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Class: Neuro > Anti-Depressants > Flashcards

Anti-Depressants Flashcards

1
Q

Pathogenesis of Depression: What is the monoamine hypothesis of mood that is the basis of all anti-depression medication therapy?

A

DECREASED MONOAMINE (Serotonin [5-HT] and(or) NE) results in DEPRESSED MOOD

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2
Q

What are the major steps of serotonin (5-hydroxytryptamine) synthesis?

A

1) Trp enters serotonergic neuron via Trp receptor
2) Trp gets hydroxylated into 5-HTP via Trp hydroxylase
3) 5-HTP gets decarboxylated into 5-HT (serotonin) via 5-HTP decarboxylase

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3
Q

What are the 3 fates of serotonin post-synthesis?

A

1) Can enter pre-synaptic vesicles via VAT for vesicular transport and release onto the post-synaptic membrane
2) Can enter pre-synaptic vesicles via VAT -> Exit -> REUPTAKE by 5-HT receptors of the serotonergic neuron
3) Stays in the serotonergic neuron -> Gets metabolized into 5-HIAA by cytoplasmic MAO

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4
Q

What are the major steps of NE synthesis?

A

1) Tyr enters the adrenergic pre-synaptic neuron by Tyr transporter
2) Tyr gets HYDROXYLATED into DOPA by tyrosine-3-monooxygenase
3) DOPA gets DECARBOXYLATED into DOPAMINE by aromatic L-AA decarboxylase
4) DOPAMINE gets HYDROXYLATED into NE by dopamine beta hydroxylase

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5
Q

What are the 4 fates of NE post-synthesis?

A

1) Enters into the pre-synaptic vesicle by VAT -> Exits -> Acts on post-synaptic tissue
2) Enters into pre-synaptic vesicle by VAT -> Exits -> Gets re-uptaken by adrenergic neuron by NE reuptake transporter
3) Enters into pre-synaptic vesicle by VAT -> Exits -> Post-synaptic COMT acts on NE and degrades it
4) Stays in the adrenergic neuron -> Pre-synaptic Cytoplasmic MAO degrades NE into de-aminated derivatives

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6
Q

What are the two targets of major classes of anti-depressants?

A

1) Block re-uptake of NT by the pre-synaptic neuron

2) Block CYTOPLASMIC MOA’s metabolic breakdown of NT in the pre-synaptic neuron

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7
Q

What are the 6 major classes of anti-depressants?

A

1) SSRIs
2) SNRIs
3) TCAs
4) MAOIs
5) 5-HT2-R antagonists (Serotonin antagonists)
6) Heterocyclics

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8
Q

What are the 2 main limitations of the monoamine hypothesis?

A

1) Anti-depressants may have a RAPID ONSET, BUT clinical effects require 3 or more weeks to present
2) Reserpine has RAPID ONSET of effect of depleting NT, BUT several weeks are required to induce depression

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9
Q

What can explain the discrepancy between the pharmacological action and delayed clinical effect of anti-depressants?

A

PRE-SYNAPTIC AUTORECEPTORS - Cell surface receptors on the pre-synaptic neuron that binds to NT released by that cell or neighboring cell
**(DIFFERENT from re-uptake transporters)

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10
Q

What is the potential model explanation of the delayed clinical effect of anti-depressants (i.e. explain the autoregulatory mechanism of pre-synaptic autoreceptors)?

A

PRE-TREATMENT: Pre-synaptic autoreceptors bind released NT -> Ligand (NT)-bound autoreceptors exert inhibitory effect on NT synthesis and release = LOW level of signaling

ACUTE TREATMENT (SSRI or TCA): Blocked re-uptake of NT -> INCREASED NT levels in the synaptic cleft -> INCREASED levels of ligand (NT)-bound autoreceptors -> ENHANCED Inhibitory effect on NT synthesis and release = LOW level of signaling

CHRONIC TREATMENT (SSRI or TCA): CONTINUOUS exposure of NT in the synaptic cleft -> DOWNREGULATION of pre-synaptic receptors -> DISINHIBITION of NT synthesis and release -> INCREASED NT release to post-synaptic cell = THERAPEUTIC level of signaling

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11
Q

Name the 3 classes of MA-reuptake transporter inhibitors.

A

1) SSRIs
2) SNRIs
3) TCAs

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12
Q

CLASS 1 SSRI) Name the 6 SSRIs with their brand names.

A

1) **FLUOXETINE (Prozac)
2) FLUVOXAMINE
3) **PAROXETINE (Paxil)
4) **SERTRALINE (Zoloft)
5) CITALOPRAM
6) ESCITALOPRAM - S-enantiomer of citalopram (LEXAPRO)

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13
Q

CLASS 1 SSRI) Name the 6 clinical usages of SSRIs.

