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Psychiatry > Mood Altering Drugs > Flashcards

Mood Altering Drugs Flashcards

1
Q

What drug is a tricyclic antidepressant?

A

amitriptyline

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2
Q

What are the 3 SSRIs?

A
  1. sertraline
  2. fluoxeline
  3. paroxetine
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3
Q

What are the “newer antidepressants”?

A
  1. bupropion
  2. trazodone
  3. duloxetine
  4. venlafaxine
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4
Q

What benzodiazepine is sometimes used as an antidepressant?

A

alprazolam

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5
Q

What are the main MAOIs?

A
  1. selegiline

2. tranylcypromine

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6
Q

What 4 drugs are used to treat bipolar disorder?

A
  1. lithium
  2. valproate
  3. carbamazepine
  4. atypical anti-psychotics
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7
Q

What is the biogenic amine hypothesis?

How was it derived?

A

Mood disorders are caused by abnormally low levels of monoamines [specifically NE and 5HT].
This theory was derived because reserpine which decreased NE caused depression in some individuals

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8
Q

Both TCAs and MAOIs increase the level of neurotransmitters in the synapse. How do they differ in MOA?

A

TCAs prevent reuptake, while MAOIs inhibit degradation

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9
Q

What is the mechanism of a1 receptors?

What is the effect on serotonergic neurons?

A

they couple to GPCR that activates PLC which breaks down PIP–>IP3, DAG

IP3–> Ca release
DAG–> activates PKC

On serotonergic neurons, it stimulates firing and enhances 5HT release

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10
Q

What is the mechanism of a2 receptors? What is the effect on serotonergic neurons? noradrenergic neurons?

A

they inhibit adenylyl cyclase –> reduced cAMP

presynaptic noradrenergic neurons –> inhibit NE release

synaptic terminal serotonergic–> inhibit 5HT release

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11
Q

What is the mechanism of B1 receptors?

A

increase cAMP–> excitatory

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12
Q

Where is more than 90% of the body’s 5HT located?

A

Periphery in platelets, mast cells, enterochromaffin cells of GI.

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13
Q

In the CNS where is 5HT released?

Where is NE released?

A

both are released from neural projections from the brainstem

NE- locus ceruleus
5HT- raphe nucleus

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14
Q

How is serotonin synthesized?

A
  1. tryptophan—tyrosine hydroxylase–> 5-hydroxytryphtophan
  2. decarboxylase –> 5HT
  3. MAO–> HIAA
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15
Q

How is dopamine and NE synthesized?

A
  1. tyrosine —tyrosine hydroxylase–>DOPA
  2. decarboxylase–> dopamine
  3. DBH–> NE
  4. MAO–> dihydromandelic acid
  5. VMA–> COMT
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16
Q

Describe the 5HT1a receptor.
Inhibitory or excitatory?
Where in the CNS are they found?
Auto or heteroreceptors?

A

inhibitory causing:

  1. decrease in cAMP
  2. opening of K channels

They are found in:

  1. raphe nuclei where they are autoreceptors for negative feedback
  2. hippocampus, amygdala, frontal cortex as postsynaptic heteroreceptors.
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17
Q

What is believed to be the major factor in precipitating serotonin syndrome?

A

activation of 5HT1a heteroreceptors [inhibitory] in the hippocampus, lateral septum, entorhinal, amygdala and frontal cortex

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18
Q

Describe 5HT1d receptors.
Is it inhibitory or excitatory?
Auto or heteroreceptors?

A

It depresses cAMP levels when activated.

It is autoreceptors on serotonergic synpapses that provide negative feedback.

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19
Q

Describe 5HT2a receptors.
Excitatory or inhibitory?
Where are they found?

A

They activate GCPR, increase PLC–>IP3, DAG–>excitatory

They are found in the hypothalamus and in the periphery [platelet aggregation, smooth muscle contraction]

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20
Q

Describe 5HT3 receptors.
How are they distinct from the other serotonin receptors in terms of structure?
Why are they of clinical importance?

A

They are ligand-gated ion channels rather than GPCR.

They are of importance because they are believed to be the cause of the uncomfortable side effects of anti-depressants –>nausea,vomiting from brainstem system

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21
Q

What serotonin receptor is responsible for triggering nausea and vomiting response due to increased serotonin due to anti-depressant use?

A

5HT3

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22
Q

In synaptic vesicles, there is often peptides co-packaged with neurotransmitters. What are examples of the co-packaged nerotransmitter/neuropeptide pairs?

In these pairs, where do the neurotransmitters come from?

