SNS agonists

Question 1

What intracellular actions happen at alpha1, alpha 2, beta1 and beta2?

Answer 1

Alpha-1: PLC, IP3, DAG
Alpha-2: decrease in cAMP
Beta-1: increase in cAMP
Beta-2: increase in cAMP

Question 2

Where are adrenoreceptors found?

Answer 2

• at effector organs in the SNS

Question 3

Relative selectivity SNS agonists

Answer 3

All Adrenoreceptors can be activated by A and NA.

• Selectivity for A: b1 = b2 > a1 = a2
• Selectivity for NA: a1 = a2 > b1 = b2

Question 4

Heart

Answer 4

Beta-1 tissue

Question 5

Lungs

Answer 5

Beta-2 tissue

Question 6

Blood Vessles

Answer 6

Alpha-1 tissue

Question 7

Noradrenaline Metabolism

Answer 7

1) Tyrosine -> DOPA (via tyrosine hydroxylase)
2) DOPA -> Dopamine (via DOPA decarboxylase)
3) Dopamine enters vesicle
4) Dopamine -> NA (via dopamine beta hydroxylase)
5) exocytosis

• NA binding to Alpha 2 receptor (prejunctional receptor)
  
  • > controls its own secretion

Question 8

Directly Acting SNS agonists

Answer 8

• Adrenaline (non-selective)
• Phenylephrine (a1)
• Clonidine (a2)
• Dobutamine (b1)
• Salbutamol (b2)

Question 9

How does NA control its own secretion?

Answer 9

• alpha-2 receptor on presynaptic cell

- NA binding negatively feeds back on NA release

Question 10

Name a non-specific SNS agonist

Answer 10

Adrenaline (e.g. epi-pen)

Question 11

Why is adrenaline used in the treatment of anaphylaxis?

Answer 11

b2 – broncho dilation
b1 – tachycardia
a1 – vasoconstriction

• suppression of mediator release

Question 12

What are the effects on alpha 2 receptors?

Answer 12

• suppresses the release of NA (neg. feedback)

Question 13

What are other clinical uses of Adrenaline?

Answer 13

• Asthma (i.m. or s.c. in emergencies) beta-2
• Acute bronchospasm (ass. with chronic bronchitis or emphysema) beta-2 mediator release
• cariogenic shock - sudden inability of the heart to pump sufficient O2 rich blood (beta-1 inotropic effect)
• spinal anaesthesia (alpha 1 maintains BP)
• local anaesthesia (alpha 1 vasoconstrictor - prolongs action)
• anaphylactic shock

Question 14

What are some unwanted effects of adrenaline?

Answer 14

Secretions – reduced and thickened mucous

• CNS – minimal
• CVS effects
  
  • tachycardia, palpitations, arrhythmias
  • cold extremities, hypertension
  • overdose – cerebral haemorrhage,pulmonaryoedema
• GIT – minimal
• Skeletal muscle - tremor

Question 15

Name an alpha-1 specific agonist?

Answer 15

Phenylephrine

Question 16

Selectivity of phenylephrine

Answer 16

a1&raquo_space; a2&raquo_space;> b1/b2

Question 17

Why might phenylephrine be used as an anticongestant?

Answer 17

• e.g. sudafed or lemsip

- vasoconstriction: less white cell infiltration, less fluid exudation

Question 18

Properties of phenylephrine

Answer 18

• chemically related to adrenaline
• more resistant to COMT but not MAO
• clinical use as a decongestant
• Mydriatic (induces pupil dilation)
• vasoconstriction

Question 19

Name an a2 selective SNS agonist

Answer 19

Clonidine

Question 20

Selectivity of Clonidine

Answer 20

a2&raquo_space; a1&raquo_space;> b1/b2

Question 21

What are the clinical uses of clonidine?

Answer 21

• Treatment of hypertension and migraine
• Reduces sympathetic tone
  
  • a2 adrenoceptor mediated
  • presynaptic inhibition of NA release
    -Central action in brainstem within baroreceptor
    pathway to reduce sympathetic outflow.
• Glaucoma

Question 22

Properties of clonidine

Answer 22

• agonist, however acts like an antagonist because a2 receptor suppresses release of NA
• a2 selective

Question 23

What is glaucoma?