A

1) Major Depression
2) Anxiety Disorder
3) OCD - obsessive compulsive disorder
4) PTSD - post-traumatic stress disorder
5) PMDD - post-menstrual dysphoric disorder
6) Bulimia

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14
Q

CLASS 1 SSRI) What is the mechanism of action of SSRIs?

A

SELECTIVELY inhibits 5-HT (Serotonin) re-uptake, compared to NE re-uptake -> INCREASES 5-HT (Serotonin) level in the synaptic cleft

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15
Q

CLASS 1 SSRI) Side effects of SSRI are due to an elevation of what neurotransmission?

A

Side effects limited to ELEVATED SEROTONIN transmission in various tissues + CNS since SSRIs selectively act on 5-HT reuptake channels

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16
Q

CLASS 1 SSRI) What are the adverse side effects of SSRIs?

A

N/H/I - nausea/headache/insomnia
AA - anxiety/agitation
E - extrapyramidal effects (early in treatment
SSS - sexual dysfunction, seizures with gross overdose, serotonin syndrome if combined with MAOI

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17
Q

CLASS 2 SNRIs) Name the 2 SNRIs

A

1) **VENLAFAXINE (Effexor)

2) DULOXETINE (Cymbalta)

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18
Q

CLASS 2 SNRI) Name the 4 clinical uses.

A

1) Major Depression
2) Menopausal symptoms
3) Chronic pain
4) Fibromyalgia

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19
Q

CLASS 2 SNRI) What is the mechanism of action of SNRIs?

A

Inhibits the re-uptake of BOTH 5-HT (Serotonin) and NE

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20
Q

CLASS 2 SNRI) Side effects of SNRIs are due to the elevation of which neurotransmission?

A

Inhibiting re-uptake of BOTH 5-HT and NE = ELEVATED neurotransmission of 5-HT and NE in various tissues + CNS

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21
Q

CLASS 2 SNRI) Name the adverse side effects of SNRIs.

A

Overlapping SSRI side effects:
N/H/I - Nausea/headache/insomnia
AA - anxiety/agitation
E - extrapyramidal effect (early treatment)
SSS - sexual dysfunction + seizures (gross overdose) + serotonin syndrome if taken with MAOI

NE-mediated side effects (“ASH”)

1) Anti-cholinergic
2) Sedation
3) Hypertension (particularly with Venlafaxine)

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22
Q

CLASS 3 TCA) Name the 5 TCAs.

A

I/C/D - A/N

1) **IMIPRAMINE
2) CLOMIPRAMINE
3) DESPIRAMINE
4) **AMITRYPTILINE
5) NORTRYPTILINE

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23
Q

CLASS 3 TCA) Name the 3 clinical uses of TCAs.

A

1) Major Depression
2) Chronic Pain
3) OCD (particularly CLOMIPRAMINE)

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24
Q

CLASS 3 TCA) What is the mechanism of TCAs? (2)

A

1) PRE-SYNAPTIC LEVEL: Blocks re-uptake of BOTH 5-HT (serotonin) and NE
2) POST-SYNAPTIC LEVEL: Blocks post-synaptic alpha-adrenergic receptors + muscarinic receptors + histamine receptors

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25
Q

CLASS 3 TCA) Do TCAs have a narrow or wide range of side effects? Why?

A

BROAD range of side effects because they act on a variety of other receptors (e.g. the post-synaptic alpha-adrenergic receptors)

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26
Q

CLASS 3 TCA) How are DESPIRAMINE and IMIPRAMINE related to each other?

A

They are SEPARATE TCA drugs, but DESPIRAMINE is a metabolite of IMIPRAMINE

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27
Q

CLASS 3 TCA) IMIPRAMINE and DESPIRAMINE each have a greater affinity (i.e. selectivity) for a particular receptor. Which ones?

A

IMIPRAMINE - More selective for the serotonin reuptake transporter
(“I Scream …[for ice cream]” lol)
DESPIRAMINE - More selective for the NE reuptake transporter

28
Q

CLASS 3 TCA) What are the side effects of TCAs?

A

Overlapping side effects of SSRIs:
N/I/H, A/A, E, S/S/S - Nausea/Insomnia/Headache, Anxiety/Agitation, Sexual Dysfunction/Stroke with Gross amounts/Serotonin Syndrome when taken with MAOI

Separate, non-overlapping TCA Side Effects 
"AMSA, W - AMSA War?...." 
1) Alpha-block (orthostatic hypotension)
2) Muscarinic block
3) Sedation
4) Arrhythmia + Seizures with Overdose 
5) Weight Gain
29
Q

How was evidence attained for the monoamine hypothesis explaining the pathogenesis of depression? What was the mechanism?

