Table 1. Biological Responses Mediated by Adrenergic Receptors in the Human Heart

Biological ResponseAdrenergic Receptor

Mediation

Cardiac myocyte growth ß1, ß2,  1

Positive inotropic response ß1, ß2,  1 (minimal)

Positive chronotropic response

ß1, ß2

Myocyte toxicity ß1, ß2 (?<ß1)

Myocyte apoptosis ß1

Properties of Beta-blockersProperties of Beta-blockers

PotencyMembrane stabilizing activity (quinidine-like)Structure-activity relationships: L-isomer has

the Beta-blocking action.Cardioselectivity (Beta-1 selectivity)Intrinsic sympathomimetic activity (partial

agonist activity)Lipid solubility – relation to pharmacokinetics

Pharmacologic DifferencesPharmacologic Differencesbetween between -Blockers-Blockers

Selective vs nonselectiveAlpha-adrenergic blocking propertiesAdditional properties (e.g., antioxidant)Intrinsic sympathomimetic activity (ISA)Inverse agonismReceptor upregulationEffects on catecholamine levels

Beta-Blockers Beta-Blockers PharmacokineticsPharmacokinetics

Lipid soluble agents (vs. water soluble) tend to: – Be better absorbed– Have more variable bioavailability– Be metabolized in liver– Enter the CNS– Be more widely distributed– Have shorter elimination half-lives

Beta-Blockers - Adverse Beta-Blockers - Adverse EffectsEffects

Cardiac (mechanical; electrical)Vascular (decreased perfusion)Pulmonary (bronchocostriction)Metabolic (diabetes mellitus)Central Nervous System (depression,

nightmares, etc.)Withdrawal Syndrome

Cardioselective Blockers - Cardioselective Blockers - advantagesadvantages

In asthmaIn diabetes mellitusIn peripheral vascular diseaseIn hypertension (?)

Name Pot. Beta-1

ISA MSA t1/2 (h)

Lipid

Sol.

1st Pass

% Abs.

% Bioav.

Elim

Propranolol

(Inderal)

1 ++ 3-4 High Yes >90 30 Hep;

AM

Nadolol

(Blocadren)

1 10-20 Weak 30 30 Ren

Timolol

(Blocadren)

6 4-5 Mod Little >90 75 Ren

Metoprolol

(Lopressor)

1 ++ 3-4 Mod Yes >90 50 Hep

Atenolol

(Tenormin)

1 ++ 6-9 Weak 50 40 Ren

Esmolol

(Brevibloc)

0.02 ++ 9 min Weak NA NA Blood esterases

Pindolol

(Visken)

6 ++ + 3-4 High >90 90 Ren/Hep

Acebutalol

(Sectral)

0.3 + + + 3-4 Mod Little 70 40 Ren/Hep;AM

Sotalol *

(Sotapor)

0.3 9-10 Weak 70 60 Ren

Labetalol #

(Normodyne)

0.3 3-6 Mod Yes >90 33 Hep

*: Class III antiarrhythmic; #: an alpha-1 blocker also. ISA: intrinsic sympathomimetic activity; MSA: membrane stabilizing activity. AM: active metabolite. Many other Beta blockers available.

Beta-Blockers Beta-Blockers Therapeutic UsesTherapeutic Uses

Coronary artery disease Hypertension Arrhythmias Congestive heart failure Hypertrophic

obstructive cardiomyopathy

Dissecting aortic aneurysm

Pheochromocytoma Hyperthyroidism Migraine -prophylaxis Essential tremor Anxiety – stage fright Glaucoma (topical)

Antihypertensive Effect of Beta-Antihypertensive Effect of Beta-Blockers Blockers MechanismsMechanisms

1. Decreased cardiac output

2. Inhibition of renin-angiotensin system

3. Decreased central sympathetic outflow

4. Resetting of baroreceptor

5. Others: prejunctional receptors, prostaglandins, etc.

Stable AnginaStable AnginaCurrent PharmacotherapyCurrent Pharmacotherapy

Beta-blockersCalcium channel blockersNitratesAspirinStatins? ACE inhibitors

Beta-BlockersBeta-Blockers

Decrease myocardial oxygen consumptionBlunt exercise responseBeta-one drugs have theoretical advantageTry to avoid drugs with intrinsic

sympathomimetic activityFirst line therapy in all patients with

angina if possible

Beta-BlockersBeta-Blockers

Effects of SympatheticEffects of SympatheticActivation in Heart FailureActivation in Heart Failure

1-receptors

Cardiac sympathetic activity Sympathetic activity to kidneys+ blood vessels

2-receptors

1-receptors

Activationof RAS

VasoconstrictionSodium retention

Myocyte deathIncreased arrhythmias

Disease progression

1- 1-

CNS sympathetic outflow

Adapted from Bristow MR. J Am Coll Cardiol. 1993;22(4 Suppl A):61A–71A.

In the damaged heart, the ratio of receptors shifts, increasing the relative proportion of 2- and 1-receptors

The Ratio of The Ratio of 22- and - and 11-Adrenergic -Adrenergic

Receptors in the Damaged HeartReceptors in the Damaged Heart

1 2 1

Normal heart 70 : 20 : 10

Failing heart 50 : 25 : 25

C3= legame per zuccheri pentosi, esosi; C17= anello lattonico insaturo; C14= ossidrile

Inotropo positivi non digitaliciInotropo positivi non digitalici

DopaminaDobutaminaIbopaminaAmrinoneMilrinoneLevosimendan

Blood Pressure RegulationBlood Pressure RegulationSympathetic nervous control

Centrally Acting DrugsCentrally Acting Drugs

Antihypertensive effect results from action in the CNS causing a reduced sympathetic nerve firing rate.

Prototype: clonidine

Centrally Acting DrugsCentrally Acting Drugs

Clonidine activates alpha2 and imidazoline receptors in thevasomotor center of the medulla which inhibits the sympatheticnervous system.

Considered a second-line drug or for special cases(ie methyldopa in pregnant hypertensive patients).

A reduced heart rate and cardiac output account for reductionin blood pressure.

Centrally Acting DrugsCentrally Acting Drugs

An advantage of these drugs is that they do not cause postural hypotension

Side effects - hypertensive rebound if there is an abrupt withdrawal -dry mouth, sedation