Adrenoceptor antagonists

Question 1

Learning outcomes

Answer 1

• Classify the various adrenoceptors and relate their tissue locations to their physiological functions.
• Classify beta adrenoceptor antagonists (beta blockers, -lol) in terms of their pharmacodynamic and pharmacokinetic properties and discuss how these properties influence their therapeutic and side
effect profiles.
• Explain the rationale for the use of beta blockers in the management of angina pectoris, post-MI, chronic heart failure (and hypertension).
• List absolute and relative contra-indications for beta blocker use
• List important interactions of beta blockers with other drugs
• Describe the mechanism of action, clinical use and side effect profile of alpha adrenoceptor antagonists (alpha blockers, -osin)

Question 2

Adrenoceptors- distribution and functional effects: Cardiovascular

Answer 2

Heart-

• rate of contraction: adrenergic response= increase, B1 primary receptor
• cardiac conductivity: adrenergic response= increase, B1 primary receptor
• force of contraction: adrenergic response= increase, B1 primary receptor

Blood vessels-

• arteries (arterioles): AR = constriction: A1
• skeletal muscle/periphery: AR= dilation: B2
• veins: AR= constriction: A1

Question 3

Adrenoceptors- distribution and functional effects: nonvascular smooth muscle

Answer 3

Generally A1 constrict/A2 relax smooth muscle

• airways: AR-relax (dilate), B2
• gastrointestinal: AR- relax, A1,B2
• gastrointestinal sphincters: AR- constrict, A1
• uterus: AR- relax B2
• bladder sphincter: AR- constrict,A1
• seminal tract: AR- contract ,A1
• iris (radial muscle):AR- contract (dilates, let more light in),A1
• ciliary muscle: AR- relax (long range focus),B2

Question 4

Adrenoceptors- distribution and functional effects

Answer 4

-skeletal muscle: AR-tremor, glycogenolysis- both b2
-liver:AR- glycogenolysis, A1 B2
-adipose tissue:AR thermogenesis lipolysis BOTH B3
-pancreas:AR reduced insulin secretion A2
increased glucagon B2
-kidney:AR increased renin secretion B1
-platelets:AR aggregation A2

Question 5

Distribution and functional effects

Answer 5

salivary gland: AR K+ release + amylase secretion-A1, B1
sweat glands: AR increased secretion- A1
peripheral sympathetic nerves: AR increased release/ decreased release- B2, A2
brainstem: AR decreased sympathetic outflow- A2
mast cells: AR reduced histamine release- B2

Question 6

Definition of adrenoceptor antagonists

Answer 6

drugs which occupy adrenoceptors and prevent the
action of adrenaline (epinephrine) and noradrenaline
(norepinephrine)
Includes: beta blockers (-lol)
alpha1 blockers (-osin)

Question 7

Classification of beta blockers

Answer 7

Based on
• pharmacodynamic properties
– selectivity
– partial agonist activity
– additional actions
• pharmacokinetic properties
–solubility in water vs. lipid
– ability to enter CNS
– route of elimination

Question 8

Classification of B-Blockers

Answer 8

-without partial agonist activity
non selective B1 and B2
propanolol, timolol
B1 selective
Atenolol, metoprolol, bisoprolol

-with partial agonist activity
non selective B1 and B2
pindolol, oxprenolol
B1 Selective
Acebutolol

-additional non-B adrenoceptor dependent actions
Class III antiarrhythmic activity (inhibits K+ channels)
Solatol
-selective arteriolar vasodilator(B1 adrenoceptor
antagonist or nitric oxide releasing action?)
carvedilol, labetolol, nebivolol

Question 9

Cardiovascular actions of Beta blockers

Answer 9

• reduce heart rate, cardiac conductivity
and force of contraction
• decrease cardiac work and oxygen
demand
• reduce blood pressure
• [reduce skeletal and peripheral blood flow]

Question 10

How do beta blockers lower blood pressure?

