Pharm 23: antidepressant drugs Flashcards
Definitions & classification
Monoamine theory of depression
Types of antidepressant drugs Tricyclic antidepressants (TCAs) Monoamine oxidase inhibitors (MAOIs) Selective 5-HT re-uptake inhibitors (SSRIs) Other drugs
Lithium - mood stabilizing drug
Electroconvulsive therapy (ECT)
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What are the 2 classifications of psychoses?
- schizophrenia
- affective disorders
What are the 2 classifications of affective disorders?
mania
depression
What are emotional symptoms of depression ?
Misery, apathy, pessimism
Low self-esteem
Loss of motivation
Anhedonia
What are biological symptoms of depression?
Slowing of thought & action
Loss of libido
Loss of appetite, sleep disturbance
what is Unipolar depression/depressive disorder?
onset =
- Mood swings are in same direction
- Relatively late onset
What are the 2 types of unipolar depression?
how do they differ?
do drug treatments differ between these 2 or not?
Reactive depression (75%)
- stressful life events (eg grief, divorce etc)
- non-familial
Endogenous depression (25%)
- unrelated to external stresses
- familial pattern
–> drug treatment is same for both
What is Bipolar depression /manic depression
onset =
what treatments are available for patients ?
- Oscillating depression/mania
- Less common
- Early adult onset
- Strong hereditary tendency
–> drug treatment = lithium (mood stabilizer, restricts oscillation of manic + depression)
What is Bipolar depression /manic depression
onset =
what treatments are available for patients ?
- Oscillating depression/mania
- Less common
- Early adult onset
- Strong hereditary tendency
–> drug treatment = lithium (mood stabilizer, restricts oscillation of manic + depression)
(IP3 is reduced with use of lithium)
- narrow therapeutic window
- monitored through plasma level of lithium
Monoamine theory of depression
- biochemical theory of depression:
- depression = results from functional deficit of central (monoamine) MA transmission
- Mania = functional excess of central (monoamine) MA transmission
- depression = decrease in NA + 5HT in the brain
- delayed onset of clinical effects of antidepressant drugs –> time correlates with down regulation of a2, B, 5HT receptors
other theories:
suggests involvement of HPA axis / hippocampal neurodegeneration in etiology of depression
depression is linked with a lack of ____ + ____ in the brain
NA + 5HT in the brain
Describe the MOA of tricyclic antidepressants (TCA) for depression?
- e.g amitriptyline
- neuronal monoamine re-uptake inhibitors
- Block NA & 5-HT reuptake (central)
- reduce rate of reuptake of NA/5HT –> enhances synaptic levels of NA / 5HT
- can also act on other receipts e.g a2 receptors, histamine, 5HT receptors, mAChRs etc.
- TCA inhibit a2 receptors –> reduce negative feedback –> increase release of NA into synapse
- There is also Delayed down-regulation of β-adrenoceptors & 5-HT2 receptors
- improves mood
Describe the MOA of Reserpine for depression?
- not used now
- inhibits NA storage in presynaptic terminals
- decreases mood
Describe the MOA of MAO inhibitors for depression?
- e.g Phenelzine
- MAO-A : NA & 5-HT
MAO-B : DA - mostly = non selective
- irreversible inhibition –> so has long duration of action (due to presence of hydrazine - binds covalently to MAO)
- Increase stores of NA & 5-HT
- delayed effects –> correlates with down-regulation of β-adrenoceptors & 5-HT2 receptors
- also inhibitors other enzymes
- Mood ↑
Describe the MAO of a-methyl tyrosine for depression?
Inhibits NA synthesis
Mood ↓
–> Calms manic patients
Describe the MAO of methyldopa for depression?
Inhibits NA synthesis
Mood ↓
Describe the MAO of ECT for depression?
Increases CNS responses to NA & 5-HT
Mood ↑
Describe the pharmacokinetics of TCAs?
