Pharmacology Flashcards
For the past 30 years, the leading theory to explain the biological basis of depression has been the monoamine hypothesis.
Describe this hypothesis [1]
This theory proposes that depression is due to deficiency of one or more monoamine neurotransmitters in the brain
- Evidence to date mainly implicates serotonin and noradrenaline.
Acute antidepressant drugs increase the synaptic availabilty of which neurotransmitters? [3]
noradrenaline
serotonin
dopamine
What are three key brain areas involved in regulation of mood? [3]
the ventromedial prefrontal cortex (VMPFC – noted by light-red color)
lateral orbital prefrontal cortex (LOPFC – noted by light green color)
dorsolateral prefrontal cortex (DLPFC – noted by light blue color)
Describe the changes in activity of the three core aspects in brain regulation in the pathophysiology of depression [3]
The VMPFC is hyperactive in depression1
The LOPFC is hyperactive in depression1
The DLPFC is hypoactive in depression1
What is the role of the hippocampus? [1]
What happens to the hippocampus during depression? [2]
Hippocampus: has a role in episodic, contextual learning and memory
- The hippocampus is involved in cognitive, emotional, and neuroendocrine regulation. It is rich in glucocorticoid receptors and is a recipient of significant input from excitatory glutaminergic neurons
- get shrinking / atrophy of the hippocampus during depression
- Stress impairs neo neurogenesis (develop new neurons)
NB: Chronic repeated episodes of depression may lead to progressive hippocampal atrophy over time, possibly increasing the risk for subsequent depressive relapse
Give a v brief overview of the end result of Post-receptor (membrane and intracellular effects of antidepressants [1]
Why is there a delayed onset of antidepressant actions?
Antidepressants cause an increased release of brain derived neutrophin
- Use of antidepressants with 5-HT and/or NA can possibly regulate the expression of BDNF by activating intracellular cascades that eventually lead to synthesis of BDNF2
Delayed action:
- Requirement for adaptive changes at different receptor sites
- Activation transcription factors and gene expression
- Activation of neo neurogenesis(hippocampus) possibly via ↑BDNF concentrations
Describe the acute MoA of Monoamine oxidase inhibitors
-non-selective, non-reversible (MAOIs)
-selective, reversible (RIMAs)
Give a couple of examples of each [2]
MAOIs (Monoamine oxidase inhibitors)
- Inhibition of MAO-A and MAO-B isoenzymes
- MAO-A e.g: Moclobemide
- MAO-B: e.g. Selegiline and Rasagiline
RIMAs (Reversible inhibitors of monoamine oxidase)
- Reversible Inhibition of MAO-A
-
NB: serotonin and noradrenaline are metabolised by monoamine oxidase in the presynaptic cell
Why are MAOIs not commonly used anymore? [1]
Because they work by irreversible binding, need to wait for two weeks to create new enzymes - which meant that would be without medication for a while
What are the adverse effects of Non-selective MOA-Is? [2]
Adverse effects of non-selective monoamine oxidase inhibitors
* hypertensive reactions with tyramine containing foods e.g. cheese, pickled herring, Bovril, Oxo, Marmite, broad beans
* anticholinergic effects
Describe the MoA of TCAs [1]
NA and 5-HT reuptake inhibition
- because in depression - want more activity of the NA and 5-HT systems
The tricyclic antidepressants (TCAs) have five principle pharmacological effects:
1) They block serotonin uptake
2) They block noradrenaline uptake
3) They block the cholinergic-muscarinic receptors
4) They block the –1 adrenoreceptor
5) They block the histamine receptor
Describe the side effect prolife of TCAs:
- anticholinergic [5]
- Antihistaminic [2]
- Alpha 1 adrenoreceptor antagonism [2]
Anticholinergic
* Dry mouth,
* Blurred vision
* Urinary hesitancy (urinary retention)
* Constipation
* Memory impairment
* Aggravation of narrow angle glaucoma
Antihistaminic
* Sedation
* Weight gain
Alpha1 adrenoceptor antagonism
* Orthostatic hypotension
* Cardiac effects
What cardiac effect can TCAs have? [1]
lengthening of QT interval
Describe the CV [4] and other side effects [3] of TCAs
Cardiovascular effects
* Sinus tachycardia
* Arrhythmias
* Conduction delay at AVN - risk of VT and VF (how they die if by TCA OD)
* Sudden death
Other side effects
* Sexual dysfunction
* Impaired cognitive and psychomotor skills
* Convulsions
Which TCAs are most commonly considered most dangerous in OD? [2]
Which has a lower incidence of toxicity? [1]
amitriptyline and dosulepin (dothiepin) are considered the most dangerous in overdose
lofepramine has a lower incidence of toxicity in overdose
A patient has overdosed with a TCA.
How do you reverse this? [1]
Tricyclic OD is managed by Sodium bicarbonate
Desribe the MoA of SNRIs (selective serotonin and noradrenaline reuptake inhibitors)
* Venlafaxine( Efexor)
* Duloxetine (Cymbalta)
5-HT and NA re uptake inhibition
Why should you avoid TCAs in suicidal patients? [1]
Which other drug should you also be concerned by? [1]
Overdose causes risk of sudden death due to VT and VF
NB - also be aware of with Venlafaxine
Describe the MoA of SSRIs (Selective serotonin reuptake inhibitors) [1]
5-HT re uptake inhibition
- When a selective serotonin reuptake inhibitor (SSRI) is administered, it blocks the serotonin reuptake pump. This pump normally returns the serotonin to the neurone but when blocked it increases the serotonin levels in the synapse and increases stimulation of the receptors.
- The increase in serotonin is reflected in an improvement of depressive symptoms.
- Noradrenaline uptake is not affected by the SSRIs.
Describe some AEs of SSRIs [+]
Nausea/vomiting
Abdominal pain
Dry mouth
Constipation/diarrhoea
Headache
Asthenia
Dizziness
Insomnia/somnolence
Sweating
Anorexia
Weight loss
Nervousness/agitation
Tremor
Convulsions
Dystonic reactions
Sexual dysfunction (reduced libido, anorgasmia)
You start a patient on a SSRI. How would you counsel them? [2]
How long should treatment last if a good repsonse? [1]
Patients should be counselled to be vigilant for increased anxiety and agitation after starting a SSRI
Following the initiation of antidepressant therapy patients should normally be reviewed by a doctor after 2 weeks
- For patients under the age of 30 years or at increased risk of suicide they should be reviewed after 1 week.
- If a patient makes a good response to antidepressant therapy they should continue on treatment for at least 6 months after remission as this reduces the risk of relapse.
A patient wants to stop taking an SSRI.
How would you advice them to do so? [1]
When stopping a SSRI the dose should be gradually reduced over a 4 week period (this is not necessary with fluoxetine). Paroxetine has a higher incidence of discontinuation symptoms.
Which SSRI is particularly associated with a prolonged QT interval? [1]
Citalopram (and escitalopram) and the QT interval
- associated with dose-dependent QT interval prolongation and should not be used in those with: congenital long QT syndrome; known pre-existing QT interval prolongation; or in combination with other medicines that prolong the QT interval
What is the max dose of citalopram for:
- adults [1]
- adults over 65 [1]
- adults with hepatic impairment [1]
adults: 40mg
- adults over 65: 20mg
- adults with hepatic impairment: 20mg
The combination of which anti-depressants has a high risk of causing seratonin syndrome (and therefore should be avoided) [2]
Monoamine oxidase inhibitors (MAOIs) x SSRIs - risk of serotonin syndrome
