L12 The PNS : Adrenergic Agonists And Antagonists

Question 1

Describe the biochemistry of noradrenaline

Answer 1

Precursor = tyrosine
Tyrosine converted into DOPA via tyrosine hydroxylase
DOPA converted into dopamine via DOPA decarboxylase
Dopamine into noradrenaline via DA-beta-hydroxylase

Question 2

What are the fundamentals of noradrenaline neurotransmission?

Answer 2

Synthesis - tyrosine, hydroxylase/DOPA, decarboxylase, DA beta hydroxylase
Storage - vesicles
Release - exocytosis
Receptor interaction - alpha and beta receptors
Termination - uptake and recycled by monoamine oxidase

Question 3

Which 2 main classes of NA receptor mediate the actions of noradrenaline?

Answer 3

1) alpha receptors
2) beta receptors

Question 4

Outline alpha-noradrenergic receptors

Answer 4

• alpha 1 and 2
• located on the effector tissues/targets of sympathetic system
• G-protein coupled receptors
• slow responses

Question 5

Outline beta-noradrenergic receptors

Answer 5

• beta 1,2 and 3
• located in effector tissues/targets of sympathetic system
• G-protein coupes receptors
  Slow responses

Question 6

Which sympathetic effects are mediated by alpha-1 receptors

Answer 6

1) pupils dilate
2) blood vessels to visceral organs and skin constricts
3) brain activity and general alertness

Question 7

Outline alpha-2 receptors

Answer 7

They are presynaptic receptors
- inhibit neurotransmitter release (negative feedback)
- located on the terminal

Question 8

Which sympathetic effects are mediated by beta-1 receptors?

Answer 8

Heart rate increases and the force of contraction increases

Question 9

Which sympathetic effects are mediated by beta-2 receptors?

Answer 9

• Airways in lungs dilate
• Lens of eye adjust for far vision (ciliary muscle relaxation)
• Blood vessels to limb muscles dilate

Question 10

Which sympathetic effects are mediated by beta-3 receptors?

Answer 10

Increases lipolysis - breakdown of triglycerides to fatty acids

Question 11

What effects do noradrenergic agonists (adrenaline) have on NA receptors?

Answer 11

ADRENALINE
- agonist at all NA receptors (a1, a2, b1, b2)
- given locally and can prolong and isolate local anaesthesia
- used to treat anaphylactic shock

Question 12

What effects do noradrenergic agonists (alpha2 agonist) have on NA receptors?

Answer 12

Used for hypertension : decrease NA release and dampen down overall sympathetic system

Decrease of sympathetic outflow because it involves the central effect

Used to treat withdrawal symptoms in morphine withdrawal
- inhibits central NA release which drives withdrawal symptoms

Question 13

What are alpha-2 receptors?

Answer 13

They are presynaptic autoreceptors which regulate release and the agonist inhibits NA release

Question 14

What effects do noradrenergic agonists (beta-1) have on NA receptors?

Answer 14

Beta-1 receptors - increased cardiac rate and force

Used to treat heart failure
- beta1 mediated cardiac stimulation (increased firing rate)

Question 15

What effects do noradrenergic agonists (beta-2) have on NA receptors?

Answer 15

Beta-2 receptors : bronchodilation

Used to treat asthma
- beta2 mediated bronchiol smooth muscle relaxation

Question 16

What effects do noradrenergic agonists (beta-3) have on NA receptors?

Answer 16

Beta-3 receptors : lipolysis/increased metabolism

Increases muscle bulk in athletes/body builders/livestock

Question 17

What effects do noradrenergic antagonists (alpha1) have on NA receptors?

Answer 17

Blocks alpha1 - mediated smooth muscle and vasoconstriction

PRAZOSIN
Used to treat hypertension
- a1 antagonism : vasodilation and decreased vascular resistance

Side effects : orthostatic or postural hypotension due to some loss in sympathetic reflex

TAMSULSON
Used to treat urination problems in prostate hyperplasia
-a1 antagonism : relaxation of smooth muscle in bladder neck, ease of urinary flow

Side effects : orthostatic or postural hypotension due to some loss in sympathetic reflex

Question 18

What effects do noradrenergic antagonists (b1 and b2) have on NA receptors?

Answer 18

Block b1 and b2 receptors

Used to treat hypertension and angina
- blocking b1 receptors decreased cardiac output
- decreases oxygen demand
- blocking b2 causes bronchoconstriction therefore contra-indicative in asthmatics

Question 19

What effects do noradrenergic antagonists (b1) have on NA receptors?

Answer 19

Blocks b1 receptors

Used to treat hypertension and angina
- blocking b1 decreases cardiac output and also decreases oxygen demand

Side effect : rebound hypertension/angina on abrupt withdrawal due to b1 receptor supersensitivity

Question 20

What effects do noradrenergic antagonists (b2) have on NA receptors?

Answer 20

Block b2 receptors - mediate ciliary muscles/lens of eye relaxation

Used to treat glaucoma
-antagonism of b2 : receptors cause ciliary contraction and decreased intraocular pressure

Question 21

How can drugs affect NA synthesis?

Answer 21

Inhibit enzymatic activity and synthesis with a false substrate (meDOPA)
- converted to meDA and then meNA
- meNA produced over NA which isn’t as effective on the noradrenergic receptors

Question 22

Why does meNA affect NA release?

Answer 22

It has alpha 2 agonists which decrease the NA release
- used in the treatment for hypertension

Question 23

How do drugs affect NA storage?

Answer 23

NA is stored in synaptic vesicles
- reserpine disrupts storage
- overall decrease in neurotransmission
- used to treat hypertension

Question 24

How do drugs affect NA release?

Answer 24

NA release is subject to autoinhibitory control via presynaptic a2-autoreceptor
- clonidine (a2 agonist) causes inhibition of NA release
- used to treat hypertension

Question 25

How do drugs affect NA reuptake?

Answer 25

It can be blocked by NA reuptake inhibitors which will prolong the action of NA in the synapse

Desipramine - tricyclic antidepressants
Reboxetine - selective noradrenaline reuptake inhibitors

Question 26

How do drugs affect NA metabolism?

Answer 26

NA is metabolised by monoamine oxidase and catecholamine transferase
- these enzymes are block so the amount of NA available for release is increased
- tranylcypramine blocks MAO and allows more NA to be recycled