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CNS lectures (Bal) > Module 1.1.1 (Antidepressants) > Flashcards

Module 1.1.1 (Antidepressants) Flashcards

1
Q

Drugs that deplete monoamines (5-HT and NA) induce depression, what drugs are these?

A
  • Serotonin, noradrenaline, dopamine

> Monoamines and their metabolitesa are reduced in depression

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2
Q

What are 5HT1 (inhibitory) receptors the target for?

A

Target for anxiolytics

> in cortex and amygdala

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3
Q

What are the effects of 5HT2 (excitatory) receptors?

A

Hallucinogenic effects

> in hippocampus and cortex

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4
Q

What is the concern with 5HT3 receptors?

A

Concern with vomiting

> in brainstem

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5
Q

What type of neurotransmitter is serotonin? What actions does it have?

A

Excitatory and inhibitory transmitter

> has both pre- and postsynaptic actions

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6
Q

What are SEVEN examples of tricyclic antidepressants?

Clue: ACDDDIN

A
  1. Amitriptyline
  2. Clomipramine,
  3. Desipramine
  4. Dosulepin (Dothiepin),
  5. Doxepin
  6. Imipramine
  7. Nortriptyline
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7
Q

What are SIX examples of selective serotonin reuptake inhibitors (SSRIs)?

Clue: CEFFPS

A
  1. Citalopram
  2. Escitalopram
  3. Fluoxetine
  4. Fluvoxamine
  5. Paroxetine
  6. Sertraline
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8
Q

What are THREE examples of selective serotonin & noradrenaline reuptake inhibitors (SNRIs)?

Clue: DDV

A
  1. Desvenlafaxine
  2. Duloxetine
  3. Venlafaxine
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9
Q

What are TWO examples of Monoamine oxidase inhibitors (MAOIs)?

A
  1. Phenelzine
  2. Tranycypromine
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10
Q

What are the other antidepressants?

Clue: AMMMRV

A
  • Agomelatine
  • Mianserin
  • Moclobemide
  • Mirtazapine
  • Reboxetine
  • Vortioxetine
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11
Q

What is the MOA of TCAs? Is it reversible? How long does it take to achieve therapeutic effect?

A

Inhibition of NA & 5-HT reuptake transporters (therapeutic effect)

  • Immediate increase in synaptic levels of NA and 5-HT
  • TCAs are reversible, negative, allosteric modulators of NA & 5-HT transporters on axon nerve terminals and dendrites

> Takes 2-4 weeks to achieve therapeutic effect

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12
Q

For TCA;

A) Which are NA selective?

B) Which are nonselective between NA and 5-HT?

C0 Which are 5-HT selective?

A

A)

  • Desipramine, Nortriptylline

B)

  • Imipramine, Amitriptyline

C)

  • Clomipramine
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13
Q

What are example of receptors are downregulated (takes 2-4 weeks in) by TCA?

A
  • Inhibitory presynaptic a2-adrenoceptors
  • Inhibitory presynaptic 5-HT1A autoreceptors
  • Postsynaptic B-adrenoceptors
  • Postsynaptic 5-HT2A receptors
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14
Q

What are the mechanisms of neuronal reuptake inhibitors such as TCAs, SSRIs and SNRIs?

A

The drug blocks the reuptake of 5-HT and increases its synaptic concentration –> stimulation of postsynaptic beta-1 receptors –> tachycardia (short term effect)

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15
Q

Why is the increase in serotonin level less than exepcted in TCAs?

A

increased activation of 5-HT1A receptors on the soma and dendrites –> reduces 5-HT release.

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16
Q

What does the continued use of TCA, SSRI or venlafaxine lead to?

A
  • Continued use of TCA, SSRI, or venlafaxine, increased synaptic concentrations of 5- HT cause the downregulation of presynaptic autoreceptors and an increase in the firing rate of raphe neurons.
  • There is also down-regulation of postsynaptic Beta-1 and 5HT2A receptors
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17
Q

Why is there slow onset of antidepressant action of 5-HT reuptake inhibitors?

A

Elevated level of 5-HT in the somato-dendritic region desensitises the 5-HT1A receptors

  • The need to desensitise somato-dendritic 5-HT1A receptors is what causes the slow onset of antidepressant action.
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18
Q

What are the long term effects of neuronal reuptake inhibitors (TCAs, SSRIs, SNRIs)

A

Increased therpaeutic effects and reduced side effects.

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19
Q

What are the indications for TCAs?

A
  • Major depression
  • Nocturnal enuresis, urge incontinence
  • Adjunct in pain management • ADHD (third line treatment)
  • Migraine prophylaxis
  • Clomipramine also indicated for OCD
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20
Q

Do TCA have short or long half lives?

