PHRM 845-FINAL EXAM Flashcards
Antidepressants
History and Background of antidepressants
1950s: Imipramine (1st TCA) as the 1st
antidepressant
Isoniazid (MAOI) an antituberculosis drug
Additional TCAs
Present: SSRIs, atypicals, and dual acting
Goals of therapy with antidepressants
Alleviate signs and symptoms
Types of depression
Reactive (most common)
MDD (major depressive disorder)
Bipolar affective
What generally causes reactive depression?
Death, trauma, stress
Depression is a common mental illness of the general population.
-It impacts ___% of the population
-Underdiagnosed–why?
-Undertreated
-___ if left untreated
10%
Hesitancy to get treated–suck it up and put a smile on your face
Suicidal
Physiological features of depression
-decreased sleep, appetite changes, fatigue, psychomotor dysfunctions
– Other: menstrual irregularities, palpitations, constipation, headaches and nonspecific body aches
Psychological features of depression
dysphoric mood, worthlessness, excessive guilt, loss of interest/pleasure in all or most activities
Cognitive features of depression
Decreased concentration; suicidal ideation
Diagnosis of depression
Not due to drugs, medical condition, or bereavement
Drug-induced depression
-Antihypertensive and Cardiovascular
~reserpine, methyldopa, propranolol, metoprolol, prazosin, clonidine, digitalis
-Sedative-Hypnotics
~alcohol, benzodiazepines, barbiturates, meprobamate
-Anti-inflammatory and Analgesics
~indomethacin, phenylbutazone, opiates, pentazocine
-Steroids
~corticosteroids, oral contraceptives, estrogen withdrawal
-Misc: anti-parkinson, anti-neoplastic, neuroleptics
**See if something changes prescription-wise or OTC
Neuroendocrine hypothesis of depression
Changes in Hypothalamic-Pituitary-Adrenal (HPA) Axis
Overactivity of HPA and elevated CRF found in almost all
depressed patients
Overactivity of HPA may desensitize feedback response
in hypothalamus and pituitary
Elevated CRF causes insomnia, anxiety, and decreased
appetite and libido
Antidepressants and ECT reduce CRF levels–can reverse depression symptoms
Symptoms associated with depression for neuroendocrine hypothesis
CRF1
Arousal
Anxiety-like behavior
Disruption of sexual behaviors
Disruption of sleep
Neurotrophic hypothesis of depression
Brain-derived neurotrophic factor (BDNF) is critical in
– Neural plasticity, resilience, neurogenesis
Stress and pain decrease BDNF levels in animals
Decrease in volume (5-10%) of hippocampus (memory
and regulates HPA)
BDNF has “antidepressant” activity in animals
Depressed patients have reduced BDNF levels
Antidepressants increase BDNF levels and may increase
hippocampal volume
(however, some animal studies have provided opposing
evidence, BDNF knock out animals and increase BDNF
following stress)
In neurotrophic hypothesis, what is the effect of BDNF on neuronal growth?
The more BDNF=more sprouting=neurons can reconnect
Antidepressant impact on BDNF
Antidepressants increase monoamines which increases BDNF
Integration of all the hypothesis of depression
HPA and steroid abnormalities regulate BDNF levels
Hippocampal glucocorticoid receptors are activated by
cortisol during stress (decreasing BDNF)
Chronic activation of monoamine receptors increases BDNF signaling (> 2 weeks)
Chronic activation of monoamine receptors leads to a downregulation of the HPA axis
Main classes of antidepressants
-MAOIs = Monoamine Oxidase Inhibitors
-TCAs = Tricyclic Antidepressants; tertiary and
secondary amines (a.k.a. SNRIs, see below)
-SSRIs = Selective-Serotonin Reuptake Inhibitors
-SNRIs = Serotonin-Norepinephrine Reuptake Inhibitors
-5-HT2 Antagonists
Tetracyclic and Unicyclic Antidepressants
Response to antidepressants is ____(rapid/delayed)
Delayed; ensure patient knows about delay in feeling; SSRI causes immediate increase in serotonin, but depression will not be better (takes days-weeks for effect)
Why does therapy take 2-3 weeks for effect?
Antidepressants cause the amount of neurotransmitter in the intrasynaptic space to
increase.
-Is the delay in clinical effect
due to…
Activation of presynaptic
receptors?
Presynaptic adaptation?
