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115 Cards in this Set
- Front
- Back
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What is depression and what disorders are associated with it?
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Major depression and dysthymia
(minor) are purely depressive, whereas bipolar disorder and cyclothymic disorder signify depression in association with mania. |
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Why is reserpine important to the hx of antidepressants?
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Reserpine (HTN) was found to precipitate depression by depleting dopamine, serotonin and norepinephrine in the brain
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Why is iproniazid important to the hx of antidepressants?
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Iproniazid (TB) eased depression in
chronically ill TB patients by inhibiting monoamine oxidase (MAO). |
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So, what does that tell us?
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Monoamine depletion leads to depression and
monoamine preservation leads to mood elevation. |
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What is the monoamine hypothesis?
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“Depression may be due to lowered
actual or functional monoamine neurotransmitter at brain synapses and treatment of depression may be achieved by restoring the monoamine levels or actions to normality.” |
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Which monoamines are we talking about?
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NE and 5HT
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What are 2 drug classes that strengthen MA hypothesis?
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TCAs block monoamine (NE, 5HT)
reuptake pumps permitting a longer sojourn of neurotransmitter at the receptor site. MAO inhibitors block a major degradative pathway for the amine neurotransmitters, which permits more amines to accumulate in presynaptic stores and more to be released. |
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What are weaknesses to the MA hypothesis?
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TCAs and MAO inhibitor classes of
antidepressant actions are immediate. But the clinical effects of the drugs take several weeks to become manifest. |
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So, what is the hypothesis now?
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MA hypothesis still stands but probably
has to do with a deficiency in signal transduction, leading to a deficient response. |
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How long to antidepressants (AD) take to work?
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2-4 weeks for improvement
6-8 for substantial benefit |
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What are the 3 most common mechanisms for AD?
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MC mechanism:
1. INHIBITION of 5HT transporter (SERT) 2. INHIBITION of NE transporter (NET) 3. BOTH ALL mechanisms increase the availablility of MA in the synaptic cleft. |
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What are the 7 classes of AD?
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1. Monoamine oxidase inhibitors (MAOIs).
2. Tricyclic antidepressants (TCAs) 3. Serotonin selective reuptake inhibitors (SSRIs). 4. Dual serotonin and norepinephrine reuptake inhibitors (SNRIs) 5. Serotonin-2 antagonists/reuptake inhibitors (SARIs) 6. Norepinephrine and dopamine reuptake inhibitors (NDRIs) 7. Antagonists at α2-, 5-HT2 and 5-HT3 receptors (NaSSAs) Note: 4-7 are second and third generation AD. |
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What drugs are in the MAOI class?
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Isocarboxazid
Phenelzine Tranylcypromine Selegiline |
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What is the function of MAO?
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MAO functions as a “safety valve” to
oxidatively deaminate and inactivate any excess NE, Dopamine, 5HT that leaks out of synaptic vesicles when the neuron is at rest. |
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Which isozyme of MAO deaminates NE, Epi, and 5HT?
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MAO-A
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What MAO isozyme deaminates dopamine and tyramine?
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MAO-A and MAO-B
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How do MAOIs work?
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MAOIs inactivate MAO, permitting NT to escape into the synaptic space which activates NE and 5HT receptors.
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What MAOIs are currently available?
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*Phenelzine
*Isocarboxazid *Tranylcypromine *Selegiline |
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How are MAOIs used?
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Rarely used in clinical practice d/t toxicity and lethal food and drug interactions.
ONLY used to refractive depression. 2-4 weeks to take effect. |
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What are MAOI AE?
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drowsiness
orthostatic hypotension blurred vision dry mouth dysuria constipation |
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What is 5HT syndrome?
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hyperthermia
muscle rigidity myoclonus mental status change vital signs change LIFE THREATENING |
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How is 5HT syndrome caused?
