Beta-blockers

This chapter deals with beta-blockers, and all the drugs with mixed antisympathetic effects which we tend to group with β-receptor antagonists. It is probably relevant to Section G7(ii) of the 2023 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of anti-hypertensive drugs". This topic has appeared several times in the past papers, with the questions taking on a predictable compare-em-up character. Specifically, metoprolol esmolol and carvedilol have all been singled out as important to critical care. In addition to these, the chapter covers a couple of others (atenolol, bisoprolol, nebivolol, labetalol) because they get a fair amount of use and are, therefore, worth knowing something about. Other drugs properly belonging to this class were omitted in some sort of arbitrary and unscientific process emblematic of the author's undisciplined mind, where they were viewed as either too boring (timolol, eye drops, erh) or better suited to the antiarrhythmic section (sotalol).

Anyway, the past exam content that is relevant here consists of the following SAQs:

• Question 12 from the second paper of 2023 (metoprolol, briefly)
• Question 5 from the first paper of 2022 (labetalol vs. esmolol)
• Question 14 from the second paper of 2019 (compare metoprolol and esmolol)
• Question 10 from the first paper of 2013 (carvedilol and spironolactone, weirdly)
• Question 4(p.2) from the first paper of 2010 (metoprolol and GTN)

These questions lend themselves to a tabulated format, but unfortunately there are too many drugs on the list to make a neat table. So, instead, the summary of the class is offered here. 

Beta-Blockers: Class Rules and their Exceptions

Domain	Rule	Exceptions
Administration & absorption	All beta-blockers are enterally administered	Esmolol
	All beta blockers have great GI absopriton	Esmolol  Atenolol
Distribution	Most of these drugs have a relatively large volume of distribution, and are highly protein-bound	Atenolol
Solubility	Most of these drugs are highly lipid-soluble	Esmolol Atenolol
Metabolism	All beta blockers undergo extensive hepatic metabolism, except...	Atenolol Esmolol
Clearance	None are dependent on renal excretion, except	Atenolol Sotalol
Mechanism of action	By binding to Gs-protein coupled β1 receptors, block cAMP synthesis and thus decrease intracellular calcium concentration, thereby decreasing contractility Decrease automatic self-depolarisation by affecting cAMP-sensitive If current in pacemaker cells  Some also have: α1 effects: afterload reduction, vasodilation (eg. carvedilol, labetalol) Membrane-stabilising (sodium channel blocker) effect, eg. propanolol Instrinsic sympathomimetic activity (eg. acetbutalol)
Clinical effects	β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolic coronary fillng, and decreased arrhythmogenicity. β2 effects: increased peripheral vascular resistance, bronchospasm, decreased insulin release, increased bladder and uterine tone

This generic information should be enough to claim a  workmanlike familiarity with the pharmacology of beta-blockers in general. Unfortunately, it appears that the college wanted an in-depth understanding of specific selected drugs. In their comments on Question 10 from the first paper of 2013, CICM examiners hectored the trainees for listing "class specific information  about beta blockers rather than demonstrating an understanding of carvedilol`s particular properties." Thus, the tabulated particular properties of the three drugs from past exam questions are also offered here.

