Beta Adrenergic Blockers

Question 1

What act as antagonists on your beta receptors,
some are nonspecific?

Answer 1

BETA BLOCKERS OR BETA ADRENERGIC ANTAGONISTS

Question 2

There are two types of beta receptors:

Answer 2

beta 1 and beta 2

Some are specific and act on beta 1 which is more significant for the discussion today and some act on beta 2

Question 3

What are the 2 of the most common beta-blockers prescribed after an acute MI?

Answer 3

Metoprolol and Carvedilol

Question 4

What does Metoprolol and Carvedilol do?

Answer 4

Reduced heart rate, blood pressure, and improve
blood flow

Question 5

Outcomes with Carvedilol may be superior to Metoprolol only in patients with what?

Answer 5

dysfunction in the left ventricles, such as those with left ventricular ejection fraction (LVEF) of 40% or less

Question 6

Beta-blockers for the treatment of hypertension

Answer 6

table 1 on page 1 lecture

Question 7

Cardioselctive means:

Answer 7

their effects is selectively on the heart, such as atenolol, bisoprolol, and metoprolol

Question 8

What act both on beta 1 and beta 2 receptors,
such as nadolol, propranolol, and timolol?

Answer 8

Nonselective

Question 9

What are beta blockers which contain intrinsic sympathomimetic activity?

Answer 9

Actebutolol
Penbutolol
Pindolol

Question 10

Newer beta blockers are known as third generation beta blockers with additional cardiovascular actions?

○ Some of them have anti inflammatory vasodilatory effects as well as other benefits

Answer 10

Nonselective Vasodilators
- Carvedilol
- Labetalol

Beta-1 Selective Vasodilators
- Betaxolol
- Nebivilol

Question 11

BB

Answer 11

● Shown to reduce the risk of cardiovascular mortality
○ Incidence of cardiovascular events in high risk
patients with HPN who have other risk factors such as:
> Coronary artery disease (CAD), previous myocardial infarction (MI), heart failure (HF), diabetes mellitus (DM)
> These patients with other cardiovascular risk
factors a cardio selective beta blocker is preferred when they have hypertension
○ For HPN-cardioselective beta blocker is preferred

● NOTE: Remember that all the beta blockers have the suffix -olol, calcium channel blockers have -dipine except for two, and angiotensin receptor blockers have -tan (such as losartan).

Question 12

1ST GENERATION (NON-SELECTIVE)

Answer 12

● Propranolol, Timolol, Pindolol, Nadolol, Penbutolol, Sotalol, Levobunolol, Metipranolol

● Nonselective: they act on both 𝛃1 and 𝛃2 receptors. These drugs are not good for patients with asthma or COPD because they will block the 𝛃2 receptors found in the lungs/respiratory tracts causing vasoconstriction

Question 13

2ND GENERATION (B1 SELECTIVE)

Answer 13

● Atenolol, Esmolol, Metoprolol, Acebutolol, Bisoprolol
● 𝛃1 selective drugs are the preferred drugs for patients with COPD, asthma, Raynaud’s disease.

Question 14

3RD GENERATION Β-BLOCKERS

Answer 14

● nonselective + 𝛂1 blockade: Carvedilol, Labetalol,
● 𝛃1 selective + 𝛂1 blockade: Betaxolol, Celiprolol
● Others: Nipradilol, Bupindolol, Bevantolol, Telisolol
● PROPANOLOL: prototype

Question 15

β-ADRENERGIC RECEPTOR ANTAGONISTS
(β-BLOCKERS)

