Pharmacology of the sympathetic nervous system: Noradrenaline Signalling

Question 1

Sites for potential drug intervention

Answer 1

Sympathetic nerves in CNS
Sympathetic ganglion
Neuroeffector junction

Question 2

Why are the sympathetic nerves in the CNS not a good target for drug intervention?

Answer 2

Needs to penetrate blood brain barrier

Widespread effects

Question 3

Why is the sympathetic ganglion not a good target for drug intervention?

Answer 3

Transmission is acetylcholine mediated in all autonomic ganglia
Widespread, non specific

Question 4

Why is the neuroeffector junction a good target for drug intervention

Answer 4

Specific targeting of function

Minimal off target effects

Question 5

Target areas for signaling at the sympathetic post ganglionic junction

Answer 5

NT synthesis
NT storage
NT release
NT receptor interaction
NT inactivation

Question 6

Target areas for signalling at sympathetic post ganglionic junction: inhibition of noradrenaline synthesis

Uses and side effects

Answer 6

a methyl tyrosine, inhibits tyrosine hydroxylase,
DOPA cannot form

Decreases BP in adrenal tumors

Can cause sedation, Parkinsonism, diarrhoea

Question 7

Inhibition of NA storage
Uses
Side effects

Answer 7

Reserpine blocks VMAT
Prevents uptake of NA into vesicles, metabolized by MOA into inactive metabolites

HTN treatment

Can cause profound CNS depression, diarrhea nasal congestions

Question 8

What normally happens when the NA needs to be removed

Answer 8

NA transported back into varicosity through uptake 1 channels
After NA release, release inhibited by NA activation of a2 adrenergic receptor (a2AR) on presynaptic terminal in -ve feedback mechanism

Question 9

Inhibition of NA release

Answer 9

Clonidine, a2AR agonist, inhibits NA release by activating receptors

Question 10

Promotion of NA release

Answer 10

Amphetamine, tyramine, ephedrine enters via uptake 1 channel,
Compete with NA to enter vesicles via VMAT, displace NA, causing leakage into synaptic gap

Inhibits MAO, increase [free NA] for release into synaptic gap

Question 11

Types of post synaptic adrenergic receptors

Answer 11

G protein coupled receptors
7 transmembrane spanning domains
a1, coupled to Gq
a2, coupled to Gi

b1, b2, coupled to Gs

Question 12

a adrenergic receptor antagonists (a blockers)

Answer 12

Prevent VC, decrease BP

Question 13

Non selective a blocker examples, effects

Answer 13

Phenoxybenzamine, irreversible competitive antagonist

Phentolamine, reversible competitive antagonist

Both cause reflex tachycardia
NOT CLINICALLY USED ANYMORE

Question 14

Selective a1 blocker examples, effects

Side effects

Answer 14

Doxazosin, tamulosin,
Antihypertensive agents, for benign prostatic hyperplasia

Postural hypertension, nasal congestion, impotence, priapism, diarrhoea

Question 15

b adrenergic antagonists (b blockers)

Answer 15

Directly block SN input into heart
Decreased force of contraction
Decreased contraction frequency
Decreased vascular tone
Decreased cardiac output, BP

Question 16

Non selective (block both a1, b) examples, uses and effects

Answer 16

Labetolol
Stable congestive heart failure

Decreased arteriole BP, fewer side effects than a blockers

Question 17

b1 subtype selective (cardio selective) examples, uses

Answer 17

Atenolol

Arrhythmias, MI, angina

Question 18

b selective (blocks b1, b2) examples, uses

Answer 18

Propanolol

Arrhythmias, MI, angina

Question 19

Adverse effects of b blockers

Answer 19

Fatigue, decreased CO, muscle perfusion => poor exercise response

Reduced peripheral blood flow, Reynauds, problems for those w renal, hepatic disfunction

Bronchoconstriction, problem for asthmatics

Decreased sympathetic tone => higher cardiac failure risk

Hypoglycemia harder to detect

Question 20

Example of a b2 agonist in asthma

Answer 20

Salbutamol, selective b2 agonist
Makes b receptor more sensitive to NA released.
Does not affect the -ve feedback loop of a2AR

Question 21

How is NA signaling terminated

2 types

Answer 21

Endogenous, exogenous catecholamines metabolized by 2 enzymes

MAO, within cells bound to surface membrane of mitochondria
Cathechol-o-methyl transferase (COMT), widespread enzyme found in both neuronal and non neuronal tissues

Question 22

Monoamine oxidase location, isoforms

Answer 22

Abundant in noradrenergic nerve terminals, intestinal epithelium

MAOa, in CNS liver, pulmonary vascular endothelium, GI, placenta
MAOb, in CNS, systematically in platelets

Question 23

MAO inhibitors and function

Answer 23

Phenylzine, inhibits both isoforms

Moclobemide, short acting MAOa, selective inhibitor

Selegiline, irreversible MAOb selective inhibitor for dopamine

All prolong active lifespan of signalling

Question 24

Why is the selectivity of action important

Answer 24

Higher the selectivity of action by targeting specific receptor subtypes, the greater the chances of producing therapeutic agents w reduced side effects

Question 25

What is tyramine and the cheese effect

Answer 25

Tyramine found in cheese, wine, yoghurt
If MAO inhibited, tyramine is not broken down
This can lead to a hypertensive crisis