> Each TCA contains a three-ring nucleus – An aliphatic side chain is attached to the central ring – has 2°or 3°amine

A

Long half-lives (18-70 hours)

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21
Q

What are the secondary amines that block NA reuptake more than 5HT uptake (more NA in synapse)

A

Nortriptyline and desipramine

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22
Q

What are the tertirary amines that block 5-HT uptake more than secondary amines (more 5-HT in synapse)?

A
  • Amitriptylline, clomipramine and imipramine
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23
Q

What are the adverse effects of TCAs?

Clue: Antagonism of certain receptors lead to side effects.

A

TCAs are non-selective thats why there is a lot of AE.

  • Antagonism of muscarinic receptors (anticholinergic effects): dry mouth, blurred vision, constipation, urinary retention, cognitive impairment, delirium esp. in elderly and Parkinson patients
  • Antagonism of a1-adrenoceptors: postural hypotension, sedation, sexual dysfunction
  • Antagonism of H-1 receptors: sedation, weight gain
  • Impairment of cardiac conduction –> cardiac arrythmias may result at higher doses
  • Hypomania –> elation of mood to mild mania
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24
Q

Why does overdose in TCAs occur? What happens?

A

TCA has a low therapeutic index and a low “therapeutic window”

  • Over dose can be life-threatening –> respiratory depression, seizures and cardiac toxicity, followed by COMA
25
Q

What does the TCA withdrawal symptoms consist of? How long does it last for? Which drugs is it more common in?

clue: CRASH

withdrawal syptoms not dangerous

A
  • Cholinergic rebound
  • Runny nose
  • Abdominal pain, diarrhoea
  • Sleep and sensory disturbances
  • Hypersalivation

> Lasts no longer than 2weeks

> More common with shorter acting amitriyptilline and doxepin

> similar withdrawal symptoms occur with SSRIs and venlafaxine

26
Q

Explain the following drug interactions which TCAs have with:

A) MAOIs

B) Direct acting sympathommimetics (NA, adrenaline)

C) Indirect-acting sympathommimetics (ephedrine, amphetamine)

D) Anticholinergics

E) CNS depressants

A

A)

  • severe hypertension –> hypertensive crisis

B)

  • increase sympathetic activity, accumulation of NA

C)

  • Reduce the effects of indirect-acting agents

D)

  • TCA has anticholinergic activity, hence will intensify anticholinergic effects

E)

  • sedation of TCAs exacerbated by agents such as alcohol, antihistamines, opioids, barbiturates and benzodiazepines
27
Q

What are the mechanims of action of SSRIs? How do they compare with TCAs?

A

Selective reversible inhibition of the 5-HT transporter (therapeutic effect)

Comparing with TCAs

  • Do not cause significant cardiotoxicity
  • Have higher therapeutic indices than TCAs
28
Q

What are the indications for SSRI?

A
  • Depression
  • Obsessive-compulsive disorder (OCD)
  • Social phobia
  • Generalised anxiety disorder
  • Panic disorders
  • Post-traumatic stress disorder
  • Attention deficit disorder
  • Eating disorders
29
Q

What may be more effective than SSRI for very severe depressive epsiodes?

A

Venlafaxine or TCAs may be more effective than SSRIs for very severe depressive episodes.

30
Q

What are the withdrawl symptoms of SSRIs? how long do they last? Which drug is it more common in?

clue: FLUSH

> withdrawal symptoms not dangerous

A
  • Flu-like
  • Light-headedness
  • Uneasiness
  • Sleep & sensory disturbances
  • Headache

> Lasts no longer than 2 weeks

> More common with shorter acting SSRIs such as paroxetine

31
Q

What are the adverse effects of SSRIs? Include the different types of 5-HT overstimulation.

A
  • Gastrointestinal: nausea, anorexia, diarrhoea
  • CNS: insomnia, anxiety, irritability, restlessness, tremor, headache, fatigue
  • Sexual: decreased libido, delayed orgasm, anorgasmia
  • Other: weight gain, fever, sweating, palpitations

5-HT overstimulation

> 5-HT2a = insomnia and sexual dysfunction

> 5-HT2c = anorexia

> 5-HT3 receptors (nausea, diarrhoea)

32
Q

What are the consequences of SSRI drug interactions with MAOIs;

A) MAOIs

B) Warfarin

C) TCAs andf lithium

A

A)

  • Serotonin syndrome

B)

  • Fluoxetine is highly plasma protein bound. Avoid warfarin as may cause bleeding

C)

  • Fluoxetine can elevate plasma levels of TCAs and lithium, give rise to acute toxicity
33
Q

4What are the symptoms of serotonin syndrome? Break them up into cognitive effects, autonomic effects and somatic effects.

