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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
Q

Tetracyclic and unicyclic

A

Maprotiline (Ludiomil) - tetracyclic, NET inhibitor

Amoxapine (Ascendin): NET inhibitor and D2 antagonists (Being a D2 antagonists means there can be motor symptoms)

25
Q

Mirtazapine (Remeron)

A

Its a receptor antagonist not a monoamine antagonist
Alpha 2 antagonist, 5ht2 and 5ht3 antagonist and H1 antagonist
Very sedating drug

26
Q

Bupropion (Wellbutrin)

A

NET and SERT Inhibitor
Its also a good DAT inhibitor

Treats GAD, Depression, Zyban (other trade name) for smoking cessation

27
Q

5-HT2 antagonists/ SERT inhibitor

A

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
Q

SNRIs

A

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
Q

SNRI MOA

A

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
Q

Norepinephrine selective reuptake inhibitors (NSRIs)

A

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
Q

Selectivity profiles Amitriptyline vs Nortriptyline

A

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
Q

Serotonin norepinephrine dopamine reuptake inhibitors (SNDRIs)

A

Triple blockers - example of this is cocaine

33
Q

Rapidly acting antidepressants

A

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
Q

NMDA Antagonists MOA

A

Block NMDA receptor and keep it in a partially inactive state
Excitatory neurons: glutamate and aspartate

35
Q

Clinically used NMDA antagonists

A

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
Q

Postpartum Depression

A

Fluoxetine and paroxetine and venlafaxine

Others: CBT and counseling

Brexanolone (Zulresso)

37
Q

Brexanolone (Zulresso) MOA

A

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
Q

New agents in development

A

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
Q

Non- pharm considerations

A

Electroconvulsive therapy
Psychotherapy
Hospitalization

40
Q

Pharmacology of Filbanserin (Addyi)

A

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
Q

Bipolar disorder symptoms

A

Mania, hypomania, depression, mixed mania and depression

42
Q

Features of Mania

A

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
Q

Treatment of bipolar

A

Hospitalization
Psychotherapy
Pharmacotherapy - mood stabilizers: lithium, anticonvulsants, atypical antipsychotics
Calcium channel blockers (Verapamil, nimodipine)

44
Q

Valproic acid

A

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
Q

Lithium MOA

A
  • 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
Q

Anticonvulsants that block sodium channels

A

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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