Terence (Adrenergic signalling)

Question 1

The nervous system

Answer 1

The nervous system consists of
- Central nervous system
- Peripheral nervous system
Peripheral nervous system is divided into efferent (carry signals away from CNS) or afferent (carry signals to the CNS) neurones

Question 2

What is the efferent system divided into?

Answer 2

• Autonomic nervous system (ANS): controls involuntary bodily functions. Regulates specific functions without conscious control e.g. respiration, circulation, digestion, body temperature, metabolism, secretion. Supplies smooth muscle, cardiac muscle, glands, neurones of the GI tract.
• Somatic nervous system (SNS): controls skeletal muscles movement

Question 3

What is the autonomic nervous system divided into?

Answer 3

Sympathetic (fight or flight) and parasympathetic (rest and digest) systems.

Question 4

What hormones are used in the sympathetic and parasympathetic nervous systems?

Answer 4

Sympathetic- noradrenaline, adrenaline
Parasympathetic- acetylcholine

Question 5

Sympathetic neuronal signalling

Answer 5

Effects mediated by
- noradrenaline released from adrenergic neurones (an the adrenal gland)
Hormones
- adrenaline released from the adrenal gland into the blood
Noradrenaline and adrenaline bind to adrenergic receptors on target organs or tissues and mediate the effects of the sympathetic nervous system

Question 6

Adrenergic pharmacology

Answer 6

Study of drugs that inhibit or promote the actions of adrenaline or noradrenaline and hence have effects similar to stimulating or inhibiting the sympathetic nervous system.
Many of these drugs act on/target adrenergic receptors or adrenoceptors
Adrenergic receptors are G protein-coupled receptors
Many commonly prescribed drugs target adrenergic receptors and/or adrenergic receptor signalling

Question 7

Noradrenaline and adrenaline

Answer 7

Adrenaline and noradrenaline are examples of catecholamines. These are compounds containing a catechol moiety (benzene ring with 2 adjacent hydroxyl groups) and an amine side chain. Synthesised from the amino acid tryosine.
Noradrenaline is synthesised and released from neurones and the adrenal medulla. Adrenaline is the main hormone synthesised and released from the adrenal medulla. Noradrenaline is the main neurotransmitter of the sympathetic nerves in the cardiovascular system. Adrenaline is a major determinant of responses to metabolic or global challenges to homeostasis.

Question 8

Adrenergic receptors

Answer 8

Subdivided into Alpha and Beta. The distinction was based on sensitivities of different organs to catecholamines of closely related structure i.e. adrenaline, noradrenaline, and a synthetic catecholamine isoprenaline

Question 9

What is the effect of adrenaline, noradrenaline and isoprenaline on alpha receptors?

Answer 9

Produces constriction of vascular smooth muscle. The rank order of affinities for these receptors is Adrenaline=noradrenaline>isoprenaline.
This means less adrenaline is needed compared to isoprenaline to have the same effect.

Question 10

What is the effect of adrenaline, noradrenaline and isoprenaline on beta receptors?

Answer 10

Increase the force of myocardial contraction.
The rank order of affinities for these receptors is isoprenaline>adrenaline>noradrenaline.
This means less isoprenaline is needed compared to noradrenaline to have the same effect.

Question 11

How do we know that the agonists act vis different receptors?

Answer 11

Regardless of location, agonists will bind in the same manner to the same receptor. These agonists have different relative affinities and therefore must be acting via different receptors.

Question 12

Alpha 1 adrenergic receptor

Answer 12

Smooth muscle.
Activation causes increase in intracellular calcium and contraction.
Drug example of an alpha 1 antagonist- Prazosin which is used to treat hypertension- relax smooth muscle in arteries and veins thus decrease systemic arterial blood pressure

Question 13

Alpha 2 adrenergic receptor

Answer 13

Presynaptic neurones.
Activation is inhibitory- reduced calcium and contraction and inhibits secretion of noradrenaline.
Drug examples of an alpha 2 agonist- Clonidine which is used to treat hypertension- reduces NA release so decreases both heart rate and pressure and systemic arterial blood pressure

Question 14

Beta 1 adrenergic receptor

Answer 14

Heart- increases force and rate.
Drug example- beta blockers such as propranolol. Used to treat angina and hypertension.

