pharm 2: anti-depressants + ADHD

general mechanism of anti-depressants increase

Availability of monoamines in synaptic cleft

increase availability of monoamines by: (2)

By inhibition of presynaptic uptake or Inhibition of enzyme degradation

Increase availability of monoamines by inhibition of presynaptic uptake

serotonin, NE, and dopamine

Increase availability of monoamines by inhibition of enzyme degradation, Ex:

monoamine oxidase inhibition (MAOI)

anti-depressant onset is

delayed 2 to 3 weeks despite enzyme effects within 5 days

recovery of antidepressants

effects persist 1 to 3 weeks beyond discontinuation of drug

hypothesis for pathophys of anti-depressant mechanisms

monoamine hypothesis and neurotrophic hypothesis

monoamine hypothesis is

deficit in function or amount of monoamines - boost NT by blocking metabolism or reuptake

neurotrophic hypothesis is

loss of neurotrophic support (brain derived neurotrophic factor) - NT inducible gene expression

selective serotonin reuptake inhibitors (SSRIs) examples

Fluoxetine (Prozac), Escitalopram (Lexapro), Sertraline (Zoloft), Citalopram, Paroxetine (Paxil)

MOA of SSRIs

Inhibit reuptake of 5HT into the presynaptic neuron and Inhibit the 5HT presynaptic transporter

______ receptor may mediate anti-depressant effect

5HT1A

which (SSRI) drug has a long half life

fluoxetine - discontinue 4 weeks prior to initiation of MAOI

AE of SSRIs

GI upset, Sexual dysfunction, CNS (headaches, insomnia, fatigue), Discontinuation (withdrawal) syndrome; Taper to discontinue, Serotonin Syndrome, Prolonged QT

sexual dysfunction is least common with

escitalopram

which drug is most cited to cause long QT syndrome

citalopram > escitalopram (lexapro)

fluoxetine is associated with

weight loss, take in AM, and also increased risk of drug interactions

sertraline has great incidence of

diarrhea

paroxetine is associated with

sedation, higher incidence of nausea, weight gain, sex dysfunction, withdrawal syndrome, antimuscarinic effects

SSRIs should be initiated at typical therapeutic dose then

titrated within the range every 1-4 weeks

serotonin modulators include

Trazodone, Nefazodone, Vilazodone, and Vortioxetine

serotonin modulators work by

Serotonin antagonist & agonist

(SSRI + postsynaptic serotonin receptor inhibition)

AE of serotonin modulators

Sedation, Priapism - Painful prolonged erection, Dry mouth, Dizziness, GI upset

serotonin and norepinephrine reuptake inhibitors (SNRIs) include

Venlafaxine (Effexor), Duloxetine, and Desvenlafaxine

duloxetine is also used for

neuropathic and nociceptive pain syndromes

MOA of SNRIs

Inhibit serotonin and norepinephrine uptake

SNRIs target which receptors?

Alpha 1A & 5HT1A

SNRIs generally require ______ to improve _____

dose titration; tolerability (start low and go slow)

AE of SNRIs

GI upset, Sexual dysfunction, Discontinuation syndrome, Anorexia, Insomnia, Elevation in BP, HR, and anxiety agitation

Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs) example

bupropion

MOA of NDRIs

weak NE and DA re-uptake inhibitors

Primary MOA is thought to be dopaminergic and/or noradrenergic

NDRIs can also be used as

nicotine antagonist

NDRIs do not cause

sexual dysfunction

AE of NDRIs

Agitation/Anxiety

Insomnia

Anorexia/Weight loss

Nausea

Lower seizure threshold

Potential worsening of suicidal ideation

NDRIs are contraindicated in

seizure disorder and eating disorders

tricyclic anti-depressants (TCAs) include

Amitriptyline, Nortriptyline, Clomipramine, etc.

