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SIU5 Neurology > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Describe the metabolism of AA NT: glutamate.

A
  1. Glutamate (Glu) is an excitatory NT
  2. Glucose and Glutamine (Gln) –> Glu via glutaminase
  3. Glu is stored in the vesicles of the synapse by VGluT- vesicular glutamate transporter
  4. Vesicles are released by Ca dependent exocytosis
  5. Released glu is taken up into nerve cells and glial cells (Astrocytes) by EAAT- excitatory AA transporter
  6. In astrocytes, Glu–> Gln by glutamine synthase, also recycled back to neurone
  7. Gln is recycled via transporters (GlnT) back to neurones
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2
Q

Define nociception

A

Nociception is the physical PROCESS of detection and transmission of damaging (noxious) stimuli

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3
Q

Define nociceptor

A

Structures / receptors which detect noxious stimuli

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4
Q

Define pain

A

Pain is the SUBJECTIVE CONSCIOUS perception of a stimuli that is causing tissue damage

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5
Q

Define Algesia and analgesia

A

Algesia: the induction of a condition leading to nociception and pain
Analgesia: reduction of nociception or pain without loss of conciseness

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6
Q

Describe the metabolism of GABA

A 
TCA cycle gives glutamate 
-> glutamic acid decarboxylase (enzyme) GAD->
GABA!!
- gaba transaminase ->
Succinic semialdehyde (inactive) ->
- succinic dehydrogenase 
Succinate 
- back to TCA cycle
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7
Q

List of inotropic and Metabotropic GABA receptor

describe the characeteristics of two type of rec

A

Ionotropic GABAa : cl- ion channel (hyperpolarise cells- inhibitory)
Metabotropic GABAb: B and Y subunits bind to K/Na channels
Efflux? Inhibitory
GABAc : cl- ion channel (v lil in brain )

inotropic: heterogenous rec, rapid cellular effect
metabotropic: hetero and homodimers, activate 2nd msger system from Gprotein, slower effect, may be “autorec” located Presynaptically

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8
Q

what type of ion channel is GABAa?

How many subunits are within an iontropic GABAa R?

A 
Ligand gated cl- ion channel 
- cl- influx -> IPSP
-fast hyperpol ->inhibition
5 subunits 
2a, 2b, 1 gamma
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9
Q

Where’s the orthosteric and the allosteric site of GABAa R?

A

B/w a and b sites = 2 binding sites within 5 subunits orthosteric (normal GABA binding sites)
B/w a and gamma site = 1 allosteric site (modulator site)

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10
Q

What’s the role of allosteric site of GABAa R

Name some substrates

A

Modulators site ( up and down gating of cl- ions) in presence of GABA bound to orthosteric sites

  • benzodiazepines ag/anta/in. ag
  • channel modulators
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11
Q

What are the functions of GABAa R?

A

1 anaesthetics eg etomidate and propofol
2 barbiturates eg pentobarbital has sedative and anticonvulsant effect
3 benzodiazepines multiple actions eg anxiety relieving, anticonvulsant, hypnotic - go sleepy
4 neurosteroid - Metabolites of progesterone and deoxycorticosterone

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12
Q

GABAb R are …. dimers

What are the roles of the two parts?

A

Heterodimers
R1: fly trap- gaba binding site
R2 traffics the receptor to cell surface

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13
Q

The pharmacological pathway when GABAb R is activated

A

Close ca channel presynaptically reduce NT release - autoreceptor

Open K channel postsynaptically giving a slow hyperpolarisation-inhibtion

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14
Q

The effect of GABAb R agonist
Example
Side effect

A

Treat spasticity : tremour
Motor disorder, multiple sclerosis by inhibiting the descending pathway (ventral root)
Baclofen is an ex
Cross BBB so prob w sedation

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15
Q

What are the three classes of ionotropic glutamate R?

How many subunit does each R has?

