Week 6 - Beta Adrenoceptor Agonists and Antagonists

Question 1

List the 4 main types of adrenoreceptors

Answer 1

1. α1
2. α2
3. β1
4. β2
5. β3 - has less tissue distribution than 2 / 3 = not commonly used

Question 2

What’s the difference between β-adrenoreceptor subtypes

Answer 2

There are 3 subtypes
1. β1
- expressed in heart (the SAN, AVN and myocardium)
- controls heart rate, refectory period (delays) + force of contraction
- expressed in kidneys (juxtaglomerular cells)
- controls release of renin (controls BP)
- expressed in GI smooth muscle
- controls relaxation
- expressed in vasomotor centre (baroreceptors detect BP changes = ↑ sympathetic nervous activity)

2. β2
   
   • expressed in bronchial smooth muscle
     - controls bronchodilation
   • expressed in GI smooth muscle
   • expressed in blood vessels of skeletal muscle
3. β3
   - expressed in adipocytes (fat cells)
   - control fat / lipid breakdown

Selective = binds to specific β receptor
Non-selective = binds to multiple β receptors i.e B1 and B2

Question 3

What signalling pathways do β-adrenorecpetors activate

Answer 3

• β-adrenoreceptors are coupled to adenyl cyclase (via G-alpha S protein)
• Activation causes ↑ in cAMP
• Increase cAMP activates PKA which phosphorylates Ca2+ channels
  = ↓ Ca2+ = smooth muscle relaxation

Question 4

What functional responses are activated by β-adrenoreceptors

Answer 4

Activation of β1-adrenoreceptor causes:
- ↑ heart rate and SV = ↑ CO
- ↑ force of contraction
- ↓ refectory period (delay duration shortens)
- inhibits release of renin = angiotensinogen isn’t converted into angiotensin I = vasodilation

Activation of β2-adrenoreceptor causes:
- vasodilation = ↑ blowod flow
- release of NO (nitric oxide) = vasodilation
- ↓ in histamine release (histamine causes contraction)
- mediates breakdown of glycogen = glucose availability for metabolism effected

Question 5

List the β-agonist drugs (bronchodilators)

Answer 5

Agonist = binds to receptor + causes / increase response
= ↑ heart rate, ↑ force of contraction, ↑ SV = ↑ CO = ↑ BP

Treatment of ASTHMA
- Use β2 selective agonist (bronchodilators)
- Short acting; last 2-4 hrs, acts rapidly, used when asthma attack is about to start
- e.g. salbutamol
- Long acting; lasts up to 12 hrs, slower onset
- e.g. salmeterol

Suppress premature Labour
- allows foetus to have more time to develop before birth

SIDE EFFECTS
- effects are minimised with inhalation (instead of oral route)
- Tachycardia (if B2 drug conc. is high + poor selectivity may activate B1 receptor)
- Tremor (hyper activation of spindle fibres in skeletal muscle)
- Hypokalemia (hyperstimulation of Na+/K+ pump = more K+ is removed from extracellular space)
- Nervous tension (CNS is affected)

Question 6

List the β-antagonist drugs (anti-hypertensives)

Answer 6

Antagonist = binds to receptor + prevent (slow down) response
= prevent vasodilation, ↓ heart rate, ↓ CO and BP
= can’t take if have asthma, COPD, etc.

1. Propranolol
   - a non-selective antagonist (B1/B2) used to control BP
   - has good penetration of CNS (as its lipid soluble)
   - adv: good anti-anxiety drug (acts in brain)
   - disadv: if meant to act at other site NOT CNS
   SIDE EFFECTS: hypoglycaemia (can’t use if diabetic masks symptoms of diabetic attack), vivid dreams (penetrates BBB)
2. Atenolol / Bisoprolol
   - B1 selective antagonist
   - water soluble = poor penetration of CNS = can’t get into brain

Question 7

Explain the mechanism of action of β-antagonist / β-blockers

Answer 7

AIM: block β1 receptors in heart, vasomotor centre + kidney

Most act on β1-receptor
- receptor is found in heart (SAN, AVN, myocardium)
- blocking receptor will ↓ heart rate, ↓ force of contraction, ↓ SV = ↓ CO = ↓ BP
- receptor is found in vasomotor centre
- inhibition = sympathetic nervous system isn’t activated
- receptor is found juxtaglomerular cells (kidney)
- inhibition = renin isn’t secreted = angitensiongen isn’t converted into angiotensin I
= angiotensin II isn’t formed = NO vasoconstriction

Blocking β2-receptors doesn’t have big effect on PR
- PR (peripheral resistance) is ↓ by vasodilation

Question 8

What are the clinical uses of drugs acting at β-antagonist

Answer 8

1. Angina
   - chest pain caused by reduced blood flow (cardiac ischaemia)
   - caused by in-balance between O2 supply + demand
   - atherosclerosis causes ↓ O2 supply to organ / muscle
   - when person exercises, stressed etc. heart is working more = demand ↑ and balances shifts = O2 supply DOESN’T meet demand
   - pain can radiate to arm, neck + jaw
   - B-antagonist ↓ heart rate, force + work, ↑ O2 supply
   - ↓ work = ↓ O2 demand
   
   • B-antagonist prolongs diastole = ↑ blood flow to heart
2. Arrhythmia
   
   • noradrenaline / adrenaline bind to B1 receptors (in heart) causing ↑ in cAMP leads to short AP activation + ↑ heart rate
   • short AP activation = many AP generated irregularly = heart contracts irregularly = arrhythmia
   • B-antagonist ↓ pace maker activity, causes SAN to produce all AP, ↑ AVN refectory period
3. Tumour of adrenal medulla
   - tumour secrets adrenaline which will act on heart

4, Migraines
- Propranolol can penetrate BBB = can bind to B-receptors in brain

5. Thyrotoxicosis
   - Propranolol alleviates symptoms (i.e. tachycardia, anxiety, palpitations, tremor)
   - antagonist reduces sensitisation caused by over reactive thyroid gland