Name	Metoprolol	Carvedilol	Esmolol
Class	Beta blocker	Beta blocker	Beta blocker
Chemistry	aryloxypropanolamine	aryloxypropanolamine	aryloxypropanolamine
Routes of administration	Oral or IV	Oral	IV
Absorption	50% oral bioavailability	25-35% oral bioavailability	0% oral bioavailability
Solubility	pKa 9.7, poor lipid solubility	pKa 8.77, good lipid solubility	pKa 9.5, minimal lipid solubility
Distribution	VOD 2.8-4.8 L/kg; only 12% protein bound	VOD 2 L/kg; 95% protein bound	VOD 3.4 L/kg; 60% protein bound
Target receptor	Selective β1 receptor blocker	Nonselective β1 and β2 receptor blocker, with some anti-α1 effects; also some sodium channel blocker (membrane stabilising) effects	Highly selective β1 receptor blocker
Metabolism	Mainly hepatic clearance	Mainly hepatic clearance	Rapidly metabolised in blood by hydrolysis of methyl ester linkage
Elimination	minimal renal excretion; half-life 3-4 hrs	minimal renal excretion; half-life 7-10 hrs	minimal renal excretion; half-life 9 min
Time course of action	12-24 hrs	12-24 hrs	Rapid onset and offset of effect
Mechanism of action	By binding to Gs-protein coupled β1 receptors, blocks cAMP synthesis	By binding to Gs-protein coupled β1 and β2 receptors, blocks cAMP synthesis	By binding to Gs-protein coupled β1 receptors, blocks cAMP synthesis
Clinical effects	β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolic coronary filling, and decreased arrhythmogenicity.	β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolic coronary filling, and decreased arrhythmogenicity. β2 effects: increased peripheral vascular resistance, bronchospasm, decreased insulin release, increased bladder and uterine tone α1 effects: afterload reduction, vasodilation Membrane-stabilising (sodium channel blocker) effect	β1 effects: decreased heart rate, decreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolic coronary filling, and decreased arrhythmogenicity.
Single best reference for further information	Oliver et al (2019)	Oliver et al (2019)	Oliver et al (2019)

Oliver et al. (2019) offer an excellent (free) class overview and discuss mechanisms of action. Pharmacokinetics are well covered by Johnsson & Regårdh (1976), McDevitt (1987) and Kendall (1997). In short, these drugs are well-reported and there is no shortage of peer-reviewed material; rather the bigger difficulty was sorting the abundance of data into an easily digestible summary.  Cruickshank (2007) is also excellent for a quick summary of the accepted beneficial effects.

Available beta-blockers

This class of drugs suffers from an overabundance of members. Every man and his dog seem to have brought a beta-blocker to the drug approval authorities at one stage or another. Of these, the following table is a non-exhaustive list, trimmed only by the author's self-interest. 

Beta-blockers,
Arrayed by their year of Market Availability

Drug	Year of commercial availability
Pronethalol	1962 (the first beta-blocker)
Propanolol	1965
Atenolol	1976
Labetalol	1977
Metoprolol	1982
Bisoprolol	1986
Esmolol	1987
Carvedilol	1995
Nebivolol	1997

In case one ever needs to classify these, there is in fact a formal classification system available, which is purely functional in nature. This comes from a number of sources, of which the most authoritative is probably the ESC consensus statement (López-Sendó et al, 2004). It groups the drugs by their selectivity for various receptors:

• Non-selective
  • Propanolol
  • Sotalol
• β₁-selective
  • Atenolol
  • Metoprolol
  • Bisoprolol
  • Nebivolol
  • Esmolol
• Combined α- and β-blocker effect
  • Carvedilol
  • Labetalol

This is reasonably simple to remember, and accurate enough for government work. In case detail and precision are required, Oliver et al (2019) have a nice table (their Table 1) where even receptor activity (pK_D) is listed. There are other classification systems as well, all of which seem to have been required for Question 14 from the second paper of 2019. One could also rank these drugs according to how well they block sodium channels, or according to the presence of intrinsic sympathomimetic activity (ISA), which some of them have. Thus:

Three Different Classification of Beta-blockers

According to selectivity	According to membrane stabilising effects	According to intrinsic sympathomimetic activity
Non-selective Propanolol Sotalol β1-selective Atenolol Metoprolol Bisoprolol Nebivolol Esmolol Combined α- and β-blocker effect Carvedilol Labetalol	Stabilising Propanolol Carvedilol Labetalol Non-stabilising Atenolol Bisoprolol Nebivolol Esmolol Metoprolol Sotalol	ISA Labetalol Acebutolol Pindolol Non-ISA Propanolol Atenolol Metoprolol Bisoprolol Nebivolol Esmolol Sotalol Carvedilol

Chemical structure and structure-function relationships

All beta-blockers are basically just derivative variations on one mother sauce recipe, which is the aryloxypropanolamine molecule. From this elemental material, all others are elaborated by the adding of various side chains and extra aromatic rings. Additionally, the suffix "-olol" takes its origin from these substances, supposedly taken from the propan-ol and ethan-ol elements. Following this dangerously overstretched metaphor, the Escoffier of beta blocker chemistry appears to be Sir James Black, who went on to receive the Nobel Prize in Medicine for his work on the development of propanolol.

