Lec 74 Antidepressants Flashcards
What are the classes of antidepressants?
- MAO inhibitors
- tricyclic antidepressants
- selective serotonin reuptake inhibitors
- antidepressants with multiple receptor targets
What is therapeutic use of MAO inhibitors?
atypical depression
anxiety
hypochondriasis
treatment resistant depression/panic disorder/social anxiety disorder
What is mech of action of MAO inhibitors?
- irreversibly inhibit degradation of MAOs in presynaptic terminals
- causes increase 5HT, NE, DA in presynaptic terminals and synaptic cleft
What are substrates of MAO-A vs MAO-B?
MAO-A: 5HT, NE, DA
MAO-B: phenylethylamine, DA [NOT 5HT, NE]
What is first aid mnemonic for MAO inhibitors?
MAO takes pride in shanghai
- MAO
- Tranylcypromine
- Phenelzine
- Isocarboxazid
- Selegiline
What are the side effects of MAO inhibitors?
serotonin syndrome if combined w/ other 5HT drugs
hypertension if combined with tyramine diet or drugs that are adrenergic agonists
orthostatic hypotension, weight gain, insomnia, sexual dysfunction, rare hepatotoxicity [for phenelzine + iso]
What are symptoms of serotonin syndrome?
symptoms: ab pain, diarrhea, sweating, tremor, hyperthermia, tachycardia, hypertension, myoclonus, irritability, delirium, death
What causes serotonin syndrome?
selected drugs in combo with MAOI
- other antidepressants
- cyclobenzapine
- carbamazepine
- dextromethorphan
- opiaties: meperidine, fentanyl, methadone
- tramadol
- st johns wort
- SSRI
What is a hypertensive crisis? symptoms?
defined by diastolic BP > 120
symptoms: headache, palpitations, stiff/sore neck, N/V, sweating, dilated pupils, photophobia
What triggers hypertensive crisis? what drugs to avoid?
triggered by noradrenergic drug + MAO inhibitor
avoid
- decongestants
- stimulants [amphetamines]
- appetite suppressants
- antidepressants with NRI [TCAs, SNRIs, buproprion]
What is a tyramine-induced hypertensive crisis?
- ingestion of tyramine-rich foods in presence of MAO-I can trigger hypertensive crisis
- tyramine is a catecholamine releasing agent
- intestinal wall MAO-A breaks down tyramine before absorption
- if tyramine gets access to NE sympathetic neurons –> will release NE; but don’t have to worry about it because MAO-A breaks down tyramine before it gets a chance
if you inhibit MAO-A –> can’t handle dietary tyramine, release NE and no MAO-A to destroy it –> increased BP
What foods should you avoid on MAO-I?
avoid: soy, beer, red wine, aged cheese, dried sausage, fava beans, liver, smoked fish, sauerkraut
continue diet for 2 wks after stopping MAO-I to allow re-synthesis of MAO-A
What is EMSAM?
selegiline transdermal path for treatment of depression
- at low levels selegiline inhibits MAO-B but at antidepressent level inhibits A and B
- goal to bypass GI tract and liver to minimize chance of hypertensive crisis if tyramine is ingested
dietary restriction at > 6mg/24 hr
What kind of drug is phenelzine?
MAO inhibitor
What kind of drug is tranylcypromine?
MAO inhibitor
What kind of drug is selegiline?
MAO inhibitor –> selective for MAO-B at low doses; but acts on both at anti-depressant levels
What is therapeutic use for tricyclic antidepressants?
- major depression
- OCD [clomipramine]
- fibromyalgia
depression + treatment resistant depression childhood enuresis [imipramine] generalized anxiety disorder insomnia obsessive compulsive disorder migraine cataplexy syndrome [imipramine] fibromyalgia prurits/dermatologic
What is mech of action tricyclic antidepressants?
- block presynaptic reuptake of NE and 5HT
- secondary = NE only; tertiary = NE + 5HT
- causes NT accumulation in synaptic cleft
What are side effects of TCAs?
sedation, weight gain [H1 block]
a1 blockade –> orthostatic hypotension, dizziness
atropine [anti-ACh] side effects: urinary retention, dry mouth, tachycardia
What are side effects unique to despiramine?
- less sedating [H] but higher seizure incidence
- least alpha 1 blockade
Do tertiary or secondary amines have more anticholinergic effects?
tertiary > secondary
what are the Tri-C’s of tricyclic antidepressants?
TriC = convulsion, coma, cardiotoxicity [arrhythmias]
Why should you use nortriptyline in elderly?
its a secondary amine = less anti-ACh effects
causes confusion and hallucination in elderly
How do you treat tricyclic antidepressant cardio toxicity?