A

RESERPINE (introduced as an anti-hypertensive) was found to INDUCE depression
Mech: Inhibits VAT (vesicular monoamine transporter) -> Nerve endings can not concentrate and store MA in vesicles -> MA accumulate in the cytoplasm -> Get degraded by MAO -> Little/no active MA released from nerve endings
CONCLUSION: LITTLE MA = INDUCTION of DEPRESSION

29
Q

CLASS 3 TCA: Which is the best MONOTHERAPY for treating severe MDD or BAD with psychosis?

A

AMOXAPINE (ASENDIN)

31
Q

CLASS 4 MAOI) Name the 2 MAOIs.

A

1) PHENELZINE

2) TRANYLCYPROMINE

32
Q

CLASS 4 MAOI) Name the main use of MAOI.

A

Major Depression Disorder that was UNRESPONSIVE to other drugs

33
Q

CLASS 4 MAOI) What is the binding affinity of PHENELZINE to the MAO and how does it explain its duration of action?

A

PHENELZINE = IRREVERSIBLE MAO inhibitor = LONG-LASTING inhibition

34
Q

CLASS 4 MAOI) Name the binding affinity of TRANYLCYPROMINE and its duration of action

A

TRANYLCYPROMINE = REVERSIBLE MAO inhibitor but still has PROLONGED effect

35
Q

CLASS 4 MAOI) What are the adverse effects of MAOIs?

A

“3H’s + COSBY w/o the BY”

1) Hypertensive reactions (MAOIs sensitize pts to indirect sympathomimetics [e.g. tyramine/epherine])
2) Hypertensive CRISES when taken with Tyramine-containing foods
3) Hyperthermia
4) CNS Stimulation (agitation, convulsions)
5) Orthostatic hypotension
6) Serotonin syndrome if taken with SSRI

36
Q

CLASS 5: 5-HT2-R-Ant) Name the 2 serotonin receptor antagonists.

A

“NT”

1) NEFAZODONE
2) **TRAZODONE

37
Q

CLASS 5: 5-HT2-R-Ant) Name the 2 clinical uses of these drugs.

A

1) Major Depression

2) Hypnosis (particularly TRAZODONE)

38
Q

CLASS 5: 5-HT2-R-Ant) What is the mechanism of these drugs?

A

Antagonize specifically the 5-HT2A-receptors residing in the CEREBRAL CORTEX
Inhibition of 5-HT2A-R associated with anti-anxiety, anti-depression, and anti-psychosis

39
Q

CLASS 5: 5-HT2-R-Ant) Is TRAZODONE the active form blocking serotonin receptors?

A

NO, it is a prodrug that gets converted to the active metabolite 5-HT2A antagonist

40
Q

CLASS 5: 5-HT2-R-Ant) How safe is NEFAZODONE?

A

“N for NOT safe”

NOT SAFE - “BLACK BOX WARNING” due to severe risk of HEPATOTOXICITY

41
Q

CLASS 5: 5-HT2-R-Ant) What are the 2 adverse effects of NEFAZODONE and TRAZODONE?

A

“SO”

1) Sedation (due to histamine H1 blockade)
2) Orthostatic hypotension (due to alpha blockade)

42
Q

CLASS 6 HETEROCYCLICS) Name the 2 heterocyclic anti-depressants.

A

“Cycle, a type can be mountain bike (MB)”

1) **MIRTAZAPINE
2) **BUPROPION

43
Q

CLASS 6 HETEROCYCLICS) What are 3 mechanisms of action of MIRTAZAPINE?

A

1) PRE-SYNAPTIC LEVEL: Blocks pre-synaptic alpha2receptors at BOTH adrenergic + serotonergic neurons -> Disinhibition of alpha-2-mediated inhibition of NT release -> ELEVATED NE and 5-HT RELEASE from pre-synaptic neurons
2) POST-SYNAPTIC LEVEL: Blocks several serotonin receptor isoforms
3) POST-SYNAPTIC LEVEL: Blocks histamine receptors

44
Q

CLASS 6 HETEROCYCLICS) What is the mechanism of action of BUPROPION?

A

Mechanism of action is unclear, but it is thought to ENHANCE NE and 5-HT neurotransmission

45
Q

CLASS 6 HETEROCYCLICS) What are the 3 main clinical uses of BUPROPION + MIRTAZAPINE?

A

1) Major Depression
2) Smoking Cessation (particularly BUPROPIONE)
3) Sedation (particularly MIRTAZAPINE)

46
Q

CLASS 6 HETEROCYCLICS) What clinical condition is MIRTAZAPINE highly used for?

A

Insomnia/Anxiety - used to induce sedation

47
Q

CLASS 6 HETEROCYCLICS) What clinical condition is BUPROPION highly used for?

A

Smoking Cessation

48
Q

CLASS 6 HETEROCYCLICS) What is the 1 adverse effect of BUPROPION?

