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44 Cards in this Set

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AMINE HYPOTHESIS OF AFFECTIVE DISORDERS
DEPRESSION results from a deficiency of brain monoamines, i.e. norepinephrine and perhaps serotonin, leading to decreased neuronal activity.
MANIA results from an excess of brain monoamines
Indirect Evidence for amine hypothesis of affective disorder
Effective treatments for depresion increase concentration of NE/5HT in CNS.

Effective treatments for mania (Lithium) decreases synthesis of brain amines.

Drugs that deplete brain amines (Reserpine) cause depression.
Problems w/ amine hypothesis
time course delay- biochemical changes happen immediately, therapeutic results take weeks.

Amphetimines & cocaine act on brain amines but do not treat depression they cause euphoria.
Modification of Amine hypothesis
Sustained use of ADs results in downregulation of presynaptic 5HT autoreceptors. In addition postsynaptic 5HT receptors become sensitized. This time course parallels clinical effect.
Tricyclic ADs
TERTIARY AMINES
imipramine (Tofranil )amitriptyline (Elavil)

SECONDARY AMINES
desipramine (Norpramin)
nortriptyline (Aventyl; Pamelor)
Selective Serotonin Reuptake Inhibitors (SSRIs)
fluoxetine (Prozac)
sertraline (Zoloft)
paroxetine (Paxil)
Atypical (Second & Third-generation) Antidepressants: Heterocyclics
amoxapine (Asendin)
trazodone (Desyrel)
buproprion (Wellbutrin)
venlafaxine (Effexor)mirtazapine (Remeron)
Monoamine Oxidase Inhibitors(MAOIs):
phenelzine (Nardil)
Lithium & other Mood-Stabilizing Drugs:
lithium carbonate (Eskalith)
valproic acid (Depakene)
carbamazepine (Tegretol)
MOA of TCAs
big and bulky similar MOA to phenothiazines re: blockage of α1, H1, & muscarinic.

Block reuptake of NE & 5HT. Result in downregulation of presynaptic receptors and supersensitization of postsynaptic receptors.
TCAs: Results of blockage of α1, H1, & muscarinic.
Sedation (H1)

Dry mouth, blurred vision, urinary retension, constipation, tachacardia (m)

Orthostatic HT,cardiac arrythmias (α1)
Pharmacokinetics of TCAs:
lipid soluble. Well absorbed orally. Tertiary amines are metabolized into active metabolites. 1/2 life can be 24 hrs or more in elderly patients.
Clinical uses of TCAs
1)depression (replaced by SSRIs)
2)enuresis (esp. imipramine)
3) OCD (SSRIs)
4)Panic disorder (BZDs & SSRIs
5)ADHD (imipramine)
6)Chronic pain
Side Effects of TCAs
extension of unwanted receptor blockages.

Sedation (H1)
Confusion & anticholinergic effects(m)
Orthostatic HT & arrythmias(α 1)
Siezures
Seratonin syndrome (watch out for pts on MAOIs
Contraindications and Cautions of TCAs
-hypersensitivity
-cardiac diseases
-Liver impairment
-Narrow-angle glaucoma; urinary retention
History of seizure disorders
Pregnancy, children, elderly
Limit quantities/amount prescribed
Which TCA is most sedating?
Amitryptiline
Which TCA is used for Enuresis & ADHD?
imipramine
Fluoxitine MOA
A selective inhibitor of 5-HT reuptake in the CNS
PK of Fluoxitine
Orally active. Metabolized to long acting metabolite. Long elimination half life.
Metabolized by Liver.
Clinical Uses of Fluoxitine
Depression
Obsessive-compulsive disorder (OCD)
Bulimia
Bipolar depression:fluoxetine + olanzapine (Symbyax)
UNLABELLED Uses of Fluoxitine
Alcoholism; ADHD, PMS, migraine & tension headache, Anorexia nervosa
Adverse reactions of SSRIs
Nausea, nervousness, agitation, insomnia, headache.
Decreased libido.