Postsynaptic adaptation?
→ No one really knows!
Mechanism of MAOIs
NE and 5HT-2A are normally degraded by monoamine oxidase. This process is inhibited with MAOI resulting in an increased amount of NE and 5HT packaged in vesicles.
Non-selective MAO-I
-Phenelzine (Nardil)
-Tranylcypromine (parnate)
**Irreversible
Selective MAO-B
Selegiline (Eldepryl/Ensam)
**Used in PD
**Reversible
MAO-A selective
Moclobemide (Manerix)
**Not used in US
**Used in Europe to tx depression
**Reversible
MAO-I are ___ (reversible/irreversible)
Are they a good option?
Irreversible–receptor is gone until new receptors are formed
Severe side effects with MAO-I
HA
Drowsiness
Dry mouth
Weight gain
Orthostatic Hypotension
Sexual dysfunction
**Have limited use
What foods and drugs should be avoided with MAO-i?
Foods with tyramine, such as cheese, sour cream, beer, avocados
Why should tyramine substances be avoided with MAO-I?
Hypertensive crisis
MAO-I interaction with OTCs, such as
Cold preparations and diet pills
MAO-I interaction with RX
TCAs, SSRIs, L-DOPA
Which herbal product has MAOI activity and can therefore be used for depression
St. John’s Wort
Process of reuptake
Co-transporter binds outside of the cell, then it is engulfed, and then released inside of the cell
Site of action of reuptake blockers
Link to protopedia serotonin transporter
Indications for Tricyclic antidepressants
Depression
Panic Disorder
Chronic pain
Enuresis (bed wetting)
Overdose/toxicity of tricyclic antidepressants
Extremely dangerous; depressed patients are more likely to be suicidal; Patients are more likely to commit self-harm or suicide 2 weeks into treatment
**This is because normally patients are so depressed they don’t have energy to take their own lives, but once tx starts to kick in, they get energy to do it.
MOA of tertiary amines
Inhibit NE and 5HT reuptake via NET and SERT
-Also act as receptor ANTAgonists for antihistamine (H1), antimuscarinic, and antiadrenergic
**Not great drugs and have lots of SE
Major side effects of tertiary amines
Sedation
Autonomic side effects
Weight gain
Other side effects of tertiary amines
Conduction disturbances of the heart
Tertiary amines
Imipramine (Tofranil)
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepin (Adapin, Sinequan)
Impramine (tofranil)
Metabolized to desipramine
-Used for enuresis and ADHD
Amitriptyline (Elavil)
Metabolized to nortriptyline
What are clomipramine and trimipramine used for?
OCD
**SE of clomipramine is having an orgasm while yawning
Secondary amines
**Most tertiaries are metabolized to these
Desipramine (Norpramin)
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Maprotiline (Ludiomil)
Which secondary amine is tetracyclic so it has reduced side effects
Maprotiline
MOA of secondary amines
Better NET inhibitors than SERT
Side effects of secondary amines
Less sedation
Less anticholinergic
Less autonomic
Less weight gain
Less cardiovascular than tertiary amines
In general, side effects of all TCAs (secondary and tertiary) are…
Anticholinergic, CV (elderly), neurological, weight gain
**Remember pts may be suicidal due to existing depression
Mechanism of SSRIs
- Block 5HT pumps
- Increase 5HT in synapse
- 5HT remains active longer
Meds that are SSRIs
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
Citalopram (Celexa)
Escitalopram oxalate (Lexapro)
Fluoxetine has _____ (lots/little) autonomic SE and ___ (lots/some/no) sedation
Little
No (some may become agitated/excited on it)
SSRIs have (few/lots) of SE
Few, so they are commonly prescribed
Does a pt taking an SSRI feel better immediately?