A

Cognitive: mental confusion, hypomania, hallucinations, agitation, headache, coma

Autonomic effects: fever, hypertension, tachycardia, nausea, diarrhoea

Somatic effects: muscle twitching, hyperreflexia, tremor

34
Q

What drugs should be avoided when a patient is on a SSRI to avoid serotonin syndrome?

A
  • Avoid combining SSRI with another antidepressant such as MAOI or RIMA
  • Avoid drugs that can elevate 5-HT levels
  • Avoid opioid analgesic that also inhibits 5-HT reuptake (Tramadol, pethidine, dextromethorphan)
35
Q

What is an a example of Noradrenline Reuptake Inhibitor (NRI)?

A

Reboxetine

36
Q

What is the mechanism of action of NRIs? What does it have similar efficacy to?

A

Selective reversible inhibition of NA transporters

  • Similar efficacy to imipramine (TCA) and fluoxetine (SSRI)

Reboxetine can also be used in treatment of major depression.

37
Q

What is the MOA of SNRI? What does inhibit at lower doses and higher doses?

A

Reversible inhibition of 5-HT & NA transporters

  • Lower doses selectively inhibit 5-HT reuptake.
  • At higher doses the inhibitory effect on NA reuptake predominates (150 to 200 mg/day).
38
Q

Why are SNRIs safer than TCAs?

A

Venlafaxine lacks affinity for muscarinic, D1 and H1-receptors and it does not impair cardiac conduction significantly unlike TCAs

39
Q

What are the adverse effects of SNRIs?

A

Adverse effects similar to SSRIs

  • Nausea, vomiting, anorexia, headache, sweating, rash, anxiety, dose-related increase in diastolic BP, orthostatic hypotension, tremor
40
Q

What are the drug interactions with SNRIs?

A
  • TCAs, MAOIs, SSRIs, selegiline, moclobemide - possible serotonin syndrome combination contraindicated.
  • Lithium - neurotoxicity or serotonin syndrome
  • Fentanyl, pethidine, tramadol - possible serotonin syndrome.
41
Q

What is the mechanism of action of MAOIs? What does MAOA and MAOB selectively inactivate?

A

Irreversible inhibition of MAOA & MAOB resulting in a decrease in the intraneuronal breakdown of NA & 5-HT

  • MAOA selectively inactivates 5-HT & NA
  • MAOB selectively inactivates DA

> In liver, MAOA inactivates dietary tyramine

42
Q

Compare normal monoamine transmission to effect of MAO inhibitors.

A

Normal monoamine transmission

  • MAO inactivates monoamines (norephinedrine, serotonin and dompamine) that leak from a synaptic vesicle

Effect of MAO inhibitors

  • MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space.
43
Q

What are the adverse effects of MAOIs?

A
  • Adverse-effects similar to TCAs

CNS stimulation

  • can produce anxiety, agitation, hypomania even mania
  • postural hypotension
  • Patients should be informed of signs of hypotension – dizziness, light-headedness
  • Anticholinergic, sedation and cardiotoxicity like TCAs (blocks muscarninc receptors and H1 receptors)
  • In overdose, hyperthermia and convulsions can be life-threatening (irreversible enzyme inhibition complicates management)
44
Q

Why does the tyramine reaction occur with MAOIs? How long does it take to recover?

A

Ingested tyramine - normally inactivated by MAOA & MAOB but not this is being inhibited

  • Tyramine can increase blood pressure by displacing noradrenaline from sympathetic nerve terminal
  • Ingestion of tyramine by patients on MAOIs can result in hypertensive crisis

​Recovery of MAO activity after phenelzine can require up to 2 weeks.

45
Q

Exlplain the following drug interactions for MAOIs

A) Indirect acting sympathomimetics (ephedrine and amphetamine)

B) Antidepressants such as TCAs and SSRIs

C) Antihypertensive agents

D) Interactions secondary to inhibition of hepatic MAO

E) Meperidine (demerol) –> pethidine

A

A)

  • can cause hypertensive crisis
  • Avoid sympathomimetics present in cold remedies, nasal decongestants, and asthma medications – see Doctor

B)

  • with TCA can cause hypertensive crisis (increase NA in synapse)
  • with SSRIs can cause Serotonin Syndrome (increase 5-HT in synapse)

C)

  • excessive lowering of BP

D)

  • decrease metabolism of several drugs including NA, adrenaline and DA

E)

  • can cause hyperpyrexia (excessive elevation of temperature)
46
Q

Wht does hypotension occur in MAOIs

A
  • dopamine accumulate in the peripheral sympathetic neurons displaces noradrenaline from storage vesicles.
  • Reduced noradrenaline released and sympathetic effect of noradrenaline (a1 receptors = low BP and b1 receptors = low CO and low BP)
47
Q

What is an example of a Reversible MAO-A inhibitor (RIMA)?

