Antidepressants Flashcards
What are the prototype anti-depressant drugs and anti-manic drugs?
Anti-depressant Drugs: amitriptyline, imipramine, nortriptyline, doxepin, fluoxetine, nefazodone, phenelzine, tranylcypromine, trazadone, buproprion, fluvoxamine
Anti-manic Drugs: Lithium, carbamazepine, valproate
What are the 4 categories of antidepressants? How long before they take effect? What does this suggest? What are 2 theories concerning the adaptive changes that occur as a result of these drugs?
These drugs fall into four categories – tricyclics (TCAs), monoamine oxidase inhibitors
(MAOIs), selective serotonin reuptake inhibitors (SSRIs) and the atypicals. The
mechanism of action for each class is different, suggesting that no simple answer
explains these disorders. Like the antipsychotics, the clinical effects of these drugs don’t
appear until after 2-6 weeks of administration, suggesting that an adaptive change is induced by their chronic presence in the CNS. Two current theories put forward
regarding such adaptive changes are that chronic administration of these drugs works by
(1) altering central beta-adrenergic receptor function or (2) altering transmission through serotonergic pathways. However, speculation is all that is open to us at the moment.
What are tricyclics similar to structurally? What are their mechanism? How are they absorbed? Administered? Dosing rate? Why do they have so many side effects? What side effects? What is their half-life? Elimination time? What are the two types?
Structurally similar to phenothiazines.
Mechanism: Block transmitter (5-HT and NE) reuptake sites
Absorbed well orally, long half-lives, single bedtime dosage. Eliminated 7-10 days
Act at adrenergic, cholinergic, and histaminergic receptors leading to many side effects, including increased risk of tonic-clonic side seizures
With overdose, life-threatining CV effects. Acutely manifested as excitement with dystonia, myoclonus, tonic-clonic seizures followed by coma with depressed resp., hypoxia, hypothermia, hypotension.
Tertiary Amines and Secondary Amines
What are the prototypic tertiary amines? What reuptake do they block? What side effects do they have in general? In elderly patients? How else can they be used? What is their metabolism like? When are they contraindicated and why?
Amitriptyline, imipramine, and doxepin
Blocks NE and 5-HT reuptake
Sedative effects, weight gain, strong anti-cholinergic and some anti-adrenergic actions.
In elderly, confusion, delirium, memory problems due to anti-muscarinic.
Can be used as hypnotics, decreasing number of awakenings, etc.
Metabolism by demethylation—>active metabolites (nortriptyline and desimipramine)
Should not be used in elderly due to CV effects.
What is the prototypic secondary amine? What reuptake does it block? How does it differ from tertiary amine side effects? What side effects can it have?
NOrtriptyline
Blocks NE reuptake
NO sedation or strong anti-cholinergic activity. Less weight gain. Less postural hypotension.
Can have cardiotoxic effects through depression of cardiac conduction.
What is the target of MAOIs? What is the target of their target? What is their mechanism of action? What is their absorption? How long before clinical improvement occurs? When are they used? Why then? What dietary restrictions are necessary and why? What could happen if they’re not followed? What are some side effects? What must be done before switching from MAOIs to another antidepressant? Why? What are 2 prototypes?
They target MAO-A (5-HT and MAs) and MAO-B (Monoamines). They irreversibly destroy MAOs.
Clinical improvement seen in 2-3 weeks.
Absorbed well orally.
Fallen out of favor due to side effects. Only used when other anti-depressants don’t work or when there’s a lot of anxiety involved with the depression.
Because of the lack of MAOs when taking them, MAs can build up and cause hypertensive crisis. Therefore, tyramine should be avoided (aged cheeses, bear, bean curd, wine).
Sedation, beh. excit, post. hypotension. Overdoses life threatening. Hepatotoxicity rare. Must wait two weeks before starting a new antidepr to avoid Serotonin syndrome (hyperpyrexia, convulsions, coma).
Phenelzine and Tranylcypromine
What is the mechanism of phenelzine? What does therapeutic dose result in? How is it inactivated/metabolized? What clinical application does that have? How is it thought that tranycypromine works?
