disorders (GAD, panic disorder, OCD), PTSD, chronic pain, enuresis, bulimia, PMDD (fluoxetine), alcoholism, adjunct to many conditions
What does OD on tricyclics cause
Tricyclics are the most dangerous in OD and can cause:
shock/coma, metabolic acidosis, respiratory depression, agitation/delirium, seizures, hyperpyrexia, bowel and bladder paralysis, HEART PROBS (arrhythmia, conduction defects) d/t blocking sodium channels –> prolonged QT, widened QRS (treat with sodium bicarb)
What does bupropion OD cause
Seizures
What does MAOI OD cause
agitation, delirium, seizures
What does SSRI OD caquse
can cause deaths in combo w/ other drugs, but OD fatality on just SSRIs is unlikely
Electroconvulsive shock therapy
- last resort
- may be appropriate for patients not being helped by drugs/too long of delay in drug response, pts with psychotic depression/impending suicide
Possible mechanism of bipolar
- predominance of catecholamine activity
- drugs that increase catecholamines increase mania
- drugs that reduce DA or NE relieve mania
Treatment of bipolar
Lithium: prevents mood swings in bipolar patients
Anti-convulsants: carbamazepine, valproate
MAOI for depressive phase (tricyclic may cause mania)
Concurrent use of benzo because onset of Li is slow
Benzos or antipsychotics added in severe bipolar
Lithium
- small monovalent cation
- causes depletion of inositol phosphate second messengers IP3 and DAG, important for both a-adrenergic and muscarinic-cholanergic transmission –> may cause selective depression of overactive circuits
Adverse effects of lithium
Common side effects: drowsiness, weight gain, tremor, polydipsia, polyuria
Relatively low margin of safety –> elevated Li levels may cause neurotoxicity, cardiac toxicity, renal dysfunction
Nausea w/ vom is early warning of OD
