L06 Clinical Pharmacology Adrenergic (adrenaline) Modulators a.k.a Beta Blockers

Overview

The lecture works through the three classes of adrenergic modulator used in cardiovascular medicine (beta blockers, alpha 1 blockers and centrally acting alpha 2 agonists), placed against the physiology of blood pressure control and the management of hypertension. It starts with how the autonomic nervous system and the renin-angiotensin-aldosterone system set cardiac output and peripheral resistance, then maps which adrenoceptor subtype does what in each tissue, so that each drug class can be predicted from the receptor it blocks or stimulates. Hypertension classification, why it is treated and the current first line agents provide the clinical frame; the bulk of the detail is on beta blockers (generations, actions, indications, adverse effects, pharmacokinetics and pharmacogenomics). For each drug class the stated learning target is mechanism of action, current therapeutic indications, potential adverse drug reactions, one or two important examples, and pharmacokinetics where clinically important. The lecture is the first in a cardiovascular clinical pharmacology series that continues with ACE inhibitors/ARBs, statins, antiplatelets and anticoagulants, calcium channel blockers and nitrates, diuretics, anti-arrhythmics and drugs for ischaemic heart disease, and it ties into integrated clinical cases 8 and 9.

Physiological control of blood pressure

Mean arterial pressure is the product of cardiac output and peripheral resistance: blood leaves the left ventricle into the elastic arteries (where mean arterial pressure is generated) and exits through arterioles that act as a variable resistance.

Cardiac output is controlled by:

• Rate and force of cardiac contraction (autonomic nervous system)
• Blood volume, via the kidneys (diuresis) and the renin-angiotensin-aldosterone system
• Blood viscosity

Peripheral resistance is controlled by:

• Sympathetically controlled vascular tone (rapid)
• RAAS control of tone (slow onset, more sustained)
• Substances released from endothelial cells: nitric oxide, prostacyclins, thromboxane

Autonomic control of the heart, vessels and kidney

The cardiovascular centre in the medulla oblongata receives afferent (sensory) input from baroreceptors in the carotid sinus and aortic arch via the glossopharyngeal (IX) and vagus (X) nerves. Efferent (motor) output runs down the spinal cord to the sympathetic trunk ganglion and then via the cardiac accelerator nerve to the SA node, AV node and ventricular myocardium; a separate branch runs to the kidney to trigger renin release. Sympathetic stimulation speeds the heart, parasympathetic (vagal, X) stimulation slows it.

Transmitters and receptors:

• Sympathetic innervation of the heart: noradrenaline acts on beta receptors, primarily ${\beta }_1$
• Sympathetic innervation of blood vessels: noradrenaline acts principally on alpha receptors
• Parasympathetic (vagal) innervation of the heart: acetylcholine acts on muscarinic receptors; the M2 receptor decreases atrial heart rate and atrial rate and force of contraction
• Endocrine (pancreas, kidney and others): circulating adrenaline binds and activates ${\beta }_1$ and ${\beta }_2$ receptors, and at high concentration also activates alpha receptors

The three control points that the drug classes exploit:

• Vasoconstriction is mediated by ${\alpha }_1$ adrenoceptors
• Increased heart rate and force of contraction are mediated by ${\beta }_1$ adrenoceptors
• Increased renal renin production is mediated by ${\beta }_1$ receptors, feeding the RAA system

The neuroendocrine link: the ANS also drives the renin-angiotensin system, in which angiotensin II and aldosterone are crucial to pathological pathways. Renin released from the kidney converts angiotensinogen to angiotensin I, which is converted to angiotensin II.

Adrenoceptor distribution and the effects predicted from it

Cardiorenal adrenoceptors by tissue (relative effect strength shown as + signs):

Tissue	Effect by receptor
Vascular smooth muscle (coronary, skin, renal and others)	${\alpha }_1$ constrict; ${\alpha }_2$ constrict; ${\beta }_2$ dilate muscle arterioles
Heart, chronotropy (rate)	${\beta }_1$ +++; ${\beta }_2$ +
Heart, inotropy (force)	${\alpha }_1$ ++; ${\beta }_1$ +++; ${\beta }_2$ +
Kidney, juxtaglomerular renin secretion	${\beta }_1$ +++
Nerves, reduced central preganglionic NA release	${\alpha }_2$ ++

Cardiac conduction tissue, where ${\beta }_1>{\beta }_2$ throughout:

