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Pharmacology > Anti-depressants > Flashcards

Anti-depressants Flashcards

1
Q

What can psychoses be separated into?

A

Sz and affective disorders (mania and depression)

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2
Q

How can the symptoms of depression be categorised?

A
  • emotional (psychological)

- biological (somatic)

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3
Q

What are the emotional symptoms of depression?

A

misery, apathy, pessimism, low self-esteeam, loss of motivation, anhedonia (can’t feel pleasure in things that normally would cause pleasure)

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4
Q

What are the biological symptoms of depression?

A

slowing of thought/action. loss of libido. loss of appetite, sleep disturbance

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5
Q

What are the two main groups of depression?

A

unipolar and bipolar

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6
Q

What is unipolar depression?

A
  • Mood swings are in same direction
  • Relatively late onset (adulthood)
  • Unipolar depression can be split into reactive depression and endogenous depression
  • There is drug treatment – it is the same treatment for reactive and endogenous depression
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7
Q

What are the two types of unipolar depression?

A
  • Reactive depression: depression in response to stressful life events, that is non-familial
  • Endogenous depression: depression that is unrelated to external stresses, with a familial pattern
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8
Q

What is bipolar/manic depression?

A
  • Oscillating depression and mania (hyper-excitability with symptoms opposite to depression)
  • This is less common than unipolar depression, and tends to have an early adult onset
  • There is a strong hereditary tendency
  • Drug treatment (Lithium) – not a conventional antidepressant (more of a mood-stabilising drug)
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9
Q

What is the monoamine theory of depression?

A

Depression = a functional deficit of central monoamine transmission

Mania = a functional excess of central monoamine transmission

  • Noradrenaline & 5-HT are the two monoamines involved in this hypothesis
  • The hypothesis is based on pharmacological evidence, but the biochemical evidence inconsistent
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10
Q

………..

A
  • Delayed onset of clinical effect of anti-depressant drugs (perhaps due to adaptive changes)
  • The changes in NA and 5-HT that we see are rapid, there is a rapid onset
  • However, the clinical effect can take weeks, before we see the optimal action of the drug
  • There is a dissociation in between the neurochemical change and the antidepressant effect
  • In response to many antidepressant drugs, we see a down-regulation: Ξ±2, Ξ², 5HT receptors
  • This change often correlates in a more timely fashion with the onset of clinical drug effectiveness
  • It may be these changes therefore, that are responsible for the clinical drug effects
  • General conclusions remain firm regarding the monoamine theory of depression

> HPA axis (↑ CRH levels are seen in depressed patients) – there may be a role for HPA axis?

> Hippocampal neurodegeneration is seen in chronic depression

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11
Q

LOOK AT TABLE FOR DRUGS

A

NOTES

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12
Q

What are some examples of anti-depressant drugs?

A

tricyclic anti-depressants, MAO inhibitors. reserpine, alpha-methyltyrosine, methyldopa, electroconvulsive therapy

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13
Q

Give an example of a TCA

A

amitryptiline

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14
Q

What are the 2 main chemical groups in TCAs?

A

dibenzazepines, dibenzocylcoheptanes

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15
Q

TCA structure and how they work

A
  • TCAs are three-ringed structures
  • Neuronal monoamine re-uptake inhibitors
  • TCAs prevent reuptake of NA and 5-HT much more so than dopamine
  • TCAs therefore potentiate the action of these monoamines for much longer
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16
Q

Which receptors can TCAs act on? What is the consequence of this?

A
  • Other receptor actions on Ξ±2 receptors, muscarinic AchRs, histamine receptors and 5-HT receptors
  • Some of these actions may be important in the antidepressant acitivity of TCAs
  • They may also contribute to the unwanted side effects of TCAs
  • There is a delayed down-regulation of Ξ²-adrenoceptors & 5-HT2 receptor
17
Q

What happens if TCAs bind to alpha 2 receptors?

A
  • If TCAs bind to and antagonise these receptors, they enhance the release of NA
  • They block the inhibitory control over NA, and allow a greater increase of NA into the synaptic cleft
18
Q

Pharmakokinetics of TCAs - absorption speed, metabolism, half life etc

A
  • Rapid oral absorption (all TCAs are given orally and absorbed orally)
  • Highly plasma protein bound (90 – 95% of TCAs are PPB)
  • Hepatic metabolism: TCAs are metabolised in the liver, and this generates active metabolites (weaker)
  • They then undergo renal excretion (as glucuronide conjugates)
  • Plasma t1/2 (10-20 hours) – relatively long half life, so can be given once a day (long duration of action
19
Q

What are the unwanted effects of TCAs at therapeutic doses?

A
  • Atropine like effects with amitriptyline: dry mouth, blurred vision, constipation, urinary retention
  • Postural hypotension (mediated through the vasomotor centre)
  • Sedation (TCAs cause H1 antagonism) – patients feel drowsy during the day
  • Many depressed patients have trouble sleeping, so this can be taken advantage of
20
Q

What are the unwanted effects of TCAs at high doses (toxic)?