Answer 10

• initial fall in cardiac output
– antagonise B1 adrenoceptors in heart
– but soon compensated by rise in peripheral vascular resistance via noradrenaline action on vascular A1 adrenoceptors 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 presynaptic B2 receptors on sympathetic nerve terminals

Question 11

Clinical uses of B- blockers

Answer 11

• [uncomplicated hypertension]
• arrhythmias
• angina pectoris
• post myocardial infarction
• [stable] heart failure
• migraine
• glaucoma
• physical effects of anxiety

Question 12

Beta blockers and hypertension

Answer 12

• less widely used now just for hypertension in
absence of other compelling indications / unsuitability of other drugs
– beneficial in younger Caucasian patients?
(> renin levels) especially if ACEI and ARB
contra-indicated (Lecture –RAAS)
– less protective against stroke in elderly
hypertensives vs. other drugs
– > risk of impaired glucose regulation
versus other drugs
– < compliance due to poor tolerability

Question 13

Anti- arrhythmic effect of Beta blockers

Answer 13

• attenuate sympathetic effects on cardiac
automaticity and conductivity
• management of atrial fibrillation
– chaotic electrical activity in atria resulting in fast irregularly irregular
rhythm, pumping of heart is less efficient, >risk of stroke
– useful for ventricular rate control: act at AV node to decrease number
of impulses that conduct into ventricles
• management of other supraventricular tachycardias
– abnormally fast rhythms arising in atria or AVN

Question 14

Anti- arrhythmic effect of Beta blockers

Answer 14

• attenuate sympathetic effects on cardiac automaticity and conductivity
• management of atrial fibrillation
– chaotic electrical activity in atria resulting in fast irregularly irregular rhythm, pumping of heart is less efficient, >risk of stroke
– useful for ventricular rate control: act at AV node to decrease number of impulses that conduct into ventricles
• management of other supraventricular tachycardias
– abnormally fast rhythms arising in atria or AVN

Question 15

Why are Beta blockers used in secondary prevention of MI?

Answer 15

• [some*] ↓ recurrence of myocardial infarction
• reduce morbidity and mortality
• early administration is beneficial for initial management, continue long-term
• particularly beneficial in high-risk patients
– those with left ventricular dysfunction and/or
continuing cardiac ischaemia
• unsuitable for use in some patients (see contra-indications)
*strong evidence base for metoprolol, carvedilol

Reasons for benefits Post-MI
• ↓cardiac work, oxygen demand, ischaemia
• ↓incidence of supraventricular tachycardias by slowing AV conduction
• ↓ incidence of ventricular dysrhythmias associated with sympathetic nervous stimulation
• attenuate ventricular remodelling and progression to LV dysfunction/failure

Question 16

Beta blockers and heart failure

Answer 16

• contra-indicated in acute/worsening unstable heart failure
– compromise cardiac output, promote pulmonary oedema
• some* [carvedilol, bisoprolol, metoprolol] useful in chronic
stable systolic failure
– reduce mortality in all grades of heart failure
– reduce morbidity (frequency/extent of hospitalisation)
– improve symptoms, exercise tolerance, cardiac function
– start low, go slow!! –may initially worsen

Question 17

Beta blockers and heart failure

Answer 17

• contra-indicated in acute/worsening unstable heart failure
– compromise cardiac output, promote pulmonary oedema
• some* [carvedilol, bisoprolol, metoprolol] useful in chronic stable systolic failure
– reduce mortality in all grades of heart failure
– reduce morbidity (frequency/extent of hospitalisation)
– improve symptoms, exercise tolerance, cardiac function
– start low, go slow!! –may initially worsen

Reasons for benefit in Heart Failure?
• reduce heart rate
– prolong diastole, improve chamber filling
– reduce ischaemia (improved coronary blood flow during diastole, and ↓ cardiac work ↓ oxygen demand)
• ↓ activation of renin-angiotensin-aldosterone
system (↓ pre-load and after-load) [Lecture –RAAS]
• attenuate adverse remodelling/myocyte loss
• anti arrhythmic effects (major)
– reduced risk of sudden cardiac death

Question 18

Additional uses of Beta blockers

Answer 18

• prophylaxis of migraine attack
– related to ↓ triggers of stress, anxiety?
– central action or other mechanisms?