A
  1. NE or Epi with enkaphelins
  2. 5HT with substance P

The neutrotransmitters do NOT come from synthesis in the ER and transport in the golgi
INSTEAD
1. dopamine and 5HT are transported through the synaptic vesicle membrane
2. NE is synthesized in the synaptic vesicle

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23
Q

How do glutamate and GABA enter synaptic vesicles?

How does this differ from Ach and monoamines?

A

Glut and GABA enter via electrochemical gradient

Ach and monoamines enter via pH gradient

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24
Q

What is the principle mechanism of inactivating neurotransmitters after their release?
Because of this, what are the major targets of most currently used antidepressants [and many anxiolytics and stimulants]?

A

Reuptake so presynaptic monoamine transporters are the target

DAT–> dopamine
SERT–> serotonin
NET–> NE

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25
Q

What drug/substance inhibits DAT, NET and SERT?

A

cocaine

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26
Q

What is the biological basis for antidepressant action?

A

After the antidepressant is started,

  1. synaptic monoamine levels decrease due to neg feedback on autoreceptors [5HT1a, HT1d]
  2. inhibitory autoreceptors gradually get down-regulated and synaptic monoamine again rises
  3. post-synaptic excitatory receptors are also down-regulated, but to a lesser degree so you still get desired effects
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27
Q

What is the key problem of the bioamine hypothesis for depression?

A

Antidepressants have immediate effects on synaptic monoamine levels, but therapeutic benefits are not manifested for weeks [2-4]

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28
Q

What is the transcriptional regulation model of antidepressants?

A

Anti-depressants induce increase in neurotransmitter level that activates signal transduction, upregulating factors that trigger synthesis of new proteins.

  1. B1 on 5HT4-7 increase cAMP–> activate CREB
  2. a1 on 5HT2 increases Ca and PKC –> change gene transcription

It is thought that this leads to an increase in BDNF

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29
Q

What is the neurotrophic factor hypothesis of antidepressants?

A

Stress and depression downregulate brain derived neurotrophic factor BDNF causing atrophy of neurons especially in the hippocampus.

It is thought that antidepressants inhibit MAPK phosphatase that turns off ERK-P that usually converts to BDNF

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30
Q

How does TCA differ from the antipsychotic phenothiazine?

How does this change the function of the drug?

A

Instead of a Sulfur on the middle ring, it has 2 carbons.

This results in the inability to block dopamine receptors but gained ability to block monoamine reuptake

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31
Q

What structure is the TCA amitriptyline?
What is its preferential function?
What happens when it is metabolized?

A

It is a tertiary amine that blocks the uptake of 5HT preferentially over NE.

When it is metabolized it is demethylated and becomes a secondary amine which still has antidepressant effects, but blocks NE preferentially over 5HT and has fewer side effects

32
Q

What is the MOA of TCAs?

A

They inhibit the reuptake of monoamines after exocytosis to increase the synaptic concentration of NE and 5HT

33
Q

How are TCAs metabolized?
What is the half life of most TCAs?
What drug interactions are there?

A

TCAs are metabolized in the liver by P450s and have a typical 1/2 life of about 24 hours.

Drug interactions:

  1. anti-epileptics because they induce P450s
  2. Cimetidine- blocks P450s
  3. meperidine, pressors, MAOIs –> lethal HTN
  4. TCAs block uptake of tyramine and amphetamine vasopressors
34
Q

The major adverse effects of TCAs come from their ability to do what?

A

Block muscarinic, H1 histaminic and a-adrenergic receptors.

Tertiary have more side effects than secondary.

35
Q

What are the 5 main adverse effects of TCA?

A
  1. anticholinergic- sedated, constipated, urinary retention, blurred vision, confusion
  2. anti a1-adrenergic = orthostatic hypotension
  3. cardio effects = widening of QRS interval and slowed cardiac conductance
  4. sedation because of H1 effects
  5. weight gain = slowed metabolism, craving sweets
36
Q

What are the 4 main uses for TCAs?

A
  1. 70% antidepressant response - not as good as newer drugs
  2. OCD - clomipramine bc it blocks 5HT reuptake
  3. Nocturnal enuresis - because they cause urinary retention [anticholinergic effect]
  4. panic disorder/agoraphobia [SSRIs are better]
37
Q

What is the MOA of SSRIs?

How do they differ from TCAs?

A

Selective-serotonin reuptake inhibitors [very little effect on NE]
They differ from TCAs because they have very little effect on a1, H1 or muscarinic receptors decreasing the side effects.

38
Q

For SSRIs, antidepressant and anxiolytic effects of agents that enhance 5HT neurotransmission are believed to result from stimulation of what receptors?
What receptors are most adverse effects linked to?

