Term 2 Pharm - Anxiety & Depression Drugs Flashcards
(36 cards)
Depression
- 14.3 % Medical students
- US $100 billion/yr
- ## “In all regions, neuropsychiatric conditions are the most important causes of disability, accounting for around one third of YLD among adults (years lost to disability).”
Libby Zion
- Fever (107F), agitation, shaking
- Meperidine and restraints
Main target of antidepressants?
- All the antidepressant drugs now in use modulate monoamine neurotransmission.
- Problem with Monoamines= Delay (6-8 weeks to exert their effects)
- Efficacious in 60–70% of patients.
What are amines?
In amines, the hydrogen atoms in the ammonia have been replaced one at a time by hydrocarbon groups
What are the key actors in the monoamine hypothesis of depression?
Serotonin, Norepinephrine, Dopamine
(Monoamine-deficiencyhypothesis)
Current Leading Theory: Enhanced Neuroplasticity(Structural and Functional)
Since 1955 – nothing really new or novel has emerged – 27 drugs have come to market - all work by increasing monoamines at the synapse, through a variety of different mechanisms.
First Generation: TCA and MAO-I (1955 – 1986)
Second Generation: SSRI, SNRI, other (1986 – now)
NO improvement in efficacy of drugs, just an improvement in their tolerability Old does not mean less than or worse
Old to New
Class Leaders (model drugs of each category) of Antidepressants
Serotonin
- SSRI (citalopram)
Norepinephrine
- SNRI (venlafaxine)
- TCA (nortryptiline)
Dopamine
- NDRI (bupropion)
What do SSRI’s do?
SSRI’s – selective serotonin reuptake inhibitors
The basic mechanism is that the drug, blocks the serotonin reuptake molecule (by acting as a serotonin analogue) – thus keeping more of the serotonin monoamine in the synapse.
have numerous other properties that lead to side effects. HUGE potential for cross reactivity of other unintended receptors – potentially leading to multiple side effects
Where are most of the cells that use serotonin as a primary signaling messenger?
In the Raphe Nucleus in the brain stem and mid-brain – with projections throughout the brain.
SSRI
Citalopram (Celexa)
(blocks the serotonin reuptake molecule)
Side Effects: GI, sexual problems, sleep, sweating, low Na+, mania.
Black Box: Increase SI (Suicidal Intentions) up to 25yo –> this applies to all drugs of this class*
Interactions: weak 2D6 inhibition
Can increase MAO-I’s and TCA levels
Other: QTc prolongation average 18msec at 60mg/day (dose related increase)
(>480msec – risk of Torsade’s)
What are the SSRI’s
SSRI’s:
- citalopram
- escitalopram
- fluoxetine
- paroxetine
- sertraline
- fluvoxamine
Norepinephrine (SNRI)
SNRI’s:
Most NE drugs have what is called “dual action” Meaning they increase both serotonin and norepinephrine in the synapse.
SNRI
Venlafaxine/ ER (Effexor/XR)
Side effects: GI, sexual, sleep, sweating, Na+, mania
Diastolic blood pressure increase*
Black Box: SI up to 25yo
Interactions: very weak 2D6 -, slight increase of
MAO-I & TCA’s
Other: dual re-uptake >225mg/day
discontinuation sx’s can be bad… BAD withdrawal side effects (SNRI) with FAST onset
In part because of half life (short) as opposed to other classes
TCA or tricyclic drugs
2nd group of drugs that modulate Norepinephrine
most (not all) … e.g.: of the TCA’s have “dual action”
TCA Drugs:
- nortryptiline
- imipramine
- Amitriptyline
- desipramine
TCA’s are either
- Tertiary Amines – having all three hydrogen replaced by other subgroups
- Secondary Amines – where one of the 3 side groups is cleaved off and H again in its place
(Secondary Amines are metabolites of Tertiary Amines
This (cleaving to secondary amine) does 2 things
- reduces side effects - shifts the predominant action more toward Norepinephrine reuptake inhibition.
