SNS antagonists and false transmitters

Question 1

State five adrenoceptor antagonists including the receptors that they block.

Answer 1

Non-selective (𝛼1+β1): Carvedilol
𝛼1+𝛼2 : Phentolamine
𝛼1: Prazosin
β1+β2: Propranolol
β1: Atenolol

Question 2

How is hypertension defined?

Answer 2

Having a blood pressure that is consistently above 140/90 mmHg (generally)

Question 3

Name four pathologies for which hypertension is a risk factor

Answer 3

Stroke
Heart Failure
Myocardial Infarction
Chronic Kidney Disease

Question 4

What three factors affect blood pressure, and hence can contribute to hypertension?

Answer 4

Blood volume
Cardiac output
Vascular tone

*BP = CO x TPR

Question 5

What are the tissue targets for anti-hypertensives? Of those, which can be targeted by beta-blockers?

Answer 5

Heart (β1)
Sympathetic nerves (β1/β2) 
Kidney (β1)
Arterioles (beta blockers would prevent dilation so NOT antihypertensive)
CNS (altering BP set point) (β1/β2)

Question 6

How do beta blockers affect the heart and kidneys?

Answer 6

HEART:
- blocking the β receptor = decrease in HR & FOC => decreased cardiac output

KIDNEYS:
- blocking the β receptor = decreased renin secretion => decreased Ang II and aldosterone production => decreased vascular tone + blood volume

Question 7

What do presynaptic β-adrenoceptors do, and what effect would beta blockers have?

Answer 7

These β-adrenoceptors (auto receptor) act to increase neurotransmitter release i.e. noradrenaline
Hence, blockade of this facilitatory effect may also contribute to the antihypertensive effect

Question 8

Describe the actions and selectivity of the 5 major beta blockers

Answer 8

Propranolol: ‘Equal’ affinity for β1 & β2 receptors

Atenolol: More selective for β1 receptors

Carvedilol: Mixed 𝛼 and β selectivity (𝛼1 blockade gives additional vasodilator properties)

Nebivolol: More selective for β1 receptors; also potentiates NO

Sotalol: Mixed 𝛼 and β selectivity; also inhibits K+ channels

Question 9

List and explain the six unwanted effects of beta blockers

Answer 9

• Bronchoconstriction - only important in patients with asthma and COPD
• Patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output, removal of this => heart failure
• Non-selective beta blockers with inhibit glycogenolysis (β2) => hypoglycaemia; also, beta blockers mask the symptoms of hypoglycemia (sweating, palpitations, tremor)
• Fatigue due to reduced cardiac output and reduced muscle perfusion
• Cold Extremities due to a loss of β-receptor mediated vasodilatation in cutaneous vessels
• Bad dreams

Question 10

What is the advantage of atenolol over propranolol?

Answer 10

Propranolol targets β2 receptors as well as β1, hence has side-effects (to greater degree) on the airways and liver

Question 11

What advantage does carvedilol have over atenolol and propranolol?

Answer 11

More powerful anti-hypertensive (like with most beta blockers, its effect wanes with chronic use)

Question 12

What is phentolamine used to treat?

Answer 12

(Non-selective 𝛼-blocker) used to treat phaechromocytoma-induced hypertension

Question 13

What is prazosin used for?

Answer 13

(𝛼1 specific blocker) inhibit the vasoconstrictor activity of NE

Question 14

State the unwanted effect of alpha blockers?

Answer 14

Blockade of alpha receptors in the GI tract => increased motility and tone and sphincter contraction => diarrhoea

Also, blockade of 𝛼2 receptors enhances the reflex tachycardia that occurs with any anti-hypertensive

Question 15

Why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?

Answer 15

Since phentolamine blocks 𝛼2 receptors as well, this prevents the 𝛼2 mediated inhibition (negative-feedback) of noradrenaline release. More noradrenaline released = greater competition with phentolamine for the 𝛼1 postsynaptic receptors.

Decreased baroreceptor firing due to vasodilation => increased sympathetic activity to heart and vessels and decreased vagal activity to heart => increased CO

Question 16

Compare phentolamine with prazosin

Answer 16

Prazosin:

• Less tachycardia than non-selective antagonists since they do not increase noradrenaline release from nerve terminals (no 𝛼2 effects)
• Causes a modest decrease in LDL, and an increase in HDL cholesterol

Question 17

How does Methydopa form a false transmitter? State the impact of this

Answer 17

• Taken up by noradrenergic neurons and mimics DOPA
• Decarboxylated and hydroxylated to form the false transmitter, 𝛼-methyl-noradrenaline
• The false transmitter is less active at 𝛼1/β1 receptor and isn’t metabolised (de-aminated) by MAO after uptake 1
• It therefore accumulates in larger quantities than noradrenaline and displaces noradrenaline from synaptic vesicles
• Anti-Hypertensive treatment especially in kidney disease of cerebrovascular disease

Question 18

List the side effects of methyldopa

Answer 18

Dry mouth
Sedation
Orthostatic hypotension
Male sexual dysfunction

(rarely used)

Question 19

Why are beta blockers used to treat arrhythmias?

Answer 19

Since an increase in sympathetic drive to the heart via β1 can precipitate or aggravate arrhythmias (beta blockers prevent this)

Also, AV conductance is dependent on sympathetic activity (β1) - the refractory period of the AV node is increased by β-adrenoceptor antagonists

Question 20

What is the main beta blocker used in the treatment of arrhythmias? Name the drug class of beta blockers with respect to antiarrhythmic drugs.

Answer 20

Propranolol

Class II antiarrhythmic

Question 21

Define angina

Answer 21

Chest pain (often spreading to the shoulders, arms and neck) that occurs when the oxygen supply to the myocardium is insufficient for its needs

Question 22

Describe the three different types of angina

Answer 22

STABLE:
- Pain on exertion due to a fixed narrowing of coronary vessels e.g. atheroma

UNSTABLE:

• Pain with less and less exertion culminating with pain at rest
• Atheromatous plaque begins to rupture
• Platelet-fibrin thrombus associated with the ruptured plaque without complete occlusion of the vessel
• High risk of infarction

VARIABLE:

• Occurs at rest
• Caused by coronary artery spasm
• Associated with atheromatous disease

Question 23

Explain why beta blockers can be used to treat angina. Give an example of one such beta blocker

Answer 23

THEY DECREASE MYOCARDIAL OXYGEN DEMAND

• At low doses, β1-selective antagonists, e.g. metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle.
• Therefore reducing the oxygen demand whilst maintaining the same degree of effort

Question 24

Describe the use of beta antagonists in treating glaucoma

Answer 24

They reduce the rate of aqueous humour formation by blocking the β1 receptors (coupled to carbonic anhydrase) on the ciliary body

Question 25

Name examples of beta blockers used in the treatment of glaucoma

Answer 25

Carteolol hydrochloride Levobunolol hydrochloride

Timolol maleate