Anti-Depressants Flashcards
What is the monoamine theory of depression
The monoamine theory (1965) depression results from functionally deficient monoamine (NE and/or 5-HT) transmission in the CNS • The theory was based on pharmacological evidence o the ability of known antidepressant drugs (TCAs and MAO inhibitors) to facilitate monaminergic transmission o drugs such as reserpine that depletes amines to cause depression
Does the monoamine theory of depression still hold up?
• Simple monoamine hypothesis no longer tenable as an explanation of depression, BUT pharmacological manipulation of monoamine transmission remains the most successful approach to treating depression.
Neurons containing norepinephrine are located in the ______ and innervate nearly every part of the CNS.
locus coeruleus
Neurons containing serotonin are located in two groups of _____and project to most of the brain.
raphe nuclei
Neurons containing dopamine are located in the ____(and these project to the striatum) and the _____ area of the midbrain (and these project to the prefrontal cortex and parts of the limbic syste
substantia nigra ventral tegmental
Neurons containing ACh are located in the _____, which includes the septal nuclei and nucleus basalis and project to the hippocampus and the neocortex.
basal forebrain complex
Where are the cell bodies of neurons that contain Nepi located in the brain?
locus coerules: innervate the forebrain and neolimbic cortex
Where are the cell bodies containing Serotonin located?
Raphe nulcei to cortex + basal ganglia
What is the funciton of the Alpha 2 receptor on the presynaptic neuron?
Its a NE sensor; detects amount of Nepi in the synapse adn will regulate how much is made and released
What is the function of the Post juntional alpha receptor
stimulates; its on muscles and autonomic systems
both alpha and beta are terminated by neuronal uptake and blocked by certain drugs
How is the action of Nepi terminated?
Neuronal uptake or degraded by MAO
How is Nepi made?
What do we see in the post synaptic terminal in acute TCA use
TCA blocks Nepi release from presynaptic terminal
we see More Nepi made and relased into the synpase dt loss of negative feedback
What do we see in chronic TCA use in regards to postynaptic neuron
see lots more NE but decrease in the post synpatic receptors: this leads to decreased cAMP activity.
As drug builds up we see less signal tranduciton but more NE
DEscribe how Seratonin is made
Tryptophan–> 5-OH tryptophan –> 5HT
How do SSRIs work?
Block SERT reuptake
How does Mirtazapine work
Blocks seratonin and Nepi pre-synpatic receptors thus sends the message of “hey, we have plenty of seratonin” message never gets sent and you make more
this is at the alpha-2 autoreceptor
What is a common MAO-I and what is the mechanism of action
Monoamine oxidase is found in the mitochondria; we block MAO so we increase intrneuronal conc of NTs and increase receptor binding as well and end up with same result
Phenelzine
What is the restated monamine hypothesis?
Depression is due to a biogenic amine receptor or transmission imbalance. The various drugs that we are discussing today, act to change the imbalance and restore a more normal affect.
______ prevent presynaptic reuptake of the amines noradrenaline and seratonin
_____ predominately block seratonin reuptake
____ recude amount of MAO in breaking down presynaptic amines
TCAs
SSRIs
MAOIs
Why have SSRIs replaced TCAs as drug of choice for first line therapy against major depressive disorder
more desirable side effect profile
What are five common SSRI examples and what is there side effect profile
Fluoxetine, Fluvaximine, paroxetine, sertraline, citalopram
sides = nausea, insomnia, sexual dysfunction
Why are SSRIs prefered over TCAS? what is still dangeorus about SSRIs?
less risk for overdose, less acute toxicity
Seratonin reaction: hyperthermia, msucle ridgitidy, CV collapse when given with MAOIs!
What is something we need to consider when prescribing antidepressants to younger pts
suicidal thinking; need to watch pts that just start therapy very closely
What are some symptoms of SSRI withdrawl
dizzy, lightheaded, vertigo, shock like sensations, parethesia, anxiety, diarrhea, fatigue, gait issues, headace, insomnia
Approved uses of SSRIS
- Major Depression
- Obsessive-Compulsive disorder
- Panic disorder
- Social Anxiety Disorder
- PTSD
- Generalized Anxiety disorder
- PMS – Now PDD (Premenstrual Dysphoric Disorder)
• Hot flashes associated with menopause
Fluoxitine(Prozac) is an ______ with a _____ half life
Lots of inteactions with ____
SSRI
long half live
drug metabolism via CYP 2D6
has simular action to Fluoxetine with less effects on drug metabolism
used for OCD, PTSD and Panic attacks
short 1/2 life
Sertraline (Zoloft)
Parozetine is an SSRI with additional approval for ______
hot flashes post menopause
least muscarininc effects of all drugs
Fluvovazimine is a ____ approved for ____
SSRI
OCD
- Drugs block both 5-HT and NE reuptake
- Side effect profile is more SSRI-like than TCA- Like.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
SNRI approved for Major Depressive Disorder and anxiety.