MOA of TCAs

Block reuptake of NE, 5HT, or both

MOA of blocking NE, 5HT, or both

Muscarinic receptor block

Histamine 1 receptor block

Alpha 1 receptor block

indications of TCAs

MDD unresponsive to SSRI or SNRIs

Neuropathic pain

Insomnia

AE of TCAs

Antimuscarinic

Antihistaminic

Lower seizure threshold

Orthostatic hypotension

Prolonged QT interval

anti-histaminic

Sedating, confusion, delirium

anti-muscarinic

Dry mouth, blurry vision, constipation, urinary retention

what to use in an overdose of TCAs

activated charcoal

tetracylics include

mirtazapine

MOA of tetracylics

Noradrenergic and specific serotonergic antidepressant (NaSSa)

mirtazapine work by

Presynaptic alpha 2 receptor antagonists that causes an increased release of the amines serotonin & norepinephrine from nerve endings

tetracylics have high affinity for

histamine H1 receptors (leading to its sedative, calming properties)

AE of tetracylics

Somnolence

Increased appetite, weight gain

Dry mouth, constipation

Dizziness

monoamine oxidase inhibitors (MAOIs) include

Phenelzine, Isocarboxazid, Selegiline, and Tranylcypromine

MAOIs block

monoamine oxidase enzyme

blocking monoamine oxidase enzymes inhibit metabolism of

NTs including epi, 5HT, NE, and dopamine

MAOIs may cause

orthostatic hypotensions

MAOIs can cause ______ after ingesting foods high in _____

hypertensive crisis

foods high in tyramine include

aged or fermented cheese, all aged/smoked/pickled/cured meats/poultry/fish, red wine, draft beer, & chocolates

MAOIs - increased risk of ______ if combined with SSRI or SNRI

serotonin syndrome

NMDA receptor antagonist example includes

ketamine

MOA of ketamine

NMDA receptor is an ionotropic glutamate receptor, also blocks reuptake of NE

indications of ketamine

Treatment of resistant depression in adults

Depressive symptoms in adults with MDD with acute SI

AE of ketamine

increased BP and HR

examples of benzodiazepines

Alprazolam (Xanax)

Diazepam (Valium)

Flumazenil (Romazicon)

MOA of benzodiazepines

Promote the binding of GABA to the GABA-A subtype of GABA receptors

indications of benzodiazepines

Only for acute, severe symptom management

AE of benzodiazepines

sedation

paradoxical stimulation

anterograde amnesia

tolerance

psychological dependence

physiological dependence

resp depression

sedation -

Calming effects with reduction in anxiety at low doses

paradoxical stimulation

Disinhibition of previously suppressed behavior can lead to euphoria, loss of self control, and impaired judgment

anterograde amnesia

Can't remember events occurring during drug duration of action

tolerance

Decreased responsiveness following repeated exposure

psychological dependence

Perceived relief of anxiety, euphoria, disinhibition, and promotion of sleep lead to compulsive misuse

physiological dependence

Abrupt withdrawal leading to withdrawal signs and symptoms

what is buspirone

anti-anxiety medication

onset of buspirone

onset delayed 2-4 weeks

MOA of buspirone

Partial agonist at 5HT1A receptors

Possible D2 and alpha 2 antagonist

AE of buspirone

Dizziness

Nervousness

Headache

ADHD neurochemistry hypothesis

Abnormal neurochemical transmission involving dopamine and norepinephrine in areas of the prefrontal cortex.

ADHD leads to

inattention, hyperactivity-impulsivity

types of agents for ADHD

methylphenidate agents

amphetamine agents

methylphenidate agents examples

ritalin, metadate, aptensio, quillivant, and concerta

methylphenidate agents are

synthetic stimulants

MOA of methylphenidate agents

Inhibit the presynaptic dopamine transporter and NE transporter to inhibit reuptake and increase concentration of neurotransmitter in neural synapse

methylphenidate agents stimulate

post-synaptic D1 and alpha 2A receptors

amphetamines agents examples

Dextroamphetamine, Adderall, Mudauis, Vyvanse

MOA of amphetamine agents

inhibits reuptake of dopamine and NE

additionally, as dose increases, amphetamine taken up into presynaptic terminal displaces

dopamine and NE from storage vesicles and increases release

AE of ADHD medications

GI upset

Headache

Insomnia

Weight loss (amphetamine > methylphenidate)

Physical or verbal tics