NO; serotonin goes up immediately, but does not make a patient feel better
Uses for SSRIs
Depression
Alcoholism
OCD
Enuresis
PTSD
Eating disorders
Social phobia
Panic anxiety
PMDD
GAD
SE of SSRI
N/V
HA
Sexual dysfunction
Anxiety
Tremor
SSRI discontinuation syndrome
**IF abruptly stop the SSRI
“Brain zaps” (feel like they lose 10s of their life), dizziness, sweating, nausea, insomnia, tremor, confusion, vertigo
Serotonin syndrome
EMERGENCY
When SSRI given with MAOI, TCAs, metoclopramide, tramadol, triptans, St. John’s Wort
**Way too much serotonin
Symptoms of serotonin syndrome
Hyperthermia
Muscle rigidity
Restlessness
Myoclonus (sudden, brief, involuntary jerking)
Hyperreflexia
Sweating
Shivering
Seizures
Coma
Treatment of serotonin syndrome
D/C med and manage symptoms; administer serotonin antagonist (cyproheptadine; methysergide); benzos to control myoclonus (involuntary jerking)
SSRI and 5HT1A partial agonist examples
Vilazodone (Viibryd)
Vortioxetine (Brintellix)
Vilazodone has similar 5HT1A actions to
Aripiprazole (Abilify)-atypical antipsychotic
Buspirone (Buspar)-partial 5HT1A for anxiety
Vilazodone has ____ (increased/reduced) sexual side effect vs. pure SSRIs
Reduced
Targets for Vortioxetine (Brintellix)
SERT, 5HT1A partial agonist, 5HT3
Tetracyclic and unicyclic antidepressant examples
Maprotiline (Ludiomil)
Amoxapine (Ascendin)
Mirtazapine (Remeron)
Bupropion (Wellbutrin)
Maprotiline (Ludiomil) is a _______
NET-inhibitor
Amoxapine (Ascendin) is a ___
NET inhibitor and D2 antagonist (causes low dopamine levels and may lead to EPS-motor SE)
Mirtazapine (Remeron) targets _____
Alpha-2 antagonist
5HT2 and 5HT3 antagonist
H1 antagonist
**NOT hitting transporters, only receptors
Bupropion (Wellbutrin) is a ____
DAT inhibitor
NET and SERT inhibitor
**Hits transporters
What can bupropion be used for
GAD
Smoking cessation using Zyban
5HT2 antagonists/SERT inhibitor
Trazodone (Dyserel)
Counseling point with trazodone
Very sedative, so it can only be taken at night. Get right into bed because it is a strong hypnotic–>pt will feel refreshed in the morning
**It is an off-label hypnotic (alpha1 and H1 with 5HT2)
Serotonin-Norepinephrine reuptake inhibitor (SNRI) target ____ and have (more/less) SE than previous ones.
NET and SERT
Less
**ALL behave similar to tertiary TCA with less SE
Examples of SNRIs
Venlafaxine (Effexor)
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Milnacipran (Ixel)
Levomilnacipran (Fetzima)
Venlafaxine (Effexor)
NET and SERT inhibitor
Treats GAD and panic disorder
Diabetic neuropathy?
Migraine prophylaxis?
Desvenlafaxine (Pristiq)
NET and SERT inhibitor
Tx of vasomotor sx associated with menopause?
Duloxetine (Cymbalta)
NET and SERT inhibitor
Treats GAD
Treats peripheral neuropathy
Milnacipran (Ixel)
NET and SERT inhibitor
Approved for fibromyalgia
Levomilnacipran (Fetzima)
NET and SERT inhibitor
Active enantiomer of milnacipran
Norepinephrine selective reuptake inhibitors (NSRIs)
NET selective
Examples of NSRIs
Reboxetine (Vestra; Edronax)
Atomoxetine (Strattera)
Reboxetine (Vestra; Edronax)
Possibly less SE than Prozac
FDA declined license for use in USA for unknown reasons
Atomoxetine (Strattera)
Originally intended to be an antidepressant drug (not approved!)
**Now used for ADHD
What should you do if a patient tried 2 SSRI and failed?
Try something more favorable for NET than 5HT or change med classes
Triple blocker or “Triple Reuptake Inhibitor” (TRI)
Serotonin-Norepinephrine-Dopamine reuptake inhibitor (SNDRIs)
**Example: cocaine
NMDA antagonist
**Rapidly acting antidepressant
CNS effects of esketamine
Depression, drug interactions
Clinically used NMDA antagonists
Esketamine (Spravato)–used in conjugation with oral antidepressant
Examples of NMDA antagonists
Ketamine (subanesthetic doses)
Scopolamine (Also muscarinic antagonist)
Lanicemine (“low trapping”)
GLYX-13 partial NMDA antagonist
Mechanism of “low trapping” NMDA antagonist
Block NMDA and keep in partially active state (excitatory) – glutamate
How is esketamine administered?
