Exam 2 Lecture 22, Antidepressant II Flashcards
MAO inhibitors Mechanism of action
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
MAO inhibitor time course
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
MAO inhibitor side effects
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)
MAO inhibitor drug-food interactions
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
Foods containing tyramine
Cheese, red wine, beer, pickled herring, chicken liver, snails, yeast, chocolate, coffee, canned figs, bananas
“Cheese effect”
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
MAOI Absorption, fate, excretion
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
Fast acetylators effect on MAOI
possible toxicity due to metabolite accumulation
Slow acetylators effect on MAOI
enhanced effect due to accumulation of drug
Atypical 2nd gen Antidepressants
newer series of compounds which are clinically effective as antidepressants but have structures and pharmacological properties unlike the other antidepressant classes
Trazodone
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
Nefazodone
Serzone
no longer a first line antidepressant due to hepatoxicity
5HT2a antagonist without anticholinergic or cardiotoxic effects, no priapism either
Mirtazapine
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
Mirtazapine side effects
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
Bupropion
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
SSRI and SNRI
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
SSRI and SNRI Side 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
SSRI and SNRI overdose
excessive CNS serotonin causes “serotonin syndrome” including hypertension, hyperthermia, clonus, tremor, agitation, coma and possibly death
Other uses TCA, 2nd gen, and SSRI
Enuresis (bed wetting) in children
Panic-phobic disorder
OCD, Trichotillomania (compulsive hair pulling)
Eating disorders
ADHD
PTSD
Suicidal ideation, PMS, migraine, fibromyalgia, IBS
Bipolar disorder
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
Lithium Salts
treatment initiated after manic episode is controlled by a neuroleptic drug
Li is primarily a preventive therapy
Lithium Salt Pharmacology properties
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
Lithium Salts Absorption, distribution and excretion
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
Symptoms of Lithium toxicity
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
Factors predisposing to Lithium intoxication
Sodium depletion causes lithium retention (toxicity)
Common causes of sodium depletion include excessive sweating, prolonged illness
with diarrhea and/or vomiting, low sodium diets, sodium-depleting diuretics
Lithium Salt side effects
Renal system:
Degenerative or inflammatory responses
Excessive thirst (polydipsia) and excessive urination (polyuria)
Thyroid enlargement suggesting decreased thyroid function
usually being, most patients do not become hypothyroid
Lithium Salt drug interactions
Diuretics which cause sodium loss will cause Li retention, possible intoxication
Anticholinergic effect of tricyclic antidepressants causing urinary retention is particularly uncomfortable with Li-induced diuresis
Antinausea effects of antipsychotic drugs can mask Li-induced nausea (usually the first sign of Li intoxication)
Lithium Salt drug interactions
Diuretics which cause sodium loss will cause Li retention, possible intoxication
Anticholinergic effect of tricyclic antidepressants causing urinary retention is particularly uncomfortable with Li-induced diuresis
Antinausea effects of antipsychotic drugs can mask Li-induced nausea (usually the first sign of Li intoxication)
Lithium Salt Doses, routes of admin
Li2CO3 available in 150, 300, and 600 mg tablets
Eskalith, Lithane, Lithonate, Lithotabs
Given orally, never parenterally
Appropriate plasma concentrations range from 0.8-1.25 mEq/l and are attained
with doses ranging from 500-1500 mg/day in divided doses
Carbamazepine (Tegretol)
Anticonvulsant for bipolar
a. An iminostilbene, related structurally to the tricyclic antidepressants
b. Classified as an anticonvulsant, but found to possess anti-manic and
antidepressant effects
c. Now a drug of second choice for treatment of bipolar disorder, esp. for patients
unable to tolerate Li; sometimes used in combination with Li
Valproic acid (Divalproex)
a. Another anticonvulsant with anti-manic and mood-stabilizing activity
b. Maybe better tolerated than carbamazepine; often combined with Li
Lamotrigine (Lamictal)
a. Anticonvulsant with long-term mood-stabilizing effects; especially effective for prophylactic control of bipolar disorder without risk of inducing mania
Drugs to treat OCD
Flouxetine, fluvoxamine and clomipramine
panic-phobic disorder treated with
imipramine, fluoxetine or alprazolam
Bed wetting treated by
imipramine
eating disorders treated by
tricyclics and fluoxetine
ADHD treated with
imipramine, desipramine and nortriptyline