A
  • CNS: excitement, delirium, seizures -> coma and respiratory depression
  • CVS: cardiac dysrhythmias -> ventricular fibrillation and sudden death
  • With TCAs that are muscarinic antagonists, we also affect vagal input to the heart
  • Care: we must be careful with TCAs, because they are commonly utilised in attempted suicide
21
Q

Drugs interactions of TCAs

A

PPB: we see increased TCA effects with co-administration with aspirin and phenytoin (anti-convulsant)

Warfarin can displace TCAs from their binding sites, which moves plasma levels of TCA into a toxic range

Hepatic microsomal enzymes metabolise TCAs, so TCA effects increase if co-administered with drugs that are metabolised by the same enzyme system (e.g. neuroleptics and oral contraceptives)

Potentiation of CNS depressants with TCAs (alcohol in particular)

There is an interaction with antihypertensive drugs (monitor BP closely) – difficult to predict

22
Q

………

A
  • The mechanism of action involves monoamine oxidase-A (NA & 5-HT) and monoamine oxidase-B (DA)
  • MAO-A has a preference for NA and 5-HT, whereas MAO-B has a preference for dopamine
  • Most of these drugs are non-selective MAOIs (inhibit both MAO-A and MAO-B)
  • The inhibition is irreversible, which leads to a long duration of action (patients need to take these daily)
  • We see rapid neurochemical changes: rapid increase in cytoplasmic NA & 5-HT
  • This is because we are blocking the breakdown of NA and 5-HT with MAOIs – enhanced activity in brain
  • We see delayed effects with these drugs, in terms of the clinical response
  • We see a down-regulation of Ξ²-adrenoceptors & 5-HT2 receptors
  • This corresponds with the onset of the clinical effectiveness of the drug
  • MAOIs are not entirely selective – they result in the inhibition of other enzyme
23
Q

Example of TSA

A

Phenelzine

24
Q

Describe the chemical structure of MAO inhibitors

A
  • All of the MAOIs have got a single ring structure
  • There is a range of different chemical classes
  • Phenelzine is a hydrazine. It has a single ring with a carbon side chain. On the end is a hydrazine functional group. This group is very reactive
  • It is this functional group that forms the covalent bonds with the MAO enzyme (irreversible inhibition)
25
Q

Pharmacokinetics of MAO inhibitors - absorption speed, plasma half life and how is it metabolised/excreted?

A
  • Rapid oral absorption (MAOIs are taken orally, either once a day or every other day)
  • Short plasma t1/2 (few hours) but longer duration of action due to irreversible inhibition
  • Metabolised in the liver and excreted in the urine
26
Q

What are the unwanted effects of MAO inhibitors?

A
  • Atropine-like effects (much less than with TCAs)
  • Postural hypotension (common) – probably a vasomotor mediated effect
  • Sedation with long-term usage (and seizures in over dose)
  • Weight gain (possibly excessive) – associated with increase appetite with MAOIs
  • Hepatotoxicity (due to hydrazines) – this is rare
27
Q

Drug interactions of MAO inhibitors (tyramine)

A
  • TYRAMINE: an indirectly acting sympathomimetic amine (has actions similar to activation of the SNS)
  • Under normal circumstances, there are not sufficient levels of tyramine in the body to cause problems
  • However, tyramine is metabolised by MAOs (so if they are being inhibited, we may encounter problems)
  • Cheese reaction’: Tyramine-containing foods + MAOI leads to a hypertensive crisis
  • Throbbing headache, increased blood pressure and intracranial haemorrhage
28
Q

What must patients taking MAOi avoid and why?

A
  • Foods that are high in tyramine (e.g. mature cheese, red wine).
  • MAOIs can react with TCAs to produce hypertensive episodes
29
Q

MAOIs and pethidine (opioid)

A
  • MAOIs can react with pethidine to cause hyperpyrexia, restlessness, coma & hypotension
30
Q

Moclobemide

A
  • Moclobemide is a reversible MAO-A inhibitor (RIMA) – it is selective
  • It has fewer drug interactions, but a shorter duration of action (taken 2-3 times a day)
31
Q

SSRI - what does it do and example

A
  • Fluoxetine
  • Selective 5-HT re-uptake inhibition (SSRIs selectively inhibit the reuptake of 5-HT)
  • They propose less troublesome side effects, so they are safer in the case of overdose
  • But they are less effective against severe depression – so we do still need the other classes of drugs
32
Q

Pharmacokinetics of SSRIs - half life, how is it administered, time taken to work and where does it act?

A
  • Oral administration of SSRIs
  • Plasma t1/2 (18-24 hours), given once a day, orally
  • There is a delayed onset of action (2-4 weeks before we see the optimal anti-depressant action of SSRIs)
  • Fluoxetine competes with TCAs for the hepatic enzymes (so avoid co-administration)
33
Q

Describe the chemical structure of SSRIs

A

There are a couple of ring structures with an aliphatic side chain.

34
Q

Venlafaxine

A

Venlafaxine (an SNRI): This drug shows dose-dependent Reuptake inhibition of both 5-HT and NA

5HT > NA (SNRI) – we can increase the dose to get increase of NA reuptake inhibition

If you give a very high dose of venlafaxine, you can inhibit the dopamine transporter too

This is 2nd line treatment for severe depression

35
Q

Mirtazapine

A

Mirtazapine: this is an Ξ±2 Receptor antagonist

It increases NA & 5HT release in the brain

Other receptor interactions may contribute to antidepressant activity (sedative – histamine antagonism)

Useful in SSRI-intolerant patients

Pharmacology (26 decks)

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