SNS Agonists

Question 1

From which region of the spinal cord do sympathetic fibres originate?

Answer 1

Thoracolumbar

Question 2

Most sympathetic post-ganglionic neurones release noradrenaline. State two exceptions.

Answer 2

Adrenal medulla – adrenaline (80%) and noradrenaline (20%) Sweat glands – acetylcholine

Question 3

State the difference between directly and indirectly acting sympathomimetics.

Answer 3

Directly acting – binds to the adrenoceptor and mimic the action of adrenaline and noradrenaline by stimulating the receptors Indirectly acting – inhibits the uptake and breakdown systems leading to the accumulation of neurotransmitter in the synaptic cleft

Question 4

Describe the mechanism of action of the four different types of adrenoceptor.

Answer 4

ALL adrenoceptors are G-protein coupled

Alpha 1 = PLC -> IP3 + DAG Gq

Alpha 2 = decrease cAMP Gi

Beta 1 + Beta 2 = increase cAMP Gs

Question 5

State the main actions of beta-1 receptors.

Answer 5

HEART – increase heart rate + increase contractility

KIDNEYS – increase renin release -> increase blood pressure

Lipolysis

Question 6

State the main actions of beta-2 receptors.

Answer 6

Liver: increases Hepatic glucose output – glycogenolysis + gluconeogenesis

Smooth muscle relaxation in AIRWAYS (bronchodilation), Blood vessels(vasodilation) and Uterus(detrussor relaxation)

Question 7

State some effects that are mediated by both alpha and beta-receptors.

Answer 7

Exocrine secretions (e.g. salivary gland secretions become thick)

GIT motility – decreased muscle motility and tone + contraction of sphincters to stop food going further down (sympathetic effects to STOP REST AND DIGEST)

Liver- increase Hepatic Glucose output via glycogenolysis and gluconeogenesis mediated by alpha 1 and b2

Lipolysis: a1 and b1

Question 8

What receptors are responsible for the production of aqueoushumour by the ciliary body?

Answer 8

Beta receptors

Question 9

State some effects of alpha-1 receptors.

Answer 9

Pupil: Mydriasis (pupil dilation) by acting on a1 receptors on radial muscles

Liver: Increase HGO by glycogenolysis and gluconeogensis

Adipose: lipolysis

Ureters and bladder: constriction of trigone and internal urethral sphincter (sympa stops peeing). Trigone stretching causes the reflex to pee, if you constrict it then you avoid this reflex to pee so less peeing

Blood vessels: vasoconstriction

Skin: piloerection

Question 10

Where is the principle action of beta-blockers?

Answer 10

KIDNEYS – it inhibits the beta-1 mediated increase in renin secretion It also decreases heart rate and contractility but its main action in reducing blood pressure is through the kidneys

Question 11

Describe the relative selectivity of adrenaline and noradrenaline.

Answer 11

Noradrenaline is more selective for ALPHA-receptors Adrenaline is more selective for BETA-receptors

Question 12

Describe the action of pre-synaptic alpha-2 receptors.

Answer 12

Pre-synaptic alpha-2 receptors have a negative influence on noradrenaline synthesis and release

Question 13

State five directly acting SNS agonists.

Answer 13

Phenylephrine – alpha-1

Clonidine – alpha-2

Dobutamine – beta-1

Salbutamol – beta-2

Isoprenaline – beta 1+ beta 2

Question 14

Describe the development of hypersensitivity following first exposure.

Answer 14

After the first exposure you generate antibodies to the antigen andthese circulate around the body and bind to mast cells. In the subsequent exposure, the mast cells are primed with the antibody on its surface. Cross-linking of these antibodies on the surface of mast cells causes massive release of the stored mediators leading to the symptoms of hypersensitivity.

Question 15

State some symptoms of hypersensitivity.

Answer 15

CVS: Increase in capillary permeability leads to increased movement of fluid into the tissues, leading to swelling eg in tongue and lips

This depletes the circulating fluid volume leading to adrop in blood pressure -> ANAPHYLACTIC SHOCK (and collapse the circulatory system leading to unconsciousness)

Respiratory: bronchial smooth muscle and constriction of muscles around the throat causing respiratory distress and difficulty in swallowing.

GI tract: It can also constrict GI smooth muscle causing stomach cramps, vomiting and diarrhoea

Question 16

Why is adrenaline more effective than noradrenaline in dealingwith hypersensitivity?

Answer 16

DR ABC- airway, breathing and circulation

During the hypersensitivity reaction, the most important problem to deal with is to maintain AIRWAY. Adrenaline is more selective for beta receptors than noradrenaline so is better at causing beta-2 mediated bronchodilation, thus opening up the airways.

Adrenaline also stimulates the heart via beta-1 to support blood pressure.

Adrenaline also acts on the alpha-1 receptors to cause vasoconstriction and an increase in TPR and blood pressure.

Adrenaline can also slow down the release of histamine from mast cells via beta-2.