A

Lowers SEIZURE threshold

49
Q

CLASS 6 HETEROCYCLICS) What is the 1 major adverse effect of MIRTAZAPINE?

A

Sedation - Due to histamine blockade action in the post-synaptic level

50
Q

PHARMACOKINETICS) List ADME of anti-depressants

A

A - Rapid ORAL absorption
D - Reach peak plasma levels at 2-3hrs, half-life 0.5-1day, tightly bound to plasma proteins
M - Metabolized by liver
E - Eliminated by kidney

51
Q

PHARMACOKINETICS) Which is the 1 SSRI that has a particularly LONG half-life (7-9 days)?

A

FLUOXETINE (Prozac) is metabolized to its active form NORFLUOXETINE (half-life = 7-9d)

52
Q

PHARMACOKINETICS) What is one precautionary factor when transitioning a pt from FLUOXETINE (SSRI) to a MAOI?

A

Even after fluoxetine is discontinued, it may remain in pt’s system for a while due to its long half-life (7-9d) -> Can result in SEROTONIN SYNDROME

53
Q

PHARMACOKINETICS) Which anti-depressant is extensively metabolized by CYP2D6? (*Hint SNRIs)

A

VENLAFAXINE

Thus need to be very careful if pt is taking another substance that is a CYP2D6 inducer or inhibitor

54
Q

PHARMACOKINETIC INTERACTIONS) Which is a potent CYP3A4 inhibitor?

A

FLUVOXAMINE

55
Q

PHARMACOKINETIC INTERACTIONS) Which 2 drugs are CYP2D6 inhibitors? Which drug intakes are thus affected?

A

FLUOXETINE + PAROXETINE

Drugs that are CYP2D6 substrates - VENLAFAXINE (SNRI) + TCAs + anti-psychotics (HALOPERIDOL/RISPERIDONE) + codeine/oxycodone + beta-blockers

56
Q

PHARMACODYNAMIC INTERACTIONS) Which side effect is additive with other substances such as ethanol and BZs?

A

SEDATION

Additive with other sedation-inducing anti-depressants:
Classes 2,3,5,6 (SNRIS - V,D + TCAs - I,C,D,A,N + 5-HT2A antagonists - N,T + heterocyclic - mirtazapine)

57
Q

PHARMACODYNAMIC INTERACTIONS) How can MAOIs (P,T) cause hypertensive episodes INDIRECTLY?

A

MAOIs sensitize pts to indirect sympathomimetics (e.g. tyramine + ephedrine)

58
Q

PHARMACODYNAMIC INTERACTIONS) What drug interactions can result in serotonin syndrome? (4)

A

1) SSRI + MAOI
2) SSRI + drug with MAOI activity (e.g. LINEZOLID)
3) SSRI + SEROTONERGIC drug (e.g. dextromethorphan, sumitriptan, tramodol, St John’s wort)

4) SNRI + MAOI

59
Q

PHARMACODYNAMIC INTERACTIONS) What is serotonin syndrome?

A

CNS Symptoms (2A’s)- Altered mental status + Agitation
SYMPATHETIC responses - Fever + tachycardia + HTN + Diaphoresis + shivering
GI symptoms
MOTOR - Hyper-reflexia + Myoclonus + Tremor + Ataxia + Incoordination

60
Q

CLINICAL TOXICOLOGY) Are the toxic effects of TCA overdose serious?

A

YES, very dangerous!

Prescribed on “no refill basis” + Small quantities

61
Q

CLINICAL TOXICOLOGY) Are the toxic effects of SSRIs and MAOIs overdoses severe/common?

A

Intoxication and OD fatalities are RARE

Would require supportive treatment

62
Q

CLINICAL TOXICOLOGY) What is the toxic effect of BUPROPION overdose?

A

Seizures

63
Q

CLINICAL TOXICOLOGY) What is the toxic effect of MIRTAZAPINE overdose?

A

Disorientation (“think extreme sedation”)

Tachycardia (“think serotonin syndrome”)

64
Q

CLINICAL TOXICOLOGY) What other substances are usually involved with newer anti-depressant agent overdoses?

A

ALCOHOL + Other drugs (not specified in podcast)

65
Q

LITHIUM) What clinical diagnosis is lithium most commonly used for?

A

BIPOLAR AFFECTIVE DISORDER (manic type OR depressed type) - Used to stabilize mood states

66
Q

LITHIUM) What is the supposed mechanism of the switch from mania to depression in BIPOLAR AFFECTIVE disorder?

A

Drugs that INCREASE NE/E/DA (catecholamine) activity - Exacerbates mania
Drugs that DECREASE NE/DA activity - Reduces mania

67
Q

LITHIUM) Which other drugs exhibit efficacy to treating BIPOLAR AFFECTIVE DISORDER?

A

s

Class: Neuro (10 decks)

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