Rapid oral absorption
Highly PPB (90 - 95%)
Hepatic metabolism - active metabolites - renal excretion (glucuronide conjugates)
Plasma t1/2 (10-20 hrs)
What are some unwanted effects of TCA as an anti-depressant?
at therapeutic dosage:
Atropine - like effects (amitriptyline)
–> blurred vision, dry mouth, constipation
Postural hypotension
–> TCA action on vasomotor centre
Sedation
–> TCA = H1 antagonism
at overdose:
CNS: excitement, delirium, seizures –> coma, resp depression
CVS: cardiac dysrhythmias –> ventricular fibrillation/sudden death
TCA –> can cause attempted suicide
What drug interactions might occur for TCA?
if other drugs such as aspirin given, they compete for PPB –> increases TCA effects –> due to higher TCA bioavailability
(neuroleptics; oral contraceptives) –> compete with TCA for hepatic microsomal enzymes, less metabolism, increase in TCA bioavailability, Increase TCA EFFECTS
Potentiation of CNS depressants (e.g alcohol)
–> doubling of depressant effects
Antihypertensive drugs (monitor closely)
Describe the pharmacokinetics of MAO Inhibitors
Rapid oral absorption
Short plasma t1/2 (few hrs) but longer d.o.a.
Metabolised in liver; excreted in urine
What are some unwanted effects of MAO inhibitors
Atropine - like effects (< TCAs)
Postural hypotension (common)
Sedation (Seizures in overdose)
Weight gain (possibly excessive)
Hepatotoxicity (due to –> hydrazine - rare)
What drug interactions can occur from MAO inhibitors
what is possible alternative medication with less drug interactions?
- cheese reaction –> tyramine = component of food –> indirect sympathomimetic drug
- -> binds to NA transporter –> increases release of NA out out into synapse
- -> can causes HYPERTENSIVE CRISIS (headache, Increase BP, intracranial hemorrhage)
–> avoid mature cheese, marmite etc .
- interact with TCAs
- -> can also cause hypertensive crisis
- MAOIs + Pethidine –> can cause hyperpyrexia / restlessness / coma / hypotension
what is possible alternative medication with less drug interactions?
- Moclobemide = reversible MAO - A inhibitor [RIMA]
(decreases drug interactions + decreases duration of action)
SSRI MAO
- e.g fluoxetine
Selective 5-HT re-uptake inhibition
Less troublesome side-effects
–> safer when over dosed
But less effective vs severe depression
Describe the pharmacokinetics of SSRI
p.o. administration
Plasma t1/2 (18-24 hrs)
Delayed onset of action (2-4 weeks)
Fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration)
What are some unwanted effects of SSRIs?
- generally Fewer SE than TCAs/MAOIs
- Nausea, diarrhoea, insomnia & loss of libido
- Interact with MAOIs (avoid co-administration)
- Fluoxetine (‘Prozac’) = currently most prescribed antidepressant drug
There are also other anti depressant drugs available such as venlafaxine + Mirtazapine.
How do these work?
a) venlafaxine
b) Mirtazapine
Venlafaxine:
- Dose-dependent Reuptake inhibitor
- initial dose 5HT reuptake inhibition
increase in dose –> shows NA reuptake inhibition
further increase –> shows Dopamine reuptwake inhibition
—> 2nd Line treatment for severe depression
Mirtazapine:
- α2 Receptor antagonist –> less negative feedback
- ↑ NA & 5HT release into synapse
- Other R interactions (sedative)
- Useful in SSRI-intolerant patients
Tricyclic antidepressant drugs (TCAs) work largely by:
A: Antagonism at 5HT receptors B: Inhibiting central DA reuptake C: Blocking VSCCs D: Inhibition of central NA & 5HT reuptake E: Enhancement of the action of GABA
D
The ‘cheese reaction’ is most likely to be caused by:
A: Tricyclic antidepressants (TCAs) B: Selective serotonin reuptake inhibitors (SSRIs) C: Monoamine oxidase inhibitors (MAOIs) D: Reversible MAO-A inhibitors (RIMAs) E: α2-Adrenoceptor antagonists
C
