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150 Cards in this Set
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What are the Four major diagnostic categories of mood disorders that include a compenent of depression?
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1. Major Depressive Disorder
2. Bipolar Disorder 3. Cyclothymia 4. Dysthymia |
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What is Major Depressive Disorder?
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requires the presence of at least 5 physical and psycholigical symptoms everyday for at least two weeks
including: dysphoria, diminished interest or pleasure in most activities, feelings of worthlessness or guilt, changes in appetite, sleep disturbance, decreased energy, difficulty in concentration, and suicidal ideation or attempt most patients: difficulty with early morning awakening, poor appetite, and 10-20 lbs weight loss a. Atypical depression b. Psychotic depression |
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What is Atypical Depression?
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Type of Major Depressive Disorder
increased sleep, increase appetite, and weight gain; MAOIs more effective than TCAs Tranycypromine and phenelzine use to treat these patients |
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What is Psychotic Depression?
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Type of Major Depressive Disorder
include symptoms such as delusions or hallucinations Most effective treatment is ECT |
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What is Bipolar Disorder?
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more commonly known as manic-depressive disorder, characterized by both manic and depression episodes
Treatment: antidepressant and lithium |
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What is Cyclothymia?
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mild form of bipolar illness, with numberous but less severe manic and depressive epidsodes; mood fluctuations for atleast two years
antidepressants may increase frequency of manic and depressive episodes in these patients Treatment: Lithium |
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What is Dysthymia?
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chronic, mild depressive disorder that persists for at least two years and does not include episodic mood fluctuations
patients rarely benefit from antidepressants Psychotherapy, not drug therapy, is the most appropriate treatment for Dysthymia |
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What is the "Biogenic Amine Hypothesis" of depression?
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there is a deficiency of monoamine neurotranmitters, DA, NE, and 5HT in the CNS
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DA= Pleasure, Drive
Serotonin= Impulsivity Norepinephrine= Vigilance all affect cognitive function, mood, and emotion |
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What is the "Receptor Sensitivity" hypothesis of Depression?
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Beta receptors have been down-regulated (desensitized) by chronic use of TCAs, MAOIs, atypical antidepressants, and ECT
depression is not due to lack of neurotransmitter, but to overstimulation of beta receptors |
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What is parachlorophenylalanine (PCPA)?
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tryptophan hydroxylase inhibitor
INHIBITS 5-HT synthesis |
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What is the Cortisol Theory of Depression?
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there is hypersecretion of cortisol in depression which over time will down regulate cortisol receptors
TCAs, SSRIs, and MAOs have been shown to upregulate these feedback receptors over a period of 2-3 weeks |
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How do SSRIs work?
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Serotonin Selective Reuptake Inhibitors (SSRI's)
inhibit reuptake within hours, but exert full effect after 2-3 weeks SSRI's desensitize both somatodendritic 5-HT-1A autoreceptors and terminal 5-HT-1D autoreceptors Desensitization of autoreceptors then there is an increase in 5-HT release |
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How do MAOI's work?
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Monoamine Oxidase Inhibitors (MAOI's)
Desensitizes: 1. 5HT-1A somatodendritic autoreceptors 2. alpha-2 terminal receptors Does NOT desensitize 5HT-1D terminal receptors |
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How do 5HT-1A Receptor Partial Agonists work?
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Selective 5HT-1A receptor partial agonists desensitize autoreceptors on pre-synaptic neuron, but NOT post-synaptic neurons
Less efficacious than classical antidepressant drugs There is initial suppression of firing of 5HT, but after desensitization of somatodendritic 5HT-1A autoreceptors the 5HT activity returns to normal example: buspirone (Buspar) |
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What is Buspirone?
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Buspirone (Buspar)
5HT-1A Receptor Partial Agonist desensitizes presynaptic 5HT-1A receptors but not postsynaptic 5HT-1A receptors |
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How do TCA's work?
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Tricyclic antidepressant drugs (TCA's)
do NOT modify the function of 5HT-containing neurons Progressively sensitize POSTsynaptic 5HT receptors, especially 5HT-1A receptors of the hippocamus NO effect PREsynaptically In some regions of the brain, post-synaptic responsiveness to NE is enhanced over a period of 2-3 weeks |
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How does ECT work?
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Electroconvulsive Therapy (ECT)
repeated electroconvulsant shocks that induce a progressive sensitization of post-synaptic 5HT-1A receptors Does NOT affect function of 5HT containing neurons including sensitivity of somatodendritic 5HT-1A autoreceptors |
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What is the difference between TCAs with secondary vs tertiary amino groups?
