Table 1. Biological Responses Mediated by Adrenergic Receptors in the Human Heart Biological ResponseAdrenergic Receptor Mediation Cardiac myocyte growthß 1, ß 2, 1 Positive inotropic responseß 1, ß 2, 1 (minimal) Positive chronotropic responseß 1, ß 2 Myocyte toxicityß 1, ß 2 (?<ß 1 ) Myocyte apoptosisß1ß1

Properties of Beta-blockers Potency Membrane 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 Differences between  -Blockers Selective vs nonselective Alpha-adrenergic blocking properties Additional properties (e.g., antioxidant) Intrinsic sympathomimetic activity (ISA) Inverse agonism Receptor upregulation Effects on catecholamine levels

Beta-Blockers Pharmacokinetics 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 Effects Cardiac (mechanical; electrical) Vascular (decreased perfusion) Pulmonary (bronchocostriction) Metabolic (diabetes mellitus) Central Nervous System (depression, nightmares, etc.) Withdrawal Syndrome

Cardioselective Blockers - advantages In asthma In diabetes mellitus In peripheral vascular disease In hypertension (?)

NamePot.Beta -1 ISAMSAt1/2 (h) Lipid Sol. 1 st Pass % Abs. % Bioav. Elim Propranolol (Inderal) HighYes>9030Hep; AM Nadolol (Blocadren) Weak30 Ren Timolol (Blocadren) 64-5ModLittle>9075Ren Metoprolol (Lopressor) ModYes>9050Hep Atenolol (Tenormin) Weak5040Ren Esmolol (Brevibloc) minWeakNA Blood esterases Pindolol (Visken) High>9090Ren/Hep Acebutalol (Sectral) ModLittle7040Ren/Hep ;AM Sotalol * (Sotapor) Weak7060Ren Labetalol # (Normodyne) ModYes>9033Hep *: 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 Therapeutic 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- Blockers Mechanisms 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 Angina Current Pharmacotherapy Beta-blockers Calcium channel blockers Nitrates Aspirin Statins ? ACE inhibitors

Beta-Blockers Decrease myocardial oxygen consumption Blunt exercise response Beta-one drugs have theoretical advantage Try to avoid drugs with intrinsic sympathomimetic activity First line therapy in all patients with angina if possible

Beta-Blockers

Effects of Sympathetic Activation in Heart Failure  1 - receptors  Cardiac sympathetic activity  Sympathetic activity to kidneys + blood vessels  2 - receptors  1 - receptors Activation of RAS Vasoconstriction Sodium retention Myocyte death Increased arrhythmias Disease progression 1-1- 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  2 - and  1 -Adrenergic Receptors in the Damaged Heart

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

Inotropo positivi non digitalici Dopamina Dobutamina Ibopamina Amrinone Milrinone Levosimendan

Blood Pressure Regulation Sympathetic nervous control

Centrally Acting Drugs  Antihypertensive effect results from action in the CNS causing a reduced sympathetic nerve firing rate.  Prototype: clonidine

Centrally Acting Drugs  Clonidine activates alpha 2 and imidazoline receptors in the vasomotor center of the medulla which inhibits the sympathetic nervous 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 reduction in blood pressure.

Centrally 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