The best resource for these structure and function relationships actually ended up being an ageing textbook on pharmacology by Gringauz (1997), where beta-blockers are discussed in much better detail (and with more useful detail) than any modern text. Much can be said here, but the most clinically important feature of these drugs (their selectivity) boils down to this:

In short, it appears that most of the selectivity is determined whether the side-chain of the aryl ring is in the -para, -meta or -ortho position. The molecule used here is esmolol, and it has a sidechain in para-position, which makes it highly cardioselective. There are of course many other structural elements which play a major role in the way these drugs are used and administered (eg. hydrophilic side chains which determine lipophilicity, or the features which determine hepatic metabolism), but those are probably not related to their function, i.e. how they interact with their drug target. 

Routes of administration and GI absorption

The general class rule for basically all beta-blockers is relatively poor oral bioavailability. Most of them absorb well but are defenceless against liver enzymes. The upshot of this is the much lower dose used for IV administration for drugs such as metoprolol, which are available as both oral and IV formulations.

Bioavailability of Beta Blockers

Drug	Available routes	GI absorption	Bioavailability	pKa
Propanolol	Oral	> 95%	30%	9.5
Atenolol	Oral	~ 50%	45-55%	9.6
Labetalol	Oral or IV	> 90%	25%	9.3
Metoprolol	Oral or IV	> 95%	50%	9.7
Bisoprolol	Oral	> 90%	90%	9.5
Esmolol	IV	0%	0%	9.5
Carvedilol	Oral	> 90%	25-35%	8.8
Nebivolol	Oral	> 90%	12-96%	8.1

So, the main exception to the rule is esmolol, which is only available as an IV drug. Of the rest, the only standout actor is nebivolol, which has excellent bioavailability in poor CYP2D6 metabolizers (96%), but extremely poor bioavailability (12%) in everybody else. Remarkably, somehow we are not experiencing an epidemic of catastrophic nebivolol toxicity among the slow metabolisers, and "no significant difference has been found between the two profiles in terms of safety and efficacy" (Coats & Jain, 2017).

Solubility and protein binding

The lipid solubility of beta-blockers is a determinant of several important features, not the least of which being their side-effects and hepatic metabolism. Lipid solubility is usually expressed as the partition between an organic solvent and an aqueous solvent, as was done here (parroting McDevitt, 1987). Unfortunately,  objective data on this was not available for each agent, and under some circumstances, one has to make do with vague statements (like "this drug is highly lipid-soluble") from PI documents. 

Solubility and Protein Binding of Beta Blockers

Drug	Lipid solubility	Protein binding
Propanolol	20.2 (highest lipid solubility among β-blockers)	93%
Atenolol	0.015	3%
Labetalol	lipid soluble	50%
Metoprolol	0.98	12%
Bisoprolol	4.8	30%
Esmolol	very poor lipid solubility	60%
Carvedilol	highly lipid soluble	95%
Nebivolol	highly lipid soluble	98%

Lipophilicity has various important implications for the properties of these agents (Cruickshanks, 1980).  In short, higher lipophilicity leads to:

• better GI absorption (eg. the absorption of atenolol is usually incomplete, only 50%)
• a shorter plasma half-life (mainly due to rapid distribution)
• Greater protein binding (which means less predictable pharmacokinetics during critical illness)
• higher tissue penetration (eg. the most lipid-soluble beta-blocker is propanolol, which means it penetrates the blood-brain barrier most readily (and it is debated whether this characteristic also promotes more side effects)

Distribution, metabolism and elimination

Basically, they are all reasonably widely distributed and dependent to a considerable extent upon hepatic metabolism,  with the exception of atenolol which is confined basically to body water, and which is eliminated by the kidneys in a totally unchanged form.