Answer 15

● ANS: sympath/psympath NS = regulate organ activities in response to stress

● Sympathetic stimulants:
○ Nerve terminals stimulate adrenal medulla to release norepinephrine and epinephrine (main agents that stimulate the sympathetic system (fight or flight response).
○ Norepinephrine activates adrenoRs at post synapses
○ Epinephrine transported by blood to target tissues producing predominantly inotropy, chronotropy, vasoconstriction leading to increased blood pressure.
○ It will make the heart pump faster and it will also
increase the pumping of the heart, so you will now
have an increase in your blood pressure.
○ So that is why when you are under stress, or in
extreme cases when you are under pressure, your
adrenaline will kick up, the sympathetic nervous
system kicks in and your blood pressure will increase
○ When you get mad or are under extreme stress you can do particularly anything superhuman

● 𝛃1 > 𝛃2 = ↑HR, contraction of atrium & ventricles & conduction velocity

● 𝛃2 Receptors = smooth mm (bv, GIT, bronchial, GUT) relaxation

● 𝛂1 > 𝛂2 = contraction of BV smooth mm
○ The activation of your B1 receptors more than you B2 receptors will increase your heart rate, as well as contraction of atrium and ventricles and conduction velocity of your heart
○ Activation of your B2 receptors, this is now the
problem with some beta blockers because it
produces smooth muscle relaxation, and you have to remember that your smooth muscle receptors is found in your blood vessels, in your GI tract, in your bronchial tree, and genitourinary tracts. So what does that mean? So if you block the B2 receptors you will have a problem especially those patients who are prone to bronchoconstriction like asthmatics and those who have COPD.
○ It will also stimulate your a1 receptors more than
your a2. And your a1 receptor stimulation will cause contraction of your blood vessel smooth muscle. All in all if you block your B1 and A1 receptors, it will lead to relaxation and slowing down of heart rate leading to a decrease in your blood pressure. So that is the effect of your beta blockers
○ Generally your beta blockers will inhibit cardiac
functions. What are these cardiac functions?
■ It will slow down your SA node and this is
responsible for initiating the heartbeat, so your
heartbeat will decrease.
■ It will increase your AV node refractoriness,
and this slows down the ventricular response
to your atrial fibrillation, and atrial tachycardia,
so it will slow down the conduction
■ For your arteries, it will dilate them which
contributes to the lowering of your blood
pressure.
■ It will also reduce the contractility of your
ventricles, and this will reduce your myocardial
contractility as well as your cardiac output, and
reduce ventricular contractility of your
ventricular muscles.
■ Generally it will lead to a negative function of
your heart, so it slows down heart rate, slow
down conduction velocity so it will lead to a
decrease in blood pressure
○ Generally your beta blockers will inhibit cardiac
functions. What are these cardiac functions?
■ It will slow down your SA node and this is
responsible for initiating the heartbeat, so your
heartbeat will decrease.
■ It will increase your AV node refractoriness,
and this slows down the ventricular response
to your atrial fibrillation, and atrial tachycardia,
so it will slow down the conduction
■ For your arteries, it will dilate them which
contributes to the lowering of your blood
pressure.
■ It will also reduce the contractility of your
ventricles, and this will reduce your myocardial
contractility as well as your cardiac output, and
reduce ventricular contractility of your
ventricular muscles.
■ Generally it will lead to a negative function of
your heart, so it slows down heart rate, slow
down conduction velocity so it will lead to a
decrease in blood pressure

Question 16

MECHANISM OF ACTION of BB

Answer 16

● Block 𝛃-adrenergic receptors = ↓BP via mechanisms:
○ ↓myocardial contractility, ↓HR, ↓CO
○ Blocked 𝛃1 receptors at JG apparatus → no
SNS-induced renin release → ↓Angio II = ↓BP +
↓aldosterone secretion

■ Your beta blockers will decrease BP via decreasing contractility of the heart leading to a decrease in heart rate, decrease in cardiac output, and at the same time it will also block your beta 1 receptors at your JG apparatus in your kidneys.