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5HT syndrome results from
overstimulation of 5-HT1A/2-R. An irreversible MAOI + serotonergic agent (SSRI, SNRI, TCA, meperidine) is the most toxic combination, but any drug or combination that increases 5HT can cause 5HT syndrome. |
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How do you avoid 5HT syndrome if you need to add those drugs?
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Don't switch until all of the drugs have been phased out for weeks, before you add an SSRI, for example.
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What is the cheese reaction?
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Tyramine in foods normally inactivated by MAO in GI. Patients on MAOIs can not degrade tyramine. Tyramine causes release of catecholamines:
*tachy *HTN *arrhythmias *seizures *stroke |
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Other cheese reactions?
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Sympathomimetic + MAOI = HTN
OTC cold (pseudoephedrine) CI with MAOIs. |
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What drugs are TCAs?
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Amitriptyline
Clomipramine Desipramine Imipramine Nortriptyline |
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What is the TCA mechanism of action?
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Block SERT and NET
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What results from blocking SERT and NET?
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Increased monoamine concentration in the synaptic cleft and more postsynaptic receptor activation.
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Which TCA has very little affinity for NET but potent affinity for SERT?
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Clomipramine
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Which TCAs have has potent affinity for NET?
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Desipramine
Nortriptyline |
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What other receptors do TCAs block?
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TCAs block α-adrenergic, muscarinic,
histamine and 5-HT receptors. |
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What is the effect of blocking those receptors?
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Cause many of the AE of the TCAs.
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What do TCAs accomplish clinically?
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*Elevate mood
*Improve mental alertness *Increase physical activity *Reduce morbid preoccupation in 50-70% w/major depression *Takes 2 weeks or longer *Dependence rare *LT use does not decrease effectiveness |
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What AE are from blocking muscarinic-R?
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blurred vision, xerostomia, urinary retention, constipation and aggravation of narrow angle glaucoma
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What AE from increased catecholamine activity?
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cardiac overstimulation
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How do TCAs affect cardiac conduction?
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Slow cardiac conduction causing life-
threatening arrhythmias on overdose. |
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What effects from blocking α1-adrenoceptors?
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Orthostatic hypotension and reflex tachyicardia, especially serious in the elderly.
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What effects from H1 receptor blockade?
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Sedation and weight gain.
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What effects from 5HT (SERT) receptor blockade?
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Sexual effects (clomipramine)
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Can TCAs be used in OD?
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Common in suicide attempts.
Lethal arrhythmias can occur. Sodium bicarb useful in reversing conduction block. |
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What is the therapeutic index for TCAs?
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Very narrow. 5-6 times the dose can
be lethal. Suicidal patients should not be given enough to kill themselves and monitored closely. |
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What are the SSRIs?
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Citalopram
Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline |
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Which drugs inhibit serotonin uptake?
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SSRI's
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Why are SSRI's better than TCAs?
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SSRIs have 300 to 3000x greater
selectivity for the 5HT transporter as compared to the NE transporter. TCAs nonselectively inhibit the uptake of NE and 5HT. |
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Why don't SSRIs have AE such as orthostatic hypotension, sedation, blurred vision (seen with TCAs)?
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SSRIs have little blocking activity at
muscarinic, α-adrenergic, and histaminic H1 receptors. |
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SO, what does that make SSRIs?
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Da BOMB when it comes to depression!
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How long does it take for SSRIs to work?
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2 wks for mood improvement
12 weeks for maximum benefit |
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What are the indications of SSRIs (at least 8)?
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Depression
OCD PD GAD PTSD SAD premenstrual dysphoric disorder bulimia nervosa |
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What does increased 5HT activity in the gut cause?
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Nausea
Upset GI Diarrhea |
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What does increased serotonergic tone at the level of the spinal cord cause?
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Loss of libido, delayed orgasm, or diminished arousal.
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Does 5HT affect sleep?
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Insomnia, hypersomnia, headaches
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What AE is particularly associated with paroxetine?