Distribution, Metabolism and Elimination of Beta Blockers

Drug	VOD	Hepatic metabolism	Renal excretion (%)
Propanolol	4 L/kg	Mainly hepatic clearance	minimal
Atenolol	0.3-0.6 L/kg	0%	100%
Labetalol	3-16 L/kg	Mainly hepatic clearance	minimal
Metoprolol	2.8-4.8 L/kg	Mainly hepatic clearance	minimal
Bisoprolol	3.5 L/kg	50%	50%
Esmolol	3.4 L/kg	Mainly hepatic clearance	minimal
Carvedilol	2 L/kg	Mainly hepatic clearance	minimal
Nebivolol	11.2 L/kg	Mainly hepatic clearance	minimal

This has clinical implications, elaborated further by Borchard (1990):

• You'd have to adjust the dose of atenolol (and sotalol) to compensate for impaired renal function. Which realistically means that you would probably just choose essentially any other beta-blocker, because...
• The rest of the beta-blockers are mainly metabolised by the liver, into inactive metabolites.

Half life and duration of effect

Unless otherwise specified, these data come from Feeley et al (1983). The most important take-home message here is the complete lack of correlation between the plasma elimination half-life and the duration of effect, which for most of these drugs is much longer. For example, Johannson et al (1980) found that the clinical effects of metoprolol and propanolol were still essentially the same at 24 hours after the last dose. 

Half-Life of Beta Blockers

Drug	Half life
Propanolol	2-6 hrs
Atenolol	6-9  hrs
Labetalol	3-4  hrs
Metoprolol	3-4  hrs
Bisoprolol	9-12 hrs
Esmolol	9 min
Carvedilol	7-10 hrs
Nebivolol	10-30 hrs

Again, esmolol is a dramatic exception, in that its half-life in the blood is approximately 9 minutes.

Molecular drug target

All of these drugs bind to the β₁ and β₂ receptors with varying degrees of affinity. The effects of activating catecholamine receptors is detailed elsewhere, and so here it will suffice to summarise by saying that these are all  G_s-protein coupled receptors. They normally bind catecholamines such as adrenaline and noradrenaline, which increases the synthesis of cAMP and produce downstream effects (like speeding up intrinsic pacemaker tissue or increasing the contractility of cardiac myocytes). Ergo, beta-blockade decreases cAMP concentration and counteracts all of these downstream effects.

Each mentioned beta-blocker has a different affinity for the different classes of receptor, which is usually expressed as a dissociation constant (K_d).  As you might recall, K_d is the rate constant of dissociation at equilibrium, defined as the ratio k_off / k_on; and so when K_d is high, it means that a large concentration of the drug is required to occupy 50% of the receptors, i.e. the drug and the receptor have a low affinity for one another. Confusingly, here are some ^-log(pK_d) values from Oliver et al (2019), where the higher number means a higher affinity.

β-receptor Affinities of β-Blockers

Drug	β1 receptor affinity	β2 receptor affinity	Selectivity ratio
Propanolol	8.16	8.44	0.52
Atenolol	6.41	5.09	20.89
Labetalol	7.63	8.03	0.4
Metoprolol	7.26	5.49	58.88
Bisoprolol	7.43	5.42	102.33
Esmolol	6.94	5.20	52.48
Carvedilol	8.75	8.96	0.62
Nebivolol	8.79	6.65	138.04

Now, these are base 10 log(K_d) values, and so the better value to look at would be the selectivity ratio, as that probably makes more intuitive sense. The reader is reminded that the original article did not present these values, i.e. the author calculated them himself, with his own puny maths powers, which may have resulted in a factor-of-ten error (or worse). In short, don't quote that column in your exam answers. If correct, it represents the ratio of β₁ to β₂ affinity. In other words, where the selectivity ratio of propanolol is 0.5, it means it has about 50% less affinity for the β₁ receptor than for β₂.  The same sort of low sub-1.0 values are seen for the other "non-selective" beta-blockers, such as labetalol and carvedilol. In contrast. bisoprolol has a ratio of 102.33 which means it is about 100 times more selective for the β₁ receptor. As you can see, nebivolol and bisoprolol have some of the highest cardioselectivity among these drugs. Additionally, you can use the ^-log(pK_d) values to compare between drugs; for instance, metoprolol with its ^-log(pK_d) value of 7.26 has about 34 times less affinity for the β₁ receptor than does carvedilol (8.75). 

