Beta Adrenergic Blockers Flashcards
What act as antagonists on your beta receptors,
some are nonspecific?
BETA BLOCKERS OR BETA ADRENERGIC ANTAGONISTS
There are two types of beta receptors:
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
What are the 2 of the most common beta-blockers prescribed after an acute MI?
Metoprolol and Carvedilol
What does Metoprolol and Carvedilol do?
Reduced heart rate, blood pressure, and improve
blood flow
Outcomes with Carvedilol may be superior to Metoprolol only in patients with what?
dysfunction in the left ventricles, such as those with left ventricular ejection fraction (LVEF) of 40% or less
Beta-blockers for the treatment of hypertension
table 1 on page 1 lecture
Cardioselctive means:
their effects is selectively on the heart, such as atenolol, bisoprolol, and metoprolol
What act both on beta 1 and beta 2 receptors,
such as nadolol, propranolol, and timolol?
Nonselective
What are beta blockers which contain intrinsic sympathomimetic activity?
Actebutolol
Penbutolol
Pindolol
Newer beta blockers are known as third generation beta blockers with additional cardiovascular actions?
β Some of them have anti inflammatory vasodilatory effects as well as other benefits
Nonselective Vasodilators
- Carvedilol
- Labetalol
Beta-1 Selective Vasodilators
- Betaxolol
- Nebivilol
BB
β Shown to reduce the risk of cardiovascular mortality
β 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
β For HPN-cardioselective beta blocker is preferred
β 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).
1ST GENERATION (NON-SELECTIVE)
β Propranolol, Timolol, Pindolol, Nadolol, Penbutolol, Sotalol, Levobunolol, Metipranolol
β Nonselective: they act on both π1 and π2 receptors. These drugs are not good for patients with asthma or COPD because they will block the π2 receptors found in the lungs/respiratory tracts causing vasoconstriction
2ND GENERATION (B1 SELECTIVE)
β Atenolol, Esmolol, Metoprolol, Acebutolol, Bisoprolol
β π1 selective drugs are the preferred drugs for patients with COPD, asthma, Raynaudβs disease.
3RD GENERATION Ξ-BLOCKERS
β nonselective + π1 blockade: Carvedilol, Labetalol,
β π1 selective + π1 blockade: Betaxolol, Celiprolol
β Others: Nipradilol, Bupindolol, Bevantolol, Telisolol
β PROPANOLOL: prototype
Ξ²-ADRENERGIC RECEPTOR ANTAGONISTS
(Ξ²-BLOCKERS)
β ANS: sympath/psympath NS = regulate organ activities in response to stress
β Sympathetic stimulants:
β Nerve terminals stimulate adrenal medulla to release norepinephrine and epinephrine (main agents that stimulate the sympathetic system (fight or flight response).
β Norepinephrine activates adrenoRs at post synapses
β Epinephrine transported by blood to target tissues producing predominantly inotropy, chronotropy, vasoconstriction leading to increased blood pressure.
β 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.
β 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
β When you get mad or are under extreme stress you can do particularly anything superhuman
β π1 > π2 = βHR, contraction of atrium & ventricles & conduction velocity
β π2 Receptors = smooth mm (bv, GIT, bronchial, GUT) relaxation
β π1 > π2 = contraction of BV smooth mm
β 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
β 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.
β 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
β Generally your beta blockers will inhibit cardiac
functions. What are these cardiac functions?
β It will slow down your SA node and this is
responsible for initiating the heartbeat, so your
heartbeat will decrease.
β 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
β For your arteries, it will dilate them which
contributes to the lowering of your blood
pressure.
β 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.
β 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
β Generally your beta blockers will inhibit cardiac
functions. What are these cardiac functions?
β It will slow down your SA node and this is
responsible for initiating the heartbeat, so your
heartbeat will decrease.
β 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
β For your arteries, it will dilate them which
contributes to the lowering of your blood
pressure.
β 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.
β 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
MECHANISM OF ACTION of BB
β Block π-adrenergic receptors = βBP via mechanisms:
β βmyocardial contractility, βHR, βCO
β Blocked π1 receptors at JG apparatus β no
SNS-induced renin release β βAngio II = βBP +
βaldosterone secretion
β 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.
β 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
β Other mechanisms in lowering BP:
β Altered SNS control and CNS level
β Altered baroreceptor sensitivity
β Altered peripheral presynaptic π-adrenergic receptor function β βsympathetic vasoconstrictive nerve activity
β β PGI2 biosynthesis β vasodilation
β There are also other mechanisms also where
beta blockers can lower your blood pressure
β For example, it can alter your sympathetic
nervous system.