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Secondary- more potent inhibitors of NE reuptake; lower incidence of sedation and orthostatic hypotension
Tertiary- more potent inhibition of 5HT reuptake, more affinity for alpha 1, muscarinic, and histamine receptors. Useful in patients with pyschomotor agitation or severe anxiety |
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What are Indications for TCA's?
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1. Depression
2. Enuresis 3. Panic Attacks 4. Chronic Pain 5. Migrane 6. Hyposis |
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What are CNS effects of TCA's?
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1. Elevation of mood in depressed patients. Also produces sedation, increases anxiety, impaires cognitive and affective processes in normal subjects
2. Sedation 3. Euphoria 4. Anticholinergic (tertiary) |
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Which antidepressants have the most Anticholinergic effects?
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Tertiary amine TCAs:
Amitriptyline Trimipramine imipramine doxepin |
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Which antidepressants have the most sedation?
Least sedation? |
Most Sedation:
amitriptyline trimipramine doxepin trazodone mirtazapine imipramine Least sedation: desipramine protriptyline fluoxetine sertraline buproprion venlafaxine citalopram |
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Which antidepressant has the most Extrapyramidal Syndrome (EPS)?
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Amoxapine
the metabolite can block dopamine receptors |
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Which antidepressants cause the most Agitation?
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protriptyline
fluoxetine buproprion |
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Which antidepressant can cause anxiety, nervousness, nausea, headache, and insomnia?
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Most common with Fluoxetine
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Which antidepressants are most likely to cause Seizures?
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"BAM-C"
Buproprion Amoxapine Maprotiline Clomipramine |
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Which antidepressants are most likely and least likely to have orthostatic hypotension?
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Most likely:
imipramine trazodone Least likely: bupropion nortiptyline |
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Which antidepressant is most likely to induce a resting tremor?
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Amitriptyline
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Which antidepressant is most associated with Priapism?
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Trazadone
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What receptor contributes to weight gain?
Which antidepressants are associated with weight gain? |
weight gain can be due to increased appetite, decreased physical activity due to sedative effects of drugs
Blockade of hypothalamic 5HT-2C receptor contributes to weight gain Mirtazapine Nefazodone |
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Which antidepressant classes should not be used in combination due to possibility of "serotonin syndrome"?
which shouldn't be combined because chance of hypertensive crisis? |
Serotonin Syndrome:
MAOI's and SSRI's Hypertensive crisis: TCA's and MAOI's (should have 2 week washout period before new drug is initiated) |
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Which antidepressants may produce less weight gain?
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SSRI's and SNRI's
increased 5HT in synaptic cleft stimulates 5HT-2C receptors which mediate appetite suppression |
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What are the effects of 5HT-2A receptor blockade?
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antidepressant action
increased REM sleep antianxiety effect anti-extrapyramidal symptoms |
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What are the effects of blockade of 5HT uptake pump?
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antidepressant
nausea loose stools insomnia anorgasmia |
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What are the effects of blockade of alpha 2 adrenergic receptors?
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antidepressant action
arousal increased libido |
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What are the effects of blockade of 5HT-2C receptor?
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increased appetite
decreased motor restlessness |
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What are the effects of blockade of 5HT-3 receptor?
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anti-emetic
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What happens with an acute overdose of TCA?
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Triad: "3 Cs"
convulsions cardiotoxicity coma give Diazepam for seizures sodium bicarbonate bolus for Quinidine-like cardiotoxicity (increases extracellular Na+ to counter Na+ channel blockade) |
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Name the Tertiary TCA's
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Imipramine (Tofranil)
Amitriptyline (Elvail) Doxepin (Sinequan) Trimipramine (Surmontil) Clomipramine (Anafranil) Tertiary Amines: considerable orthostatic hypotension, sedation, and anticholinergic effects |
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Name the Secondary TCA's
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Desipramine (Norprin)
Nortriptyline (Pamelor) Protriptyline (Vivactil) Secondary Amines: less anticholinergic effects and orthostatic hypotension than tertiary; tend to be activating NOT sedating |
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What happens with overdose of TCA?