• Sinoatrial node: increased heart rate ++
• Atria: increased contractility and conduction velocity ++
• Atrioventricular node and His-Purkinje system: increased automaticity and conduction velocity ++
• Ventricle: increased contractility, conduction velocity, automaticity and rate of idioventricular pacemakers +++

Vascular beds, with the receptors responsible:

• Coronary: constriction +, dilation ++ (${\alpha }_1$, ${\alpha }_2$, ${\beta }_2$)
• Skin and mucosa: constriction ++ (${\alpha }_1$, ${\alpha }_2$)
• Skeletal muscle: constriction +, dilation ++ (${\alpha }_1$, ${\beta }_2$)
• Cerebral: slight constriction (${\alpha }_1$)
• Pulmonary: constriction +, dilation (${\alpha }_1$, ${\beta }_2$)
• Abdominal viscera: constriction +++, dilation + (${\alpha }_1$, ${\beta }_2$)
• Salivary glands: constriction +++ (${\alpha }_1$, ${\alpha }_2$)
• Renal: constriction ++, dilation ++ (${\alpha }_1$, ${\alpha }_2$, ${\beta }_1$, ${\beta }_2$)
• Veins: constriction, dilation (${\alpha }_1$, ${\alpha }_2$, ${\beta }_2$)

The therapeutic predictions that follow: giving a ${\beta }_1$ blocker gives a decrease in heart rate (and no increase), so less exertion and lower cardiac output; giving an alpha blocker gives vasodilation.

Warning

The vascular bed table carries superscript footnote letters (e, f, d) with no visible footnote key on the slide, so what those qualifiers mean is not recoverable from the lecture.

Hypertension: classification, rationale and epidemiology

New 2024 ESC blood pressure categories:

• Non-elevated: <120/70 mmHg. Insufficient evidence confirming the efficacy and safety of pharmacological BP treatment.
• Elevated: 120-139/70-89 mmHg. Risk stratify to identify individuals at high cardiovascular risk for pharmacological BP treatment.
• Hypertension: $\ge$140/90 mmHg. Cardiovascular risk is sufficiently high to merit initiating pharmacological BP treatment.

Diagnosis of hypertension and of elevated BP requires confirmation using out-of-office measurements (HBPM or ABPM) or at least one additional subsequent office measurement. (The full citation line on the ESC graphic was too small to transcribe.)

Why treat:

• Hypertension damages organs: kidneys, heart, eyes, brain and others
• Lowering BP reduces the risk of cardiovascular disease: atherosclerosis, myocardial infarction, diabetic vascular injury
• Goal of therapy: maintain blood pressure at near normal limits with minimal adverse drug reactions

Age and sex pattern:

• Incidence of hypertension increases progressively with age
• Systolic BP increases throughout life; diastolic BP rises until about 50 years then levels off and falls over the next decade (on the plotted data, systolic rises from roughly 110-130 mmHg in the 18-29 band to about 150 mmHg by 70-79, while diastolic peaks around 80-85 mmHg in the 40-59 bands before declining)
• Isolated systolic hypertension (ISH) is the term for elevated systolic BP with normal diastolic BP
• Diastolic BP is a more potent risk factor for coronary heart disease than systolic until age 50; systolic is more important thereafter
• Increased arterial stiffness is the vascular phenotype of systolic hypertension, especially of the large arteries
• At or under 50 years hypertension is more prevalent in men, but after menopause (around 65 years) it is more common in women than men

Treating hypertension

Lifestyle measures come first and continue alongside drugs (exercise, diet, cessation of the usual obnoxious elements). The measures listed as feeding into BP reduction and cardiovascular risk reduction:

• Aerobic exercise training: at least 150 min/week moderate intensity or 75 min/week vigorous intensity (brisk walking, jogging, cycling, swimming), Class I
• Increase daily physical activity: steps per day, take the stairs, walk or cycle
• Avoid a sedentary lifestyle
• Isometric resistance exercise training: low to moderate intensity, 3 sets of 1-2 min contraction (hand grip, plank, wall sit)
• Dynamic or isometric resistance training to complement aerobic training: 2-3 times/week, Class I
• Dynamic resistance exercise training: large muscle groups, low to moderate intensity, 2-3 sets of 10-15 repetitions (squat, push-ups, sit-up)

Drug selection when lifestyle measures are insufficient:

• A single drug class will control BP in 40-50% of patients; if one agent does not control BP, consider two or more classes together
• With no contraindications, current guidelines recommend starting with a low dose ACE inhibitor or ARB as a general first line, particularly with compelling indications; or a dihydropyridine calcium channel blocker; or a thiazide diuretic (generally the preferred initial agent in those 65 and over)
• Beta blockers are not a first choice for control of isolated systolic hypertension, which is predominantly seen in the elderly
• Compelling indications include diabetes, coronary disease risk, ischaemic heart disease, AF or heart failure, chronic kidney disease and recurrent stroke, as well as contraindications such as drug intolerability, asthma/COPD, or drug resistance

Evidence-based regimens for hypertension with compelling indications:

• Heart failure: diuretic, low dose beta blocker, ACE inhibitor, ARB, mineralocorticoid receptor antagonist, SGLT2 inhibitor
• Atrial fibrillation: ACE inhibitor, ARB, with beta blocker or CCB (diltiazem or verapamil for rate control)
• Post myocardial infarction: ACE inhibitor, ARB, beta blocker, mineralocorticoid receptor antagonist
• High coronary disease risk: diuretic, beta blocker, ACE inhibitor, CCB
• Diabetes: diuretic, beta blocker, ACE inhibitor, ARB, CCB
• Chronic kidney disease: ACE inhibitor, ARB, diuretic, SGLT2 inhibitor
• Recurrent stroke prevention: diuretic, ACE inhibitor and others
• Statins are added where indicated for all of the above conditions

Alpha 1 blockers: doxazosin

• Position: second or third line treatment of hypertension. Selective vascular ${\alpha }_1$ blocker with limited cardiac action.
• Use: reduces BP in mild to moderate hypertension but is not generally suitable as monotherapy (ALLHAT 2002).
• Mechanism: a vasodilator that blocks ${\alpha }_1$-mediated sympathetic tone, relaxing smooth muscle of both resistance vessels (arterioles) and veins, so peripheral vascular resistance falls and venous capacitance increases. On the vasomotor-centre schematic the site of action is the sympathetic nerve to the blood vessel.
• Value: less reflex tachycardia than non-selective alpha blockers, because roughly 1000-fold selectivity at ${\alpha }_1$ makes it less likely to block presynaptic ${\alpha }_2$ receptors.
• Other indications: intimal ureteric hyperplasia and benign prostatic hyperplasia.
• Pharmacokinetics: good oral absorption, good bioavailability, hepatic metabolism, highly protein bound.
• Lipids: doxazosin has a better LDL/HDL profile than other adrenergic modulators.
• Side effects: postural hypotension, depression, drowsiness, nasal stuffiness, increased GI motility with diarrhoea, inhibited ejaculation, urinary incontinence.

Centrally acting alpha 2 agonists: clonidine and alpha-methyldopa

• Site: ${\alpha }_2$ receptors on the posterior hypothalamus and medulla, acting presynaptically. Within therapeutic doses they stimulate presynaptic ${\alpha }_2$ adrenoceptors in the brainstem.
• Mechanism in sequence: central presynaptic ${\alpha }_2$ activation reduces sympathetic outflow and increases parasympathetic (vagal) outflow from the medulla; at the synapse, clonidine bound to the presynaptic ${\alpha }_2$ receptor blocks further noradrenaline release onto a postsynaptic cell bearing beta and ${\alpha }_1$ receptors; decreased sympathetic and increased vagal firing then act at the SA node (reduced heart rate, reduced stroke volume), on arteries (vasodilation, reduced total peripheral resistance) and on veins (venodilation, reduced venous return); the net result is reduced cardiac output and peripheral resistance, and so a fall in BP.
• Initial paradoxical effect: alpha 2 agonists produce an initial short-lived hypertensive response through direct binding to vascular ${\alpha }_2$ receptors. Preliminary or high doses can directly affect vascular smooth muscle ${\alpha }_{2B}$ and cause initial vasoconstriction.
• Clonidine specifics: reduces BP by decreasing noradrenaline release, acting on the heart (negative chronotropy and decreased stroke volume) and on the peripheral vasculature (venodilation and vasodilation). In supine patients it further reduces autonomic stimulation of heart rate and stroke volume; in upright patients it negates autonomic vasoconstriction of the peripheral vasculature and may initially cause postural hypotension. Prolonged negative chronotropic and negative inotropic effects may promote congestive heart failure in susceptible patients. Clinically it has very limited use in BP control (not first line) plus off-label uses.
• Alpha-methyldopa specifics: limited to the treatment of hypertension in pregnancy, and used in eclampsia in pregnancy.