β Proposed mechanisms of 3rd generation contributing to vasodilatation:
β Nitric oxide production
β Ξ±1 receptor blockade
β Ca2+ entry blockade
β K+ channel opening leading to vasodilation
β Ξ²2 receptor activation
β Antioxidant activity
β 3rd generation with vasodilation properties:
β NO2 production: Celiprolol, Nebivolol, Carteolol,
Bopindolol, Nipradolol
β Ξ²2 receptor agonism: Celiprolol, Carteolol,
Bopindolol
β Ξ±2 receptor agonism: Carvedilol, Bucindolol,
Bevantolol, Nipradilol, Labetalol
β Calcium entry blockade: Carvedilol, Betaxolol,
Bevantolol
β K+ channel opening:Tilisolol
β Ξ² blockers = competitive antagonists (meaning: to prevent binding of) of endogenous catechols (epinephrine and norepinephrine) and Ξ² agonists at Ξ²-adrenergic receptors
β Most Ξ² 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 βconcentration of catechols or moderately activate receptors in the absence of endogenous agonists)
PHARMACOLOGIC PROPERTIES OF BB
β Lipophilicity, selectivity for Ξ² receptors, presence of partial agonist activity (ISA), membrane stabilizing properties, block of Ξ± receptors, ability to produce vasodilation β important factors in Ξ² blocker efficacy
β Anti-hypertensive effect resides in antagonism of Beta 1 receptor
β Major side effect result from antagonism of Beta 2 receptors- peripheral vasoconstriction, bronchoconstriction, hypoglycemia
β (-) antihypertensive effect in normal subjects but βBP in hypertension or in patients with βSNS activity (stress or exercise)
β Nonselective Ξ² blockers β βBP primarily as a result of dec in CO
β Other Ξ² blockers β may βCO or βPVR to variable degrees, depending on cardiovascular selectivity and ISA
β Despite these differences, all Ξ² blocker are equally effective antiHPNs for mild to moderate HPN
β Severe HPN Ξ² blocker especially useful for preventing reflex tachycardia by direct vasodilators
β Rxtic efficacy of Ξ² blocker: undoubtedly attributed to adrenergic receptors blockade.
β Total antiHPN effect of Ξ² blocker is also contributed by Ξ² blockade in the brain, kidney & peripheral adrenal neurons
β 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).
β Also referred to as intrinsic sympathomimetic effect, this term is used particularly with Ξ² blocker that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (Ξ² blocker) and the concentration of the antagonized agent (usually
endogenous compound such as norepinephrine).
β Some Ξ² blockers (oxprenolol, pindolol, penbutolol, and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents can exert low-level agonist activity at the Ξ²-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be
useful in individuals exhibiting excessive bradycardia with sustained Ξ² blocker therapy.
β 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 Ξ² blockers in the management of angina and tachyarrhythmia.
INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA)
SYMPATHOMIMETICS
β Classification: According to the source
β Natural; Norepinephrine, Epinephrine, Dopamine
β Synthetic, Isoproterenol,ephedrine,amphetamine
SYMPATHOMIMETICS
β Classification: B-chemically
β Catecholamines, Norepinephrine, Epinephrine, Dopamine and isoproterenol
β Non catecholamines, ephedrine, amphetamine, tyramine
DRUGS WITHOUT ISA (INTRINSIC SYMPATHOMIMETIC ACTIVITY)
β initialβCO (cardiac output) + reflex-induced βPVR (peripheral vascular resistance) w/ no net change in blood pressure
β In patients who respond with βBP β PVR returns to pre-therapeutic values in a few hours to days
β Delayed fall in PVR in the face of a persistent
reduction - in CO = characteristic antihypertensive
effect of this type of Ξ² blockers
DRUGS WITH ISA
(INTRINSIC SYMPATHOMIMETIC ACTIVITY)
β Can stimulate Ξ² receptors partially (in the absence of catechols) but ISA activity is inferior to that of a full agonist drug
β milder β in resting HR and CO
β fall in BP correlates with βPVR below therapeutic levels; possibly due to stimulation of vascular Ξ²2
adrenergic receptors
β ISA => counterproductive to desired antihypertensive response of Ξ² blockers but may be beneficial in preventing profound bradycardia
β May be hazardous in post MI
β Drugs with (+) ISA according to rank: Pindolol >
Carteolol > Celiprolol <-> Penbutolol <-> Acebutolol <-> Labetalol
DRUGS WITH LOCAL ANESTHETIC AND MEMBRANE STABILIZING EFFECT INDEPENDENT OF Ξ² BLOCKADE
β Propranolol, Acebutolol, Carvedilol > > > Pindolol, Metoprolol, Metaxolol and Labetalol
β Renal blood flow:
β acute reaction β decreased β especially with
nonselective agents β block both Ξ²1 and Ξ²2
receptors
β chronic β rare renal dysfunction
β Effective: monotherapy, but often used as adjunct drugs with diuretics or vasodilators
β Acute administration of 1st generation blockers => βCO <β increase PVR to maintain blood pressure (consequence of blocking both vascular Ξ²2 receptors and compensatory reflexes (ex. SNS activation) β activation of vascular Ξ±-receptors
β Chronic use of 1st generation blockers => total PVR returns to initial values or β in hypertensive patients
β Ischemic Heart Disease (IHD) and MI
β βfrequency of angina attacks and improve exercise tolerance due to block of heart Ξ² receptors βcardiac work +βO2 demand via slowing of HR
β Propranolol, Timolol, Metoprolol
β Relative contraindication: bradycardia, hypotension, moderate LV failure, shock, heart block, active airway disease
Other Indications
β Arrhythmias - supraventricular/ventricular
β Chronic Heart Failure: Metoprolol, Bisoprolol, Carvedilol
Therapeutic uses
β Dissecting aneurysms (lessens systolic BP)
β Hyperthyroidism (blocks adrenergic receptors and inhibits peripheral conversion of thyroxine to triiodothyronine)
β Glaucoma (reduce IOP secondary to reduced production of aqueous humor by ciliary body - Ex. Timolol ophthalmic solution. Caution: may be absorbed systematically)
β Migraine, anxiety βstage frightβ, alcohol withdrawal
β Reduction of skeletal muscle tremor (d/t decreased SNS activity)
β Decreased portal venous pressure in liver cirrhosis, decrease bleeding of esophageal varices
LIPOPHILIC BETA BLOCKERS
β Metoprolol, Bisoprolol, Carvedilol, Propranolol
β Greater antiarrhythmiac efficacy than hydrophilic compounds (Atenolol, Nadolol, Labetalol)
β Related to central mode of action