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1. slow cardiac conduction (Quinidine life effect)
2. lowered seizure threshold- seizures common in overdose |
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Name the SSRI's
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Fluoxetine (Prozac)
Sertraline (Zoloft) Paroxetine (Paxil) Citalopram (Celexa) Escitalopram (Lexapro) Fluvoxamine (Luvox) SSRI's: minimal antichloinergic effects, little or no orthostatic hypotension, may tend to be activating, not sedating, no significant effect on cardiac conduction, lowered seizure threshold, much safer in overdose than TCA's |
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Name the SNRI's
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Venlafaxine (Effexor)
Duloxetine (Cymbalta) Nefazodone SNRI's: slight ability to block the reuptake of NE and greater effect on blocking reuptake of serotonin |
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What are signs of "Serotonin Syndrome"?
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hyperthermia
rigidity myoclonus autonomic instability with rapid fluctuation of vital signs mental status change ranging from extreme agitation to delirium and coma |
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Describe Amitripyline
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Amitriptyline (Elavil)
Tertiary TCA most potent anticholinergic effects highly sedating significant orthostatic hypotension most cardio toxic TCA metabolized to nortriptyline |
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Describe Doxepin
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Doxepin (Sinequan)
Tertiary TCA most potent histamine receptor blocker; therefore, highly sedating high incidence of othrostatic hypotension |
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Describe Imipramine
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Imipramine (Tofranil)
Tertiary TCA less anticholinergic effects than other tertiary TCAs greatest incidence of orthostatic hypotension amonst TCAs |
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Describe Trimipramine
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Trimipramine (Surmontil)
Tertiary TCA significant anticholinergic effects, sedating, and high incidence of orthostatic hypotension |
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1. Name the most anticholinergic tertiary TCA
2. Name the most potent histamine receptor blocker of the tertiary TCA 3. Name the tertiary TCA with the greatest incidence of orthostatic hypotension |
1. anticholinergic: Amitriptyline
2. H1 blocker: Doxepin 3. orthostatic hypotension: Imipramine |
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Describe Nortriptyline
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Nortriptyline (Pamelor)
Secondary Amine TCA metabolite of amitriptyline narrow therapeutic window less orthostatic hypotension (amongst TCAs) low incidence of sedation |
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Describe Desipramine
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Desipramine (Norpramin)
Secondary amine TCA metabolite of Imipramine least amount of anticholinergic effects amongst TCAs low incidence of sedation and orthostatic hypotension |
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Describe Protriptyline
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Protriptyline (Vivactil)
Secondary Amine TCA "activating" antidepressant may cause agitation and motor restlessness low incidence of orthostatic hypotension sometimes used in the treatment of sleep apnea |
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Name the Miscellaneous Second Generation Antidepressants
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Maprotiline (Ludiomil)
Amoxapine (Asendin) Trazodone (Desyrel) Bupropion (Wellbutrin) Mirtazapine (Remeron) Miscellaneous second generation antidepressant= less anticholinergic effects |
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Describe Maprotiline
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Maprotiline (Ludiomil)
Miscellaneous second generation antidepressant selective NE reuptake inhibitor significant antihistamine activity (Sedating) high incidence of seizures |
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Describe Amoxapine
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Amoxapine (Asendin)
Miscellaneous second generation antidepressant antidepressant most likely to produce EPS (related to loxapine) somewhat higher incidence of seizures NE and 5HT reuptake blocker |
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Describe Trazodone
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Trazodone (Desyrel)
Miscellaneous second generation antidepressant very weak but selective serotonin reuptake inhibitor major metabolite is m-CPP which is an antagonist at 5HT-2A receptors and partial agonist at 5-HT-2C receptors potent blocker of alpha 1= orthostatic hypotension H1 blocking activity= significant sedation alpha 2 blocking due to metabolite= Priapism used to counteract insomnia from SSRIs (take buproprion at night for this use) |
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Describe Bupropion
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Buproprion (Wellbutrin)
Miscellaneous second generation antidepressant weak, but selective dopamine reuptake blocker also potent NE reuptake inhibitor increases synaptic levels of both NE and dopamine Side Effects: Agitation, nausea, and dry mouth High incidence of seizures (Max daily dose 450mg) Wellbutrin SR- BID Wellbutrin XR- QD Lower incidence of sexual dysfunction than with SSRA or TCA Contraindication with MAOI |
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Describe Mirtazapine
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Mirtazapine (Remeron)
Miscellaneous second generation antidepressant alpha 2 adrenergic auto and hetero receptor ANTAGONIST blocking alpha 2 autoreceptor= increase release of NE blocking alpha 2 heteroceptor= increase 5HT release antagonist at 5HT-2 and 5HT-3 receptors= anxiolytic and sleep improval potent H1 blocker= sedation Side Effects: increased appetite (5-HT-2C and H1 blockade), weight gain, dizziness, dry mouth, and constipation |
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Describe Fluoxetine