■ So this will lead to the inhibition of your renin
release, decrease in angiotensin II, leading to a decrease in BP as well as a decrease in aldosterone secretion

● Other mechanisms in lowering BP:
○ Altered SNS control and CNS level
○ Altered baroreceptor sensitivity
○ Altered peripheral presynaptic 𝛃-adrenergic receptor function → ↓sympathetic vasoconstrictive nerve activity
○ ↑ PGI2 biosynthesis → vasodilation

■ There are also other mechanisms also where
beta blockers can lower your blood pressure

■ For example, it can alter your sympathetic
nervous system.

● Proposed mechanisms of 3rd generation contributing to vasodilatation:
○ Nitric oxide production
○ α1 receptor blockade
○ Ca2+ entry blockade
○ K+ channel opening leading to vasodilation
○ β2 receptor activation
○ Antioxidant activity

● 3rd generation with vasodilation properties:
○ NO2 production: Celiprolol, Nebivolol, Carteolol,
Bopindolol, Nipradolol
○ β2 receptor agonism: Celiprolol, Carteolol,
Bopindolol
○ α2 receptor agonism: Carvedilol, Bucindolol,
Bevantolol, Nipradilol, Labetalol
○ Calcium entry blockade: Carvedilol, Betaxolol,
Bevantolol
○ K+ channel opening:Tilisolol

● β blockers = competitive antagonists (meaning: to prevent binding of) of endogenous catechols (epinephrine and norepinephrine) and β agonists at β-adrenergic receptors

● Most β blockers are pure antagonists (without intrinsic sympathomimetic activity/ISA), but some are partial agonists (w/ ISA cause partial activation of receptors in the presence of ↑concentration of catechols or moderately activate receptors in the absence of endogenous agonists)

Question 17

PHARMACOLOGIC PROPERTIES OF BB

Answer 17

● Lipophilicity, selectivity for β receptors, presence of partial agonist activity (ISA), membrane stabilizing properties, block of α receptors, ability to produce vasodilation → important factors in β blocker efficacy

● Anti-hypertensive effect resides in antagonism of Beta 1 receptor

● Major side effect result from antagonism of Beta 2 receptors- peripheral vasoconstriction, bronchoconstriction, hypoglycemia

● (-) antihypertensive effect in normal subjects but ↓BP in hypertension or in patients with ↑SNS activity (stress or exercise)

● Nonselective β blockers → ↓BP primarily as a result of dec in CO

● Other β blockers → may ↓CO or ↓PVR to variable degrees, depending on cardiovascular selectivity and ISA

● Despite these differences, all β blocker are equally effective antiHPNs for mild to moderate HPN

● Severe HPN β blocker especially useful for preventing reflex tachycardia by direct vasodilators

● Rxtic efficacy of β blocker: undoubtedly attributed to adrenergic receptors blockade.

● Total antiHPN effect of β blocker is also contributed by β blockade in the brain, kidney & peripheral adrenal neurons

● Brain is unlikely to be the primary site of HPOT action of the drug since some blockers that fail to pass BBB are still effective antiHPN agents (Nadolol).

Question 18

● Also referred to as intrinsic sympathomimetic effect, this term is used particularly with β blocker that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (β blocker) and the concentration of the antagonized agent (usually
endogenous compound such as norepinephrine).

● Some β blockers (oxprenolol, pindolol, penbutolol, and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents can exert low-level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be
useful in individuals exhibiting excessive bradycardia with sustained β blocker therapy.

● Agents with ISA are not used in post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other β blockers in the management of angina and tachyarrhythmia.

Answer 18

INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA)

Question 19

SYMPATHOMIMETICS
● Classification: According to the source

Answer 19

■ Natural; Norepinephrine, Epinephrine, Dopamine

■ Synthetic, Isoproterenol,ephedrine,amphetamine

Question 20

SYMPATHOMIMETICS
● Classification: B-chemically

Answer 20

■ Catecholamines, Norepinephrine, Epinephrine, Dopamine and isoproterenol

■ Non catecholamines, ephedrine, amphetamine, tyramine

Question 21

DRUGS WITHOUT ISA (INTRINSIC SYMPATHOMIMETIC ACTIVITY)