Question 17

State some other clinical uses of adrenaline other than to deal with hypersensitivity

Answer 17

Asthma (adrenaline helps bronchodilation)

Acute bronchospasm (which narrows bronchi) associated with chronic bronchitis or emphysema

Cardiogenic Shock- sudden inability of heart to pump sufficient oxygen rich blood, can happen in MI which causes heart to lose its ability to work properly

Spinal Anaesthesia- spinal anaesthesia decreases BP because it could interfere with the sympathetic outflow

Local Anaesthesia- Vasoconstriction near point of local anaesthesia – Prolongs action of anaesthesia because you stop blood flow from carrying anaesthesia away

Question 18

Which receptors are involved in the generation of aqueous humour in the eye?

Answer 18

Alpha-1 involved in vasoconstriction of the vessels in the ciliary body

Alpha 2 decreases humour production

Beta-receptors control the enzyme that makes the aqueous humour and stimulation promotes humour production

Question 19

Why is adrenaline used as a treatment for glaucoma?

Answer 19

Adrenaline can stimulate the alpha-1 receptors to cause vasoconstriction of the vessels in the ciliary body thus reducing the blood flow within the ciliary body -> reduced production of aqueous humour

Question 20

State some unwanted actions of adrenaline.

Answer 20

Secretions – reduced and thickened mucous, so dry mouth

The production of saliva is stimulated both by the sympathetic nervous system and the parasympathetic.

The saliva stimulated by sympathetic innervation is thicker, and saliva stimulated parasympathetically is more fluid-like.

CNS – minimal

CVS effects (main side effects)

• tachycardia, palpitations, arrhythmias
• cold extremities, hypertension
• overdose – cerebral haemorrhage, pulmonary oedema

GIT – minimal

Skeletal muscle - tremor caused by adrenergic receptors on the skeletal muscle

Question 21

Describe the resistance to degradation of phenylephrine.

Answer 21

Phenylephrine is MORE resistant to COMT (uptake 2) degradation than adrenaline but it is NOT resistant to MAO (uptake 1) degradation

Phenylephrine- resistant to COMT

Isoprenaline- resistant to MAO-A

Question 22

State some clinical uses of phenylephrine.

Answer 22

Mydriatic (pupil dilation)

Nasal decongestant

It causes vasoconstriction

Congestion is caused by inflammation in nasal nose. Inflammation causes fluid leakage from capillaries. Phenylephrine causes vasoconstriction so theres less blood flow and hence less fluid leakage, so less inflammation in the nose

Question 23

Describe the mechanism of clonidine.

Answer 23

• Clonidine is an a2 agonist and it causes less NA synthesis and release.
• Central action: Central action by binding to a2 receptors in brainstem within the baroreceptor pathway to reduce central sympathetic outflow (baroreceptor reflex uses cranial nerves). This leads to a global antisympathetic effect

It is an antihypertensive that acts by reducing NA binding to B1 receptors in kidneys, hence less A2 formed via the RAAS pathway

Question 24

State some clinical uses of clonidine.

Answer 24

It is used to treat hypertension and migraine.

Question 25

Describe the susceptibility to breakdown of isoprenaline compared to adrenaline.

Answer 25

Isoprenaline is resistant to uptake 1/MAO breakdown(MAO is the enzyme in the uptake 1 pathway, COMT is the enzyme in uptake 2)

Question 26

State three clinical uses of isoprenaline.

Answer 26

Cardiogenic Shock

Myocardial Infarction (can then lead to cardiogenic shock)

Acute Heart Failure (can then lead to cardiogenic shock)

Question 27

What is a big problem with isoprenaline with regards to its action on beta 2 receptors?

Answer 27

Isoprenaline brings about positive effects via Beta-1 stimulation However, stimulation of Beta-2 leads to vasodilation of blood vessels in the muscles -> pooling of blood within the muscles -> reduced venous return Via the baroreceptors, you get a reflex tachycardia So the beta-1 effects are good for patients with heart failure but the beta-2 effects are not

Question 28

State a clinical use of dobutamine.

Answer 28

Cardiogenic shock

Why its good:

• Lacks isoprenaline’s reflex tachycardia which is why it is used instead of isoprenaline now
• Plasma half life 2 minutes (rapidly metabolised by COMT), good for emergency and allows control

Question 29

Describe the relative resistance of salbutamol to degradation.

Answer 29

Relative resistance to MAO and COMT

Question 30

State and explain two clinical uses of salbutamol.

Answer 30

1. Asthma
   - b2-relaxation of bronchial smooth muscle
   - inhibition of release of brochoconstrictor substances from mast cells (mast cells have B2 receptors too which are inhibitory).
2. Treatment of threatened premature labour
   - b2-relaxation of uterine smooth muscle

Question 31

State some side effects of salbutamol.

Answer 31

Reflex tachycardia because salbutamol has selectivity of B2 over others

Tremor (beta receptors are on skeletal muscle and so can cause tremor when stimulated),

blood sugar dysregulation (beta receptors on islet cells can affect glucose regulation)

Question 32

State two indirectly acting SNS agonists.

Answer 32

Cocaine Tyramine