Pharmacology of Depression - Core Drugs & Case Study Flashcards
What are the 5 core drugs for depression treatment
Learned about in Phase 1 medicine
Sertraline
Citalopram
Fluoxetine
Venlafaxine
Mirtazapine
In 2020 - sertraline was the 16th most commonly prescribed drug in West London area
What is the primary mechanism of action of sertraline?
Inhibition of sertraline re-uptake transporter
Results in accumulation of serotonin
Serotonin plays role in CNS in the regulation of mood, personality and wakefulness
What role does serotonin play in the CNS?
Regulation
- Mood
- Personality
- Wakefulness
What is the drug target for Sertraline?
Serotonin transporter
What are the main side effects of taking sertraline?
GI side effects
- Nausea
- Diarrhoea
Sexual dysfunction
Anxiety
Insomnia
How does sertraline effect the dopamine transporter?
Mild inhibition of dopamine transporter
What does sertraline inhibit at high doses?
Partial inhibition of CYP2D6 at high doses (150mg)
How should one discontinue use of sertraline?
Must be gradually decreased on discontinuation
In 2020 - Citalopram was 27th most commonly prescribed drug in West London area
What is the primary mechanism of action of Citalopram?
Inhibition of serotonin reuptake
Results in an accumulation of serotonin which plays role in CNS in the regulation of mood, personality and wakefulness
What is the drug target of Citalopram?
Serotonin transporter
What are the main side effects of taking Citalopram?
GI side effects
- Nausea
- Diarrhoea
Sexual dysfunction
Anxiety
Insomnia
How might Citalopram affect muscarinic and histamine (H1) receptors?
Mild antagonism of muscarinic and histamine (H1) receptors
What metabolises Citalopram?
CYP2C19
- An enzyme protein
- Member of CYP2C subfamily of cytochrome P450
What must be done in the discontinuation of Citalopram?
Must be gradually decreased on discontinuation
What is CYP2C19?
- An enzyme protein
- Member of CYP2C subfamily of cytochrome P450
What is CYP2D6?
- An enzyme
- Part of cytochrome P450 family
In 2020 - Fluoxetine was 68th most commonly prescribed drug in West London area
What is the primary mechanism of action of Fluoxetine?
Inhibition of serotonin re-uptake
Results in an accumulation of serotonin which plays role in CNS in the regulation of mood, personality and wakefulness
What is the drug target of Fluoxetine?
Serotonin transporter
What are the main side effects of taking Fluoxetine?
GI side effects
- Nausea
- Diarrhoea
Sexual dysfunction
Anxiety
Insomnia
What effect can Fluoxetine have on 5HT2A and 5HT2C receptors?
Mild antagonism of these receptors
What effect can Fluoxetine have on CYP2D6 and CYP2C19?
Complete inhibition of CYP2D6
Significant inhibition of CYP2C19 (caution with warfarin)
In 2020 - Venlafaxine was 83rd most commonly prescribed drug in West London area
What was the primary mechanism of action of Venlafaxine?
Inhibition of serotonin re-uptake + norepinephrine re-uptake
Results in an accumulation of neurotransmitter in synapse
What are the drug targets of Venlafaxine?
Serotonin transporter
Noradrenaline transporter
What are the main side effects of taking Venlafaxine?
GI effects
- Nausea
- Diarrhoea
Sexual dysfunction
Anxiety
Insomnia
Hypertension (at higher doses)
What must be done in the discontinuation of Venlafaxine?
Must gradually decrease Venlafaxine on discontinuation
In 2020 - Mirtazapine was 30th most commonly prescribed drug in West London area.
What is the primary mechanism of action of Mirtazapine?
Antagonises presynaptic alpha-2-adrenergic receptors
This causes an increased release of serotonin and norepinephrine
Antagonises central 5HT2 receptors, which leaves 5HT1receptors unopposed —> antidepressant effects
In 2020 - Mirtazapine was 30th most commonly prescribed drug in West London area.
What is the primary mechanism of action of Mirtazapine?
Antagonises presynaptic alpha-2-adrenergic receptors
- This causes an increased release of serotonin and norepinephrine
Antagonises central 5HT2 receptors, which leaves 5HT1 receptors unopposed causing anti-depressant effects
What are the drug targets of Mirtazapine?
Alpha-2 receptor
5-HT2 receptor
What are the main side effects of taking Mirtazapine?
Weight gain
Sedation
Low probability of sexual dysfunction
May exacerbate REM sleep behaviour disorder
What sleep behaviour disorder may be exacerbated by taking Mirtazapine?
May exacerbate REM sleep behaviour disorder
What is the PHQ-9?
A 9 item questionnaire designed to screen for depression in primary care
What are the 3 most commonly prescribed SSRIs?
Setraline
Citalopram
Fluoxetine
For SSRIs:
What is the general
- Target?
- Location?
- Effect?
- 5-HTT
- Pre-synaptic neuron
- Increased serotonin availability = anti-depressant effect
For SSRIs:
What is the general
- Target?
- Location?
- Effect?
- 5-HTT
- Pre-synaptic neuron (in brain, e.g. in hippocampus)
- Increased serotonin availability = anti-depressant effect
A patient who is currently on sertraline is being switched to a new anti-depressant.
Why do you think the GP slowly weaned the patient off sertraline first before starting the new anti-depressant?
Caution is required when switching from one anti-depressant to another
Due to risk of drug interactions, serotonin syndrome, withdrawal symptoms, or relapse
Washout required before starting new drug
Below is the binding affinity for some of the key drug targets for mirtazapine. The key effect of each receptor subtype is also given.
Mirtazapine drug targets & key effect
Affinity (highest —> lowest):
- Histamine (H1) receptor – sedation
- Alpha-2 receptor – Anti-depressant effect
- 5HT2 receptor – Anti-depressant effect
- 5HT3 receptor – Anti-emetic effect
Explain this information.
Consider selectivity, affinity and efficacy
H1-R:
- Highest affinity for this receptor so will preferentially block H1-R at low doses
- Most selective for this receptor
- First thing patients will experience will be Mirtazapine’s sedating effects
- Will experience sedation at lower doses than needed for anti-depressant and anti-emetic effect
A2-R & 5HT2-R
- As you increase the dose, start experiencing anti-depressant effects
- This reduces the sedative effect somewhat
5HT3-R
-
Below is the binding affinity for some of the key drug targets for mirtazapine. The key effect of each receptor subtype is also given.
Mirtazapine drug targets & key effect
Affinity (highest —> lowest):
- Histamine (H1) receptor – sedation
- Alpha-2 receptor – Anti-depressant effect
- 5HT2 receptor – Anti-depressant effect
- 5HT3 receptor – Anti-emetic effect
- Explain how the effect felt by a patient on Mirtazapine would change with increasing dose, considering affinity and selectivity for each of these targets.
- Describe the efficacy of Mirtazapine at each of these targets
- H1-R:
- Highest affinity for this receptor so will preferentially block H1-R at low doses
- Most selective for this receptor
- First thing patients will experience will be Mirtazapine’s sedating effects
- Will experience sedation at lower doses than needed for anti-depressant and anti-emetic effect
A2-R & 5HT2-R
- As you increase the dose, start experiencing anti-depressant effects
- This reduces the sedative effect somewhat as antihistamine activity is offset by increased noradrenergic transmission
5HT3-R
- Lowest affinity for this receptor
- This will help with nausea + vomiting
- This response will only be seen with very high doses
- EFFICACY - zero at each of these targets because Mirtazapine is an ANTAGONIST —-> (it has no effects/doesn’t produce a response, it blocks one instead)
