Exam 2 Lecture 22, Antidepressant II

Question 1

MAO inhibitors Mechanism of action

Answer 1

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

Question 2

MAO inhibitor time course

Answer 2

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

Question 3

MAO inhibitor side effects

Answer 3

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)

Question 4

MAO inhibitor drug-food interactions

Answer 4

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

Question 5

Foods containing tyramine

Answer 5

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

Question 6

“Cheese effect”

Answer 6

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

Question 7

MAOI Absorption, fate, excretion

Answer 7

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

Question 8

Fast acetylators effect on MAOI

Answer 8

possible toxicity due to metabolite accumulation

Question 9

Slow acetylators effect on MAOI

Answer 9

enhanced effect due to accumulation of drug

Question 10

Atypical 2nd gen Antidepressants

Answer 10

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

Question 11

Trazodone

Answer 11

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

Question 12

Nefazodone

Answer 12

Serzone

no longer a first line antidepressant due to hepatoxicity

5HT2a antagonist without anticholinergic or cardiotoxic effects, no priapism either

Question 13

Mirtazapine

Answer 13

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

Question 14

Mirtazapine side effects

Answer 14

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

Question 15

Bupropion

Answer 15

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

Question 16

SSRI and SNRI

Answer 16

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

Question 17

SSRI and SNRI Side effects

Answer 17

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

Question 18

SSRI and SNRI overdose

Answer 18

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

Question 19

Other uses TCA, 2nd gen, and SSRI

Answer 19

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

Question 20

Bipolar disorder

Answer 20

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

Question 21

Lithium Salts

Answer 21

treatment initiated after manic episode is controlled by a neuroleptic drug

Li is primarily a preventive therapy

Question 22

Lithium Salt Pharmacology properties

Answer 22

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

Question 23

Lithium Salts Absorption, distribution and excretion

Answer 23

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

Question 24

Symptoms of Lithium toxicity

Answer 24

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

Question 25

Factors predisposing to Lithium intoxication

Answer 25

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

Question 26

Lithium Salt side effects

Answer 26

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

Question 27

Lithium Salt drug interactions

Answer 27

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)

Question 28

Lithium Salt drug interactions

Answer 28

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)

Question 29

Lithium Salt Doses, routes of admin

Answer 29

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

Question 30

Carbamazepine (Tegretol)

Answer 30

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

Question 31

Valproic acid (Divalproex)

Answer 31

a. Another anticonvulsant with anti-manic and mood-stabilizing activity
b. Maybe better tolerated than carbamazepine; often combined with Li

Question 32

Lamotrigine (Lamictal)

Answer 32

a. Anticonvulsant with long-term mood-stabilizing effects; especially effective for prophylactic control of bipolar disorder without risk of inducing mania

Question 33

Drugs to treat OCD

Answer 33

Flouxetine, fluvoxamine and clomipramine

Question 34

panic-phobic disorder treated with

Answer 34

imipramine, fluoxetine or alprazolam

Question 35

Bed wetting treated by

Answer 35

imipramine

Question 36

eating disorders treated by

Answer 36

tricyclics and fluoxetine

Question 37

ADHD treated with

Answer 37

imipramine, desipramine and nortriptyline