A

Anti-depressant, anxiolytic = 5HT1

Adverse effects = 5HT2, 5HT3

39
Q

How do the SSRIs differ in terms of half-lives?

What is the implication?

A

Sertraline and paroxetine have a 1 day half life [same as TCAs]

Fluoxetine has a 2 day T1/2 but its active metabolites last for 7 days so it takes 4-5 weeks to get to steady state

40
Q

How do the SSRIs differ in terms of drug interactions?

A

Paroxetine and fluoxetine inhibit P450s decreasing metabolism of TCAs and other anti-psychotics

Sertraline has less effect on P450s

41
Q

What drugs should be specifically avoided with ALL SSRIs?

A

MAOIs because they can cause serotonin syndrome

42
Q

What are the adverse effects of SSRIs due to interaction with:

  1. 5HT2
  2. 5HT3
  3. general effects
A
  1. headache, insomnia, agitation, anxiety, sexual dysfunction
  2. nausea, vomiting
  3. falls/fractures in elderly, teratogenic effects
43
Q

What is serotonin withdrawal syndrome?

When is the onset and duration?

A

When the drug is removed, the patient will experience:
insomnia, fatigue, dizziness, chills, vomiting diarrhea

Onset: several days after cessation of the drug
Persistance: 3-4 weeks [except fluoxetine due to long 1/2 life]

44
Q

Which SSRIs have non-linear kinetics?

A

fluoxetine, paroxetine [due to p450 induction]

45
Q

In addition to depression, what are the other indications for SSRIs?

A
  1. panic disorders
  2. bulemia, anorexia
  3. OCD
  4. PTSD
  5. generalized anxiety
  6. PMDD [only fluoxetine]
46
Q

What is the MOA of venalfaxine?
What is the main use?
What is the side effect?

A

Inhibits reuptake of NE and 5HT without blocking muscarinics, H1 or adrenergics.

Behaves like TCA, but without the harsh side effects

Main use: treatment of chronic pain
Side effect: possible increased BP at high doses. discontinuation insomnia, flu-like symptoms and irritability

47
Q

What is the MOA of duloxetine?
What is the main use?
What are the side effects?

A

Like, venlafaxine, it is a 5HT and NE uptake inhibitor.

Main use: diabetic neuropathic pain
Side effects: less increase in BP than venlafaxine and less rebound symptoms, but there is induction of p450s so warn alcoholic or liver disease patients

48
Q

What is the MOA of trazadone?

A
  1. inhibits 5HT reuptake
  2. activates 5HT1a
  3. antagonizes 5HT2a

It also antagonizes a1-adrenergics and histaminergic receptors [sedation, orthostatic hypotension]

49
Q

What is the MOA of bupropion?

A

We used to think it was a dopamine uptake blocker, but now we think it blocks NE reuptake by an active metabolite, hydroxybupropion.

*only available NDRI -NE, dopamine reuptake inhibitor

50
Q

What is the only known NDRI?
What are the uses?
What are the negative effects?

A

Bupropion - it blocks NE and DA
It does NOT cause sexual dysfunction like most SSRIs but, it does have a low seizure risk.

Uses:

  1. antidepressant
  2. aid in smoking cessation
  3. ADHD

Negative effects:

  1. slight seizure risk
  2. worsens and induces panic in panic disorders
51
Q

What non-SSRI antidepressant can actually WORSEN panic in panic disorders?

A

Bupropion

52
Q

What benzodiazepine is useful as an anti-depressant, and is used in panic disorders and agoraphobia?

A

alprazolam

53
Q

What are considered to be the best drugs for “atypical depression” where there is overeating, oversleeping?

A

MAOIs - tranylcypromine

54
Q

What are the 2 types of MAOs?

A 
MAO-A = NE and 5HT
MAO-B = dopamine
55
Q

What receptor does selegiline act on at low and high doses?

What is the possible negative effect of this drug?

A

it is a selective MAO-B inhibitor at low doses and can also inhibot MAO-A at high doses.

Skin patch delivery allows inhibition of both types MAO in the brain and restricts the inhibition of tyramine degradation in the gut.
This leads to a dangerous rxn with cheese.

56
Q

What is the MOA of MAOIs?

A

MAO enzymes are on the outer surface of mitochondria and oxidize cytoplasmic monoamines [not those amines in synaptic vesicles].
MAOIs increase cytoplasmic amines which can than be transferred into secretory vesicles.

They are IRREVERSIBLE

57
Q

What is the pharmacokinetics of MAOIs?

A

They are irreversible, so their action will persist until the resynthesis of MAO.