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weight gain
(some reports of this with other SSRIs too) |
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Do SSRIs cause arrythmias like TCAs?
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OD on SSRI will still not cause arrythmias.
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What does OD on SSRIs cause?
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Dying from too much SSRI is extremely low.
However, seizures are possible because all antidepressants lower the seizure threshold. |
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What does CYP2D6 do?
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It is a cyt enzyme responsible for elimination of TCAs, neuroleptic drugs, some antiarrhythmic, and B-blockers.
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What SSRIs block CYP2D6?
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Fluoxetine and paroxetine
High potential for drug interactions. |
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What other SSRI blocks cyt enzymes?
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Fluvoxamine blocks CYP3A4, 2C19, 1A2
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What SSRIs have low drug interactions?
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Citalopram, escitalopram, and sertraline
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So, when is it useful to use citalopram, escitalopram, and sertraline?
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When the patient is on other medications.
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Which SSRIs can cause serotonin syndrome?
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All of them in the presence of MAOI or other serotonergic rx.
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What to do to decrease the risk of 5HT syndrome?
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Extensive wash-out of each drug class prior to administration of a new drug class.
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What drugs block 5HT and NE reuptake but not H1, muscarinic and α1 receptors?
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SNRIs
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What other drug class block 5HT and NE?
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TCAs
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Why are SNRIs better than TCAs?
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Do not have all the AE associated with blocking H1, muscarinic and α1 receptors.
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What are the 2 SNRIs?
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Venlafaxine
*low dose 5HT blocking only *high dose 5HT, NE, and dopamine Duloxetine *block 5HT and NE at all doses |
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When would SNRIs be used?
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To treat depression in those patients in whom SSRIs are ineffective.
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Do SNRIs have drug interactions?
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Have fewer interactions. "Clean"
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What class inhibits NE and dopamine uptake?
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NDRIs
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What drug is in this class?
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Buproprion
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Since it lacks the 5HT component, what AE does it lack?
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Not associated with sexual dysfunction.
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What AE is buproprion associated?
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Seizures in OD.
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What happens when 5HT reuptake is blocked by SSRIs?
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All 5HT receptors get a buzz of 5HT NT.
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Which 5HT receptor is beneficial for depression?
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5HT1A in the raphe
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What happens when 5HT2 is stimulated in the forebrain and spinal cord?
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Forebrain: anxiety and agitation
Spinal cord: sexual dysfunction So extra 5HT here is not good. |
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What to do about that?
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Design a drug that blocks 5HT reuptake for the beneficial depression effects but also antagonizes 5HT2 to minimize the agitation and sexual dysfunction.
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What are SARIs?
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5HT2 ANTAGONIST/REUPTAKE INHIBITORS
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What are the 2 SARIs?
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Nefazodone
Trazodone |
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Which SARI is a weak inhibitor of SERT and NET and a potent antagonist of postsynaptic 5HT2?
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Nefazodone
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Which SARI is a selective but weak SERT inhibitor and potent 5HT2 antagonist?
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Trazadone
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Which SARI also blocks α1and H1 and what are the effects?
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Trazodone.
Extremely sedating and hypnotic. Can cause priapism (sustained erection over 4 hours) |
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Which SARI is associated with hepatotoxicity and CYP3A4 inhibition?
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Nefazodone
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So, lets make it even more complicated, shall we?
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No, lets not.
But wait, there's more! |
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What class is a potent antagonist of central presynaptic α2-adrenergic-R, increasing NE and 5HT AND an antagonist at 5-HT2 and 5-HT3 receptors AND (are you getting tired yet?) a potent H1 antagonist?
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NORADRENERGIC & SPECIFIC
SEROTONERGIC ANTIDEPRESSANTS (NASSA) |
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What drug is a NASSA?
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Mirtazapine
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What is H1 associated with?
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Sedation and weight gain
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Remember to review?