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Fluoxetine (Prozac)
Serotonin Selective Reuptake inhibitor (SSRI) No affinity for cholinergic, histamine, or alpha 1 receptors "activating" antidepressant Active metabolite= Norfluoxetine (5 weeks to reach steady state) "Serotonin syndrome"= SSRI should not be combined with MAOI (wait 5 weeks) Sexual dysfunction Inhibits CYP2D6 |
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Describe Sertraline
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Sertraline (Zoloft)
Serotonin Selective Reuptake inhibitor (SSRI) "activating" antidepressant Metabolite= desmethylsertraline Less inhibition of cyt P 450 and only requires 2 week washout when switching to MAOI compared to fluoxetine |
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Describe Paroxetine
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Paroxetine (Paxil)
Serotonin Selective Reuptake inhibitor (SSRI) Most Potent 5HT reuptake inhibitor may be more sedating no active metabolites Potent 2D6 inhibitor * DOES exhibit mild anticholinergic activity |
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Describe Citalopram
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Citalopram (Celexa)
Serotonin Selective Reuptake inhibitor (SSRI) less ability to inhibit cyt P450 therefore less drug interactions less side effects and less agitation compred to other SSRIs PROLONGATION OF QT INTERVAL and SEIZURES |
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Describe Escitalopram
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Escitalopram (Lexapro)
Serotonin Selective Reuptake inhibitor (SSRI) Pure S-enantiomer of citalopram MOST POTENT of SSRI's currently available less likely to cause agitation compared ti other SSRIs |
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Describe Fluvoxamine
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Fluvoxamine (Luvox)
Serotonin Selective Reuptake inhibitor (SSRI) also used for obsessive compulsive dissorder (OCD) |
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Describe Venlafaxine
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Venlafaxine (Effexor)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) blocks reuptake of both 5-HT and NE, but 50 times more potent at blocking 5-HT reuptake little or no blockade of muscarinic, histamine, or alpha adrenergic receptors produces severe withdrawal syndrome if withdrawn too quickly; dose must be tapered off |
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Describe Duloxetine
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Duloxetine (Cymbalta)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) chemically related to venlafaxine but has equal ability in blocking 5-HT and NE marketed to relieve EMOTIONAL AND PAINFUL physical symptoms of depression |
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Describe Nefazodone
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Nefazodone (generic only)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) chemically related to Trazodone blocks reuptake of 5HT and NE, but more so effects due to blockade of 5HT-2 receptors also blocks alpha 1 receptors, but orthostatic hypotension has low incidence LIVER TOXICITY Side effects: weight gain and low sexual dysfunction potent blocker of P-450 CYP3A4 so contraindicated if taking cisapride or theophyline has anxiolytic profile due to blockade of 5HT2 receptors BLACK BOX WARNING: hepatic failure |
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Which antidpressants inhibit CYP 2D6
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Fluoxetine
Paroxetine Bupropion |
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MAO-A vs MAO-B
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MAO-A= specific for serotonin and NE
MAO-B= metabolizes dopamine and phenyethylamine both catalyze the deamination of primary amines and some secondary amines FAD is a required cofactor |
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Name the 3 major structural classes of MAOI's
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1. Hydrazines (R-NH-NH-R)
2. Propargylamine (C=-C) 3. Cyclopropylamines Side effects: ORTHOSTATIC HYPOTENSION |
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Name the Hydrazines
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1. phenelzine (Nardil)
2. Isocarboxazid (Marplan) Hepatotoxic |
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Name the Cyclopropylamines
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1. Tranylcypromine (Parnate)
causes the most agitation |
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Name the Propargylamines
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1. Pargyline (Eutonyl)
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What is the major incompatibility with MAOI's?
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"cheese" effect= hypertensive crisis
any food containing tyramine: aged cheese, wine, beer, pickled herring, chicken livers, etc. sympathomimetic agents (OTC cold remedies) they are contraindicated when using MAO-A inhibitors; MAO-B inhibits do NOT exhibit the cheese effect MAOI+tyramine= increase in NE= vasoconstriction= hypertensive crisis= stroke |
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the overwhelming preoccupation with the compulsive use of a drug
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addiction
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physiological adaptation to the chronic admininstration of a substance resulting in a withdrawal or abstinence syndrome
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Dependence
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Decreased response to the same drug following repeated dosing; after chronic dosing, a higher dose is required to produce the same effect as originally produced
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Tolerance
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Chronic dosing with one drug results in tolerance to another drug
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Cross Tolerance
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Which antianxiety drug is not cross tolerant
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Buspirone (Buspar)
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Which antianxiety drugs are cross tolerant?