NaHCO3
Which TCAs have least anticholinergic effects?
secondary amines [desipramine, nortriptyline]
Which TCAs have most antihistamigeric effect?
doxepin
Which TCAs have least alpha 1 blockade?
secondary amines [desipramine, nortriptyline]
What happens in TCA overdose?
lethal
Who should you avoid TCA in?
pts with narrow angle glaucoma, recent cardiac events, cardiac conduction delays, prolonged GTc
Are tertiary or secondary amines beter in elderly?
secondary
What is the phrase for anticholinergic toxicity?
red as a beet dry as a bone blind as a bat mad as a hatter hot as a hare full as a flask
How are TCAs metabolized?
by cyp450
tertiary –> secondary
1/2 life 10-70 hrs
What drug-drug interactions with TCAs?
- block effect of antihypertensives
- additive tox with anti-arrhythmics/QTc prolonging agents, anticholinergics, CNS depressants, sympathomimetics
- drugs that increase TCA level: cimetidine, fluoxetine, ritonavir
- drugs that decrease TCA: carbamazepine, rifampin, phenytoin, nictonie, barbituates
MAOIs: wait 14 days between MAOI and TCA
What is dosing/monitoring of TCA?
- narrow therapeutic index
- similar dose range and plasma levels for most
- lower doses for pain
- unclear value in monitoring drug levels
What are uses for SSRIs?
- depression
- generalized anxiety
- panic disorder
- PTSD
- OCD
- premenstrual dysphoric disorder
- social phobias
- bulimia
What is mech of action SSRIs?
bind to serotonin transporter and inhibit reuptake of 5HT into presynaptic nerve terminals
What is first aid mnemonic for SSRI names?
Flashbacks paralyze senior citizens
- Fluoxetine
- paroxetine
- setraline
- citalopraom
Which SSRI has highest potency for DA?
setraline
Which SSRIs have highest potency for NE?
fluvoxamine
paroxetine
Which SSRIs are most selective for 5HT reuptake?
citalopram
fluoxetine
What are common side effects of SSRIs?
GI distress sexual dysfunction (anorgasmia and decrease libido) weight gain tremor sweating
serotonin syndrome with any drug that increases 5HT [MAOI, SNRI, TCA] –> hyperthermia, confusion, myoclonus, flushing, diarrhea, seizures
What is treatment for serotonin syndrome?
cyproheptadine = 5HT2 receptor antagonist
What is metabolism of SSRI?
significant 1st pass
metabolized in liver by CYP enzymes
Which SSRIs have less drug-drug interactions?
citalopram and escitalopram
Which SSRIs have more drug drug interactions?
fluxoamine
Which SSRI has longest half life and least withdrawal?
fluoxetine
What are properties of fluoxetine?
- activating, may cause insomnia
- long half life
- least withdrawal symptoms
- more drug-drug interactions than others
What are properties of sertraline?
- activating
- mild DA reuptake inhibitor
What are properties of paroxetine?
- short half life
- withdrawal symptoms
- control release form available
- blocks NE reuptake, some anti-ACh activity, more sedation, dry mouth, weight gain
What happens in SSRI withdrawal? treat?
- if abrupt discontinuation after >6 wks of treatment
- dizziness, weakness, nausea, headache, anxiety, insomnia, paresthesias, flu-like symptoms, muscles aches
usually resolves within 3 wks
can treat with fluoxetine
What are advantages of SSRIs over older agents?
standard dosing = easy to titrate
often get clinical response at starting dose
usually not lethal in overdose
no arrhythmias/disturbance in BP/seizure/coma/resp depression
fewer drug-drug interactions
no special diet
What is use of SNRIs?
- depression
venlafaxine = also generalzie anxiety + panic disorders
duloxetine = also diabetic peripheral neuropathy
fibromyalgia, painful physical symptoms of depression, stress urinary incontinence, vasomotor symptoms
What is mech of SNRIs?
at low dose < 150mg/day act as SSRI
at higher doses –> SNRI = inhibit 5HT and NE reuptake
What are side effects of SNRIs?
increase BP [more in venlafaxine than duloxetine], stimulant effects, sedation, nausea
What is unique about bupropion’s side effects?
no sexual dysfunction or weight gain
stimulant effects: tachycardia, insomnia; headache, seizure in bulimic pts
What are side effects of mirtazapine?
Sedation [may be desirable in depressed pts with insomnia]
increased appetite, weight gain [may be desirable in elderly or anorexic]
dry mouth
What is use of mirtazapine?
- depression
- insomnia
- appetite stimulation
Which anti-depressant is known for its priapism effects?
trazodone
What causes the therapeutic delay in onset of antidepressant action?
downregulation of serotonergic receptors
may enhance neruonal regeneration process + restore cortical dendrites
Which type of antidepressants best for co-morbid pain disorders?
SNRI