A

Moclobemide

48
Q

What is the MOA of RIMA? What are the properties of it?

A
  • Reversible selective inhibition of MAOA resulting in a decrease in the intraneuronal breakdown of NA & 5-HT

> Moclobemide is rapidly absorbed

> short-acting, it acts for about 12 h

> Short half-life 1.5 h

49
Q

When is moclobemide (RIMA) used?

A

Moclobemide is useful for fatigued depressed patients and it can be used as an alternative to a SSRI if sexual dysfunction produced by a SSRI becomes a problem

50
Q

What is the benefit to RIMAs compared to MAOIs? What are the AE?

A

Benefits

  • It produces less side-effects than MAOIs and it is safer
  • With moclobemide, the “tyramine reaction” is not a significant problem because ingested tyramine can still be inactivated by MAOB.

AE

  • nausea, dizziness, agitation, insomnia, headache

> absence of sexual side effects

51
Q

What is an example of Noradrenaline-Serotonin Specific Antidepressant? Why is it used?

A

Mirtazapine

  • Mirtazapine may be useful in depressed individuals requiring sedation or as an alternative to a SSRI if insomnia or sexual dysfunction produced by an SSRI are problematic.
52
Q

What is the MOA of mirtazapine?

A
  • Mirtazapine antagonises presynaptic a2- adrenergic autoreceptors, 5-HT2A, 5-HT2C, 5-HT3 and H1-receptors.
  • Antagonism of inhibitory presynaptic a2- adrenoceptors on NA & 5-HT nerve terminals –> immediate increase in synaptic levels of 5-HT and NA
53
Q

What is a benefit and negative of mirtazapine?

A

Benefit

  • Antagonism of 5-HT2A & 5-HT3 receptors reduces side-effects of insomnia, sexual dysfunction, nausea and diarrhoea

Negative

  • Antagonism of 5-HT2C and H1-receptors causes weight gain and excessive drowsiness
54
Q

What should mirtazapine be avoided with?

A

Mirtazapine is relatively safe. It is a weak inhibitor of CYP 450 isozymes and thus there are few drug interactions. However, it should not be combined with CNS depressants (alcohol, benzodiazepines)

55
Q

What are the AE of mirtazapine?

A

Side-effects include: dizziness, drowsiness, dry mouth, constipation, weight gain

56
Q

For Agomelatine;

A) What is the MOA

B) What is the indication

C) What is rapidly metabolised by?

D) What are some common AE?

A

A)

  • Melatonin (MT1 & MT2) receptor agonist
  • Serotonin 5HT2C antagonist

B)

  • Major depression.

C)

  • Rapidly metabolised by the CYP1A2

> Precautions with potent CYP1A2 inhibitors and those with hepatic impairment

D)

  • Abdominal pain, dizziness, increased aminotransferase
57
Q

For Vortioxetine;

A) What is the MOA?

B) Indication?

C) Common AE?

D) Metabolised by?

E) Caution in?

A

A)

  • Enhances CNS serotonergic activity
  • Inhibits serotonin (5-HT) reuptake
  • 5-HT1A receptor agonist
  • 5-HT1B receptor partial agonist
  • 5-HT3, 5-HT1D, and 5-HT7 receptors antagonist

B)

Major depression

C)

  • Similar to other antidepressants
  • Nausea & dizziness are dose-dependent.

D)

Rapidly metabolised by liver

  • Oxidation via cytochromeP (CYP)450
  • CYP2D6 (primary)

E)

  • Co-administered with CYP2D6 inhibitors or CYP3A4 inducers for ≥14 days
  • In poor CYP2D6 metabolizers
58
Q

Provide examples of the following drug interactions for Vortioxetine

A) Serotonin toxicity (life threatening)

B) Risk of bleeding including stomach bleeding

C) Risk of low blood sodium levels

D) Decreased effectiveness

A

A)

Co-administration with serotonergic medications - triptans, other antidepressants, and tramadol

B)

Anticoagulants (eg, warfarin), aspirin, or NSAIDs (eg, ibuprofen, intranasal ketorolac)

C)

Diuretics (eg, furosemide, hydrochlorothiazide)

D)

Carbamazepine, phenytoin, or rifampicin

CNS lectures (Bal) (29 decks)

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