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Barbiturates
Benzodiazepines Meprobamate Ethanol Chloral Hydrate |
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What part of brain is in charge of...
Anxiety Alertness Rage Panic |
Anxiety- Amygdala
Locus coeruleus- alertness hypothalamus- rage Periqueductal grey- panic |
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Name the prototypic Benzodiazepines
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1. Chlordiazepoxide (Librium)
2. Diazepam (Valium) |
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How do Benzodiazepines work?
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They allosterically increase affinity of GABA for its sites (potentiates inhibitory GABA-ergic neurotransmission at all levels of neuroaxis)
depresses the descending reticular tracts that maintain muscle tone, then their muscle relaxant effects Increases threshold for convulsions, thus used as anticonvulsants |
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Name Side Effects of Benzodiazepines
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drowsiness and ataxia
worsening of depression paradoxical excitement, disorientation, confusion, and aggresion memory impairment slight REM sleep impairment addiction and dependence psychological dependence birth defects respiratory depressant euphoria, headache, skin rash NO big drug interactions |
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What drug can be used to reverse the CNS depressant effects of benzodiazepine overdose?
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Flumazenil (Mazicon)
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Describe Buspirone
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Buspirone (buspar)
Anxiolytic does NOT posses hypnotic, muscle relaxant, or anticonvulsant properties increases firing of locus coeruleus which increases NE metabolism anxiolytic effects worsen at first, but help after 10th day of treatment Buspirone binds to D2 (blockade) and 5HT-1A receptors (agonist) presynaptic 5HT-1A= full agonist postsynaptic 5HT-1A= partial agonist is NOT cross tolerant can be used with alcohol since its effects are not additive with those of ethanol |
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What are some Miscellaneous Agents used for Anxiety
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1. Beta Blocking Agents- good for examinations, stage fright, fear of public speaking, etc
2. Clonidine- decreases the firing of the locus coeruleus (LC) neurons and the release of NE by activation of alpha 2 adrenergic receptors |
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What are some Classical Agents used to treat Anxiety
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1. Meprobamate (Miltown)
2. Tybamate (Tybatran) these agents have been replaced by benzodiazopines and buspirone due to safety profile they can suppress REM sleep , can cause addiction, tolerance, and dependence |
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What is Meprobamate?
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Meprobamate (Miltown)
Classical Agent used for Anxiety replaced by benzodiazopines |
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What is Tybamate?
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Tybamate (Tybatran)
Classical Agent used for Anxiety replaced by benzodiazopines |
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Name Agents used in the Treatment of Obsessive Compulsive Disorder (OCD)
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1. Clomipramine (Anafranil)
2. Fluvoxamine (Luvox) |
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Describe Clomipramine
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Clomipramine (Anafranil)
Treats OCD and panic disorder tricyclic antidepressant with same structure as imipramine with addition of a chloride moiety give in divided doses or at bedtime with food highly protein bound active metabolite: desmthylclomipramine onset of action: 1-6 weeks action due to selective blockade of 5HT reuptake Sides Effects: higher incidence of seizures, sexual dysfunciton, othrostatic hypotension, confusion, convulsions some women reach orgasm everytime they yawn Drug interactions: MAOI's Sympathomimetics Alcohol Other CNS depressants |
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Describe Fluvoxamine
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Fluvoxamine (Luvox)
treatment of obsessive compuslive disorder low protein binding inhibits the 5HT transporter side effects: nausea, insomnia, nervousness, sexual dysfunction just as efficacious as clomipramine inhibits cyt P450 therefore be careful with theophylline, warfarin, diazepam, alprazolam, astemizole, terfenidine, lithium, tryptophan, and clozapine needs 14 day washout of MAOI's before starting SSRI |
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Which benzodiazepines are best to use with liver damage?
