Beta Blockers

Question 1

What are partial agonists

Answer 1

Counter sympathetic hyperactivity but partially stimulate beta adrenoreceptors when sympathetic activity low

Question 2

When are partial agonists adventageous

Answer 2

And safer in situations where some cardiac stimulation is beneficial (concomitant heart failure?)

Question 3

Describe water soluble beta blockers (example and feature)

Answer 3

Atenolol, sotalol
Little metabolism (mainly eliminated by kidney)
Long half lives/ less frequent administration reduce dose in renal impairment
Less likely to cross blood-brain barrier
Less sleep disturbance

Question 4

Describe lipid soluble beta blockers

Answer 4

Propranolol; o pre look
Extensive metabolism ( greater variation)
Short half lives/more frequent administration
Reduce dose in hepatic impairment
More likely to cross blood-brain barrier
Poor quality sleep and nightmares

Question 5

Cardiovascular actions of beta blockers

Answer 5

Reduce heart rate, cardiac conductivity and force of contraction
Decrease cardiac work and oxygen demand
Reduce BP
Reduce skeletal and peripheral blood flow

Question 6

Stimulation of b1 adrenoceptors by (nor)adrenaline leads to activation of….

Answer 6

Adenylate cyclase and elevation of cyclic AMP resulting in contraction of heart muscle
This process is inhibited by B1 adrenoreceptor antagonists

Question 7

Why doe beta blockers lower BP?

Answer 7

• initial fall in cardiac output
– antagonise b1 (and b2) adrenoceptors in heart
– but compensated by rise in peripheral vascular resistance via noradrenaline action on vascular a1 adenoceptors so fall in BP modest
THEN
• delayed indirect fall in peripheral vascular resistance (with continued reduction in cardiac output), BP ↓
– due to ↓renin secretion (blockade of b1 receptors in kidney)
– and ↓ central sympathetic outflow and blockade of facilitator pre- synaptic b2 receptors on sympathetic nerve terminals

Question 8

Beta blockers used in ……. Of ……. Angina

Answer 8

Prophylaxis of stable angina

Question 9

Describe beta blockers and angina pectoris

Answer 9

Blunt sympathetic response to expertise, Reducing cardiac work
Decr myocardial oxygen consumption by reducing HR and contractility
Prolonged diastole improves perfusion of sub-endocardia’s myocardium, enhance o2 delivery
Decr peripheral vascular resistance; reduces after-load, cardiac oxygen demand

Question 10

Describe the anti-arrhythmic effects of beta blockers

Answer 10

• attenuate sympathetic effects on automaticity and conductivity
• especially in managing symptoms of excess thyroid hormone, exercise, mental stress
• management of supraventricular tachycardias
– periods of abnormally fast heart beat
• control ventricular response in atrial fibrillation
– chaotic electrical activity in atria resulting in irregular rhythm, pumping of heart is less efficient – beta blockers useful for rate (and rhythm – sotalol) control

Question 11

Secondary prevention post MI (Bea blockers)

Answer 11

Some decreased recurrence of MI
Reduce morbidity and mortality
Particularly beneficial in high risk patients
-those with LV dysfunction and/or continuing cardiac ischaemia
- less effective in modern era of improved fibrinolytic and rapid revascularisation
Unsuitable for use in some patients

Question 12

Reasons for benefits post MI?

Answer 12

Decreased cardiac work, oxygen demand
Attenuate ventricular remodelling
Decr incidence of supraventricular tachycardia’s by slowing AV conduction
Decr incidence of ventricular dysrhythmias associated with Sympathetic nervous stimulation

Question 13

When are beta blockers contra-indicated

Answer 13

Acute/worsening unstable heart failure
As it compromises cardiac output and promoted pulmonary oedema

Question 14

What beta blockers are useful in chronic stable heart failure and how

Answer 14

Bisoprolol and metoprolol
Reduce mortality in al grades of HF
Reduce morbidity (frequency of hospitalisation)
Improve symptoms, exercise tolerance, cardiac function
Start low, go slow, -> may initially worsen
Other beta blockers unproven , harmful?

Question 15

Mechanisms of beta blocker action in HF

Answer 15

• reduce heart rate
– prolong diastole, improve chamber filling
– ↑coronary blood flow during diastole
– ↓ cardiac work ↓ oxygen demand, ↓ ischaemia
• ↓ activation of renin-angiotensin system
– reduced pre-load and afterload
• attenuate adverse remodelling/myocyte loss
• reduce central sympathetic outflow?
• anti arrhythmic effects (major)

Question 16

Additional uses of beta blockers

Answer 16

• symptomatic relief in anxiety
– ↓ physical symptoms mediated via b adrenoceptors:
palpitations, tachycardia, trembling
– do NOT ↓feeling of anxiety

Question 17

Adverse effects of beta blockers

Answer 17

• bradycardia
– lowered heart rate leading to reduced cardiac output resulting in hypotension, fainting, weakness, dizziness
– less marked with partial agonists
typically <55 bpm in adult, awake at rest, average fitness

Question 18

Describe atrioventricular block

Answer 18

Adverse side effect of beta blockers
• 1st degree: electrical impulse moves through AV node more slowly than normal
• 2nd degree: some signals from atria don’t reach ventricles, resulting in dropped beats
• 3rd degree: heart’s electrical impulse does not pass from atria to ventricles, bradycardia may result
‒ secondary pacemaker cells in ventricles take over
‒ ventricles contract and pump blood, but at a slower rate

Question 19

Central effects of beta blockers and what class re they less common with?

