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PHRM 845 exam 5 > Antidepressants - Dr. Watts > Flashcards

Antidepressants - Dr. Watts Flashcards

1
Q

Clinical features of depression

A

decreased sleep, appetite changes, fatigue, psychomotor dysfunctions, dysphoric mood, worthlessness, excessive guild, loss of interest/ pleasure in all or most activities

decreased concentration, suicidal ideation

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2
Q

Biogenic amine hypothesis of depression

A

Reserpine is a small molecule that depletes NE and Seretonin which leads to depression

Found that agents that INCREASE NE and serotonin can treat depression

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3
Q

Neuroendocrine hypothesis of depression

A

Overactive hypothalamic pituitary adrenal axis and elevated CRF was found in most depressed patients
The over active hypothalamic pituitary adrenal axis may desensitize feedback response in hypothalamus and pituitary
Elevated CRF causes insomnia, anxiety, and decreased appetite and libido

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4
Q

Neurotrophic hypothesis of depression

A

Brain derived neurotrophic factor (BDNF) is important for neural plasticity, resilience, neurogenesis

BDNF in depressed patients is decreased and we see a decreased volume of hippocampus

BDNF has antidepressant activity and it is shown that antidepressant drugs increase the levels of BDNF and may increase hippocampus volume

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5
Q

Integration of hypotheses of depression

A

Chronic activation of monoamne receptors leads to increased BDNF signaling and downregulation of the HPA axis

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6
Q

Drug response

A

There is a delayed clinical response of the drug but it causes an immediate biochemical effect (immediate increase of serotonin)

Its important to mention to patients these drugs take about 3-4 weeks to see full affect

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7
Q

Mechanism of MAOIs

A

MAOs are found in the presynaptic cleft and they lead to break down of NE and serotonin

MAO inhibitors work by blocking this degradation of norepinephrine and serotonin and thus lead to an increased amount of NE and serotonin in the vesicles that can be released to the synapse causing increased amount in the synapse

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8
Q

Non selective MAO inhibitors

A

Irreversible
Phenelzine (nardil)
Tranylcypromine (Parnate)

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9
Q

Selective MAO-B inhibitors

A

Reversible
Selegiline (eldepryl/Ensam)
Safinamide (Xadago)

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10
Q

Selective MAO-A selective

A

Reversible
Moclobemide (manerix)

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11
Q

MAOi structures

A

benzo ring with long side chain

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12
Q

MAO inhibitors Side effects and points

A

Severe side effects : headache, drowsiness, dry mouth, weight gain, ortostatic hypotension, sexual dysfunction

Hypertensive crisis: avoid certain foods and drugs

Interactions with Rx: TCAs, SSRIs, L-Dopa

Avoid foods with Tyramine (partial list): Cheeses, sour cream, sausage, bologna, pepperoni, salami, beer, red wine, avocado, bananas

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13
Q

Targets of reuptake blockers

A

Target VMAT on the vesicles inside the synapse
Target monoamine transporters (DAT, NET, SERT) located on the plasma membrane and are targets for antidepressant activities

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14
Q

Monoamine transporters (DAT,NET,SERT)

A

They transport serotonin, norepinephrine, or dopamine along with sodium and chloride (Co-Transporter)

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15
Q

How reuptake inhibitors work

A

Antidepressants bind at an allosteric site and cause a transformation change that blocks the release of dopamine, serotonin, and norepinephrine into the synapse Leaving more seretonin in the extracellular space

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16
Q

Tricyclic antidepressants

A

Used for Depression, panic disorder, chronic pain, and enuresis

Overdose/toxicity: extremely dangerous, depressed patients are more likelty to be suicidal

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17
Q

CLASS OF TRICYCLIC ANTIDEPRESSANTS: Tertiary amines MOA, SIDE EFFECTS

A

MOA: bind allosterically to both NET and SERT to block the reuptake of NE and serotonin and cause an increase of these two in the extracellular space
They also act as receptor antagonists: antihistamine, antimuscarinic, antiadrenergic

Major side effects: these agents cause the mose sedation, autonomic side effects, and weight gain

Another side effrect is conduction disturbances of the heart due to its antagonist activity at alpha 1 receptor