Beta blockers: classes and mechanism

Beta adrenergic receptor antagonists (“olol” drugs) are sympatholytics and form a large drug family with varying properties. They reversibly antagonise the binding of noradrenaline and adrenaline to beta adrenoceptors, so the degree of response is proportional to the level of sympathetic stimulation (for example in atrial fibrillation, during exercise, or during stress). Their main cardiovascular use works through inhibition of cardiac ${\beta }_1$ receptors.

Generations:

• 1st generation, propranolol: ${\beta }_1$ and ${\beta }_2$; contraindicated in asthma
• 2nd generation, metoprolol and atenolol: ${\beta }_1$-selective, sparing respiratory airways, but not exempt from cross-reactivity
• 3rd generation, carvedilol: ${\beta }_1$, ${\beta }_2$ and ${\alpha }_1$ antagonist, with added vasodilator capability

Pharmacological actions:

• Primarily antagonise the cardiac and renal beta adrenoceptor response to adrenergic stimulation
• Cardiac output and BP fall through negative chronotropy (decreased rate of contraction), negative inotropy (decreased force of contraction) and decreased renal renin output
• The antihypertensive effect is mainly adrenergic receptor block. Reduction in cardiac output is the initial primary action; that initial drop in cardiac output produces an initial increase in peripheral resistance, which then adjusts. Inhibition of ${\beta }_1$-stimulated renin release from renal juxtaglomerular cells reduces the RAAS, and chronic use ultimately decreases peripheral resistance.
• Chronic use also reduces noradrenaline secretion by the CNS and alters baroreceptor sensitivity

Inverse agonism: unoccupied beta adrenoceptors exert basal levels of intrinsic adenylate cyclase activity and cAMP production. Beyond blocking the response to catecholamines, some beta blockers are also strong inverse agonists that inhibit this basal activity. Metoprolol does this to a higher degree than carvedilol, which is a weak inverse agonist, so metoprolol and carvedilol have different negative inotropic effects at equivalent levels of receptor occupation.

The signalling pathway being interrupted: noradrenaline or adrenaline binds the beta adrenoceptor (with its Gs subunits), activating adenylate cyclase, which produces cAMP from ATP and engages PKA (anchored by AKAP); PKA phosphorylation acts on the ryanodine receptor and sarcoplasmic reticulum to trigger Ca${}^{2+}$ release, which acts on troponin I and the myofilaments. A muscarinic M2/acetylcholine pathway runs alongside it.

Receptor coverage differs by drug, which is what differentiates them: metoprolol and atenolol block the fewest receptor types, propranolol more, carvedilol the most. Block at ${\beta }_1$ and ${\beta }_2$ removes chronotropic, inotropic, lusitropic and dromotropic cAMP-mediated effects; block at ${\alpha }_1$ removes peripheral vasoconstriction; both routes converge on preventing cardiac injury.

Warning

The beta blocker site-of-action diagram carries unexplained ”(?)” marks beside the heart and kidney branches, with no accompanying explanation on the slide.

Beta blockers: pharmacological value and therapeutic uses

Value on the heart:

• Rate control: negative chronotrope, since inhibiting cardiac ${\beta }_1$ receptors decreases the rate of contraction
• Decreased work of the heart: negative inotropic and chronotropic actions reduce cardiac oxygen consumption
• Decreased conduction through the AV node: a negative dromotrope reduces ventricular responsiveness to fast beating atria, as in AF
• Increased rate of myocardial relaxation: the lusitropic effect (lusitropy is the rate of myocardial relaxation) improves ventricular relaxation and filling

Principal therapeutic uses:

• Cardiac rate control: anti-arrhythmic in atrial fibrillation; as Vaughan Williams class II drugs they decrease heart rate, conduction, excitability and automaticity
• Angina and myocardial infarction: negative inotropy and chronotropy reduce cardiac oxygen consumption and so reduce workload and demand
• Heart failure: metoprolol and carvedilol are effective at reducing adrenergic workload effects in the failing heart, carvedilol as a vasodilating sympatholytic
• Hypertension: not generally used. Blockade of cardiac ${\beta }_1$ receptors is only valuable where the sympathetic nervous system is overactive, and most hypertensive patients have atherosclerosis; used as an add-on in resistant hypertension. Selective beta blockade has no value in reducing systolic hypertension. Carvedilol may be indicated for primary hypertension because it has an improved lipid profile and does not produce reflex tachycardia.
• Glaucoma: for example timolol eye drops to reduce intraocular pressure
• Anxiety: a condition associated with tremors and increased heart rate

Why 1st and 2nd generation agents are not first line for hypertension: metoprolol and atenolol lower BP through negative chronotropic and inotropic effects without producing vasodilation, while adversely affecting lipid metabolism. The newer 3rd generation agents have vasodilating capability without major adverse effects on heart rate or lipids: carvedilol through ${\alpha }_1$ block, nebivolol through nitric oxide release.

