Week 10 - Antidepressants Flashcards
Where are neurotransmitters stored?
In vesicles within the terminal of the pre-synaptic neurone
Where is monoamine oxidase found and what does it do?
-found on the membrane of mitochondria
- breaks down monoamines
- involved in removing the neurotransmitters norepinephrine, serotonin and dopamine from the brain (MAOIs prevent this from happening making these chemicals more available)
Where is most serotonin in the body found?
-mast cells and platelets in the blood
What are the serotonin neurones and pathways which lie in or near the midline of the brain stem?
Raphé nuclei
-nine main clusters of cells
What is the chemical name for serotonin?
5-hydoxytryptamine (5-HT)
Name the monoamine transmitters mad why they are called that
- serotonin
- noradrenaline
- dopamine
(Derived from amino acids)
What enzyme can inactivate serotonin (5-HT)?
Monoamine oxidase
How are serotonin, dopamine and noradrenaline taken out of the synaptic cleft?
-specific reuptake transporters
- takes neurotransmitter out of the synaptic cleft and back in to the presynaptic terminal to end its ‘transmission’
- can be repackaged in vesicles and used again
-some drugs act by inhibiting reuptake transporters which means the transmitter stays in the synaptic cleft and have a prolonged action
Name the categories of SERT inhibitors
- tricyclic antidepressants (also affect NA reuptake)
- selective serotonin-reuptake inhibitors
- SERT inhibitors/5-HT releasers
Name some tricyclic antidepressants
- desipramine
- imipramine
Name some selective serotonin-reuptake inhibitors
-sertraline
-citalopram
Fluoxetine (Prozac)
Name some SERT inhibitors/5-HT releasers
- fenfluramine
- MDMA (methylenedioxymethamphetamine)
How do the classic tricyclic antidepressants work?
- inhibit both serotonin and noradrenaline reuptake in to mere terminals
- later antidepressants - more selective inhibitors of serotonin reuptake
What do the action of SERT inhibitor drugs have an effect on?
-maintain higher levels of monoamines in the synaptic cleft
What is the mechanism of SERT inhibitors/5-HT releasers?
- maintain higher levels of monoamines in the synaptic cleft
- transporters can sometimes function in the opposite direction to release transmitters from the terminal
- fenfluramine and MDMA act on the serotonin transporter and not only inhibit the transport of serotonin in to the cell but also facilitate its outward transport
What does serotonin bind to?
- 14 known serotonin receptors, fall in to 7 families
- 7 trans-membrane spanning G-protein-coupled receptors
- have an external amino terminal which contains the ligand binding site, and an internal carboxy terminal linked to GTP-binding proteins
- when receptor is activated by serotonin, the G-proteins bind GTP which causes dissociation of the a-subunit (then can activate messenger systems)
What is the 5-HT3 receptor?
A ligand-gated ion channel
- includes the NMDA glutamate receptors and GABAa receptors
- ionotropic NOT metabotropic
- 5-HT3 receptor forms a channel which is non-selective for positively charged ions (e.g. Na+, K+ and Ca2+)
What are dopamine and noradrenaline?
Catecholamines
What is Parkinson’s disease caused by!
Loss of dopamine and noradrenaline from neurones in the substantia nigra of the midbrain
What does the substantia nigra do?
Projects to parts of the brain, the basal ganglia and dorsal striatum, involved in voluntary movement
-another group of dopaminergic neurones in the ventral tegmental area that give rise to the mesocorticolimbic system - these are the dopaminergic neurones involved in mood
Explain the synthesis of catecholamines
Tyrosine –> L-DOPA –> Dopamine –> Noradrenaline
What enzymes break down dopamine?
- monoamine oxidase (MAO)
- catechol-O-methyl transferase (COMT)
What are adrenergic receptors?
-bind to both adrenaline and noradrenaline
- a-receptors have a higher affinity for noradrenaline
- a1-adrenergic receptors are linked to phospolipase C and a2-adrenergic receptors block adenylate cyclase
- B-receptors are linked positively to adenylate cyclase
What do people with depression often have high levels of?
Cortisol
What are monoamine oxidase inhibitors (MAOIs)?
- non-selective blockers of the metabolism of all monoamines
- still used commonly for severe depression in patients who have failed to respond to other treatments - but last line for pharmacological intervention
- phenelzine (Nardil) - treats depression and bi-polar
- tranylcypromine (parnate) - severe depression
What are the side effects of monoamine oxidase inhibitors?
- hypertensive crisis -especially due to interactions with other drugs
- foods high in tyramine (cheese effect)
- inhibition of cytochrome P450 (degrades other drugs)
- tryptophan supplements or other psychoactive drugs should be avoided or there is risk of ‘serotonin syndrome’
- weight gain
- oedema
- sexual dysfunction
- sedation
What are the contraindications of MAOIs?
- impaired renal or hepatic function
- hypertension
- pregnant or lactating women
How do tricyclic antidepressants work?
-non-selectively blocking the reuptake of noradrenaline and serotonin, leading to an increase in the availability of these transmitters at their respective receptors
Name some tricyclic antidepressants and what they treat
-tricyclic antidepressants are most useful for treating major depressive episodes (can be prescribed for panic disorder and for OCD)
- imipramine - depression
- amitriptyline - depression
- doxepin - depression and anxiety
What are the side effects of tricyclic antidepressants?
- weight gain
- sexual dysfunction
- inhibition of cytochrome P450
- adrenergic effects - contraindicated for patients with CV problems
- antihistaminergic effects - sedation (avoid other CNS depressants or anti-histamines e.g. cimetidine)
- anticholinergic effects - dry mouth, blurred vision, dizziness, headache and constipation
What system in the brain controls our moods and emotions?
The limbic system
Name some SSRIs and what they treat
Most widely prescribed class of antidepressants
Fluoxetine (Prozac) - depression and OCD
Paroxetine (Paxil) - depression and panic disorders
Sertraline - depression and panic disorders
Citalopram - depression
What is the delay to therapeutic effects for SSRIs?
- 2-4 weeks
- but effect on serotonin levels is almost immediate
What are the side effects of selective serotonin-reuptake inhibitors (SSRIs)?
- sexual dysfunction
- dependence and withdrawal
- weight loss
- MAOIs (serotonin syndrome -concurrent use between SSRIs and MAOIs can cause serotonin syndrome - characterised by severe agitation, disorientation, ataxia, muscle spasms and exaggerated autonomic function)
- cimetidine (decreases SSRI breakdown), warfarin
Contraindications - patients with a history of mania and/or anxiety - exacerbate mania/anxiety
Name some miscellaneous next generation antidepressants
Bupropion - (aminoketone - inhibits the reuptake of serotonin, noradrenaline and dopamine) - depression
Venlafaxine - (strong inhibitor of serotonin and noradrenaline reuptake, but a weak blocker of dopamine reuptake) - depression
Name some mood stabilisers and what they treat
Lithium carbonate - prophylaxis and treatment of acute mania
Lithium citrate - prophylaxis and treatment of acute mania
Carbamazepine (anticonvulsant) - mania, epilepsy
Valproate (anticonvulsant) - mania, epilepsy
What are the side effects of mood stabilisers?
-contraindicated for patients with renal dysfunction, leukaemia, dehydration or sodium depletion
- sodium bicarbonate
- other antipsychotic drugs, diuretics and NSAIDS
- dizziness, headache, confusion, hair loss, oedema, cardiac dysrhythmias, nephrotoxicity
- toxicity and withdrawal
- anticonvulsants - birth deformities
