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Pharm (Geisel M2) > Term 2 Pharm - Anxiety & Depression Drugs > Flashcards

Term 2 Pharm - Anxiety & Depression Drugs Flashcards

1
Q

Depression

A
  • 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).”
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2
Q

Libby Zion

A
  • Fever (107F), agitation, shaking

- Meperidine and restraints

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3
Q

Main target of antidepressants?

A
  • 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.
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4
Q

What are amines?

A

In amines, the hydrogen atoms in the ammonia have been replaced one at a time by hydrocarbon groups

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5
Q

What are the key actors in the monoamine hypothesis of depression?

A

Serotonin, Norepinephrine, Dopamine

(Monoamine-deficiencyhypothesis)

Current Leading Theory: Enhanced Neuroplasticity(Structural and Functional)

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6
Q

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.

A

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

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7
Q

Class Leaders (model drugs of each category) of Antidepressants

A

Serotonin
- SSRI (citalopram)

Norepinephrine

  • SNRI (venlafaxine)
  • TCA (nortryptiline)

Dopamine
- NDRI (bupropion)

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8
Q

What do SSRI’s do?

A

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

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9
Q

Where are most of the cells that use serotonin as a primary signaling messenger?

A

In the Raphe Nucleus in the brain stem and mid-brain – with projections throughout the brain.

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10
Q

SSRI

Citalopram (Celexa)

A

(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)

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11
Q

What are the SSRI’s

A

SSRI’s:

  • citalopram
  • escitalopram
  • fluoxetine
  • paroxetine
  • sertraline
  • fluvoxamine
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12
Q

Norepinephrine (SNRI)

A

SNRI’s:

Most NE drugs have what is called “dual action” Meaning they increase both serotonin and norepinephrine in the synapse.

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13
Q

SNRI

Venlafaxine/ ER (Effexor/XR)

A

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

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14
Q

TCA or tricyclic drugs
2nd group of drugs that modulate Norepinephrine
most (not all) … e.g.: of the TCA’s have “dual action”

A

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)

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15
Q

TCA
Nortriptyline (Pamelor)
(A secondary amine)

A

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.

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16
Q

NDRI

3rd group of drugs, those that modulate dopamine

A

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

17
Q

NDRI

Bupropion (Wellbutrin/SR/XL, Zyban)

A

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).

18
Q

MAO-I

A

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
19
Q

These are the 2 primary MAO-I’s

A

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.

20
Q

Serotonin syndrome:

excess Serotonin

A

(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

21
Q

Hypertensive Crisis:
(excess DA/NE)
“Cheese Syndrome”

A

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
22
Q

Quickly some other AD’s – that again work on 5HT and NE – but from different mechanisms
(Increasing S AND NE)

A

NaSSA
- mirtazapine

SARI

  • Nefazodone
  • Trazodone
23
Q

NaSSA(Dual Reuptake)

- Mirtazapine (Remeron)

A

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

24
Q

SARI’s (serotonin 2A antagonists)

Dual Reuptake

A

Dual Action but different mechanism from SNRI, TCA, or MAO-I’s

Trazodone.Nefazodone ALWAYS used as a sleep aid usually

25
Q

SUMMARY of Anti-Depressants

A
  • AD’s are all working by increasing 1 or all 3 of the monoamines.
  • it is not this increase alone that gives them their efficacy
  • but rather appears to be effects on Receptors/Transporters and Signal Transduction (resulting in Plasticity, Resilience, & Neurogenesis)
26
Q

AD effects on Receptors/Transporters and Signal Transduction (resulting in Plasticity, Resilience, & Neurogenesis)

A 
Including Protein Kinases- 
	that cause cytoskeletal changes 
	that result in a modification in gene expression related to 
Gene Expression/Neuroplasticity
Transcription factors- CREB
Neurotrophic Factors- BDNF, VEGF, GDNF

*BDF (brain derived neutophic factor)  substance involved in all pathways

27
Q

Benzodiazepines

A

Class leader is Diazepam (Valium).