Intranasal, phased dosing (twice weekly, weekly, and every 2 weeks)–VERY EXPENSIVE
**Must be in presence of someone (can do MD on zoom call)
**Only available through restricted program (REMS)
Tx for post-partum depression
SSRIs (fluoxetine and paroxetine) and venlafaxine
-Others: CBT and counseling
-Newer drug: Brexanolone (Zulresso)
MOA of Brexanolone (Zulresso)
Binds allosterically to GABA-A receptors to enhance its function
What happens to allopregnanolone levels during pregnancy? How about post-partum?
They increase; return to normal once the mother gives birth
Brexanolone ____ GABA-A receptors
Resensitizes; cannot gate Cl- so membrane potential goes up and spikes
Brexanolone is a _____ drug that is a ____ hr infusion and very expensive.
**It is very effective, but not used much
REMS
60
New agents in development
-Psychedelics: MDMA (ecstasy), psilocybin, and LSD (acid) —– doses will be much lower than people use for psychedelic effect.
-5HT2C receptor antagonists
-Metabotropic glutamate receptor agonists
-Reversible inhibitors of monoamine oxidase-A (RIMA)
~Moclobemide
~Brofaromine
~Are as effective as TCAs and better tolerated
Non-pharmacological considerations for depression
-Electroconvulsive therapy: resets action potentials and a way to treat drug-resistant depression
-Psychotherapy: counselor
-Hospitalization: protect pt from themselves
Pharmacotherapeutic considerations
-Severity of depression (typically don’t medicate for SAD)
-Onset of drug action (SSRI could take weeks)
-Endogenous vs. exogenous depression
-Unipolar vs. bipolar
-Drug selection
-Dosing
-Duration of tx
-Compliance
-Other factors
Do not take trazodone in ___ or SSRI in ____
AM; PM
Antidepressants (especially TCA) works on ___ pathways
Descending
Filbanserin (Addyi)
-“Female viagra”
-Hypoactive sexual desire disorder
-Originally created as antidepressant
-Agonist of 5HT1A and an antagonist of 5HT2A/C
-Regional selectivity in the prefrontal cortex
-Controversial approval
-NOT rapid acting
Approximately ___ % of americans have bipolar disorder. Onset is < ____ y/o
1.5-3
30
Etiology of bipolar disorder
-Genetic predisposition
-Biological 5-HT and DA
-Environmental (infections, birth complications, etc)
Types of bipolar disorder
-Bipolar I
-Bipolar II
-Cyclothymia disorder
-Unspecified bipolar and related disorder
-Substance-induced mood disorder
Symptoms of bipolar disorder
-Mania
-Hypomania
-Depression
-Mixed mania and depression
What is mania?
Euphoria/elation, irritability/anger, impulsive high risk behavior, aggressive, grandiose ideas, decreased sleep and appetite, difficulty concentrating, delusions, flight of ideas, hallucinations
What is hypomania?
Less severe mania
Depression
Physiological and psychological symptoms of depression
Treatment of bipolar disorder
-Hospitalization
-Psychotherapy
-Pharmacotherapy (to stabilize neuronal signaling)
Pharmacotherapy of bipolar disorder
Mood stabilizers: lithium, anticonvulsant
Atypical antipsychotic
**CCB (verapamil, nimodipine)
Combination tx + benzodiazepine
Actions of lithium
Ion similar to sodium
-Variety of targets (“dirty drug”)
-Goes everywhere in the cell
Lithium (light) pharmacotherapy
-Mechanism not clearly understood (depletion of PIP2 and associated signaling–IP3 and PKC; modulate GSK3–phosphorylation and binding partners)
-Small therapeutic index
-Acute (give large loading dose) vs. chronic
-Lag time for effectiveness
-Loading dose
Anticonvulsants
-Valproic acid and sodium valproate
**Multiple MOA
~Increase GABAergic tone (increase GAD activity, inhibit GABA transaminase)
~Block sodium channels
~Block T-type calcium channel
~Inhibits histone deacetylase (HDAC5)
Atypical antipsychotics
-Olanzapine (Zyprexa)
-Olanzapine + fluoxetine (Symbyax)
-Quetiapine (Seroquel)
-Risperidone (Risperidol)
-Ziprasidone (Geodone/Zeldox)
-Lurasidone (Lutada)
-Aripiprazole (Abilify)