A

NMDA -subunit gluN1,N2A-D,N3
AMPA - gluA1-4
KAINATE -glu K1-5
4 subunits = tetrameric

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16
Q

NMDA (ionotropic gluR) is readily blocked by what ion?

How to unblock the R?

A

Mg2+

is Voltage sensitive and disappears when cell is depolarised

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17
Q

What agonists are required for the Activation of NMDA (ionotropic gluR)

A

glutamate on orthosteric site

glycine on allosteric site

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18
Q

What are the selective antagonists of NMDA Rs

A

polyamine ag/antag
Ketamine (sedative)
Phencyclidine (sedative hallucinogenic)

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19
Q

Metabotropic glutamate R has how many different GPCR?

Can be classified into how many groups

A

8 different GPCR : mGluR1-8

3 groups: I,II,III

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20
Q

Characteristics of mGluRs

A

Homo, heterodimers
Slow neuromodulatory role
Connect to diff second messenger system (Gq- increase IP3, Ca) (Gi/ Go reduces cAMP)

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21
Q

NMDA R is highly permeable to which ions

A

ca and Na (excitatory) ->can cause excitotoxicity

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22
Q

What are the effects of presynaptic NMDAR and mGluR

A

NMDAR increase glutamate release by increase Ca influx

mGluR decrease glutamate release by decreasing Ca influx

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23
Q

is amino acid transmitters localised to brain regions?

A

no, they are ubiquitous
glutamate mostly found in pyramidal neurones
GABA mostly found in short local interneurones also in longer projection neurones

24
Q

what is the full name for GABA

A

g-amino butyric acid

25
Q

GABAa rec pharmacology

what type of drug bind to it?

A

ABBN
Anaesthetics- etomidate and propfol (valatile)
Barbiturates- pentobarbital (sedative/anticonvulsant)
BZS (anxiety/anticonvulsant/hypnotic)
Neurosteroid- meabolites of progesterone and deoxycorticosterone

26
Q

How does glutamate bind so many rec?

A

its is NOT a rigid molecule, diff constituents can rotate along the single bonds, gives diff conformations =9 ‘rotamers’ are possible

27
Q

whare are amine NTs?

A 
NADH5: 
NA
Ach
DA
Histamine
5-HT serotonin
28
Q

where are NA and Adr orginated?

A

NA: locus coeruleus in the brain stem
Adr: C1 group

29
Q

where does NA and Adr exert an effect?

A

diffuse activation of forebrain, particularly cerebral cortex and hippocampus
also ascending/ descending pathway

30
Q

what are the effect of amine NTS?

A

arousal, attention, sleep and survival

31
Q

what are the functions of NA in CNS?

A
  1. brainstem- BP control via baroreceptor reflex
  2. descending- movement and pain
  3. ascending- arousal and mood, cognitive process eg learning, memory, attention
32
Q

what are the results of depletion/ overactive NA in brain?

A

depletion of NA in forebrain - depression

overactive NA- mania (bipolar)

33
Q

describe the process of NA synthesis/ then inhibition

A
  1. tyrosine from diet
  2. tyrosine->DOPA (tyrosine hydroxylase)
  3. DOPA-> dopamine (dopa decarboxylase)
  4. dopamine-> NA (DA -b- hydroxylase: only NA neurons express this! occur in vesicles via VMAT- vesicular monoamine transporter)
  5. high level of NA swtich off tyrosine hydroxylase- end product inhibtion
34
Q

what are the transporters that involved in reuptake / degradation of NA

A

NET- norepinephrine transporter

MAO/ COMT

35
Q

what effect does cocaine have on NA pathway

A

block reuptake of NA (block NET and DAT- reward)

36
Q

what effect does ampehtamine have on NA pathway

A

NA replacement- block NET and DAT-reward

37
Q

Classification of overweight and obesity (adults) BMI

A 
healthy 18.5- 24.9
overweight 25-29.9
obesity I 30-34.9
obesity II 35- 39.9
obesity III 40 or more
38
Q