Answer 21

● initial↓CO (cardiac output) + reflex-induced ↑PVR (peripheral vascular resistance) w/ no net change in blood pressure

○ In patients who respond with ↓BP → PVR returns to pre-therapeutic values in a few hours to days
○ Delayed fall in PVR in the face of a persistent
reduction - in CO = characteristic antihypertensive
effect of this type of β blockers

Question 22

DRUGS WITH ISA
(INTRINSIC SYMPATHOMIMETIC ACTIVITY)

Answer 22

● Can stimulate β receptors partially (in the absence of catechols) but ISA activity is inferior to that of a full agonist drug
○ milder ↓ in resting HR and CO
○ fall in BP correlates with ↓PVR below therapeutic levels; possibly due to stimulation of vascular β2
adrenergic receptors
○ ISA => counterproductive to desired antihypertensive response of β blockers but may be beneficial in preventing profound bradycardia
○ May be hazardous in post MI
○ Drugs with (+) ISA according to rank: Pindolol >
Carteolol > Celiprolol <-> Penbutolol <-> Acebutolol <-> Labetalol

Question 23

DRUGS WITH LOCAL ANESTHETIC AND MEMBRANE STABILIZING EFFECT INDEPENDENT OF β BLOCKADE

Answer 23

● Propranolol, Acebutolol, Carvedilol > > > Pindolol, Metoprolol, Metaxolol and Labetalol

● Renal blood flow:
○ acute reaction → decreased – especially with
nonselective agents → block both β1 and β2
receptors
○ chronic → rare renal dysfunction

● Effective: monotherapy, but often used as adjunct drugs with diuretics or vasodilators

● Acute administration of 1st generation blockers => ↓CO <→ increase PVR to maintain blood pressure (consequence of blocking both vascular β2 receptors and compensatory reflexes (ex. SNS activation) → activation of vascular α-receptors

● Chronic use of 1st generation blockers => total PVR returns to initial values or ↓ in hypertensive patients

● Ischemic Heart Disease (IHD) and MI
○ ↓frequency of angina attacks and improve exercise tolerance due to block of heart β receptors ↓cardiac work +↓O2 demand via slowing of HR
○ Propranolol, Timolol, Metoprolol
○ Relative contraindication: bradycardia, hypotension, moderate LV failure, shock, heart block, active airway disease

Other Indications
● Arrhythmias - supraventricular/ventricular
● Chronic Heart Failure: Metoprolol, Bisoprolol, Carvedilol

Therapeutic uses
● Dissecting aneurysms (lessens systolic BP)
● Hyperthyroidism (blocks adrenergic receptors and inhibits peripheral conversion of thyroxine to triiodothyronine)
● Glaucoma (reduce IOP secondary to reduced production of aqueous humor by ciliary body - Ex. Timolol ophthalmic solution. Caution: may be absorbed systematically)
● Migraine, anxiety “stage fright”, alcohol withdrawal
● Reduction of skeletal muscle tremor (d/t decreased SNS activity)
● Decreased portal venous pressure in liver cirrhosis, decrease bleeding of esophageal varices

Question 24

LIPOPHILIC BETA BLOCKERS

Answer 24

● Metoprolol, Bisoprolol, Carvedilol, Propranolol
● Greater antiarrhythmiac efficacy than hydrophilic compounds (Atenolol, Nadolol, Labetalol)
● Related to central mode of action

Question 25

NON-SUBTYPE-SELECTIVE Β-ADRENERGIC ANTAGONISTS

Answer 25

Propanolol
Nadolol
Timolol
Pinedolol
Labetalol
Carvediol

Question 26

● Interacts with β1 & β2 receptors with equal affinity

● Lack intrinsic sympathomimetic activity

● Does not block α-adrenergic receptors

● Highly lipophilic

● Almost completely absorbed after oral administration

● Great inter-individual variation in presystemic clearance by liver
○ Enormous variability in plasma concentration
○ Wide range of doses in terms of clinical efficacy