- Also approved for neuropathic pain syndromes, fibromyalgia, back pain and osteoarthritis pain.
- Use with caution in patients with liver disease
• Duloxetine (Cymbalta®)
SNRI approved for Major Depressive Disorder and anxiety.
Venlafaxine (Effexor®)
SNRI approved for fibromyalgia
Milnacipran (Savella)
Duloxetine, Venlafaxine and Milnaciprin are all examples of
SRNIs
What is Duloxetine and what can it treat
SNRI, for antidepression but also fibromyalgia
o Weakly blocks NE and dopamine uptake.
o also approved for nicotine withdrawal and seasonal affective disorder.
o No weight gain or sexual dysfunction.
Buproprion
blocks presynaptic alpha2 receptors in brain
Increases appetite ***AIDS patients.
Mirtazapine (Remeron®)
o Weak SSRI-like effect. Sedating
o also used for insomnia.
o low incidence of cardiovascular side effects,
o can cause priapism.
Trazodone (Oleptro®)
o The newest drug approved to treat MDD. Has a SSRI-like action in addition to 5- HT1A agonist and 5-HT3 antagonist activity.
Vortioxetine (Brintellix®)
What are my atypical antidepressant drugs
Buprioprion
Mirtazapine
Trazadone
Vortioxetine
Amitriptyline, Timipromine, Nortryptiline, Protriptyline are all examples of
TCAs
What is the volume of distribution like in TCAs?
What about half life?
Very large volume of distribution, very lipophilic
long half life thus high risk for overdose
see high concentrations in heart and brain
Mechanism of action of TCAs
Block NE and 5-HT reuptake
(now second line to SSRIS for depression)
Effect of TCAs on mood and sleep
MOod is elevated in 2-3 weeks
DECREASED REM and Increased stage 4
What type of anticholinergic effects do we see from TCAs?
Dry mouth, blurred vision, urniary retention
(as well as orthostatic hypotension, cardiac abnormalities)
What cardiac side effects are seen d/t TCAs
- Due to anticholinergic effects and increased NE concentrations
- Palpitations, tachycardia and arrhythmias
- EKG changes such as lengthened QRS intervals and flattened or inverted T-waves reflect a slowed conduction time and significant alterations in the electrophysiology of the heart.
What do we see as a result of TCA overdose
Symptoms include hyperpyrexia, changes in blood pressure, seizures, coma and cardiac conduction defects.
Treatment is symptomatic. Observe for at least 3 days because of long half-lives.
What type of drug interactions do we see with TCAs?
- Guanethidine - blocks guanethidine uptake
- Sympathomimetic drugs - particularly indirect acting agents
- Effects absorption and metabolism of other drugs.
Therapeutic uses for TCAs
- Major depressive disorder
- Enuresis in childhood - imipramine
- Chronic pain - amitriptyline
- OCD – clomipramine and SSRIs
What is the MOA for Phenelzine and Tranylcypromine
Both are MAO-Is
Phenelzine is irreverislbe inhibitor
Tranylcypromine is reversible
How long does MAO-Is take to work?
What affect does it have on mood?
sleep?
- Antidepressant action takes about 2 weeks.
- Produces mood elevation in depressed patients. Mayprogress to hypomania particularly in bipolar disease.
• Corrects sleep disorders in depressed patient.
How do ‘Normals’ respond to MAOIs?
what do we see with BP?
Acute toxicity from MAOIs
- May produce stimulation in normals.
- Lowers blood pressure; often produces orthostatic hypotension.
- Acute toxicity can produce agitation, hallucinations, hyperpyrexia, convulsions and changes in blood pressure.
What food needs to be avoided when on MAOIs?
Tyramine foods: can cause Hypertensive crisis; tyramine goes through liver and is usually metabolized to inactivce metabolite but MAOIs block that thus you ahve active tyramine which stimulates dumping of NE–> to areterioles of heart == hypertensive crisis!
Uses of MAOIS
Major depression (NOT first choice)
Narcolepsy
What are some options if Antidepressants alone aren’t enough?
- Augmentation with antipsychotic agents.
- Approved drugs for treatment resistant major depressive disorder include:
Olanzapine (Zyprexa)
Aripiprazole (Abilify)
Quetiapine (Seroquel
- Ketamine – experimental treatment
- Physiological treatments
ECT (Electroconvulsive therapy)
TMS (Transcranial Magnetic Stimulation)
(Experimental) Deep Brain Stimulation
Why does St. Johns wort work for depression?
Has Ypericin which causes MAOI activity; but it upregulates Cyp3A4 thus lowers effectiveness of BC, protease inhibitors in AIDS pts and Cyclosporine
MOA for Imipramine and Amitryptyline
Nonspecific blockers of NE and 5-HT: dirty drugs with bad side effect profile
MAO of Fluoxetine, Sertraline, Paroxetine, Citalopram and Escitalopram
SSRIs
MOA of Venlafaxine and Duloxetine
SNRIs
Phenelzine is a
MAOI
