Depression - Drugs used in it Flashcards
Drug targets for depressive disorders:
-Transporters SERT and NET belong to a larger SLC6 family of transporters.
-They use the co-transport of NA+ as a driving force to move substrates.
-Antidepressants are dependent on extracellular Cl-
-and some SLC transporters also move K+
How is serotonin levels controlled with reuptake inhibitors?
-The SSRI’s are selective serotonin re-uptake inhibitors, as their name suggests they increase synaptic 5-HT(serotonin) by reducing their re-uptake into the synapse.
-However 5-HT can act of 5-HT 1A to inhibit the release of more 5-HT –> so this leads to opposing effects. (canceling out some of the SSRI’s effects)
-BUT with long term (chronic) administration of SSRI’s, the elevated 5-HT levels will induce the desensitisation of 5-HT 1A receptors. This in turn will reduce the inhibitory effect of 5-HT.
-This need to desensitisation could explain the slow onset of action.
Can NA control 5-HT levels?
The answer is YES.
-Noradrenaline can control 5-HT release, it can act on excitatory alpha 1 receptors to enhance 5-HT release.
-a2 (alpha) receptors are also down-regulated by antidepressants. an a2 receptor antagonist could further enhance 5-HT release (e.g mirtazapine (TCA), mainserin)
MOA inhibitors effects on depression:
-Monoamine Oxidase (MOA) controls the degredation of monoamine neurotransmitters
-There are two forms of MAO – A and B
-MAO-A has substrate prefrence for 5-HT and NA
-Inhibitors of this enzyme will cause an increase in tissue monoamines (5-HT, NA, Dopamine)
Mechanism of Action:
-MAO inhibitors increase cytoplasmic stores of NA and 5-HT in nerve terminals
-Irreversible non-selective inhibitors e.g. Phenelzine and Isocarboxazid,
iproniazid (but discontinued due to hepatotoxicity - jaundice)
-Most MAO inhib are non-selective
-Reversible MAO-A selective inhibitors - Moclobemide
Side Effects:
-Hypotension – common side effects
-Central stimulation – tremors, excitement, isomnia
-Increased appetite causing weight gain
-Drug and Food interactions - the CHEESE reaction
–Ingestion of tyramine in foods such as ripe cheese and marmite. tyramine typically degraded by MAO in the gut.
– With MAO I, the tyramine will be absorbed into circulation and will have sympathomimetic effects (e.g Acute hypertension and severe headaches)
Which of these drugs is NOT a MAO inhibitor?
a)Phenelzine
b)Moclobemide
c)Ropinirole
d)Iproniazide
Answer is C
Phenelzine and Iproniazide are irreversible non selective MAO inhib
Moclobemide is a reversible MAO-A inhibitor
Theories of depressions:
Monoamine theory:
-Inhibition of NA and 5-HT neurotransmitter reuptake seem equally effective.
-Direct neurochemical action are rapid but clinical anti-depressant effects take weeks to develop.
-Secondary adaptive changes are through to be responsible.
-Drugs may have acute affects on cognition - a positive effect on emotions.
Neuroendocrine mechanisms:
-Increased plasma cortisol levels in sever depression
-Impaired glucocorticoid induced feedback control
-Injection of CRF (Corticotropin releasing factor) into the brain can mimic aspects of depression.
-Cushing’s syndrome - often causes depression.
Inflammatory mechanisms:
-Behavioural change experienced with infections can mimic depressive-like symptoms
-Cytokines cause these changes.
-Infusion of particular cytokines induces depression in humans and rodents. (e.g IL-2 and IGN-y)
-People with autoimmune disease more likely to have depression
-post-mortem evidence of microglial activation in patients with depression.
Structural changes in the brain:
-Regional specific neuronal cell loss, will cause changes in the synaptic activity causing the imbalances in neurotransmitters.
-Functional imaging studies show a decrease in grey matter volume in pre-frontal cortex and hippocampus.
-Smaller volume of important brain structures.
-Post-mortem studies confirm a loss in GABAergic neurons, astrocytes and oligodendrocytes in the pre-frontal cortex
Which of the following statements is FALSE?
a)Tricyclics can have a sedating effect, anticholinergic effects, confusion, motor incoordination effect and a higher risk with overdose.
b)MAOI side effects include CNS stimulation, weight gain, insomnia, and postural hypotension.
c)A major problem with SNRI’s is the cheese reaction -tyramine-containing foods cause sympathomimetic effect. (acute hypertension, extreme headache)
d)SSRI’s S/E include nausea, insomnia, sexual dysfunction, Paroxetine linked to increase in suicidality, risk of drug intrx with CYP.
e)SNRI’s have side effects including sedation, dizziness, nausea, and some can have withdrawal effect.
Answer is C as MAOI are the class responsible for the tyramine reaction.
Which of the following is a TRUE statement regarding Bi-polar treatment?
a)Anti-epileptic drugs like Levetiracetam, Phenobarbital and Phenytoin can be used to treat BP.
b)Quetiapine, olanzepine and other atypical anti-psychotic drugs can be used.
c)Benzodiazepines are used as prophylaxis and treatment of mania
d)Lithium is C/I in Bi-Polar
e)Use of anti-depressants is recommended
Answer is B,
a)Anti-epileptics such as Carbamazepine, Valproate, and lamotrigine are used and not the ones mentioned above.
c)Benzo’s are used for their calming effects
d) lithium is what is used in prophylaxis and treatment of Mania
e) the used of antidepressants is NOT recommended as they can lea to switching to manic phase.
What is the pathophysiology of anxiety disorders?
-Anxiety arises from am abnormal regulation of the fear response.
-Fear itself is subjective, which is why it is expected to have a subjective response to threatening stimulus.
-Anxiety disorders in their nature are longer lasting and can be persistent due to lack os signs of safety.
-Disorders are distinguished based on Symptoms and Precipitating factors.
-The fear response activates the amygdala, neuroimaging suggests patients have heightened activity in their amygdala circuits
list of the main drugs used in anxiety disorders:
1- Antidepressants (SSRIs, SNRIs): Increase 5HT and NA levels.
–SSRIs considered to be first line, Escitalopram and paroxetine are licensed; other ssri’s similar efficacy and used widely.
2- Benzo’s: enhance the action of GABA on GABA a receptors containing a2 subunit (e.g. lorazepam, diazepam, flurazepam)
3- Buspirone (5HT 1A receptor agonist): can be used to treat GAD.
–5HT 1A receptors can act as an inhibitory autoreceptors on serotonergic neurons, posy synaptic 5HT 1A receptors are involved in emotional behaviours.
4- Gabapentin, Pregabalin, Valproate: All affect NaV and CaV - Anxiolytic properties.
5- Atypical antipsychotics: Olanzepine and Quetiapine can be effective in GAD and PTSD
6- Propranolol: a Beta-Blocker which can be used for relief of situational anxiety and GAD
7- Non-Pharma treatments:
Counselling, Cognitive therapy, Dietary and lifestyle changes.