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1. Lorazepam
2. Oxazepam 3. Temazepam these agents already have -OH group and can go straight to conjugation doesnt require liver to do as much work |
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Name the agents that only bind to GABA A receptor isoforms that contain alpha 1
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1. Zolpidem
2. Zaleplon 3. Eszopiclone AKA BDZ-1 subunit these three agents do not pass anxiolytic, muscle relaxant, or anticonvulsant properties as the benzodiazepines do, rather they are selective HYPNOTICS |
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What blocks the actions of GABAa receptor
binding of GABA opens the Cl Channel which results in membrane hyperpolarization |
Bicuculline
blocks actions of GABA |
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What agent blocks the actions of Benzodiazepines
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Flumazenil (Romazicon)
this agent competes with benzodiazepines for the BDZ binding site on the Chloride Ioniphore Complex which prevents benzos from being able to increase the frequency of the channel openings |
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How does Benzodiazepines affect the Chloride Ionophore Complex
How does Barbituates affect the Chloride Ionophore Complex |
Benzodiazepines- allostericaly increase the affinity of GABA for its binding site which facilitates the process of chloride channel opening; increases FREQUENCY
Barbituates- binds to different site on chloride ionophore complex but also allosterically increases affinity of GABA for its site; they also increase affinity of benzos to their site; they increase the DURATION of the chloride channel opening produced by GABA Barbituates are not as safe becuase they can produce Cl conductances alone (without dependence of GABA) |
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What agent blocks the actions of Barbiturates
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Picrotoxinin
Holds Cl channel in closed state or prevents it from opening |
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Describe
1. benzo receptor agonist 2. benzo receptor inverse agnoist 3. benzo receptor antagonist |
1. agonist- minic action of benzo
2. inverse- opposite effect as benzo; decrease affinity of GABA to site 3. antagonist- blocks action of both agonist and inverse agonists |
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Describe Flumazenil
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Flumazenil (Mazicon)
antagonist at BDZ binding sites; blocks both effects of receptor agonists and inverse agonists, but NOT the effects of classical sedative hypnotics used to reverse CNS depressant effects of BZD overdose not very effective in reversing respiratory depression associated with BZD overdose patients with combined BZD and TCA overdose when treated with flumazenil may develop seizures and cardiac arrhythmias |
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What directly blocks the open state of Cl channel
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Pentylenetetrazole
and Picrotoxin |
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What are the Benzodiazepines that already are hydroxylated in the 3-position and undergo direct conjugation?
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1. Lorazepam (Ativan)
2. Oxazepam (Serax) 3. Temazepam (Restoril) drugs of choice for liver failure patients |
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What is required for metabolism of Benzodiazepines?
What is required for metabolsim of Triazolobenzodiazepines? |
1. N-dealkylation
2. 3-hydroxylation 3. Conjugation 1. alpha hydroxylation 2. Conjugation |
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Give Examples of Triazolobenzodiazepines
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1. Alprazolam (Xanax)
2. Triazolam (Halcion) 3. Midazolam (Versed) 4. Estazolam (Prosom) |
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What does chlordiazepoxide, diazepam, prazepam, and clorazepate turn into after N-dealkylation (slow) and then after 3-hydroxylation?
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Desmethyldiazepam
then hydroxylated to Oxazepam then ready for conjugation |
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Name the Benzodiazepines with Shorter Duration of Action
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LOTTZZZAE
Lorazepam Oxazepam Temazepam Triazelam Zolpidem Zalepon Eszopiclone Alprazolam Estazolam |
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Which Benzodiazepines have SLOW onset of action?
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POT
Prazepam Oxazepam Temazepam |
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What is the mechanism of action for barbituates?
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allosteric agonists by binding to the barbituate side on teh chloride ionophore complex thus potentiating GABA induced chloride ion conductance
increases DURATION of channel opening at high doses can produce chloride ion conductances alone enhances binding of GABA and benzodiazepines to their receptors antagonized by Picrotoxinin also depresses neurotransmission and inhibits spinal reflex |
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What are non-specific actions of barbituates?
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barbiturates depress oxygen consumption and metabolic activity
barbituates depress synaptic activity; stabilization of post synaptic membrane and reduction in the amount of neurotransmitter released by decreasing calcium influx into presynaptic terminal |
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What are side effects of Barbiturates
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1. Respiratory Depression
-Neurogenic Drive (ventilation during conciousness) -Chemical Drive (ventilation during sleep) -Hypoxic drive (sensitive to arterial oxygen tension) 2. at toxic doses they inhibit myocardial contractility and cause cardiac collapse 3. increases incidence of night mares and lacks the well rested felling upon awakening- "barbiturate hangover" 4. Withdrawal symptoms- disturbed sleep patterns, hyperexcitability, agitation, confusion, hallucinations, convulsions 5. paradoxical hyperactivity 6. cross tolerance and dependence 7. barbiturate induced porphyria 8. high abuse potential 9. drug interactions 10. POTENT INDUCER OF CYT P450 |
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What are the 4 main uses of Barbiturates?
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1. Anxiolysis/ Sedation (intermediate or long acting)
2. Hypnosis (short acting) 3. Anesthesia (ultra short acting) 4. Anticonvulsive action |
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Which barbituates have selective anticonvulsant actions?