Interestingly (and unsurprisingly) minor variations in how you test these receptor-ligand interactions will give you wildly different values, eg. Oliver et al (2019),  Baker (2005) and Baker (2017) all give completely different selectivity ratios. It does not help that some studies are in humans, and some in rats. The esmolol data in the table above appears to have originated from guinea pig studies. 

Intrinsic sympathomimetic activity of β-blockers

To make things more complicated,  some beta-blockers have intrinsic sympathomimetic activity, i.e. they act as agonists or partial agonists. There are many such drugs, but none of them made the exclusive list in this chapter, as they are either ancient, not available in Australia, or presented exclusively in the form of eyedrops. In case a list is required for some reason, here is one extracted from a table in Feeley et al (1983):

• Oxprenolol
• Pindolol
• Timolol
• Acebutolol
• Practolol

Nebivolol is apparently also a partial β₂-agonist (Erickson et al, 2013), which adds to its positive vasodilatory afterload-reducing effects, and probably makes it more attractive to patients who are prone to bronchospasm (or who have severe peripheral vascular disease). Additionally, some of these agents have some anti-α effects, which give them afterload reducing properties. There are really two agents which fall into this category, those being labetalol and carvedilol. Coming from the perspective of "what do I really need to know about this", Wong et al (2015) report that these drugs are still much better as beta-blockers than they are as alpha-blockers, i.e. by the time you start seeing a real measurable drop in blood pressure due to vasodilation, your β₁ receptor effects are already quite prominent, i.e the patient is so bradycardic that you can't bring yourself to increase the dose any further. 

One may ask, how significant is this intrinsic sympathomimetic effect? Kostis et al (1981) asked the same question, in an era when one was able to prescribe pindolol to patients with angina as an oral agent. It appears that this effect mostly manifests as the blocker's failure to drop the resting heart rate, where "pure" blockers tend to produce a bradycardia.  "It is therefore possible for a β-blocker to
possess enough ISA to counterbalance the depressant effects of β-blockade at rest without losing its therapeutic efficacy in exercise-induced angina", the authors suggested. Also, perhaps the effect of bronchoconstriction may be attenuated, because the continued low-grade β-stimulation should continue to exert some protective bronchodilating effect.

But is any of this meaningful? The only β-blocker with any ISA in current systemic use is labetalol, but its game is weak. Tadepalli & Novak (1986) infused it into cats who were marinaded in reserpine, and determined that it, with 1mg/kg IV, achieved the same as 30 μg/kg of pindolol, i.e. it was 33 times less potent. This means that its ISA effect is minimal even at massive doses, and in fact clinicians reporting cases of labetalol overdose complain about the preposterously large doses of adrenaline that are required to overcome the competitive blocker effect. 

Membrane stabilising effects of β-blockers

Some beta-blockers have an intrinsic "membrane stabilising" effect which is completely unrelated to their beta-blocking properties. A surprisingly large number of them have this property, according to Aronson (2008). Perhaps by coincidence, they are also the non-selective agents, propanolol and carvedilol. Metoprolol and labetalol are also listed there, but unfortunately Aronson decided to go with the highly uninformative "pluses and minuses" version of data visualisation, and these drugs are tagged with an ambiguous ±, which, under the table of agents, is explained as "it is not clear whether it does" (i.e. the author could not make up his mind as to whether metoprolol and labetalol have this property).  Unfortunately, there appears to have been very little attention to this subject in recent history. The phrase "membrane stabilising effects" seems to be disappearing from the lexicon. Historically, it was believed that these effects were due to some direct activity of the agents on the lipid bilayer, as Imai (1991) pointed out that this effect was proportional to their lipid solubility:

This graph lines up the concentration of the drug required to produce local anaesthetic effect with the change in surface tension of a buffer solution, which was used as a surrogate for lipid solubility. As one can see, the most stabilising agents are clustered close to the left lower corner of the chart. Perhaps it would be possible, and even desirable,  to compile a more modern table of membrane stabilising beta blockers?