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That BIG A@@ table in the notes pg 12.
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DOC for depression?
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SSRI
SSRI SSRI SSRI Ease of use, safety in OD, tolerability |
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What is the only choice for kids?
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Fluoxetine for major depressive disorder in kids taking no other interacting drugs.
Can also be a first choice for adults taking no other interacting drugs. |
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What would be the first choice for adults that are taking interacting drugs?
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Citalopram
Sertraline |
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What other indications for DOC for SSRIs?
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Depression
GAD SAD PTSD PD OCD |
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What is buproprion less useful for?
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anxiety
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DOC in CHRONIC PAIN?
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TCAs
Other drugs w/NE and 5HT reuptake blocking properties are useful in pain. |
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What was the first anti-depressant approved for treatment of pain associated with diabetic neuropathy and fibromyalgia?
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SNRI duloxetine
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Are SSRIs effective for chronic pain?
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NO
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Are antidepressants useful in treating anorexia nervosa?
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NO, only bulemia (Fluoxetine- like puke "flux")
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What SSRIs are useful for premenstrual dysphoric disorder?
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Fluoxetine (like menstrual "flux")
Sertraline (like "sert"ifiably crazy when she has her period) |
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What drug is good for smoking cessation?
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Bupropion
just as good as nicotine patches |
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What drug is useful in bed-wetting (enuresis)?
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TCAs - though they are not used due to adverse effects
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What drugs is used for bipolar disorder?
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LiLiLiLiLiLiLiLiLi
Lithium |
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When is Li used?
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To prevent manic episodes in manic depressives and to treat manic episodes themselves.
Also effective in 60-80% patients with mania and hypomania. |
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What is the inositol depletion theory?
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Li inhibits 2 enzymes (inositol mono and poly phosphatase) responsible for free inositol which is a precursor to PIP2 which decreases formation of IP3 and DAG, which DECREASES SIGNAL TRANSDUCTION.
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Why is this an issue?
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Inositol is not able to cross the BBB. It is only available De NOVO in the brain, the processes of which are inhibited by Li inhibiting formation of PIP2. Therefore, IP3/DAG/PLC won't work in those cells.
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So, what is the bottom line?
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By blocking regeneration of PIP2,
lithium inhibits central adrenergic, muscarinic, and serotonergic neurotransmission. |
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What is an uncompetitive antagonist?
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Has to bind to a enzyme-substrate complex.
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Why is this important?
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Li is an uncompetitive antagonist,
therefore only neurons with active receptors will be affected by lithium. In those cells, PIP2 will decrease and PLC-coupled receptors will become inactive. |
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What does this accomplish?
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Prevents actions of NT responsible for mood swings.
HOWEVER, we STILL don't know which NT is involved in mood swings. |
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What is the distribution of Li and how is it cleared?
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Li is distributed throughout body H2O and cleared by the kidney.
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Length of therapeutic window of Li?
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NARROW
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What are the effects of acute Li toxicity?
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confusion and motor impairment
to coma, convulsions, death if plasma Li reach 3-5 mM |
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What are Li AE?
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Tremor, sedation, ataxia, aphasia
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Can you use Li during pregnancy and nursing?
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Pregnancy:
Category D - may increase congenital cardiac anomalies Nursing: CI in nursing mothers. |
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What are 2 alternatives to Li?
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Valproate
Carbamazepine |
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What 3 drugs are approved for bipolar maintenance therapy as an alternative to Li?
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Atypical antipsychotics:
Olanzapine Aripiprazole Antiepileptic: Lamotrigine (blocks voltage gated Na channels) |
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What 3 drugs are approved for acute mania or mixed episodes as an alternative to Li?
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Atypical Antipsychotics:
Quetiapine Risperidone Ziprasidone |
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What combination of drugs is approved for depression associated with bipolar disorder as an alternative to Li?
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Olanzapine with fluoxetine
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