INCREASED SUICIDAL TENDENCIES, EXTREME ANXIETY, VIOLENT BEHAVIOR– have been reported.—esp. in children and adolescents: MANIC OVERSHOOT

*Prefered to TCAs because less side effects
Drug interactions of Fluoxetine (Prozac) and paroxetine (Paxil)
can block metabolism of tricyclic antidepressants, benzodiazepines, carbamazepine

DO NOT give with MAO inhibitors–“Serotonin Syndrome”

SUMATRIPTAN (IMITREX)
Atypical AD: amoxapine (Asendin)
metabolite of antipsychotic so retains some dopamine antagonism and antipsychotic activity. Used for depression in psychotic patients. Can cause EPS side effects.
Atypical AD: trazodone (Desyrel)
5HT agonist. Also blocks 5HT uptake. Causes marked sedation. Used for Depression with anxiety & insomnia.
Atypical AD: Bupropion (Wellbutrin)
weak effect on NE & 5HT uptake. Also inhibits dopamine reuptake.

Used for smoking cessation.

Can cause, CNS exitation, anxiety, & irritability. Risk of siezures.
Atypical AD: venlafaxine (Effexor)
Inhibits both NE and 5-HT uptake equally.

intense withdrawal symptoms can occur.

used in chronic pain
Atypical AD: mirtazapine (Remeron)
Antihistamine with strong sedating effects. also blocks 5-HT2 ,α1 and muscarinic R. Blocks presynaptic α2–R to ↑ release of NE & 5-HT.

Causes sedation, weight gain, agranulocytosis--REVERSIBLE
MAOI: phenelzine (Nardil)
Produce irreversible inhibition of MAO and ↑ biogenic amines in brain and periphery. It takes 1-2 weeks to restore MAO activity.

MAO inhibitors provide nonselective inhibition. They inhibit both MAO-A (NE, 5-HT and tyramine metabolism) & MAO-B (DA metabolism).
Cautions with MAOIs
WAIT 2 wks before changing from a MAOI to a TCA or SSRI, or an OTC decongestant.
Clinical use of MAOIs
- refractory or atypical depressions

-panic disorders or phobias (BZs or SSRIs used more commonly)
Adverse reactions MAOIs
stimulation, euphoria, restlessness
Overdose toxicity of MAOIs
Agitation, delirium, hallucination, convulsion
Coma, shock, hyperthermia
Supportive and symptomatic treatment
Drug Interactions or food-drug interactions with MAOIs
Sympathomimetic amines (e.g., OTC decongestant; EPHEDRINE)

SSRIs, tricyclic antidepressants– “Serotonin Syndrome”

Food/beverages rich in tyramine: aged cheese, beer, certain wines, herring--Severe Hypertensive Crisis may occur
MOA of Lithium in manic patients
prevents the recycling of second messangers (IP3 & DAG)
Pharmacokinetics of Li+
rate of Na+ intake is equal to rate of Li+ excretion

Na+ depletion, Li+ rise.

Therefore Li+ levels depend on renal fx & Na+ levels
Clinical Uses of Li+
DOC for treatment of acute mania and bipolar disorder (effective in 60-70% of pts) May require concurrent use of TCAs, antipsychotics, or BZs.
Drug has a slow onset of action.
Cautions of Li+
Drug has many side effects and a low therapeutic index.
Side effects of Li+
Tremor (treat w/ propanolol)
Involuntary movements, motor hyperactivity,ataxia, dysarthria, aphasia, mental confusion
Nephrogenic diabetes insipidus with polydipsia and polyuria
Edema
Depression of SA node. ECG changes.
NVD, leukocytosis, acne.
Thyroid problems (TSH every 6 mo)
Overdose toxicity of Li+
NV, involuntary movements, confusion, stupor, seizures, coma, death.
Treatment: Discontinue drug; gastric lavage, moniter fluid and electrolytes; hemodialysis

Teratogenic: CV and other birth defects have been reported; LOW RISK
Lithium precautions
Avoid marked dehydration or sodium depletion
CAUTION in Renal and cardiac disease
Moniter serum concentration
Elderly
Pregnancy
Lithium Drug Interactions
Diuretics and NSAIDs: ↑ lithium toxicity by reducing excretion BY 25%

Sodium salts: ↑ renal excretion of lithium

Antipsychotics
Carbamazepine (Tegretol)
sxlly similar to TCAs

alternative to Li+

MOA: Inhibits voltage-sensitive sodium channels ↓ SENSITIZATION of brain to mood swings

also used for Trigeminal neuralgia & Glossopharyngeal neuralgia
Valproic acid (Depakene)
Alternative to Li+

Possible bipolar MOA: ↑ GABA

Nausea is limiting factor