SNS antagonists and false transmitters Flashcards
State five adrenoceptor antagonists including the receptors that they block.
Non-selective (𝛼1+β1): Carvedilol 𝛼1+𝛼2 : Phentolamine 𝛼1: Prazosin β1+β2: Propranolol β1: Atenolol
How is hypertension defined?
Having a blood pressure that is consistently above 140/90 mmHg (generally)
Name four pathologies for which hypertension is a risk factor
Stroke
Heart Failure
Myocardial Infarction
Chronic Kidney Disease
What three factors affect blood pressure, and hence can contribute to hypertension?
Blood volume
Cardiac output
Vascular tone
*BP = CO x TPR
What are the tissue targets for anti-hypertensives? Of those, which can be targeted by beta-blockers?
Heart (β1) Sympathetic nerves (β1/β2) Kidney (β1) Arterioles (beta blockers would prevent dilation so NOT antihypertensive) CNS (altering BP set point) (β1/β2)
How do beta blockers affect the heart and kidneys?
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
What do presynaptic β-adrenoceptors do, and what effect would beta blockers have?
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
Describe the actions and selectivity of the 5 major beta blockers
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
List and explain the six unwanted effects of beta blockers
- 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
What is the advantage of atenolol over propranolol?
Propranolol targets β2 receptors as well as β1, hence has side-effects (to greater degree) on the airways and liver
What advantage does carvedilol have over atenolol and propranolol?
More powerful anti-hypertensive (like with most beta blockers, its effect wanes with chronic use)
What is phentolamine used to treat?
(Non-selective 𝛼-blocker) used to treat phaechromocytoma-induced hypertension
What is prazosin used for?
(𝛼1 specific blocker) inhibit the vasoconstrictor activity of NE
State the unwanted effect of alpha blockers?
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
Why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?
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
Compare phentolamine with prazosin
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
How does Methydopa form a false transmitter? State the impact of this
- 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
List the side effects of methyldopa
Dry mouth
Sedation
Orthostatic hypotension
Male sexual dysfunction
(rarely used)
Why are beta blockers used to treat arrhythmias?
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
What is the main beta blocker used in the treatment of arrhythmias? Name the drug class of beta blockers with respect to antiarrhythmic drugs.
Propranolol
Class II antiarrhythmic
Define angina
Chest pain (often spreading to the shoulders, arms and neck) that occurs when the oxygen supply to the myocardium is insufficient for its needs
Describe the three different types of angina
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
Explain why beta blockers can be used to treat angina. Give an example of one such beta blocker
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
Describe the use of beta antagonists in treating glaucoma
They reduce the rate of aqueous humour formation by blocking the β1 receptors (coupled to carbonic anhydrase) on the ciliary body
Name examples of beta blockers used in the treatment of glaucoma
Carteolol hydrochloride Levobunolol hydrochloride
Timolol maleate