● Readily enters the CNS

● Clearance varies with
○ Hepatic blood flow
○ Liver disease
○ Administration of other drugs with hepatic
metabolism effects

● Therapeutic uses
○ Treatment of Hypertension and Angina
■ Initial Oral dose: 40-80 mg/day
■ Full BP response may not develop for several
weeks
■ Administration of IV propranolol for
management of life threatening arrhythmias or
to patients under anesthesia

Answer 26

Propanolol

Question 27

● Long-acting; equal affinity to β1 & β2 receptors
● Very soluble in water
● Not extensively metabolized
● Largely excreted intact in urine
● t½: 20 hours: administered once daily
● Dosage reduced in patients with renal failure

Answer 27

Nadolol

Question 28

● No intrinsic sympathomimetic activity
● Well-absorbed from GIT
● t ½ : 4 hours
● Excellent ocular hypotensive effects
● Excellent for use of patients with glaucoma

Answer 28

Timolol

Question 29

● Nonselective β-blocker with intrinsic sympathomimetic activity

● Produce smaller reduction in resting Heart rate and BP

● Preferred antihypertensive agent for patients with diminished cardiac reserves or propensity for bradycardia because of its sympathomimetic activity

● Almost completely absorbed after oral administration

● Moderately high Bioavailability

● t ½ : 4 hrs

Answer 29

Pindolol

Question 30

● Competitive antagonist at both α1 and β-adrenergic receptors

● Actions on both receptors contribute to fall in BP in patients with Hypertension

● Blockade to α1-receptor: relaxation of arterial smooth muscle

● β1- blockade: fall in BP ( blocking sympathetic stimulation of the heart) because of the negative chronotropic and ionotropic effects on the heart

● Oral form: Treatment of Chronic Hypertension

● IV form: Hypertensive emergencies

● Extensive first pass clearance

● Can be given to pregnant women but unfortunately not found in the Philippines

Answer 30

Labetalol

Question 31

● Non-subtype selective

● Antagonist of α1 receptors which leads to vasodilation

● Also has antioxidant activity

● Starting dose: 6.25 mg BID

Answer 31

Carvedilol

Question 32

● Acts only to block β1 but not on β2 receptors
● Can be given to patients with asthma or COPD
● It has a potent negative chronotropic and inotropic effect on the heart

Answer 32

Β1 - SELECTIVE ADRENERGIC ANTAGONISTS

Question 33

Β1 - SELECTIVE ADRENERGIC ANTAGONISTS

Answer 33

Metroprolol
Atenolol
Esmolol
Nebivolol

Question 34

● Devoid of intrinsic sympathetic activity

● Almost completely absorbed after oral administration

● Low bioavailability (40%)

● t1/2 = 3-4 hours

● Initial dose: 100 mg/day frequently given in 2 divided doses, may be given once daily (OD)

● Contraindicated for the treatment of acute myocardial infarction in patients with HR < 45 bpm, heart block > 1st degree (PR interval ≥ 0.24 seconds), systolic BP < 100mmHg or moderate to severe heart failure

Answer 34

Metroprolol

Question 35

● Commonly used antihypertensive

● Very hydrophilic

● Incompletely absorbed but most of absorbed dose reaches systemic circulation

● Excreted largely unchanged in urine

● Accumulates in patients with renal failure

● Initial dose: 50 mg/day

● If given together with a diuretic = effective in elderly patients with isolated systolic hypertension

Answer 35

Atenolol

Question 36

● Very short duration of action

● Administered IV

● It’s not given PO because of it’s very short half-life

● Used when β blockade of short duration is desired or in critically ill patients in whom adverse effects of bradycardia, heart failure or hypotension may necessitate rapid withdrawal of the drug

● Used in hypertensive emergencies, for example, you cannot guarantee the safety of giving your beta blocker to the patient or in areas where you don’t have any other medication present