Important

Carvedilol’s extra ${\alpha }_1$ blockade blocks adrenergic stimulation of vascular ${\alpha }_1$ receptors, producing vasodilation with no reflex tachycardia as a consequence of the imposed ${\beta }_1$ blockade.

Beta blockers: adverse drug reactions

Arising directly from the mechanism of action:

• Bronchospasm through ${\beta }_2$ interaction, seen with high doses or non-selective blockers; avoid non-selective beta blockers in asthma and COPD
• Decreased cardiac output, which can promote heart failure
• Reduced exercise tolerance and fatigue
• Peripheral vasoconstriction giving cold peripheries
• Worsening heart block (cardiac conduction pathways)
• CNS effects such as nightmares
• Teratogenicity (noted for metoprolol and propranolol)

Other adverse effects:

• Worsened lipid profile: beta blockers inhibit ${\beta }_2$ stimulation of vascular lipoprotein lipase, which blocks hydrolysis of plasma triglycerides carried in VLDL and LDL and causes an adverse increase in the TG:HDL and LDL:HDL ratios
• Non-selective beta blockers may blunt catecholamine-induced hepatic glycogenolysis in response to hypoglycaemia, and so can delay hypoglycaemic recovery in diabetes

Beta blockers: pharmacokinetics and administration

Water soluble (hydrophilic) drugs, exemplified by atenolol:

• Lack of hepatic first-pass effect, lowering the chance of drug interactions and food interference
• Often a longer half-life, because of reduced hepatic metabolism, allowing once daily dosing
• Low penetrability into the CNS, so few CNS side effects
• Largely excreted unchanged by the renal route
• Overall fewer off-target effects and an improved adverse reaction profile

Lipid soluble (lipophilic) drugs, exemplified by metoprolol, propranolol and carvedilol:

• Improved oral absorption
• Hepatic metabolism, with a greater chance of significant first pass effect; metoprolol and propranolol are mostly metabolised through CYP2D6
• Extensive first pass metabolism giving only 25-50% bioavailability, with dose-dependent half-life
• Often a shorter half-life
• Larger volume of distribution, resulting in adverse drug reactions
• Higher CNS penetration through the blood brain barrier, giving nightmares, hallucinatory effects and behavioural changes
• Carvedilol specifically is highly lipophilic, metabolised in the liver by oxidation and conjugation, with extensive first pass metabolism and an absolute bioavailability of about 25%

Clearance rule: renal failure prolongs the half-life of hydrophilic drugs, while hepatic injury prolongs the half-life of lipophilic drugs.

Selectivity is dose dependent: with oral administration, high doses reduce selectivity and allow ${\beta }_1$ blockers to act on ${\beta }_2$ receptors.

Administration:

• Oral: metoprolol, carvedilol, atenolol, propranolol, taken with food to slow absorption
• Metoprolol tartrate salt is immediate release, dosed 2-3 times daily; metoprolol succinate salt allows extended release, dosed once daily
• Titrate the dose up gradually (fortnightly) to effect, and monitor closely
• Withdraw or taper slowly over several months to prevent rebound effects
• Intravenous rapid administration is available in some emergency cases, and for short acting beta blockers such as esmolol and labetalol

Beta blockers: pharmacogenomics

Two sources of variation in response:

1. Variation in the alleles encoding the beta adrenergic receptor determines how well beta blockers prevent noradrenaline or adrenaline binding. A single nucleotide polymorphism in the ADRB1 gene causing a Gly to Arg substitution increases inherent receptor sensitivity to beta blockers, and in 1000 Genomes Project data C-allele carriers responded to beta blocker treatment much better than G-allele carriers. A Ser to Gly substitution results in a smaller number of beta receptors and loss of response to beta blockers.
2. Genetic variation in CYP2D6 affects how quickly beta blockers are metabolised, giving a large spectrum from ultra-rapid to poor metabolisers. Plotted against an optimal therapeutic range, an ultra-rapid metaboliser’s plasma concentration rises quickly and falls away quickly, spending only a brief interval in the therapeutic range, while a poor metaboliser’s concentration rises and stays elevated at or above the therapeutic band for much longer.