Phenelzine
This compound acts by inactivating the flavin prosthetic group of the enzyme.
Therapeutic doses result in >85% inhibition of platelet MAO activity. This hydrazine compound is inactivated through acetylation. About one-half the population are ‘slow’ acetylators, a fact that may explain the exaggerated effects of standard doses of the drug in some patients.
Tranylcypromine
It is thought this agent works by reacting with a sulfhydryl group in the active center of the enzyme.
What is the mechanism of action of SSRIs? What is their advantage? How long before clinical improvement is seen? What is a prototype?
Due to suggestive preclinical studies in animals, compounds were developed that could
selectively inhibit the reuptake of 5-HT with the aim of producing more efficacious
antidepressants. These agents, named SSRIs, have been found to be equal in efficacy
with the more traditional drugs, but without the side effects. They have little or no
sedative effects, no anti-cholinergic/anti-adrenergic properties and very little or no effect
on seizure thresholds. It is difficult to overdose on these agents, making them useful in
the treatment of suicidal patients. They too require 2-4 weeks of administration before
clinical improvements are noted.
Fluoxetine
What is the half life of fluoxetine? What is the time frame for metabolism/elimination? How is it metabolized? What are the clinical implications of that? Give examples of this. What are some side effects? Other drug interactions?
This compound has a very long half-life, of around 50 hours, while its N-demethylated
metabolites extend these values up to 150-200 hours. This means that elimination takes
weeks to occur. This compound competes with other drugs for hepatic microsomal
enzymes and thus can cause significant and potentially dangerous drug-drug interactions.
This is especially seen with TCAs, which can reach toxic levels in the presence of
fluoxetine, and these levels can persist for days after fluoxetine is discontinued due to its
slow elimination rate. It can also cause toxicity if co-administered with alprazolam, beta-
blockers, trazodone, carbamazepine and lithium. Akathisia is one side effect observed,
along with headaches, sexual dysfunction and anorexia. Tryptophan can cause agitation,
restlessness and decreased responsiveness to fluoxetine.
What are 4 atypical antidepressants?
nefazodone, buproprion, mirtazapine, trazadone
What is the mechanism of action of nefazodone? Absorption? Halflife? Side effects? With what other drug is it contraindicated? Why?
This compound not only blocks 5-HT re-uptake, but also antagonizes 5-HT2 receptors. It
is absorbed orally, has a half-life of some 18 hours and has very few side effects. It does
cause more sedation than the SSRIs and can induce some orthostatic blood pressure
changes. Can cause impotence. Not to be used with terfenadine (Seldane) due to
competition with hepatic microsomal enzymes, which can result in life-threatening
cardiotoxicity.
Mechanism of buproprion? Side effects?
Buproprion
This agent blocks DA reuptake. Can cause seizures in patients. Otherwise, little or no autonomic side effects, no sedation and little or no weight gain. It can act as a stimulant, leading to anorexia, agitation and sleep impairment.
Mechanism of mirtazapine? Side effects?
This is an alpha2-adrenergic receptor antagonist, and also blocks 5-HT2, 5-HT3 and H1 receptors. It has a sedative effect and can cause orthostatic hypotension. The most common side effect is somnolence and in rare instances, agranulocytosis.
Mechanism of action of trazadone? When is it used? Side effects?
A 5-HT receptor antagonist. Is a less-effective drug used as a second drug for SSRI-induced sleep distrubances. Can induce arrythmias, orthostatic hypotension, nausea,
sedation and priapism.
What is the mechanism of action of noradrenergic regulation of release of 5-HT?
Noradrenergic nerves innervate the raphe nuclei. The enhanced release of norepinephrine
in the raphe nuclei caused, for example, by blockade of inhibitory autoreceptors on
noradrenergic terminals, activates 1-adrenoceptors, which may lead to an increase of the
rate of firing of serotonergic soma. This can lead to enhanced release of 5-HT at
serotonergic terminals. In addition, there appear to be 2-adrenoceptors on serotonergic
terminals, which, when activated, can inhibit the release of 5-HT. Blockade, then, of such
heteroceptors could further enhance the release of 5-HT.
