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Pharmacology > Serotonergic Neurotransmission and Serotonergic Drugs > Flashcards

Serotonergic Neurotransmission and Serotonergic Drugs Flashcards

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1
Q

most important location of 5-HT in the brain (+ others)

A

raphe nuclei

dorsal raphe nuclei project to cortex, hippocampus, amygdala, striatum and hypothalamus

ventral raphe nuclei project to cerebellum, medulla and spinal cord

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2
Q

Synthesis, storage, release, termination and metabolism of 5-HT

A
  1. tryptophan is taken into neuron via carrier mediated transport
  2. tryptophan is converted to 5-HT in 2 steps catalysed by tryptophan hydroxylase and aromatic AA (DOPA) decarboxylase
  3. 5-HT is actively packaged into vesicles by an amine transporter
  4. release is via classical Ca2+-mediated exocytosis
  5. termination is via uptake by a serotonin transporter
  6. Degradation is via monoamine oxidase and aldehyde dehydrogenase
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3
Q

receptor targets of 5-HT

A
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4
Q

physiological response - 1A

A

Gi

Presynaptic (inhibitory autoreceptors) on raphe neurons

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5
Q

physiological response - 1B

A

Gi

Presynaptic (inhibitory) on basal ganglia neurons

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6
Q

physiological response - 1D

A

Gi

Presynaptic (inhibitory) on basal ganglia neurons

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7
Q

physiological response - 2A

A

Gq

pre and postsynaptic - excitatory or inhibitory

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8
Q

physiological response - 2B

A

Gq

pre and postsynaptic - excitatory or inhibitory

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9
Q

physiological response - 2C

A

Gq

pre and postsynaptic - excitatory or inhibitory

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10
Q

physiological response - 3

A

ion channel

pre and post synaptic

excitatory on cortical and area postrema neurons

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11
Q

physiological response - 4

A

Gs

pre and postsynaptic

excitatory (including as facilitatory autoreceptors)

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12
Q

physiological response - 5 and 6

A

unknown

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13
Q

physiological response - 7

A

Gs

not known

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14
Q

function of 5-HT

A

sleep

wakefulness

mood

feeding and appetite - overall effect of serotonin is to reduce appetite

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15
Q

MOA of some anti-emetics

A

serotonin antagonist

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16
Q

pathophysiology of depression

A

deficiency in monamine (NA and 5-HT) transmission is thought to underlie depression

SSRIs used to treat depression

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17
Q

treatment for anxiety

A

Busiprone = 5-HT1A receptor partial agonist (anxiolytic)

5-HT1A receptor = inhibitory autoreceptor

activating it will REDUCE 5-HT release initially

but over time it is thought that this may lead to desensitisation of 5-HT1A receptors and ultimately INCREASED synaptic 5-HT

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18
Q

most important site of NA in the brain

A

cells in locus ceruleus which project to hippocampus, cortex and cerebellum

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19
Q

Synthesis, storage, release termination, metabolism of NA

A
  1. Tyrosine is taken into neuron via carrier mediated transport
  2. tyrosine is converted to NA in 3 steps catalysed by tyrosine hydroxylase and dopamine β-hydroxylase
  3. dopamine is actively packaged into vesicles by an amine transporter and conversion to NA then occurs
  4. release is via classical Ca2+-mediated exocytosis
  5. termination is via uptake by a NA transporter
  6. degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase
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20
Q

receptor targets

A

α-adrenoceptors

α1 via Gq (PLC and increased IP3/DAG)

α2 via Gi (AC and decreased cAMP)

β-adrenoceptors

β1 via Gs (AC and increased cAMP)

β2 via Gs (AC and increased cAMP)

β3 via Gs (AC and increased cAMP)

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21
Q

physiological response of α-adrenoceptors

A

widespread in the brain

located both pre and postsynaptically

presynaptic - function as inhibitory receptors and autoreceptors and autoreceptors reducing NA release

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22
Q

physiological response of β-adrenoceptors

A

widespread in the brain

located both pre and postsynaptically

inhibitory and excitatory effects on pre and postsynaptic neurons

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23
Q

what behaviours is NA responsible for

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A

mood

CNS arousal

24
Q

pathophysiology of depression

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A

deficiency in monoamine (NA and 5-HT) transmission is thought to underlie depression

