Anti-depressants Flashcards
Ionotropic vs. metabotropic glutamate receptors
Ionotropic - NMDA, AMPA, kainate
-NMDA –> involved in synaptic plasticity (imp. for memory and learning), excess activation leads to cells death, NMDA antagonist is a treatment for alzheimer’s disease
Metabotropic - can be excitatory or inhibitory
- can result in G-protein activation of phospholipase C or inhibition of adenylyl cyclase
Types of depression
Reactive - could pass without intervention
Major depressive disorders - endogeneous
Bipolar affective disorder - mania, depression…
Symptoms of depression
Emotional –> enhancement of 5-HT mediated transmission
-negative thoughts, low self-esteem, loss of reward, loss of motivation, pessimism
Biological –> enhancement of NA mediated transmission
-retardation of thought and action, loss of libido, loss of appetite, sleep disturbance
Principles of the treatment (4)
- onset of action is slow, it should be continued from 4-6 weeks before concluding that the drug is ineffective
- if there is a partial response, should be continued for several weeks before increasing the dose
- treatment should be continued for 4-5 months after goal is achieved
- long term treatment –> not recommended
Mono-amine theory of depression (3)
- disease is a result from functionally deficient mono-aminergic (NA and 5-HT) transmission in CNS
- weak response of plasma cortisol to exogeneous steroid may be the reason for defective monoamine transmission in the hypothalamus
- may be associated with neuro-degeneration and reduced neurogenesis in hippocampus
5-HT and NE pathways in the brain
- pre-frontal cortex, limbic system, hippocampus, amygdala
- 5-HT source –> raphe nuclei, NE source –> locus coeruleus
- descending pathways
Structural and functional changes (4)
- most areas of the brain decreases in volume
- pituitary is the only one that increases in volume
- increase cortical levels of glutamate
- abnormalities in these key areas: amygdala, hippocampus, prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex
Treatment with anti-depressants (2)
- normalization of 5-HT and NE in the pre-frontal cortex and limbic system –> normalization of activity in the prefrontal cortex, hippo-campus, amygdala
- restore homeostasis by modulating balance between excitatory and inhibitory inputs in brain and by optimizing neuroplasticity, neurogenesis, cellular resilience
Anti-depressants
-“groups” (4)
- TCA (tri-cyclic anti-depressants)
- SNRI (serotonin and noradrenalin re-uptake inhibitors)
- SSRI (selective serotonin re-uptake inhibitors)
- MAOi (mono-amine oxidase inhibitors)
Anti-depressants
-names by group
- TCA –> amitryptyline
- SSRI –> fluoxetine, citalopram, escitalopram, sertraline
- SNRI –> duloxetine
- MAOi –> moclobemide
- Other mode –> mirtazapine, agomelatine
Anti-depressants
-pharmacokinetics (8)
- metabolized in liver by CYP enzymes
- active metabolties, inactivation by glucuronic conjugation
- excretion in urine
- TCA and SSRI metabolites are active, accumulation is possible
- lipophilic
- strong binding with plasma proteins
- high volume of distribution
- elimination of main drug and its metabolite is slow
TCA
- pharmacokinetics (5)
- unwanted side effects (7)
- most are long acting –> converted to active metabolites
- narrow therapeutic window
- treatment start from low doses
- used to treat moderate to severe depression
- block alpha, muscarinic and histamine receptors
-side effects: convulsion, sedation, hypotension, muscarinic block, weight gain, sexual dysfunction, heart toxicity
SSRIs (4)
- pharmacokinetics
- unwanted side effects (3)
- inhibition of 5-HT reuptake
- acute toxicity (especially cardiotoxicity)
- similar efficacy and time course of TCA
-side effects: nausea, GI effects, sexual dysfunction
SNRIs (4)
- pharmacokinetics
- unwanted side effects (3)
- 5-HT and NA reuptake inhibition
- efficacy and safety similar to SSRIs
- used for neuropathic pain and depression with somatic symptoms
-side effects: nausea, GI effects, sexual dysfunction
MAOi (5)
- pharmacokinetics (4)
- unwanted side effects (6)
- inhibit MAO = increases NA and 5-HT in pre-synaptic neuron
- all could cause “cheese reaction”
- 2 weeks window needed before stopping
- short-action, reversible
-side effects: convulsions, sedation, hypotension, muscarinic block, weight gain, sexual dysfunction