The slide asks what impact poor metabolism of metoprolol has on cardioselectivity, but does not give an answer [slide does not elaborate].

Metoprolol in the practical lab: prescribing detail

Drug used: Apo-metoprolol (metoprolol tartrate, immediate release) 50 mg orally.

Contraindications and cautions: caution when taking other medications or with any of known or suspected pregnancy, hypotension (systolic under 100 mmHg), bradycardia (under 45 beats per minute), asthma, uncontrolled heart failure, Prinzmetal’s angina, marked bradycardia, sick sinus syndrome, second or third degree AV block, cardiogenic shock, diabetes, metabolic acidosis, severe peripheral arterial disease, phaeochromocytoma.

Important

Anaphylaxis risk: while taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline/epinephrine used to treat an allergic reaction.

Potential adverse drug reactions by frequency:

• Common: fatigue, exertional dyspnoea, bradycardia, postural disorder, palpitation, cold hands and feet, dizziness, headache, GI upset
• Uncommon: psychiatric effects including depression, somnolence, insomnia, first degree AV block, oedema, precordial pain, paraesthesia, muscle cramp, bronchospasm, worsened heart failure, low increased risk of cardiogenic shock in patients with acute myocardial infarction
• Rare: visual disturbance, arrhythmia, sexual dysfunction, alopecia
• Very rare: hallucination, thrombocytopenia, hepatitis, tinnitus, photosensitivity

Self-test

1. Write the relationship between mean arterial pressure, cardiac output and peripheral resistance, and list the factors controlling each of the two components.
2. Trace the baroreceptor reflex arc as drawn in the lecture, from sensory input to the effector organs.
3. State which adrenoceptor mediates vasoconstriction, which mediates increased heart rate and force of contraction, and which mediates increased renal renin production.
4. Which receptor subtypes mediate cardiac chronotropy and inotropy, and with what relative strengths?
5. Describe the steps of the renin-angiotensin system as drawn in the lecture, and state which receptor links the sympathetic nervous system to it.
6. Give the 2024 ESC blood pressure categories with their numerical cut-offs and the treatment action recommended for each.
7. What confirmation is required before diagnosing hypertension or elevated blood pressure on an office reading?
8. Describe how systolic and diastolic blood pressure change with age, and explain what isolated systolic hypertension is and in whom it predominates.
9. Which is the more potent risk factor for coronary heart disease, systolic or diastolic blood pressure? Explain how the answer depends on age.
10. What proportion of patients are controlled by a single drug class, and what is the next step if one agent is insufficient?
11. List the recommended first line antihypertensive options in a patient with no contraindications, and state which agent is preferred as an initial choice in those 65 and over.
12. A patient has hypertension and atrial fibrillation. Which drug classes does the evidence-based list give for this compelling indication?
13. Explain the mechanism of doxazosin and describe the two vascular consequences it produces.
14. Why does doxazosin cause less reflex tachycardia than a non-selective alpha blocker?
15. Describe the steps by which clonidine lowers blood pressure, from receptor to haemodynamic outcome.
16. Predict what happens to blood pressure immediately after a high dose of an alpha 2 agonist, and explain why.
17. Distinguish the three generations of beta blocker by their receptor targets, giving an example of each.
18. Explain why beta blockers reduce blood pressure over the long term even though their initial action raises peripheral resistance.
19. Describe what an inverse agonist does at the beta adrenoceptor, and distinguish metoprolol from carvedilol on this property.
20. List the four aspects of cardiac performance that beta blockade modifies, naming the term for each.
21. Explain the mechanism by which beta blockers worsen the blood lipid profile.
22. Why should non-selective beta blockers be avoided in asthma and COPD, and what other mechanism-derived adverse effects should be anticipated?
23. Distinguish atenolol from metoprolol on lipid solubility, and predict the consequences for first pass metabolism, half-life, CNS effects and route of clearance.
24. A patient with chronic kidney disease is taking atenolol. What happens to its plasma concentration and what should be done?
25. How should a beta blocker be started and how should it be stopped, and why?
26. Describe the two genetic sources of variable beta blocker response, and predict the plasma concentration profile of an ultra-rapid metaboliser compared with a poor metaboliser.
27. A patient with a history of severe anaphylaxis is started on metoprolol. What specific risk does this create?
28. Describe the pharmacological properties of carvedilol and what it is used for.
29. Integrative: a patient with heart failure, hypertension and a history of asthma is being considered for a beta blocker. Using receptor selectivity, vasodilator capability and adverse effect profile, explain which agent characteristics matter and what the lecture says about each candidate class.

