Pharm: Pharmacology of Antidepressants

Question 1

Biogenic amine hypothesis of mood disorders

Answer 1

• Depression = too little NE and/or 5HT in the CNS

- Therefore most antidepressants block reuptake/increase activity of NE and/or 5HT

Question 2

What is a spooky mystery about how antidepressants work?

Answer 2

• 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

Question 3

Neurotrophic hypothesis

Answer 3

Depression is a/w a drop in BDNF, and effective antidepressant therapy increases BDNF gene transcription and neurogenesis

Question 4

What is the controversy over the serotonin hypothesis over depression?

Answer 4

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

Question 5

What is the controversy over the placebo effect?

Answer 5

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

Question 6

HDRS

Answer 6

mild: 8-13
Moderate: 14-18
Severe: 19-22
Very severe: 23+

Question 7

What are the older drug classes?

Answer 7

MAOIS: monoamine oxidase inhibitors, eg. tranylcypromine

Tricyclics: inhibitors of both NE & 5HT reuptake, eg. imipramine, amitryptyline

Question 8

What are the newer drug classes?

Answer 8

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

Question 9

MAO types

Answer 9

MAOa: oxidizes mainly NE, 5HT, tyramine
MAOb: oxidizes mainly DA, phenyethylamine

Question 10

What do MAOIs do? + 2 examples

Answer 10

Irreversibly inhibit both MAOa and MAOb

Tranylcypromine, Phenelzine

Question 11

MAO side effects

Answer 11

Some anticholinergic, pronounced orthostatic hypotension, sexual dysfunction, weight gain, sedation

Question 12

LIFE THREATENING SIDE EFFECTS of MAOI

Answer 12

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

Question 13

Serotonin syndrome

Answer 13

when u combine MAOIs and SSRIs. potentially lethal increases of serotonin in synapse
- hyperthermia, muscle rigidity, myoclonus, rapid mental status changes, changes in vitals…

Question 14

Tricyclics, SSRIs, atypicals features

Answer 14

1. varying potencies and selectivities to inhibit reuptake transporter for NE, 5HT, or both
2. Many have active metabolites that are longer acting than parent compound

Question 15

Tricyclic drugs (4)

Answer 15

Desipramine, Imipramine, Amitriptyline, Nortriptyline

Question 16

Tricyclic factoids

Answer 16

• “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

Question 17

Tricyclics that form active metabolics

Answer 17

imipramine > desipramine

amitriptyline > nortriptyline

Question 18

Tricyclic adverse effects

Answer 18

Antimuscarinic: blurred vision, constipation, confusion
a- antagonist: orthostatic hypotension
Antihistamine; sedation, addictive sedative w/ alcohol
Sympathomimetic: tremor, insomnia
CARDIAC ARRYTHMIAS + CONDUCTION DEFECTS
seizures!!

Question 19

SSRI drugs (5)

Answer 19

Fluoxetine, Paroxetine, Sertraline, Escitalopram, Citalopram

Question 20

SNRI drugs (2)

Answer 20

Duloxetine, venlafaxine

Question 21

SSRI differences from tricyclics

Answer 21

• 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

Question 22

SSRI drug-drug interactions

Answer 22

• 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)

Question 23

Atypical antidepressant types

Answer 23

• Tetracyclics + Unicyclics, eg. Bupropion and mirtazapine

- 5HT2a agonists (also inhibit serotonin reuptake), eg. nefazodone, trazodone

Question 24

How is bupropion unique

Answer 24

• Only agent w/ notable selectivity for the DA uptake transporter
• Lowers seizure threshold
• Useful in improving nicotine abstinence in smokers

Question 25

Ketamine

Answer 25

• NMDA receptor antagonist

- produces a rapid antidepressant response (within hours) and is effective in treatment-resistant depressed patients

Question 26

What are antidepressants used for?

Answer 26

Obvi depression, but also: anxiety disorders (GAD, panic disorder, OCD), PTSD, chronic pain, enuresis, bulimia, PMDD (fluoxetine), alcoholism, adjunct to many conditions

Question 27

What does OD on tricyclics cause

Answer 27

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)

Question 28

What does bupropion OD cause

Answer 28

Seizures

Question 29

What does MAOI OD cause

Answer 29

agitation, delirium, seizures

Question 30

What does SSRI OD caquse

Answer 30

can cause deaths in combo w/ other drugs, but OD fatality on just SSRIs is unlikely

Question 31

Electroconvulsive shock therapy

Answer 31

• 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

Question 32

Possible mechanism of bipolar

Answer 32

• predominance of catecholamine activity
• drugs that increase catecholamines increase mania
• drugs that reduce DA or NE relieve mania

Question 33

Treatment of bipolar

Answer 33

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

Question 34

Lithium

Answer 34

• 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

Question 35

Adverse effects of lithium

Answer 35

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