58
Q

What are the drug and food interactions with MAOIs?

A
  1. tyramine- cheese and wine. It is metabolized by MAO-A in the liver and gut and since it is blocked, tyramine builts up and causes HTN, headache, chest pain
  2. TCA/SSRI that increase 5HT can cause serotonin syndrome which presents similarly to malignant hyperthermia [sweating, diarrhea, myoclonus, hyperthermia, convulsions]
  3. Sympathomimetics- enhances the effects of amphetamines, methylphenidate, ephedrine
  4. meperidine and DM
59
Q

How long should you wait when switching from an MAOI to another antidepressant? Why?

A

2 weeks because if MAOI and SSRI/TCA are given together, there is increased risk of serotonin syndrome with changes in mental status, hyperthermia, sweating, diarrhea, myoclonus

60
Q

What are the 4 major adverse effects of MAOIs?

A
  1. orthostatic HTN
  2. dizziness, headache, insomnia
  3. constipation, dry mouth, blurred vision [antichol]
  4. hepatotoxicity
61
Q

What are the therapeutic uses of MAOIs?

A

second-line drugs that are administered to patients that were refractory to TCA/SSRI treatment

62
Q

What is required for a patient to be considered “responsive” to antidepressants?
What is necessary for remission vs. recovery?

A

50% reduction in symptoms of depression as judged by a psychiatric rating scale

Remission is complete loss of all symptoms over a given period.

Recovery is loss of all symptoms for 6-12 months.

63
Q

What is likely to increase remission rates for antidepressants?

A

If the drug affects 5HT and NE pathways

64
Q

After the first recurrence, what is the probability of further recurrence?

A

50-90%

After 2nd recurrence, there is greater than 90% and the patient should be on medication permanently

65
Q

What has been the standard drug for treatment of bipolar disorder since the 1950s? What are the effects?

A

Lithium is anti-manic and anti-depressant so it is a “mood stabilizer”.
It has greater effect on the manic episodes than depressive.
It is the most protective drug against suicide

66
Q

What is the MOA of lithium?

A

The exact mechanism is unclear, but it is thought that it:

  1. attenuates phosphoinositide signaling [by inhibiting inositol-1-phosphatase] and decreasing Ca release
  2. inhibit activation of PKC

Effect takes days to weeks so it is believed that long-term neuronal changes take place

67
Q

What are the pharmacokinetics of lithium?
What are the effects of Na on Li?
What is the target plasma concentration of Li? How does it vary with age?

A

It is absorbed rapidly with a peak serum concentration in 3 hrs.
If Na is depleted [sweat, vomit, diarrhea] the kidney will absorb more Li in the prox tubule and increase risk of toxicity .

Target concentration is 1mEq/l for acute episodes and 0.6-1.2mEq range once the acute episode is cleared. Young adults need more, elderly need less

68
Q

What drugs slow Li excretion and may lead to toxicity?

A

NSAIDs, diuretics, anything that depletes Na

69
Q

What are the adverse effects of Li?

A
  1. Early GI effects:
    - nausea, vomiting, diarrhea
  2. Chronic renal effects:
    - nephrogenic diabetes insipidus [kidney doesnt respond to ADH]
  3. hypothyroidism
  4. weight gain
  5. lethargy
70
Q

A bipolar patient taking Lithium develops tremor, spasticity, confusion, slurred speech, convulsion, vomiting. What is the most likely reason and what is treatment?

A 
Lithium toxicity due to depleted sodium.
You need to:
1. stop giving the drug
2. saline infusion to increase Na
3. hemodialysis
71
Q

What drugs are usually used as anti-epileptics but can be anticonvulsants given in bipolar disorder [esp. mixed mania and rapid cycling]?

A
  1. valproic acid -antimanic and given with lithium

2. carbamazepine

72
Q

What adverse effects are associated with valproic acid?

A

tremor, sedation, GI upset, hair loss, weight gain, impaired cognition
*teratogenic

73
Q

What are the adverse effects of carbamazepine?

A

LESS cognitive dysfunction than valproic acid, but increased risk of :
1. leukopenia–> aplastic anemia

74
Q

What adverse effect do all three bipolar drugs share?

A

teratogenic

75
Q

What is thought to be the major cause of manic euphoria in bipolar disorder?
What are the implications of this?

A

dopamine hyperactivity THEREFORE, antipsychotics that block dopamine may be used for tranquilizing effects that take place in hours instead of days like lithium

76
Q

What are the adverse effects of haliperidol?

A
  1. EPS

2. tardive dyskinesia

Psychiatry (18 decks)

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