Antidepressants Flashcards
Types of depression
Reactive Depression
Endogenous Depression
Bipolar
Reactive Depression
Causes and Symptoms
Loss of relatives/friends
Severe disease
Drugs/Toxins (ex alcohol)
Core depressive syndrome:
stress, anxiety, physical issues, sense of guilt
Endogenous Depression
Causes and Symptoms
Unipolar
Core depressive syndrome, sleep disorder, decreased motor activity + libido + appetite (although can also be increased)
Shows familiar pattern
Dysthymia: milder form
Bipolar
Causes and Symptoms
Depression with periods of mania
Shows familiar pattern
Cyclothymia: milder form
Hypothesis: Pathogenesis of Endogenous Depression
Monoamine theory: depression caused by functional deficit of monoamine transmitters (NA, 5HT, A)
Evidence in support:
TCA and MAO inhibitors have antidepressant effect
Methyl DOPA, reserpine worsen depression
Inconsistence of hypothesis:
Amphetamine: stimulate NA release and blocks reuptake–> but it is not an antidepressant
Cocaine also a reuptake inhibitor but doesn’t have any antidepressant effect
L DOPA: increases NA synthesis, has no effect in depression
Mechanism of Depression
1) Stress–> increase Glutamate–> activate NMDA R–> neural apoptosis–> depressive symptoms
2) Stress–> cortisol release–> detrimental gene transcription response–> inhibition of neurogenesis + increased neural apoptosis–> depressive symptoms.
Monoamine Pathway
NA, 5HT–> inhibit detrimental gene transcription +
increase beneficial transcription response
Main prodepressive pathway: hypothalamic-pituitary-adrenal axis (Number 1 above)
Mechanism of Action of Anti Depressants
Early Phase:
5 HT uptake inhibition has no effect on concentration of 5HT in synapse as 5HT binding of presynaptic neuron acts as negative feedback–> no further release of 5HT
Late Phase (2-3 weeks post th):
5HT R of cell bodies are desensitised--> no negative feedback--> concentration of 5HT in synapse
Action of alpha 2 antagonists:
NA controls 5HT release: blocking of R increases release of both NA and 5HT
Indications for Antidepressant use
All types of depression
Panic Disorders: ((more effective than benzos as
immediate effect))
OCD: mainly SSRIs
Chronic Pain: TCA in combo with analgesics
Anorexia Nervosa/ Bulimia
Categories: Reuptake Inhibitor
Tricyclic Antidepressants
Selective Serotonin Reuptake Inhibitor
Serotonin Noradrenalin Reuptake Inhibitor
Noradrenaline Dopamine Reuptake Inhibitor
Noradrenaline Reuptake Inhibitor
Tricyclic Antidepressants
Names, Pharmacokinetics, Side Effects
Imipramine, clomipramine, trimipramine, amitiptyline, protriptyline, nortiptyline
First generation
NA and 5 HT reuptake inhibitors
Significant first pass metabolism (dose should be increasing), lipid soluble, large Vd
Metabolism: N demethylation–> active metabolite, hydroxylation–> glucuronide conjugation (inactive)
Side Effects:
Antagonism of M1 R: anticholinergic (dry mouth, urinary retention, blurred vision)
Antagonism of H1 R: sedation/ weight gain
Antagonism on alpha R: orthostatic Hypotension
Direct membrane effects: convulsion/ arrhythmias
Toxicity: the “3 Cs”: coma, convulsions, and cardiotoxicity
Drug interactions:
− Hypertensive crisis with MAO inhibitors
− Serotonin syndrome with SSRIs, MAO inhibitors, and meperidine
− Prevent antihypertensive action of α2 agonists
!!! TCAs potentiate the sedative effect of ethanol !!!
Selective Serotonin Re-uptake Inhibitors
Names, Pharmacokinetics, Side Effects
Citalopram, Escitalopram, Fluoxetine, Paroxetine
Inhibit 5 HT reuptake (5HT selective)
Interactions:
Fluoxetine inhibits enzymes of drug metabolism
NEVER combo with MAO inhibitors as can cause serotonin Syndrome (hyperthermia, muscle rigidity, seizures) same to a certain extent with ex TCA
Side Effects:
Loss of libido, weight gain, suicide, aggressive behaviour, headache, nightmares
Serotonin- Noradrenaline Re-uptake Inhibitors
Names, Pharmacokinetics, Side Effects
Velafaxine, Duloxetine
Slightly greater effect than SSRIs and fewer side effects (no effect on M/ H/ alpha Rs)
Side Effects:
convulsions, arrhythmia
Noradrenaline- Dopamine Re-uptake Inhibitors
Name, Pharmacokinetics, Side Effects
Bupropion
Mech of Action same as SSRIs and SNRI + also inhibit dopamine re-uptake
Has weak central effect on nicotinic R (useful in stopping smoking)
Side Effects:
Convulsions
Suicidal Tendency
Noradrenaline Re-uptake Inhibitors
Names, Pharmacokinetics, Side Effects
Reboxetine, Atomoxetine
Used in th for ADHD (inhibitor of NA reuptake)
Side Effects:
Insomnia
Anticholinergic effect (mind blockage of M R)
MAO Inhibitors
General Background
MAO = enzyme bound to external membrane of mitochondria
MAO a–> CNS neurons/ symp nerve ending/ gut wall
inhibition of NA and Serotonin degradation
MAO b–> predominantly in brain (neurons)
inhibition of dopamine and NA degradation
Act via irreversibly inhibition of enzyme
Side Effects:
Consumption of high tyramine (= indirectly acting sympathomimetic agents) containing food –> hypertensive crisis as MAO inhibitors allow tyramine to be absorbed.
SSRIs+MAO inhibitors–> serotonin syndrome
MAO Inhibitors
Names and characteristics
Phenelzine
Nonselective MAO a and MAO b inhibitor
Selegiline
selective MAO b inhibitor
Atypical Antidepressants
Drug groups
Serotonin Antagonists Re-uptake Inhibitors
Alpha 2 and 5 HT 2A/C Antagonists
Serotonin Antagonists Re-uptake Inhibitors
Names and characteristics
Trazodone, Nefazodone
Presyn Membrane: Inhibition of serotonin reuptake
Postsyn Membrane: inhibits 5HT 2A/C as antagonist–> inhibits sexual dysfunction and insomnia
–> serotonin acts only on 5 HT1 A (responsible for antidepressive effect)
Alpha 2 and 5 HT 2A/C Antagonists
Names and characteristics
Mitrazepine, Minaserin
Alpha 2 antag: enhance NA and 5HT release by blocking presynaptic inhibition (blocking - feedback)
5HT 2A/2C antag: inhibits 5HT 2A/C as antagonist–> inhibits sexual dysfunction and insomnia
–> serotonin acts only on 5 HT1 A (responsible for antidepressive effect)
Side Effects:
Sedation
Weight gain
Other Antidepressants
St John’s Wart
Inhibition of NA and 5HT reuptake
Used for mild depression
Lithium
Mood stabiliser
Mechanism:
Prevents recycling of inositol (↓ PIP2) by blocking
inositol monophosphatase–>↓ cAMP
Increase of 5HT release