Answer 19

Fatigue, nightmares, depression, insomnia
Less common with less lipid-soluble eg atenolol

Question 20

Describe b2-adrenoreceptor antagonism

Answer 20

• b2 -adrenoceptor antagonism?
(b1-selective better tolerated)
– poor tissue perfusion in peripheral vascular disease, intermittent claudication (cramping of calf, thigh muscles), exacerbation of
Raynaud’s disease
– coldness of extremities (less marked with partial agonists)
– bronchospasm in asthmatics/ COPD

Question 21

Additional adverse effects of beta blockers

Answer 21

• adverse metabolic effects
– ↑ triglycerides, ↓ HDL cholesterol?
– prolonged hypoglycaemia (less hepatic glycogenolysis, less pancreatic glucagon secretion, b2)
– interfere with autonomic and metabolic responses to hypoglycaemia (esp. during exercise)
• weight gain in some patients?
– reduced metabolism and energy expenditure
• diarrhoea, nausea
• impotence?

Question 22

Contra-indications for beta blocker use

Answer 22

Asthma
Bradycardia and heart block
Acute decompenasted heart failure
Insulin dependent diabetes
Claudication

Question 23

Sudden discontinuation of beta blockers may cause what and why?

Answer 23

Hypertension, angina pectoris/MI, acute myocardial infarction
Rebound sympathetic stimulation of heart following prolonged blockade - withdraw gradually!!

Question 24

Important drug interaction of beta blockers

Answer 24

drugs which slow the heart and/or depress cardiac function and conduction
– verapamil, diltiazem (cardiac calcium channels)
– class one anti-arrhythmic agents such as lidocaine (cardiac sodium channels)

Question 25

Beta blockers and hypertension

Answer 25

less used now for hypertension in absence of other compelling indications, unsuitability of other drugs
• other drug classes now preferred for routine management of uncomplicated hypertension
• still useful as a Step 4 agent in resistant hypertension?
• no clear evidence that one conventional b-blocker superior or inferior to any others for ↓blood pressure?

Question 26

Consider an …… if further diuretic therapy is not tolerated or is contraindicated or ineffective

Answer 26

Alpha blocker or beta blocker

Question 27

Why have betas blockers fallen from favour?

Answer 27

• ASCOT Anglo-Scandinavian Cardiac Outcomes Trial population of hypertensive adults at moderate risk of developing cardiovascular disease, a regimen starting with amlodipine and adding perindopril as required reduced the risk of strokes by about 25%, coronary events and procedures by 15%, cardiovascular deaths by 25%, and new cases of diabetes by 30% compared with atenolol plus a diuretic as required
• LIFE Losartan-based compared with atenolol-based antihypertensive therapy was associated with reduction in combined primary endpoint of cardiovascular death, stroke or MI (-13%), fewer strokes (-25%), similar blood pressure reduction, reduced rate of new-onset diabetes (-25%)

Question 28

Comparison of beta blockers and other therapies

Answer 28

• b blockers tend to reduce peripheral blood pressure (brachial) similar to other classes but lesser effect on central (aortic) blood pressure which is more predictive of stroke, MI
• conventional b blockers have a similar effect to thiazides on systolic BP but greater effect on diastolic BP so less impact on pulse pressure so less benefit in elderly/those with ISH?
• > risk of impaired glucose tolerance
– esp. + thiazides
• < attenuation of left ventricular hypertrophy
• < compliance due to poor tolerability

Question 29

Describe vasodilator beta blockers and hypertension

Answer 29

• vasodilator b-blockers have additional a1 adrenoceptor blocking (carvedilol, labetolol) or nitric oxide releasing action (nebivolol) in blood vessels
• lower BP more due to ↓ peripheral vascular resistance rather than cardiac output than for conventional b blockade
• > ↓central (aortic) pulse pressure vs. atenolol?
– dilating small arteries reduces pressure related to wave reflection
• vasodilator ability attenuates adverse metabolic and lipid parameters, less risk of new onset diabetes

Question 30

Describe the actions of vasodilator beta blockers

Answer 30

Tend not to cause reflexes increase in HR, CO in contrast to other dilators?
Nebivolol reduction in endothelial dysfunction attributed to improved NO bioavailability - echini’s? Antioxidant or b3 receptor coupled with eNOS
Carvedilol prove benefit for secondary prevention post MI and reduced mortality in chronic heart failure
Labetolol indicated for hypertension in pregnancy

Question 31

Beta blockers vs vasodilators?

Answer 31

wider application than conventional b-blockers especially in difficult to treat
– elderly, Afro-American, diabetes, metabolic syndrome?
• more clinical trials needed