Question 15

Beta 2 adrenergic receptor

Answer 15

Airway smooth muscle- dilation.
Drug example- b2-adrenergic agonist such as salbutamol. Used to treat asthma

Question 16

Beta 3 adrenergic receptor

Answer 16

Adipose tissue- activates lipolysis.
Drug example- mirabegron. Used to treat overactive bladder syndrome

Question 17

Fight or flight response (beta receptors)

Answer 17

Adrenergic system
-> b1 receptors -> cardiac contraction -> increased blood supply
-> b2 receptors -> bronchial relaxation -> increased oxygen supply

Question 18

Alpha 1 receptors

Answer 18

-> Smooth muscle -> contraction (blood vessels, eye, bladder, prostate, uterus)
-> Liver -> glycogenolysis (generate glucose for energy)
-> Salivary gland -> secretion

(At GI smooth muscle, a1 receptors produce relaxation instead of constriction)

Question 19

Adrenergic receptor signalling
(- Sub-type- location of receptors, type of GPCR, basic pathway)

Answer 19

• Alpha 1- smooth muscle, Gq, phospholipase C-cleaves PIP2 leading to IP3and DAC
• Alpha 2- presynaptic nerves, Gi, inhibits adenyl cyclase so decreases cAMP
• Beta 1- heart, Gs, stimulate adenyl cyclase so increase in cAMP
• Beta 2- smooth muscle, Gs, stimulate adenyl cyclase so increase in cAMP
• Beta 3- fat tissue, Gs, stimulate adenyl cyclase so increase in cAMP

Question 20

GqPCR signalling- a1 smooth muscle cells

Answer 20

Activation by NA causes smooth muscle contraction e.g. constricts blood vessels = increased blood pressure.
A1 antagonists are used for hypertension treatment (e.g. prazosin).
A1 agonists used for nasal decongestion (e.g. oxymetazoline)- constricted blood vessels allow less fluid to leave the blood and enter the nose, throat and sinus linings

Question 21

GiPCR signalling- a2 presynaptic neurones

Answer 21

Opens G-protein gated K+ channel. K+ efflux causes hyperpolarisation which reduces NA release from presynaptic neurones.
A2 agonists are used to treat hypertension (e.g. clonidine)

Question 22

GsPCR signalling- b1 in heart

Answer 22

Increase force (inotropic) and rate (chronotropic) in cardiac muscle.
B1 antagonists (beta blockers) are used to treat angina, heart failure, and control blood pressure.

Question 23

GsPCR signalling in smooth muscle

Answer 23

Airway relaxation- increase in cAMP promotes relaxation.
B2 agonists (e.g. SABAs (salbutamol), LABAs) are used to treat asthma.

Question 24

Drugs acting on adrenergic nervous system

Answer 24

Sympathomimetic- adrenergic drugs
- Produce action similar to that of adrenaline and noradrenaline and hence their pharmacological effects are similar to those observed when the sympathetic nervous system is stimulated.
Sympatholytic- anti-adrenergic drugs
- Interfere with the actions of sympathetic nervous system stimulation.
Direct acting- drugs that directly target the adrenergic receptor
Indirect acting- drugs acting on adrenergic nervous system indirectly by regulating neurotransmitter release, synthesis, breakdown, uptake, etc
Mixed acting- drugs that act directly and indirectly. (Dirty drugs- non-selective- hits many different targets)

Question 25

Commonly prescribed direct acting sympathomimetics

Answer 25

Sympathomimetic drugs can be used to treat cardiac arrest and low blood pressure, delay premature labour, and treat asthma.
- Pseudoephedrine is used as a nasal/sinus decongestant or as a wakefulness-promoting agent used in combination with other drugs (e.g. antihistamines). Non- selective- acts as an alpha and b2 agonist
- Salbutamol is used to treat asthma and COPD. Selective b2 agonist

The concentration of the drug determines what receptors it will bind to. Many side effects are from the binding to similar receptors elsewhere

Question 26

Direct acting sympatholytics are commonly used for hypertension

Answer 26

Alpha 1 blockers (ends in osin)
- Doxazosin
- Prazosin
- Terazosin

Beta blockers (ends in olol)
- Atenolol
- Bisoprolol
- Metoprolol
- Propranolol

Question 27

Name a sympatholytic drug and its pathway

Answer 27

Alpha 1 blockers -> vasodilation -> decreased blood pressure -> relieve hypertension

Beta blockers -> decrease heart rate and force of contraction -> decrease in blood pressure -> relieve hypertension