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Phenobarbital
Mephobarbital Metharbital |
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Describe the different stages of sleep
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Stage 0- awake (beta)
Stage 1- dozing; transition between wakefulness and sleep (alpha) Stage 2- Unequivocal sleep; light sleep (low voltage and spindles) Stage 3- Deep sleep (theta waves) Stage 4- Cerebral sleep; night terrors and somnambulism (delta waves) REM- Dreams; rapid eye movements; muscle twitching and oxygen consumption (beta waves) |
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What stages of sleep do you need to reduce for Bed wetting
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Reduce stages 3 and 4
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What stages of sleep do you need to decrease in patients with night terrors?
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reduce stages 3 and 4
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Which hypnotics can cause REM rebound upon weithdrawal
Which do not cause REM rebound? |
Pentobarbital
Glutethimide Methyprylon Triazolam (1 mg) NO REM rebound: Chloral Hydrate Flurazepam Temazepam Triazolam (0.5mg) |
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What is different about Elderly sleeping patterns?
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They seldom descend into Stage 4 (delta/slow wave)
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All hypnotics lose effectiveness within 1-2 weeks except which ones
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except:
benzodiazepines benzodiazepine receptor agonists |
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Name the OTC hypnotics
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H1 histamine receptor antagonists:
Diphenhydramine (Sominex, Sleep-Eze, Sleepinal, Benadyl, Befferin AF at night) Doxylamine (Unisom) Promethazine (Phenergan) all are lipid soluble amines Alocohol and other CNS depressants potentiate effects |
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Describe Chloral Hydrate
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Chloral Hydrate (Noctec, Aquahchloral, Supprettes)
low cost hypnosis less paradoxical excitement; reduced to trichloroethanol (active substance) within minutes; if oxidized to trichloroacetic acid it is toxic decreases sleep latency and awakenings; REM unchanged; effects disappear after two weeks; don;t affect respiratory and blood pressure Side effects: Toxic doses produce respiratory depression and GI side effects if not diluted enough TAKE WITH LARGE AMOUNT OF WATER contraindicated with liver and/or renal impairment dependence and tolerance may develop Michey Finn Effect if given with alcohol; ethanol and chloral hydrate are metabolized by alcohol dehydrogenase; reduction of chloral hydrate to tricloroethanel is accelerated |
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What are the most common barbituates used as hypnotics
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Amorbital (Amytal)
Pentobarbital (Nembutal) Secobarbital (Seconal) |
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Describe the use of barbituates as hypnotics
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decreases waking and movement; stages 3 and 4 are shortened. REM sleep is diminished; effects are mainly first 1/3 of the night; tolernance to sleep effects within a few weeks
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Name the long acting benzodiazepines used as hypnotics
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1. Flurazepam (Dalmane)
2. Quazepam (Doral) more daytime sedation and falls in the elderly; fewer early morning wake-ups and less daytime anxiety |
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Name the Intermediate-acting benzodiazepines used as hypnotics
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Estazolam (ProSom)
and Temazepam (Restoril) |
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Name the Short acting benzodiazepines used as hypnotics
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Triazolam (Halcion)
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Describe Flurazepam
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Flurazepam (Dalmane)
Long Acting benzodiazepine used as hypnotic Hydroxylated to N-hydroxyflurazepam (short) then to N-desalkyflurazepm (long) Elimination slow due to metabolites (24-100 hrs) |
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Describe Quazepam
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Quazepam (Doral)
Long acting benzodiazepine used as hypnotic two active metabolites: 2-oxoquazepam N-desalkylfurazepam (same as flurazepam) Half life > 10 hrs Elimination is slow |
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Describe Lorazepam
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Lorazepam (Ativan)
Intermediate acting benzodiazepine used as hypnotic no active metabolite; first choice for elderly and liver damage patients Elimination over 10-18 hrs |
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Describe Estazolam
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Estazolam (ProSom)
Intermediate-acting benzodiazepine used as hypnotic peak plasma levels in 1.5 hrs eliminated in urine half life is 10-24 hrs |
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Describe Temazepam
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Temazepam (Restoril)
Intermediate-acting benzodiazepine used as hypnotic slow onset of action; directly undergoes glucuronidation (no active metabolites) with short to intermediate half life TAKE 1 HR BEFORE WANTING TO SLEEP |
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Describe Triazolam
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Triazolam (Halcion)
Short acting benzodiazepine used as hypnotic Half life= .5-4 hours Elimination is rapid rage and hostility reactions may occur |
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Name the Non-Benzodiazepine Hypnotics that act at Benzodiazepine Receptors
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1. Zolpidem
2. Zalepon 3. Eszopiclone Benzodiazepines alter sleep stages but the 3 Zs do NOT significantly change the sleep stages |
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Describe Zolpidem
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Zolpidem (Ambien)
Non-benzodiazepine Hypnotic that Acts at Benzodiazepine Receptors indicated for short term treatment of insomnia (7-10 days) rapid onset of action; food intake can delay the time to peak plasma levels half life= 2.5 hrs binds selectively to BZD-1 site on the GABA-A receptor no anticonvulsant, muscle relazation, nor anxiolytic activity decreases sleep latency Drug interaction: Alcohol and CNS depressants as well as TCA |
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What drug reverses an overdose of the Non-benzodiazepine Hypnotics that Acts at Benzodiazepine Receptors?
