Exam 2 Lecture 22, Antidepressant II

Block oxidative deamination of catecholamines and 5HT by monoamine oxidase (A and B) isoforms intracellular levels of these amines increase, more transmitter is available for release from neuron with each action potential

Blockade of MAO occurs within days Clinical antidepressant effect requires 2-3 weeks Recovery of amine metabolism requires 2 weeks after discontinuation of drug due to it being an irreversible inhibitor, need to make more enzyme

Side effects and drug/food interactions make these drugs hazardous and use limited Postural hypotension - unknown mechanism Liver Toxicity Blockade of liver amine oxidases which metabolize other drugs (results in potentiation of other drugs actions…other drugs last longer)

foods containing tyramine must strictly be avoided by patients taking MAOI Tyramine is taken up by catecholamine nerve terminals and causes release of transmitter into synapse (amount released is much more than normal action potential release) Patients taking MAO-A inhibitors will have increased levels of NE in presynaptic terminals Tyramine cause massive release NE both Centrally and peripherally = hypertensive crisis

Cheese, red wine, beer, pickled herring, chicken liver, snails, yeast, chocolate, coffee, canned figs, bananas

Interaction of MAOI and tyramine-containing foods Indirectly acting sympathomimetics are drugs that release catecholaimes….ex tyramine and amphetamine MAOI increase amount of releasable catecholamine in nerve terminal, tyramine then causes release

Readily absorbed orally Maximal MAOI inhibition in 5-10 days Blockade of enzyme is irreversible so new enzyme has to be made Inactivation by acetylation

possible toxicity due to metabolite accumulation

enhanced effect due to accumulation of drug

newer series of compounds which are clinically effective as antidepressants but have structures and pharmacological properties unlike the other antidepressant classes

Desyrel relatively selective blocker of 5HT reuptake Antidepressant activity comes from potent blockade of 5HT2a receptors Few cardiotoxic or anticholinergic side effects, BUT prominent sedative effect limits use for depression (unless treating insomnia also) Reported side-effect “priapism” = prolonged, painful boner leading to impotence

Serzone no longer a first line antidepressant due to hepatoxicity 5HT2a antagonist without anticholinergic or cardiotoxic effects, no priapism either

Remeron Antidepressant effect attributed to central a2 adrenergic receptor antagonism, increasing NE and 5HT release (a2 receptors on serotonin terminals, “herteroreceptors”, function to regulate 5HT release) Blocks 5HT2, and 5HT3, histamine H1, muscarininc, a1 receptors As effective as other antidepressants in treating major symptoms, >50% response rate, antidepressant effect within 1-4 weeks

Mild: increased appetite and weight gain, sedative effect (due to h1 blockade), orthostatic hypotension (due to a1 blockade), dry mouth and constipation (due to muscarinic blockade) Serius side effect: agranulocytosis (rare, 3:2800) report any sign of infection and discontinue if low WBC

Wellbutrin; zyban Used both antidepressant and aid smoking cessation Mechanism uncertain; may act primarily on noradrenergic or dopaminergic system Few cardiac or anticholinergic side effects May cause seizures (0.4%), shouldn’t use in patients with seizure disorders

Currently most prescribed Most are potent and selective blockers of serotonin reuptake with little to no effect on NE reuptake (aside from SNRI, which inhibit both) Little cardiac, anticholinergic or sedative effects

insomnia, anxiety, nervousness, headache, nausea, sexual dysfunction (delayed orgasm or anorgasmia) All shouldn’t be taken with MAO inhibitors because they can cause serious, sometimes fatal drug interactions

excessive CNS serotonin causes “serotonin syndrome” including hypertension, hyperthermia, clonus, tremor, agitation, coma and possibly death

Enuresis (bed wetting) in children Panic-phobic disorder OCD, Trichotillomania (compulsive hair pulling) Eating disorders ADHD PTSD Suicidal ideation, PMS, migraine, fibromyalgia, IBS

Unknown etiology, mechanism of drug action uncertain Illness characterized by recurrent swings in mood from depression to mania Overlaps with psychosis, so antipsychotic drugs often used

treatment initiated after manic episode is controlled by a neuroleptic drug Li is primarily a preventive therapy

No psychotropic effects in normal individual Stabilizes mood, mechanism unknown Blocks phosphatidyl inositol second messenger pathway used by monoamines transmitters Also blocks glycogen synthase kinase -3 (GSK-3), involved in signaling cascade for neurotrophic factors including BDNF Corrects sleep disorder characteristic of mania

Rapid, almost complete absorption from GI tract Peak plasma concentrations 2-4 hours after oral dose Distribution widespread; Vd - total body water Crosses blood-brain barrier slowly, but eventually reaches concentration in CSF equal to 40% of plasma concentration Eliminated primarily in urine - 95% Rapid phase of excretion; 1/3 - 2/3 excreted in first 6-12 hours Slower phase of excretion; 10-14 days for remainder Li is subject to renal reabsorption - 80% of filtered ion reabsorbed Equilibrium between intake and excretion eventually reached Drug has low therapeutic index (2-3) so careful monitoring of plasma levels must be done to insure safe use Divided daily doses should be given to avoid peak plasma levels above 0.8-1.2 mEq/l

Diarrhea, vomiting, dowdiness, weakness, thirst, hand tremors, ataxia and muscle fasciculation (mild symptoms) Hyperactive reflexes, convulsions, mental confusion, gross tremor (severe symptoms) Can ultimately progress to coma, death