Answers

Reveal answers

1. Mean arterial pressure is the product of cardiac output and peripheral resistance. Cardiac output is controlled by rate and force of cardiac contraction (ANS), blood volume via the kidneys (diuresis) and the RAAS, and blood viscosity. Peripheral resistance is controlled by sympathetically controlled vascular tone (rapid), RAAS control of tone (slow onset and more sustained), and endothelial substances (nitric oxide, prostacyclins, thromboxane).
2. Baroreceptors in the carotid sinus and aortic arch send afferent signals via the glossopharyngeal (IX) and vagus (X) nerves to the cardiovascular centre in the medulla oblongata. Efferent output passes down the spinal cord to the sympathetic trunk ganglion and via the cardiac accelerator nerve to the SA node, AV node and ventricular myocardium, with a separate branch to the kidney triggering renin release. Sympathetic output speeds the heart, vagal output slows it.
3. Vasoconstriction is mediated by ${\alpha }_1$; increased heart rate and force of contraction by ${\beta }_1$; increased renal renin production by ${\beta }_1$.
4. Chronotropy: ${\beta }_1$ +++ and ${\beta }_2$ +. Inotropy: ${\beta }_1$ +++, ${\alpha }_1$ ++ and ${\beta }_2$ +.
5. Sympathetic stimulation of ${\beta }_1$ receptors on the kidney increases renin production; renin acts on angiotensinogen to give angiotensin I, which is converted to angiotensin II. Angiotensin II and aldosterone are crucial to the pathological pathways.
6. Non-elevated is under 120/70 mmHg, where there is insufficient evidence confirming the efficacy and safety of pharmacological BP treatment. Elevated is 120-139/70-89 mmHg, where patients should be risk stratified to identify those at high cardiovascular risk for pharmacological treatment. Hypertension is 140/90 mmHg or above, where cardiovascular risk is sufficiently high to merit starting pharmacological treatment.
7. Confirmation using out-of-office measurements (home or ambulatory BP monitoring) or at least one additional subsequent office measurement.
8. Systolic BP increases throughout life; diastolic BP rises until about age 50 then levels off and falls over the next decade. Isolated systolic hypertension is elevated systolic BP with normal diastolic BP, predominantly seen in the elderly; increased arterial stiffness, especially of the large arteries, is its vascular phenotype.
9. Diastolic BP is the more potent risk factor for coronary heart disease until age 50; systolic BP is more important thereafter.
10. A single drug class controls BP in 40-50% of patients. If a single agent does not control BP, consider using two or more classes together.
11. A low dose ACE inhibitor or ARB as a general first line, particularly with compelling indications; a dihydropyridine calcium channel blocker; or a thiazide diuretic, which is generally the preferred initial agent in those 65 and over. Beta blockers are not a first choice, particularly for isolated systolic hypertension.
12. ACE inhibitor or ARB, with a beta blocker or a calcium channel blocker (diltiazem or verapamil for rate control).
13. Doxazosin is a selective vascular ${\alpha }_1$ blocker that blocks ${\alpha }_1$-mediated sympathetic tone and relaxes the smooth muscle of both resistance vessels (arterioles) and veins, so peripheral vascular resistance falls and venous capacitance increases.
14. Because its selectivity at ${\alpha }_1$ is about 1000-fold, so it is less likely to block presynaptic ${\alpha }_2$ receptors.
15. Clonidine stimulates presynaptic ${\alpha }_2$ receptors in the brainstem (posterior hypothalamus and medulla), blocking further noradrenaline release. This reduces sympathetic outflow and increases vagal outflow, which at the SA node reduces heart rate and stroke volume, in arteries produces vasodilation and reduced total peripheral resistance, and in veins produces venodilation with reduced venous return. Cardiac output and peripheral resistance both fall, so BP falls.
16. An initial short-lived rise in blood pressure, because preliminary or high doses bind directly to vascular smooth muscle ${\alpha }_2$ receptors (${\alpha }_{2B}$), causing vasoconstriction before the central effect predominates.
17. First generation propranolol blocks ${\beta }_1$ and ${\beta }_2$ and is contraindicated in asthma. Second generation metoprolol and atenolol are ${\beta }_1$-selective and spare the respiratory airways, though not exempt from cross-reactivity. Third generation carvedilol blocks ${\beta }_1$, ${\beta }_2$ and ${\alpha }_1$, adding vasodilator capability.