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Flumenazil
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Describe Zaleplon
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Zaleplon (Sonata)
Non-benzodiazepine Hypnotic that Acts at Benzodiazepine Receptors selectively binds BDZ1 receptor LESS memory impairment Half life= 1 hr least likely to cause next-day effects good for sleep latency |
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Describe Eszopiclone
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Eszoplicone (Lunesta)
Non-benzodiazepine Hypnotic that Acts at Benzodiazepine Receptors treatment of insomnia for at least 6 months, with no evidence of tolerance, dependence, or abuse mild, transient memory impairment; headaches, next-day somnolence and dizziness |
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Can you use Zolpidem with SSRIs?
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Zolpidem + SSRIs= hallucinations
SSRIs should use Trazodone for sleep |
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Compare the half life of the three Zs
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Zaleplon= 1 hr
Zolpidem= 2.5 hrs Eszopiclone= 6 hrs |
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Which agents acting at the Benzodiazepine Receptors are most likely to affect memory?
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Triazolam (Halcion)
and Lorazepam (Ativan) more apt to cause anterograde amnesia after a single dose |
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Name the Melatonin Agonist
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Ramelteon (Rozerem)
selective and potent MT1 and MT2 receptor agonist MT1= attenuates an alerting signal MT2= maintains the circadian rhythm MT1 and MT2 receptors are in the suprachiasmatic nucleus (SCN) of the hypothalamus |
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Describe Ramelteon
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Ramelteon (Rozerem)
Melatonin Agonist at MT1 and MT2 rapidly absorbed under fasting conditions; take this medication while FASTING and withing 30 MINUTES of sleep time highly bound to plasma protein metabolized by CYP1A2; does not induced or inhibit CYP450 Drug interactions: fluvoxamine niacin mexelitine norfloxacin ziluton barbiturates rifampin carbamazepine smoking don'ts use with CYP1A2 inhibitors ZERO evidence of abuse, dependence, tolerance, CNS depression, hangover effects indicated for difficulty with sleep onset |
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What are the Miscellaneous Older Hypnotic Agents
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Most likely will never see these:
Ethchlorvynol (Placydil) Glutethimide (Doriden, Doriglute) Methyprylon (Noludar) Ethinamate (Valmid) all suppress REM and have REM rebound |
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What are drugs used for Treatment of Narcolepsy?
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Narcolepsy: excessive sleep especially early onset REM
Methylphenidate Pemoline d-amphetamine TCA and MAO inhibitors can also be used |
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How do Benzodiazepines affect the sleep cycles and REM?
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they prolong the first two stages of sleep and suppress stages 3, 4, and REM
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Which drugs have been used effectively dosed at bedtime to relieve insomnia in depressed and non-depressed patients, including patients on SSRI or buproprion
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Trazodone (Desyrel)
Nefazodone (Serzone) Mirtazapine (Remeron) |
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Stages of Sleep and their Waves
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Alert Wakefulness (Beta waves)
Quiet Wakefulness (Alpha waves) Stage 1 (low voltage and spindles) Stages 2 and 3 (theta waves) Stage 4 (delta waves) REM (beta waves) 50% of sleep is in Stage 2 |
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Nightmare
vs Night Terror |
Nightmare= REM sleep (remember)
Night terrors= Stage 4 (don't remember) |
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What is the dominate chemical in:
Delta sleep REM |
Delta sleep= 5-HT
REM= Ach |
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Which stages of sleep are best for Psychological recovery and which for Physical recovery
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Psychological Recovery= REM (beta waves)
Physical Recovery= Stage 4 (Delta) |
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