Classification of overweight and obesity (adults) waist circumference

A

men 94- 102 cm high risk, >102 v high risk
women 80-88 cm high risk, >88 v high risk
8 cm range for both

39
Q

what is the recommended time per week for moderate intensity physical activity

A

150 min per week 30min for 5 days

40
Q

Lesion (damage) of the dorsal raphe nuclei (5HT origin) = low 5HT induces …

A

HYPER phagia

41
Q

5HT in the periphery is stored in

it generates what signal after feed

A

enterchromaffin cells in GI mucosa

5HT is release after food to generate satiety signal

42
Q

how can we increase level of 5HT to REDUCE food intake?

A

administer precursor tryptophan or 5-hydroxytryptophan (5HTP)

43
Q

which 5HT rec are involved in satiety effect in brain

A

5HT1B/ 5HT2C (both in arcuate nuclues ARC)/5HT6

44
Q

Leptin therapy in humans only effective in

A

congenital leptin deficiency NOT Leptin resistant

45
Q

Only anti-obesity drug currently licensed in the UK

A

orlistat

46
Q

MOA of orlistat

A

Lipase inhibitor, stop fat from broken down to FA and glycerol, fa wont be absorbed, they stay in gut then come out with faeces

47
Q

s/e of orlistat

A

“Oily stools” (fats still ingested so..) , abdominal cramps, flatus (gas) with discharge

48
Q

what is Fenfluramine
what is the MOA
s/e

A

an analogue of amphetamine w low abuse/addictive potential
metabolised to norfenfluramine –>5HT releasing agent + reuptake inhibitor–> more 5HT–> activate 5HT2C rec –>reduce food intake
heart valve problem via 5HT2B action

49
Q

does fenfluramine work effectively?

A

Only produced moderate weight loss, effects temporary

50
Q

what is phentermine
why is it w/d?
MOA

A

a releasing agent of NA,DA, 5HT
cause pulmonary hypertension due to peripheral NA effect
- central action on hypothalamus b2 rec- induce apptite suppresion
- increase 5HT, inhibit MAO, increase basal metab rate

51
Q

is A fixed-dose combination of phentermine and the anticonvulsant topiramate better or worse
what are the effects of topiramate?

A

better
possible effect on (increase?)mitochondrial carbonic anhydrase metabolism: Mitochondrial CA is known to supply HCO3- for the initial reactions of gluconeogenesis and ureagenesis.
also effect on VGSC

52
Q

moa of Bupropion/Naltrexone

A

bupropion - NDRI, increase NA, DA

naltrexone - opioid antagonist - reduce reward - reduce food intake

53
Q 
Sibutramine
what is it 
MOA
does it work?
why w/d
A

sibutramine is a NDRI - increase NA and DA originally an antidepressant
- stimulate the POMC, anorexigenic pathway, inhibit AGRP, orexigenic pathway in arcuateARC
- increase E expenditure via thermogenesis
- short term effect 10%wt loss, but rebounce once stopped
= w/d bc increased CVR with high NA

54
Q

what is rimonabant?
MOA
why is it w/d

A

a cannabinoid CB1 GPCR INVERSE AGONIST
endocannabinoid bind to pre-synaptic CB1, inhibitory response, reduce Ca influx 5HT and DA release. (like weed increase food intake)
rimonabant reduce this inhibitory response
-w/d due to suicidal thought

55
Q

what drug has similar moa to fenfluramine but better?

what is it and what is its moa

A

locaserin
locaserin is a high affinity 5HT2C rec full agonist and relatively selective for 5HT2B rec (that causes heart valve prob)
also stimulate POMC- anorexigenic pathway

56
Q

List the anti obesity meds

A
  1. Olistat
  2. Fenfluramine
  3. Phentermine (fen-phen)
  4. Phentermine + topiramate
  5. Bupropion + naltrexone
  6. Sibutramine
  7. Rimonabant
  8. Locaserin

SIU5 Neurology (13 decks)

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