Beta Blockers Flashcards
What are partial agonists
Counter sympathetic hyperactivity but partially stimulate beta adrenoreceptors when sympathetic activity low
When are partial agonists adventageous
And safer in situations where some cardiac stimulation is beneficial (concomitant heart failure?)
Describe water soluble beta blockers (example and feature)
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
Describe lipid soluble beta blockers
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
Cardiovascular actions of beta blockers
Reduce heart rate, cardiac conductivity and force of contraction
Decrease cardiac work and oxygen demand
Reduce BP
Reduce skeletal and peripheral blood flow
Stimulation of b1 adrenoceptors by (nor)adrenaline leads to activation of….
Adenylate cyclase and elevation of cyclic AMP resulting in contraction of heart muscle
This process is inhibited by B1 adrenoreceptor antagonists
Why doe beta blockers lower BP?
• 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
Beta blockers used in ……. Of ……. Angina
Prophylaxis of stable angina
Describe beta blockers and angina pectoris
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
Describe the anti-arrhythmic effects of beta blockers
• 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
Secondary prevention post MI (Bea blockers)
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
Reasons for benefits post MI?
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
When are beta blockers contra-indicated
Acute/worsening unstable heart failure
As it compromises cardiac output and promoted pulmonary oedema
What beta blockers are useful in chronic stable heart failure and how
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?
Mechanisms of beta blocker action in HF
• 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)
Additional uses of beta blockers
• symptomatic relief in anxiety
– ↓ physical symptoms mediated via b adrenoceptors:
palpitations, tachycardia, trembling
– do NOT ↓feeling of anxiety
Adverse effects of beta blockers
• 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
Describe atrioventricular block
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
Central effects of beta blockers and what class re they less common with?
Fatigue, nightmares, depression, insomnia
Less common with less lipid-soluble eg atenolol
Describe b2-adrenoreceptor antagonism
• 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
Additional adverse effects of beta blockers
• 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?
Contra-indications for beta blocker use
Asthma
Bradycardia and heart block
Acute decompenasted heart failure
Insulin dependent diabetes
Claudication
Sudden discontinuation of beta blockers may cause what and why?
Hypertension, angina pectoris/MI, acute myocardial infarction
Rebound sympathetic stimulation of heart following prolonged blockade - withdraw gradually!!
Important drug interaction of beta blockers
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)
Beta blockers and hypertension
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?
Consider an …… if further diuretic therapy is not tolerated or is contraindicated or ineffective
Alpha blocker or beta blocker
Why have betas blockers fallen from favour?
• 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%)
Comparison of beta blockers and other therapies
• 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
Describe vasodilator beta blockers and hypertension
• 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
Describe the actions of vasodilator beta blockers
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
Beta blockers vs vasodilators?
wider application than conventional b-blockers especially in difficult to treat
– elderly, Afro-American, diabetes, metabolic syndrome?
• more clinical trials needed