Answer 23

• raised intraocular pressure in the anterior chamber of the eye

Question 24

What causes glaucoma?

Answer 24

• poor drainage of aqueous humour

- If untreated, it permanently damages the optic nerve, blindness.

Question 25

What produces the aqueous humour in the eye?

Answer 25

- the cilary body

Question 26

Why are sympathomimetics used in Glaucoma?

Answer 26

Think about the receptors on the ciliary body: - a1: vasoconstricton -> effective for glaucoma because restricted blood flow -> restricted humour production - a2: negative feedback, interferes with beta function

Question 27

What is the difference between blood vessel control in the brain and in other parts of the body?

Answer 27

- body: predominantly alpha-1 controlled, vasoconstriction | - brain: predominantly beta-2 controlled, vasodilation (associated with increased blood flow)

Question 28

Isoprenaline

Answer 28

- beta selective but not for b1 or 2 - chemically related to adrenaline - more resistant to MAO and uptake 1

Question 29

Selectivity of Isoprenaline

Answer 29

b1 = b2 >>>> a1/a2

Question 30

Clinical use of isoprenaline

Answer 30

- cariogenic shock - MI - acute HF

Question 31

What do you have to be careful about earn giving beta2 receptor agonists?

Answer 31

Caution - b2-stimulation in vascular smooth muscle in skeletal muscle results in fall in venous blood pressure which triggers a reflex tachycardia via the stimulation of baroreceptors. massive vasodilation + reflex tachycardia

Question 32

Dobutamine selectivity

Answer 32

b1 >> b2 >>> a1/a2

Question 33

Name a b1 selective agonist

Answer 33

Dobutamine

Question 34

What are the properties of dobutamine?

Answer 34

- short acting - lacks isoprenaline's reflex tachycardia - plasma half life is 2 minutes (rapid metabolism by COMT)

Question 35

What are the clinical uses of Dobutamine?

Answer 35

- Cardiogenic shock - Lacks isoprenaline’s reflex tachycardia - Plasma half life 2 minutes (rapidly metabolised by COMT)

Question 36

Name a beta-2 selective agonist

Answer 36

Salbutamol (ventolin)

Question 37

Selectivity of Salbutamol (Ventolin)

Answer 37

b2 >> b1 >>> a1/a2

Question 38

What are the properties of salbutamol?

Answer 38

- Synthetic catecholamine derivative with relative resistance to MAO and COMT - more resistant to breakdown!!

Question 39

What are the clinical uses of salbutamol?

Answer 39

- Treatment of Asthma - b2-relaxation of bronchial smooth muscle - inhibition of release of brochoconstrictor substances from mast cells. - Treatment of threatened premature labour - b2-relaxation of uterine smooth muscle Side effects- Reflex tachycardia, Tremor, blood sugar dysregulation

Question 40

Which ventilators are salbutamol?

Answer 40

the blue ones

Question 41

How does salbutamol cause dilation of airways?

Answer 41

- inhalation - binds to b2R - increase in ic cAMP - almost hyperpolarisation - K+ efflux - relaxation of the muscle - dilation of airways -> breathing is easier

Question 42

How does adrenaline help in anaphylactic shock?

Answer 42

- it produces the opposite effect of that of histamine = physiological antagonism - effects like bronchodilation, tachycardia, vasoconstriction

Question 43

Which enzyme converts dopamine to NA?

Answer 43

dopamine beta hydroxylase

Question 44

Directly acting SNS agonists

Answer 44

APCDS ``` Adrenaline (non-selective) Phenylephrine (a1) Clonidine (a2) Dobutamine (b1) Salbutamol (b2) ```

Question 45

What happens during anaphylaxis?

Answer 45

- IgE coated mast cells - degranulation and release of inflammatory mediators a) heart and vasculature: increased capillary permeability, entry of fluid into tissues, swelling of tissues incl. tongue, fall in BP, reduced O2 to tissues, irregular heart beat, anaphylactic shock, loss of conciusness b) resp: contraction of SM and constriction of throat and airways; difficulty swallowing; difficulty breathing wheezing; c) GIT: contraction of SM, cramps, vomiting, fluid outflow into gut, diarrhoea.

Question 46

Clinical use of phenylephrine

Answer 46

- nasal decongestant - mydriatic - vasoconstriction