• topically in glaucoma [timolol]
– reduce aqueous humour production by ciliary
body, so reduce intraocular pressure

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

Performance enhancement
(non-approved use)
• lower heart rate and reduce muscle tremor
– beneficial for musicians and in sport (shooting, archery)

Question 19

Adverse effects of Beta blockers

Answer 19

• 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

• heart block (atrioventricular block)
– impaired conduction of electrical impulse from atria to ventricles resulting in dropped beats

• central effects
– fatigue, nightmares, confusion, depression, insomnia?
– less common with water-soluble
(less lipid- soluble) e.g. atenolol

• B2 -adrenoceptor antagonism? (B1
-selective better)
– poor tissue perfusion in peripheral vascular disease, intermittent claudication (cramping of skeletal muscles in calf, thigh)
– exacerbation of Raynaud’s disease
– cold hands and feet (less marked with partial agonists)
– bronchospasm in asthmatics/ COPD

• adverse metabolic effects
– prolonged hypoglycaemia (less pancreatic glucagon secretion, less hepatic glycogenolysis)
– interfere with autonomic and metabolic responses to
hypoglycaemia, worsening glycaemic control
– tendency to dyslipidaemia

• weight gain in some patients?
– reduced metabolism and energy expenditure
• diarrhoea, nausea
• impotence?

Question 20

Contraindications of B- Blockers

Answer 20

• bradycardia and heart block
• asthma
• [acute decompensated heart failure]
• [Type 1 diabetes mellitus]
• [claudication]

Question 21

Sudden discontinuation of B-blockers

Answer 21

• may cause
– hypertension
– angina pectoris / myocardial ischemia
– acute myocardial infarction
• explanation
– rebound sympathetic stimulation of heart following
prolonged beta receptor blockade
• withdraw medication gradually!

Important drug interactions of B blockers
• other drugs which slow the heart and/or depress cardiac function and conduction
– rate-limiting calcium channel modulators
(verapamil, diltiazem

Question 22

A- adrenoceptor antagonists and their cardiovascular effect

Answer 22

• A1 adrenoceptor-selective
– prazosin, doxazosin
– tamsulosin (A1A selective)
• non-selective (A1 and A2)
– phentolamine (competitive reversible)
– phenoxybenzamine (competitive irreversible)
Cardiovascular effects of A adrenoceptor antagonists
• reduce peripheral vascular resistance
– antagonise postsynaptic A1 adrenoceptors especially on smaller arteries/arterioles
• BUT cause rebound increase in heart rate, cardiac work and oxygen demand
– due to sympathetic activation, A-adrenoceptor
stimulation
– less marked for A1
-selective antagonists since –ve feedback (A2
-mediated action) on noradrenaline release intact
-ve feedback A2 adrenoceptor blocked by non-selective A-antagonists only

Question 23

Clinical uses and side effects of A-adrenoceptor use

Answer 23

Clinical uses of A adrenoceptor antagonists
• management of resistant hypertension
– clinical use generally limited due to adverse effects
• hypertension secondary to phaeochromocytoma
• relieve urinary retention in prostate hyperplasia
– blockade of A1A adrenoceptor-mediated contraction of bladder sphincter

Adverse effects of A adrenoceptor antagonists
• postural hypotension, dizziness and fainting
– loss of reflex activation of 1adrenoceptor mediated
venoconstriction (needed to ensure adequate return of
blood to heart to maintain cardiac output)
– loss of reflex vasoconstriction of arteries (needed to
maintain blood pressure and flow to cerebral arteries)
– esp. in combination with other vasodilators
(give 1st dose in evening)
• headache
– due to dilation of meningeal vessels
• nasal congestion
– due to dilation of nasal mucosal arterioles
• stress incontinence
– especially overweight females
– relaxation of bladder sphincter due to A1A blockade