● t1/2 = 8 minutes

● Peak hemodynamic effects = within 6-10 minutes of administration of LD

Answer 36

Esmolol

Question 37

● Selective for β1 adrenergic receptor
● Lacks intrinsic sympathomimetic activity and
membrane-stabilizing activity
● Has vasodilatory effects

Answer 37

Nebivolol

Question 38

Adverse Effects

Answer 38

● Most of these are due to its β2 receptor blockage

● Patients with COPD - if you give them nonselective β-blockers => it can trigger life threatening bronchospasm => you might end up with a dead patient

● CAUTION!!! Even with drugs that are β1 selective and β2 selective partial agonist. Might as well give another agent not β blockers

● Bronchial asthma - β2 block → bronchospasm

● If no other drug is available, give β1 selective or agents with intrinsic sympathomimetic activity = less likely bronchoconstriction

● Otherwise if you have agents other than β blockers, the patient is better off if you do not give a β blocker

● Cardiovascular system
○ May induce congestive heart failure in susceptible patients since the sympathetic nervous system provide critical support for the heart’s performance thus, β blockade may exacerbate heart failure in patients with acute myocardial infarction, compensated heart failure and cardiomegaly
○ So, if you block the sympathetic nervous system
(e.g., block epinephrine or norepinephrine), it can
exacerbate heart failure

● CAUTION in the use of these drugs!

● Normal response to β blockers: bradycardia because of the negative chronotropic and inotropic effects of the heart
○ CAUTION: AV conduction defects → induce
life-threatening bradyarrhythmias
○ Special CAUTION: patients on Verapamil
(Calcium-channel blocker; cardio-depressant) or
other antiarrhythmic agents → may impair SAN/AVN function

● May worsen peripheral vascular disease complain of cold extremities.

● CNS: The side effects are fatigue, insomnia, nightmares, depression
○ This is due to or Blamed on lipophilicity of drug (it will enter the Blood-Brain Barrier)

● In patients with pheochromocytoma, the beta-blockers are contraindicated especially when alpha-receptors blockers are used as a treatment.
○ E-secreting tumor → mediates vasoconstriction ← Rx: alpha-Rs blocker

● Withdrawal syndrome - After chronic treatment (Rx) → may involve upregulation of Beta-Receptors (𝛃Rs) treatment (Rx)
○ Taper dose before d/c, esp those w/short t½
(Propranolol & Metoprolol)
○ Note: If you discontinue the Rx abruptly and
the patient was using Rx For 6 months or more. Since it will increase the number/formation of Beta-Receptors in this patient. So what you have to do is to taper down the dose of Beta-Blocker beforediscontinuation.

● Hypoglycemic episodes - “x” (cause is unknown) - rate of recovery from hypoglycemia is slow.
○ If the patient is diabetic it may cause hypoglycemic episodes and lead to hypoglycemic shock since the rate of recovery from hypoglycemia is slow.
○ Alternative: B1 selective

● There may be rare rash, fever and allergy

● When taken with Verapamil (which is a calcium channel blocker), it can cause severe hypotension, bradycardia, heart failure and conduction abnormalities.
○ Never take these two drugs together

● Abrupt discontinuation is hazardous, especially with short t1/2 like propranolol and metoprolol due to up-regulation of B receptors. Need to do gradual tapering

Question 39

SELECTION OF A BETA - ADRENERGIC ANTAGONIST

Answer 39

● B1 - selective antagonists
○ In patients with bronchospasm, diabetes, peripheral vascular disease, Raynaud’s phenomenon (Ideally you do not give a beta blocker)
○ Patients with hypertension, occlusive peripheral
arterial disease, congestive heart failure
○ Give a B-blocker that dilates peripheral vasculature via A1 adrenergic blockade, selective b2-receptor partial agonism. (Choose one with a
sympathomimetic activity)

● Beta blockers
○ Highly preferred drugs for hypertensive patients with conditions such as MI, ischemic heart disease, or congestive heart failure