18. The initial primary action is a reduction in cardiac output, which provokes an initial rise in peripheral resistance, but this adjusts. Inhibition of ${\beta }_1$-stimulated renin release from juxtaglomerular cells reduces RAAS activity, and with chronic use peripheral resistance ultimately decreases (chronic use also reduces CNS noradrenaline secretion and alters baroreceptor sensitivity).
19. Unoccupied beta adrenoceptors have basal intrinsic adenylate cyclase and cAMP production; an inverse agonist inhibits that basal activity as well as blocking the catecholamine response. Metoprolol is a strong inverse agonist, carvedilol a weak one, so they have different negative inotropic effects at equivalent receptor occupation.
20. Chronotropy (rate, decreased), inotropy (force of contraction, decreased), dromotropy (AV nodal conduction, decreased, reducing ventricular responsiveness to fast atria in AF), and lusitropy (rate of myocardial relaxation, increased, improving ventricular relaxation and filling).
21. They inhibit ${\beta }_2$ stimulation of vascular lipoprotein lipase, which blocks hydrolysis of plasma triglycerides carried in VLDL and LDL, adversely increasing the TG:HDL and LDL:HDL ratios.
22. Because ${\beta }_2$ blockade provokes bronchospasm, seen with high doses or non-selective blockers. Also anticipate decreased cardiac output that can promote heart failure, reduced exercise tolerance and fatigue, peripheral vasoconstriction with cold peripheries, worsening heart block, and CNS effects such as nightmares.
23. Atenolol is hydrophilic: no hepatic first pass effect, so fewer drug and food interactions, a longer half-life allowing once daily dosing, low CNS penetration with few CNS side effects, and largely unchanged renal excretion. Metoprolol is lipophilic: improved oral absorption, hepatic metabolism through CYP2D6 with extensive first pass and only 25-50% bioavailability, shorter and dose-dependent half-life, larger volume of distribution with more adverse reactions, and blood brain barrier penetration giving nightmares, hallucinatory effects and behavioural changes.
24. Atenolol is water soluble and renally excreted, so its plasma half-life may be prolonged depending on the extent of injury; consider a dose reduction.
25. Titrate the dose up gradually, fortnightly, to effect with close monitoring; withdraw or taper slowly over several months to prevent rebound effects.
26. Variation in the alleles encoding the beta adrenergic receptor (an ADRB1 SNP causing Gly to Arg increases receptor sensitivity, with C-allele carriers responding much better than G-allele carriers; a Ser to Gly substitution gives fewer receptors and loss of response) and variation in CYP2D6 affecting metabolic rate. An ultra-rapid metaboliser’s plasma concentration rises quickly and falls quickly, spending only a brief period in the optimal therapeutic range, whereas a poor metaboliser’s concentration rises and remains elevated at or above the range for much longer.
27. Patients with a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline/epinephrine used to treat an allergic reaction while they are taking a beta blocker.
28. Carvedilol is a non-selective adrenergic antagonist blocking ${\alpha }_1$, ${\beta }_1$ and ${\beta }_2$ receptors. Its beta blockade has negative chronotropic and negative inotropic effects by blocking catecholamine action at cardiac receptors; it has some antioxidant effects, inhibiting lipid peroxidation of cell membranes and suppressing reactive oxygen species formation; it is lipid soluble and depends on hepatic rather than renal clearance. It is indicated in angina, heart failure including left ventricular dysfunction, and hypertension as an add-on with other interventions to improve cardiac function in the face of increased sympathetic discharge to the heart.
29. Beta blockade helps the failing heart by reducing adrenergic workload, and metoprolol and carvedilol are the agents named as effective in heart failure. Asthma makes non-selective agents (propranolol, and at high dose any agent, since high doses reduce selectivity and allow ${\beta }_1$ blockers to act on ${\beta }_2$) hazardous because of ${\beta }_2$-mediated bronchospasm, so non-selective blockers should be avoided in asthma and COPD. For the hypertension component, first and second generation agents lower BP without vasodilation and worsen lipids, so they are not first line; carvedilol adds ${\alpha }_1$ blockade giving vasodilation with no reflex tachycardia and an improved lipid profile, which is why it may be indicated in primary hypertension, but it is a non-selective beta blocker and so carries the ${\beta }_2$ bronchospasm concern. The lecture does not resolve the resulting trade-off for this combination of conditions [slide does not elaborate].