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Pharmacology > Serotonergic Neurotransmission and Serotonergic Drugs > Flashcards

Serotonergic Neurotransmission and Serotonergic Drugs Flashcards

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

A

mood

CNS arousal

24
Q

pathophysiology of depression

A

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

25
Q

biological symptoms of depression

A

slowness of thought and action

loss of libido

sleep disturbances

loss of appetite

26
Q

unipolar vs bipolar depression

A

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
Q

monoamine theory of depression

A

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
Q

neuroendocrine theory of depression

A

depression is caused by overactivity in the stress responsive hypothalamic pituitary adrenal (HPA) axis

29
Q

trophic factor theory of depression

A

caused by reduced levels/functional activity of brain-derived neurotrophic factor (BDNF)

30
Q

glutamate theory

A

depression is caused by excessive glutamate activity at NMDA receptors

31
Q

Neurodegeneration theory

A

depression is caused by neurodegeneration and reduced neurogenesis in the hippocampus

32
Q

HYPOTHESIS for depressive symptoms

A
33
Q

categories of monoamine reuptake inhibitors (type of antidepressant drug)

A

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
Q

3 MOA for antidepressants

A

monoamine reuptake inhibitors

monoamine receptor antagonists

monoamine oxidase inhibitors

35
Q

how do monoamine reuptake inhibitors work

A

block reuptake of

  • NA and 5-HT (TCAs and SNRIs)
  • 5-HT selectively (SSRIs)
  • NA selectively
36
Q

how do monoamine receptor antagonists work

A

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
Q

chronic MOA of antidepressants

A

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
Q

main SSRIs

A

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
Q

vortioxetine - where else does it function (apart for serotonin reuptake)

A

agonist/antagonist activity at several 5-HT receptors

40
Q

where else does fluoxetine act (apart from serotonin reuptake)

A

antagonist activity at 5-HT2C receptors

41
Q

what else do SSRIs treat

A

less SEs than TCAs

less dangerous in overdose than TCAs

no “cheese rxn”

also treat various anxiety disorders

treat premature ejaculation

42
Q

Side effects of SSRIs

severe side effects when given with __________

A

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
Q

what are the main TCAs

A

imipramine

desipramine

clomipramine

amitriptyline

nortriptyline

44
Q

what else are TCAs used to treat

A

neuropathic pain (persistent pain following nerve damage)

45
Q

Side effects of TCAs

A

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
Q

examples of SNRIs

A

venlafaxine

desvenlafaxine

duloxetine

also used to treat anxiety disorders, menopause symptoms, neuropathic pain, fibromyalgia, urinary incontinence

47
Q

NA reuptake inhibitors

A

bupropion

reboxetine

atomoxetine

also used to treat nicotine dependence, ADHD

48
Q

risk with St Johns Wort

A

serious risk of drug-drug interactions due to effects on CYP450 enzymes

49
Q

main monoamine receptor antagonists

A

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
Q

where is the α2 adrenoceptor

A

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
Q

main non-selective MAO inhibitors

A

phenelzine

tranylcypromine

isocarboxazid

52
Q

main MAO-A selective inhibitors

A

moclobemide

clorgyline

53
Q

what are the isoforms of MAO

A

MAO-A

MAO-B

54
Q

what does MAO-A metabolise

A

5-HT

NA

dopamine

55
Q

what does MAO-B metabolise

A

NA

dopamine

phenylthylamine

56
Q

what do MAO inhibitors interact with and what does this cause

A

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
Q

what happens when MAO inhibitors interact with certain foods

A

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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