• Propanolol is firmly in this territory, but its "membrane stabilising" properties were ultimately well explained by the discovery of its sodium channel blocker effects. The same study investigated metoprolol and nadolol, finding they had no effect on Na_V1.5, which suggests that Aronson's ambiguous ± should really be a flat - .
• Carvedilol was not released for another four years and is not plotted by Imai,  but Naccarelli & Lukas (2005) clearly list Class IA activity among its properties and Strein et al (1987) remark that the magnitude of this effects "is approximately the same as that of propranolol". 
• Labetalol is enough of a sodium channel blocker that Hord et al (2003) were able to use it successfully as a part of a Bier block, 
• The other agents in the graph are alprenolol and oxprenolol, which are no longer on the market, and "KL 255" which later became known as bupranolol. This stuff was apparently marketed to humans ("Betadrenol",  by Desma) and had enough propanololish membrane stabilising properties that it could be used with equal effect to benzodiazepines in the management of anxiety. It quietly disappeared from the market before anybody reading this was ever born. Kö 592, on the other hand, appears to have never left the laboratory. 

The most important thing to remember here is that none of these agents have a clinically relevant sodium channel blocker effect within their normal dose range. In other words, you would only ever see these effects in the context of a severe overdose.

Mechanism of action

Effect on heart rate: The lowering of heart rate is probably the most therapeutically important effect of beta-blockade, so it makes sense to know a little bit about the mechanism of this. In short, it is the specific effect of blocking the  β₁ receptors on the duration of the action potential of pacemaker cells.  Noma (1996) explains these mechanisms very well, and they are covered to some minor extent in the chapter dealing with spontaneous cardiac electrical activity. Catecholamines influence pacemaker cell depolarisation by altering the "funny current", If.  This is the constant inward sodium / outward potassium flow which occurs via HCN channels (hyperpolarization-activated, cyclic-nucleotide–gated), which are controlled by intracellular cAMP concentrations (hence the "cyclic-nucleotide–gated" bit).

So: decrease the concentration of cAMP by blocking the  β₁ receptor, and the If current slows down, making the pacemaker cells depolarise less frequently. One might think that somebody at some stage might have recorded such a slowed action potential, but no - wherever you see this mentioned, they generally reproduce this image from Difrancesco (1993), which demonstrates a rate increase with a nonselective β₁ receptor agonist (isoprenaline).

Effect on contractility: The inotropic effects of systemic catecholamines and of the sympathetic nervous system is mediated by the β-1 receptors, which are G_s-protein coupled receptors. The increase in cyclic AMP which results from their activation increases the activity of protein kinase A, which in turn phosphorylates calcium channels. Calcium influx ensues, and with more calcium available intracellularly, the cardiac contractility increases. Thus, by dampening this cAMP-mediated calcium orgy,  conventional wisdom suggests that beta-blockers should probably reduce cardiac contractility.

They probably do, but not by very much, and the effect tends to be obscured by their effect on the heart rate, which typically drops - resulting in increased LV diastolic filling time, a higher end-diastolic volume, and therefore higher contractility. To eliminate this influence, Bourdillon et al (1979) gave healthy volunteers about 0.1mg/kg of IV metoprolol while they were being atrially paced. They observed a 10% fall in mean left ventricular dP/dT, which is a reasonable measure of contractility.

Effect on blood pressure:  Yes, these drugs are grouped with antihypertensives, and yes, as at least one reader (Tejas Jade) has pointed out in a personal communication, this makes absolutely no sense. Consider: a decrease in cardiac output due to lower stroke volume and heart rate would usually lead to a compensatory baroreceptor-mediated increase in arteriolar resistance. Moreover β-2 receptor antagonism should actually lead to peripheral vasoconstriction in muscle vascular beds.

