E.8 Chemistry of beta-blockers

Question 1

What is an adrenoceptor?

Answer 1

Membrane bounded receptor located throughout the body and non-neuronal tissues where they mediate and diverse a range of responses to the endogenous catecholamines adrenaline and noradrenaline

Question 2

What are adrenoceptors coupled to?

Answer 2

G-protein coupled receptors

Question 3

What is the principle effect of an agonist binding to an alpha 1 receptor ?

Answer 3

Vasoconstriction
relaxation of the GI smooth muscle
Salivary secretion
Hepatic glycogenolysis

Question 4

What is the principle effect of an agonist binding to an alpha 2 receptor ?

Answer 4

Inhibition of neurotransmitters (inc NA and ACh)

Platelet aggregation

Question 5

What is the principle effect of an agonist binding to a beta 1 receptor ?

Answer 5

Increased cardiac rate and force
Relax GI smooth muscle
Lipolysis

Question 6

What is the principle effect of an agonist binding to a beta 2 receptor?

Answer 6

Broncodilation 
Vasodilation
Relaxation of visceral smooth muscle 
Hepatic glycogenolysis 
Muscle tremor

Question 7

What does beta receptors consist of ?

Answer 7

7 trans-membrane hydrophobic alpha helices which contains a binding site for the agonist and antagonist

Question 8

What is the amino acid in the third hydrophobic domain and what does it interact with?

Answer 8

Asp-113 and interacts with amino group of catecholine

Question 9

What is the amino acid in the fifth hydrophobic domain and what does it interact with?

Answer 9

Ser-204 and Ser-207 which interact with the catecholine hydroxy group

Question 10

How do beta blockers work? Briefly

Answer 10

They bind to beta receptors in the heart acting as an antagonist slowing the heart rate down and reducing the force of contraction

Question 11

Why didn’t 1st gen isoprenaline not work as a beta-blocker but why was it beneficial in improving selectivity of beta-blockers?

Answer 11

Isoprenaline acted as a beta agonist rather than an antagonist.

However, it showed selectivity to only beta two receptors

Further investigations showed that beta receptors contained a hydrophobic pocked, which alpha receptors did not have.

This meant that the hydrophobic methyl groups in isoprenaline could bind to the pocked, making it selective to only beta receptors.

Question 12

What is a full agonist

Answer 12

can elicit maximal tissue response

Question 13

What is a partial agonist

Answer 13

Cannot elicit maximal response, no matter how high their concentration

Question 14

What is intrinsic activity?

Answer 14

Maximum response to test agonist/ maximal response to full agonist acting through the same receptor

If alpha=1 then full agonist

If alpha between 0-1 then its a partial agonist

If alpha=0 the competitive agonist

Question 15

What properties should beta-blockers have ?

Answer 15

Ethanol-amine side chain (present in natural lignds such as ACh and NA)

Aryl

Oxymethylene (-O-CH2-) chemical linkage: Most effective structure in beta- blockers

Question 16

What are the clinical uses of beta-blockers?

Answer 16

decrease contractility
decrease relaxation rate 
decrease heart rate
decrease conduction velocity
smooth muscle contraction

Angina
myocardial infarction arrhythmia
hypertension

Question 17

Why is atenolol (2nd gen) used today

Answer 17

it is as potent as atenolol, cardio selectivity and isn’t a partial agonist

less side effects

Question 18

Why are 3rd gen beta-blockers useful

Answer 18

They allow additional binding of hydrogen, meaning the interaction stronger with better selectivity