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18
Q

TERTIARY AMINES

A

Imipramine (tofranil) - active metabolite desipramine (Secondary amine) , enuresis and ADHD

Amitriptyline (elavil): active metabolite nortriptyline ( secondary amine)

Clomipramine (anafranil): used for OCD

Doxepin (Adapin, Sinequan)

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19
Q

CLASS OF TRICYCLIC ANTIDEPRESSANTS: Secondary amines MOA, SIDE EFFECTS and drugs

A

Better NET inhibitors than SERT inhibitors Block the reuptake of NET and increase the amount of norepinephrine in the extracellular
Desipramine (Norpramin)
Nortriptyline (Pamelor)
Maprotiline (Ludiomil) - NEt inhibitor

SIDE EFFECTS: less sedation, less anticholinergic, less autonomic, less weight gain, less cardiovascular than tertiary amines

19
Q

Side effects of ALL TCAs

A

Anticholinergic, (worried about hypotension in elderly), neurological, weight gain, and remember patients may be suicidal)

20
Q

Mechanism of SSRIs

A

Block serotonin pumps on the presynaptic neuron and by doing this it increases the amount of serotonin in the synapse which allows for serotonin to stay in the synapse longer and remain active longer

21
Q

SSRI Drugs

A

Fluoxetine (prozac): little autonomic side effects, no sedation
Fluvoxamine (luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
Citalopram (celexa)
Escitalopram oxalate (Lexapro): isomer of citalopram

22
Q

SSRIs Use, Side effects, serotonin syndrome

A

Use: depression, alcoholism, OCD,, Enuresis, PTSD, Eating disorders, Social Phobias, panic anxiety, PMDD, GAD

SE: Brain zaps, dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo

Serotonin syndrome: when given with MAOis, TCAs, also metoclopramide, tramadol, triptans, st. johns wort
symptoms of serotonin syndrome: hyperthermia, muscle rigidity, restlessness, myoclonus, hyperreflexia, sweating, shivering, seizures, and coma
Treatment: discontinuation of medication and management of symptoms, administration of serotonin antagonists (cyproheptadine or methysergide)

23
Q

SSRI + 5HT1a partial agonists

A

Vilazodone (Viibryd): reduces sexual side effects vs Pure SSRIs

Vortioxetine (Brintellex)