  • previous the options were Barbituates and typical neuroleptics (overall fairly harsh meds with many serious side effects and quite dangerous)
    - Difference Between barbituates and BZD
    - BZD cannot activate the GABA- R alone(this makes them safer)
  • 1969 to1982 -most prescribed drug in America
  • Since 2002 – rates of Rx are on the decline (concerns of dependence, withdrawal concerns of dependence, withdrawal)
28
Q

5 Therapeutic Uses of Benzodiazepines

A
  • sedative – hypnotics
  • anxiolytics
  • Seizure control
  • Muscle relaxant
  • anterograde amnestics/anesthtics – eg. colonoscopy (to forget unpleasant experiences)
29
Q

GABA Receptor

A

GABA is most abundant inhibitory receptor in the brain.
Account for 20-30% of all neurons in the brain
GABA receptors are made of 5 subunits.
only those with alpha 1-3 and alpha 5 are BZD specific
Most BZD, like valium are non-specific – activating all of these receptors no matter where they are in the brain – conferring all of the 5 therapeutic functions mentioned earlier.

  • whereas something like Zolpidem (ambien) is called “alpha 1 specific” non-BZD, BZD – this specificity makes it sedating and an amnestic, but lacks the other therapeutic functions.

The GABA receptor is actually a pore or hole.
- BZD themselves do not alter the pores activity themselves (Barbituates and alcohol do)

Once a BZD binds, they act as Positive Allosteric Modulators

	- they increase the receptors affinity for endogenous GABA
	- and increase the frequency of opening of the chloride channel when activated by GABA.

They do NOT activate GABA receptor –> they just prime receptor to be more easily activated & stay activated longer by endogenous GABA
Benzos are HARD to harm yourself (barbituates ARE easy to) but it’s easy to do it if you combine it with alcohol

(Can be used for alcohol withdrawal, both bind to same receptor)

30
Q

Action Potential- Inhibition

A

By filling the inside of the cell with negative charges
This drives the resting potential lower – or “hyperpolarizes the cell” - which means more energy or stimulation is required to make that nerve cell fire.

31
Q

5 therapeutic functions which are ALL inhibitory functions - or basically functions achieved by turning off nerve cells.

A

1) sleep
2) amnesia – turning of memory
3) anxiety
4) seizures
5) muscle contraction

32
Q

Diazepam or valium (our prototypical BZD) is non-selective

A

it binds to all receptors with alpha 1-3, and 5 subunits and turns them down or off - wherever they are in the brain

Receptors containing the α1, α2, α3or α5subunit are benzodiazepine sensitive

33
Q

Benzodiazepine (BZD)

Diazepam (Valium)

A

Dose: 4 - 40mg/day

Half-life: 20-50 hours

Side effects: sedation, depression, amnesia, ataxia, dependence, withdrawal

Interactions: CNS depressants, (opiates), cimetidine.

Other: Hepatically cleared, Active metabolites

flumazenil - reverses

LONG half life!

34
Q

Which 2 Benzodiazepines should you NEVER give to someone who is an alcoholic

A

Diazepam & Chlordiazepoxide
(Metabolites build up in cirrhosis)

see slide 45

35
Q

Zolpidem – α 1selectiveBZD agonist

A

zolpidem
zalaplon
eszopiclone

(preferential affinity for α1receptors)

or those that selective bind to GABA receptors with alpha 1 subunits.
- they more specifically mediate sleep (do NOT help with anxiety)
this alpha 1 specificity helps explain the memory – or more accurately – the absense of memory related behaviors or zolpidem that are so notorious

36
Q

Buspirone

A

BuSpar

5HT-1A partial agonist
For GAD (generalized anxiety disorder) and Augment MDD

Side effects: Dizziness, HA, sedation, nervous/restless

Interactions: MAO-I

Other: No sexual SE, No dependence, No withdrawal

Takes 4 weeks + to work

Pharm (Geisel M2) (15 decks)

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