(See slide 21 for specifics)
TCA
Nortriptyline (Pamelor)
(A secondary amine)
Dose: 75 – 150mg/day
Level:50 – 150 ng/ml
(Inverted U shape efficacy curve (levels between 50 – 150 are ideal anything below or above are less efficacious)
Side effects: wt gain, sedation, ACh, hypotension, arrhythmia, sexual, sweating
Interactions: 2D6 inhibition
MAO-I, TCA’s, tramadol
Other: Lethal in overdose (LD50
is 2000-3000mg)
*it has an easy to follow blood level and well established serum level correlated to clinical effect.
NDRI
3rd group of drugs, those that modulate dopamine
Buproprion
Buproprione is the ONLY purely elevating drug
(acts on norepinephrine AND dopamine, it has no serotonin action)
There are 5 clusters of dopamine neurons - only a subset are involved in mood
Main tract focus is in the mesolimbic tracts - goal is to elevate DA
NDRI
Bupropion (Wellbutrin/SR/XL, Zyban)
Key things to remember with bupropion:
Does NOT effect serotonin –> no sexual side effects
It’s effect is on NE and D – acts much like a stimulant
May cause:
insomnia, tremors, tinnitus and seizures
___________________________
Don’t give to ppl with epilepsy or ppl with a metabolic disorder (eating disorder)
This class is least likely to cause weight gain - (most likely is in histamine class)
Does NOT affect sex drive
LEAST likely to cause mania
(Also marketed as Zyban for smoking cessation) - because it blocks nicotinic receptors (again part of that monoamine receptor tree).
MAO-I
They increase all 3 monoamine transmitters (Serotonin, Norepinephrine, Dopamine)
*prevent the breakdown of endogenous molecules & after they undergo reuptake they can be redistributed into synapse
- NOT like all the other drugs described (by blocking re-uptake at the synapse) – RATHER by permanantly killing the intracellular enzyme monoamine oxidase (thus MOA-I)
- Monoamine oxidase (normally inactivates all 3 monoamines as they are brought back into the cells) - these are called “suicide inhibitors” – because they basically kill the enzyme. –> but with a MAO-I you’re blocking the breakdown of 3 monoamines
- thus – when you switch from other AD’s to MAO-I’
- 2 week “wash-out” period
- either let prior drug get metabolized out
- or allow MAO enzyme to replenish
These are the 2 primary MAO-I’s
Phenelzine (Nardil)
- Developed as TB drug
- sedating
Tranylcypromine (Parnate)
- Developed as Amphetamine
- stimulating
*Because of potential side effects due to this broad mechanism of action they are 3rd line AD’s
But are likely more efficacious that others as well – due to this triple action.
Serotonin syndrome:
excess Serotonin
(drug induced)
when drugs that increase serotonin are added
Triad
- MS changes
- Autonomic instability
- Neuromuscular signs
Avoid combos of:
- SSRI, SNRI, TCA
- Tramadol
- meperidine (dilaudid) - an opiate
- Dextromethorphan
- Amphetamines
in 1984 – meperidine was given by an apparently overworked and tired intern and resident to a young woman taking phenelzine – she died from Serotonin syndrome (Libby Zion)
- the investigation later resulted in the new resident duty hour guidelines. - so you can thank phenelzine, meperidine and Libby for your shorter shifts.
Fever/Agitation/Shaking
Hypertensive Crisis:
(excess DA/NE)
“Cheese Syndrome”
hypertensive crisis – when dietary sources of tyramine are added.
Low tyramine diet
Aged, smoke, fermented
- tyramine is a precursor to D and NE - excess D and NE – cause the high blood pressure, headaches, seizures, stroke and death - Again remember those adrenergic receptors on the monoamine receptor tree
Quickly some other AD’s – that again work on 5HT and NE – but from different mechanisms
(Increasing S AND NE)
NaSSA
- mirtazapine
SARI
- Nefazodone
- Trazodone
NaSSA(Dual Reuptake)
- Mirtazapine (Remeron)
Dose: 15-45mg/day
Side effects: sedating!, wt gain! (histamine)
Interactions:no P450
Do not combine w/ MAO-I
Other:low sexual SE’s
*is used in ppl with low weight & have trouble sleeping – increases appetite & helps sleep
SARI’s (serotonin 2A antagonists)
Dual Reuptake
Dual Action but different mechanism from SNRI, TCA, or MAO-I’s
Trazodone.Nefazodone ALWAYS used as a sleep aid usually