24
Tetracyclic and unicyclic
Maprotiline (Ludiomil) - tetracyclic, NET inhibitor Amoxapine (Ascendin): NET inhibitor and D2 antagonists (Being a D2 antagonists means there can be motor symptoms)
25
Mirtazapine (Remeron)
Its a receptor antagonist not a monoamine antagonist Alpha 2 antagonist, 5ht2 and 5ht3 antagonist and H1 antagonist Very sedating drug
26
Bupropion (Wellbutrin)
NET and SERT Inhibitor Its also a good DAT inhibitor Treats GAD, Depression, Zyban (other trade name) for smoking cessation
27
5-HT2 antagonists/ SERT inhibitor
Trazadone (dyserel): this is a receptor antagonist that has some weak SERT activity Have to have large doses for antidepressant effect, its extremely sedating due to its activity at the histamine receptors
28
SNRIs
Venlafaxine (Effexor) - NET and SERT inhibitor, treats GAD and panic disorder as well as depression Desvenlafaxine (Pristiq) - NET and SERT Inhibitor - treatment of vasomotor symptoms associated with menopause Duloxetine (Cymbalta) - NET and SERT Inhibitor - Treats GAD, peripheral neuropathy, depression Milnacipran (Ixel) - NET and SERT Inhibitor - approved for fibromyalgia Levomilnacipran (Fetzima) - NET and SERT Inhibitor - active enantiomer of milnacipran
29
SNRI MOA
Work at the NET and SERT to block the reuptake of serotonin and norepinephrine which leads to increased amount of these in the synapse. these drugs work similar to the TCA drugs BUT they have less side effects compared to TCAs
30
Norepinephrine selective reuptake inhibitors (NSRIs)
Reboxetine (Vestra, edronax) - FDA declines the license for use in the USA Atomoxetine (Straterra) - not great at antidepressant activity so now used for ADHD
31
Selectivity profiles Amitriptyline vs Nortriptyline
Amitriptyline is a tertiary amine TCA - its selectivity ratio is 1/7 (5-HT:NE) - binds to serotonin a little bit better than the norepinephrine transporter Nortriptyline is a secondary amine TCA - its selectivity ratio is 8/1 (5-HT: NE) - binds to NET better than serotonin
32
Serotonin norepinephrine dopamine reuptake inhibitors (SNDRIs)
Triple blockers - example of this is cocaine
33
Rapidly acting antidepressants
NMDA antagonists - these show some antidepressant activity Ketamine subanesthetic doses Scopolamine - muscarinic and NMDA antagonists Lanicemine NMDA - excitatory amino acid ionotropic receptor which takes calcium and sodium
34
NMDA Antagonists MOA
Block NMDA receptor and keep it in a partially inactive state Excitatory neurons: glutamate and aspartate
35
Clinically used NMDA antagonists
Ketamine - subanesthetic doses Esketamine (spravato) - in conjunction with oral antidepressants CNS Side effects: depression of CNS function, drug interactions Esketamine is a intranasal product with phased dosing (twice weekly, weekly, and every 2 weeks) Available only through restricted programs (REMS)
36
Postpartum Depression
Fluoxetine and paroxetine and venlafaxine Others: CBT and counseling Brexanolone (Zulresso)
37
Brexanolone (Zulresso) MOA
works on the GABA-A receptor (Inhibitor amino acid receptors) (Makes cells more negative) In pregnancy we have a steroid hormone known as allopregnanolone which is increased in preganancy that leads to the gaba-a receeptors being desensitized and once birth theses allopregnanolone levels drop back to normal and the GABA-a receptors are still desensitized which means they can no longer can gate chloride and inhibit membrane potential, so this leads to spike of membrane potential and this causes post partum depression Brexanolone works by binding to the neurosteroid site (allosteric) of the gaba-a receptor which enhances its function allowing for the receptors to gate chloride and make potential negative when needed Problem with this drug is that patients have to go through restricted programs to get the drug REMS
38
New agents in development
Phychedelics: MDMA, psilocybin, and LSD 5HT2c receptor antagonists Metabotropic glutamate receptor agonists Reversible Inhibitors of monoamine oxidase- A (RIMAS) - MOCLOBEMIDE (MOC; Manerix), Brofaromine (BRO), are as effective as TCA and better tolerated
39
Non- pharm considerations
Electroconvulsive therapy Psychotherapy Hospitalization
40
Pharmacology of Filbanserin (Addyi)
Female viagra - increase sexual desire in females Hypoactive sexual desire disorder Developed as antidepressant Polypharmacology agonist at 5HT1A, antag at 5HT1a, antagonists at 5HT2a/c Regional selectivity preffrontal cortex controversial approval
41
Bipolar disorder symptoms
Mania, hypomania, depression, mixed mania and depression
42
Features of Mania
euphira/elation, irritability/anger, impulsive high risk behavior, aggression, grandiose ideas, decreased sleep and appetite, difficulty concentrating Depression Hypomania - is just less sever symptoms of mania
43
Treatment of bipolar
Hospitalization Psychotherapy Pharmacotherapy - mood stabilizers: lithium, anticonvulsants, atypical antipsychotics Calcium channel blockers (Verapamil, nimodipine)
44
Valproic acid
Anticonvulsant increase GABAenergic tone by blocking GABA transaminase (this breaks down GABA) which prevents the breakdown of GABA Block Na channels and prevent firing Block T-Type CA Inhibits histone deacetylase
45
Lithium MOA
- normal Activation of Gq which activates Phospholipase C which this cleaves PIP2 to IP3 and PKC then the IP3 goes back into the membrane as recycled PIP2 - Lithium works by inhibiting this recycling of PIP2 which depletes the membrane of PIP2 - now when PLC (Phospholipase C) is activated there is no PIP2 to cause signaling - lithium is a dirty drug that has many targets and inactivates all Gq receptors and causes many side effects - Because it depletes PIP2 it takes a while to see full effect of Lithium
46
Anticonvulsants that block sodium channels
Carbamazepine/ oxcarbazepine Lamotrigine Topiramate these prolong the inactivation state of the sodium channel, channel has to be activated first for it to be blocked

PHRM 845 exam 5 (12 decks)

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