So how do these drugs even do the thing we expect from them? The antihypertensive effect remains poorly explained. Gorre & Vandekerckhove (2010) maeke mention of a "incompletely understood late lowering of peripheral vascular tone, minutes to hours after oral intake", which they hold responsible for the blood pressure drop. In their paper it is attributed to either a decrease in circulating noradrenaline levels due to presynaptic β-2 receptor antagonism (which would not explain the antihypertensive effects of highly selective β-1 receptor antagonists), or to an effect on the adrenal medulla which results in decreased renin and catecholamine release. No references are offered,  but these speculations resemble the content and arguments of a much earlier paper, by Smits & Struyker-Boudier (1982), where the authors attempted to explain the mechanism in these exact terms. Their idea was that the late fall in peripheral vascular resistance was due to the adaptation of the baroreceptors and that their other antihypertensive effects were due to reduced renal tubular reabsorption of sodium or the decrease in angiotensin levels or some intrinsic nitric oxide synthase effects. To demonstrate how little we have advanced in this field, to list the possible mechanisms of the antihypertensive effects of β-blockers, William Frishman (2011) referred to his own publication from 1988:

 Proposed Mechanisms to Explain the Antihypertensive Actions
of β‐Blockers

1.	Reduction in heart rate and cardiac output
2.	Central nervous system inhibitor effect
3.	Inhibition of renin release
4.	Reduction in venous return and plasma volume
5.	Reduction in peripheral vascular resistance (intrinsic sympathomimetic activity drugs, α/β‐blockers, potentiation of nitric oxide)
6.	Improvement in vascular compliance
7.	Resetting of baroreceptor levels
8.	Effects on prejunctional β‐receptors: reduction in norepinephrine release
9.	Attenuation of pressor response to catecholamines with exercise and stress

In short, yes β-blockers do produce a reasonably predictable decrease in BP. However, it is not massive. For example, Sannerstedt & Wasir (1977) gave 0.15mg/kg of metoprolol to hypertensive volunteers, and found their resting systolic dropped from about 150m mmHg to about 140 mmHg. In the abovementioned paper by Bourdillon et al (1979), there was little change in blood pressure while the patients were atrially paced.

Effect on myocardial oxygen consumption: So, now that you are beta-blocked,  your heart rate is lower, your afterload is (slightly) reduced, and your contractility is decreased. All the main determinants of myocardial oxygen demand are therefore controlled. In addition, you now get a longer diastolic coronary filling time. In short, you should expect beta-blockers to have a highly positive effect in any scenario where myocardial oxygen supply is stressed. That was indeed illustrated by such studies as MIAMI (metoprolol) and ISIS-1 (atenolol), which demonstrated a 13-15% reduction in in-hospital cardiovascular mortality for patients treated with a beta-blocker after their acute MI.

Effect on arrythmogenicity: beta-blockers act as antiarrhythmics, which is a topic for a whole separate discussion.  Reiter & Reiffel (1998) listed the following factors as contributing to these effects:

• Decrease in the automaticity of ectopic pacemakers (thus, less arrhythmogenesis)
• Prolonged refractory period for all excitable myocardial tissues. (thus, reduced propagation of malignant arrhythmias)
• Decrease in ventricular fibrillation threshold
• Prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects
• Reversal of ischaemia/reperfusion induced proarrhythmic tendency by their effects on myocardial oxygen supply and demand

Clinical effects

In summary, beta blocker effects are:

• β₁ receptor blockade
  • slows sinoatrial node
  • decelerates ectopic pacemakers
  • decreases contractility of the heart
  • decreases lusitropy
  • decreases renin release by the kidney
• β₂ receptor blockade
  • Opposes the relaxation of vascular smooth muscle in skeletal muscle arterioles, and therefore increases systemic vascular resistance
  • Opposes the relaxation of bronchiolar smooth muscle
  • Contracts gut wall smooth muscle
  • Contracts the bladder wall
  • Contracts the pregnant uterus
  • Decreases gluconeogenesis and glycogenolysis in the liver
  • Decreases insulin release