25
biological symptoms of depression
slowness of thought and action loss of libido sleep disturbances loss of appetite
26
unipolar vs bipolar depression
unipolar - mood swings in same direction bipolar - depression alternates with mania mania = * excessive exuberance, enthusiasm, self-confidence * impulsive actions * irritability, impatience, aggression * grandiose delusions
27
monoamine theory of depression
most established - underpins current drug therapy depression is caused by a deficit of monoamines NA and/or 5-HT in certain sites in the brain
28
neuroendocrine theory of depression
depression is caused by overactivity in the stress responsive hypothalamic pituitary adrenal (HPA) axis
29
trophic factor theory of depression
caused by reduced levels/functional activity of brain-derived neurotrophic factor (BDNF)
30
glutamate theory
depression is caused by excessive glutamate activity at NMDA receptors
31
Neurodegeneration theory
depression is caused by neurodegeneration and reduced neurogenesis in the hippocampus
32
HYPOTHESIS for depressive symptoms
33
categories of monoamine reuptake inhibitors (type of antidepressant drug)
SSRIs TCAs Serotonin/NA reuptake inhibitors (SNRIs) NA reuptake inhibitors other reuptake inhibitors e.g. St Johns Wort and hyperforin (this inhibits monoamine oxidase - not a pure compound)
34
3 MOA for antidepressants
monoamine reuptake inhibitors monoamine receptor antagonists monoamine oxidase inhibitors
35
how do monoamine reuptake inhibitors work
block reuptake of * NA and 5-HT (TCAs and SNRIs) * 5-HT selectively (SSRIs) * NA selectively
36
how do monoamine receptor antagonists work
block the action of NA at α2 receptors and/or 5-HT at 5-HT receptors exert their effect very quickly but mood doesn't change immediately adaptive process takes place
37
chronic MOA of antidepressants
given that the clinical effects of antidepressants take weeks to develop, their acute pharmacological effects cannot account for their antidepressant activity * Some NA receptors are consistently downregulated (especially β1 and β2) * 5HT1A receptor (inhibits 5-HT release) may become desensitised over time, leading to increased synaptic 5-HT levels * possible changes in gene expression via transcription factors (e.g. CREB, Fos, NF-κB), leading to neurogenesis
38
main SSRIs
fluoxetine - prozac (also antagonist activity at 5-HT2C receptors) fluvoxamine paroxetine citalopram escitalopram sertraline vortioxetine (also agonist/antagonist activity at several 5-HT receptors)
39
vortioxetine - where else does it function (apart for serotonin reuptake)
agonist/antagonist activity at several 5-HT receptors
40
where else does fluoxetine act (apart from serotonin reuptake)
antagonist activity at 5-HT2C receptors
41
what else do SSRIs treat
less SEs than TCAs less dangerous in overdose than TCAs no "cheese rxn" also treat various anxiety disorders treat premature ejaculation
42
Side effects of SSRIs severe side effects when given with \_\_\_\_\_\_\_\_\_\_
Nausea anorexia insomnia loss of libido and failure to orgasm not recommended for children \< 18 yrs - potential risk of suicide ideation when given in combination with MAO inhibitors they can lead to **serotonin syndrome** - tremor, hyperthermia, CV collapse
43
what are the main TCAs
imipramine desipramine clomipramine amitriptyline nortriptyline
44
what else are TCAs used to treat
neuropathic pain (persistent pain following nerve damage)
45
Side effects of TCAs
*_normal clinical doses_* **anticholinergic effects (due to muscarinic block)** ⇒ dry mouth, constipation, blurred vision, urinary retention **postural hypotension (due to α-adrenoceptor block)** **sedation (due to H1 block)** ⇒ often causing daytime drowsiness and difficulty in concentrating **potentiation of the effects of alcohol** ⇒ can lead to respiratory depression and even death *_overdose_* **ventricular dysrhythmias - sudden cardiac death** **excitement, delirium and convulsions** **respiratory depression and coma**
46
examples of SNRIs
venlafaxine desvenlafaxine duloxetine also used to treat anxiety disorders, menopause symptoms, neuropathic pain, fibromyalgia, urinary incontinence
47
NA reuptake inhibitors
bupropion reboxetine atomoxetine also used to treat nicotine dependence, ADHD
48
risk with St Johns Wort
serious risk of drug-drug interactions due to effects on CYP450 enzymes
49
main monoamine receptor antagonists
mirtazapine (antagonist at α2, 5-HT2A, 5-HT2C, 5-HT3) trazodone (antagonist at 5-HT2A, 5-HT2C) mianserin (antagonist at α1, α2, 5-HT2A, histamine H1)
50
where is the α2 adrenoceptor
α2 adrenoceptor is on the presynaptic terminals of 5-HT neurons where it reduces 5-HT release therefore antagonising it will enhance 5-HT release
51
main non-selective MAO inhibitors
phenelzine tranylcypromine isocarboxazid
52
main MAO-A selective inhibitors
moclobemide clorgyline
53
what are the isoforms of MAO
MAO-A MAO-B
54
what does MAO-A metabolise
5-HT NA dopamine
55
what does MAO-B metabolise
NA dopamine phenylthylamine
56
what do MAO inhibitors interact with and what does this cause
**SSRIs** * serotonin syndrome **Pethidine (opiate analgesic)** * may lead to severe hyperpyrexia (high fever) with restlessness, coma and hypotension * reason is unclear, but likely that an abnormal pethidine metabolite is produced due to inhibition of normal pethidine metabolic enzymes
57
what happens when MAO inhibitors interact with certain foods
TYRAMINE indirectly acting sympathomimetic amine diet derived (e.g. fermented meats, ripe cheese, beers, marmite, bovril) normally metabolised by MAOs in gut so does not reach circulation but serious drug-drug interaction with MAOIs when tyramine enters blood stream EFFECTS: potentially fatal hypertensive crisis severe throbbing headaches intracranial haemorrhage

Pharmacology (23 decks)

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