Cardiac Pharmacology Ted Williams Pharm D Candidate OSU/OHSU College of Pharmacy

The big, scary picture

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Breaking it Down • • • Direct Cardiac Agents Peripheral Vascular Agents Renal Agents

Reality Check • The pharmacology really isn’t that simple, but it is a helpful framework

Direct Cardiac Agents 1. Beta Blockers (BB) 2. Non-Dihydropyridine Calcium Channel Blockers (Non-DHP CCB) 3. Digitalis Glycoside (De-GOX-in) 4. Aldosterone antagonists – Well explain why this is here later

Peripheral Vascular Agents 1. Dihydropyridine CCB 2. Nitrates 3. Hydralazine 4. Phosphodiesterase Inhibitors 5. Alpha 1 Antagonists 6. Phentolamine

Renal Agents 1. ACE Inhibitors 2. Angiotensin 2 Inhibitors 3. Diuretics i.

Carbonic Anhydrase Inhibitors ii. Loop iii. Thiazide Diuretics iv. Aldosterone Antagonists v. Potassium Sparing Diuretics

Mixed Bag • Selective I-1 Imidazoline Receptor Agonists

Hypertension in 30 seconds • • • Excessive vascular volume Low Compliance of vasculature Increased activity of the Renin Anginotensin System

Ischemic Heart Disease in 30 Seconds • • Cardiac Muscle has insufficient oxygen Two Solutions – Reduce cardiac Oxygen demand • Increase Preload • Reduce Contractility • Reduce Afterload – Increase cardiac oxygen supply • Increase Coronary Flow • Increase Oxygen extraction

Heart Failure in 30 Seconds • • • Chronic overwork of the heart muscle causes hypertrophic remodeling Reduced cardiac output Fluid retention

Cardiac Fluid Dynamics in 30 Seconds

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Renin Angiotensin Pathway

Direct Cardiac Agents – BB • • Selectivity – Beta 1 Selective – Beta 1/2 Non-Selective – Alpha 1, Beta 1/2 Non-Selective – Alpha 2, Beta 1/2 Non-Selective Intrinsic Sympathomimetic Activity (ISA) – ISA • No long term mortality benefit Post MI • Non-ISA do have benefit post MI – Non-ISA

Beta Blocker Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Beta Blocker Targets • • Beta 1 blockade – – “Cardioselective” Inhibits sympathetic contractility, inotropy, and conductivity of the heart – Inhibits sympathetic renin secretion in the kidneys Best Tolerated Beta 1 Blockers – – Atenolol Acebutolol – – Bisoprolol Metoprolol

Beta Blocker Targets • • Beta 2 blockade – Beta 2 receptors inhibit smooth muscle contractions in the lungs and GI tract – Beta 2 blockade is useful for restricting hepatic blood flow for patient with Liver Cirrhosis, but generally not a therapeutic effect for CVD Commonly Used Beta 2 Blockers – Propranolol – Nadolol

Beta Blockers and Hypertension • • • Primarily a function of Beta 1 Blockade – Inhibition of sympathetic cardiac stimulation of the SA node – Inhibition of Renin secretion Secondary effects of Beta 2 Blockade – Vasodilation of GI Vasculature Place in Therapy – Second line monotherapy for uncomplicated hypertension – Important agent for Hypertension with other cardiovascular co morbidities • Stroke • • MI CHF

Beta Blockers and Ischemic Heart Disease • • Reduces Cardiac Oxygen Demand by limiting maximum stimulation (Heart Rate) Place in Therapy – First Line for Stable Angina – Decreases Morbidity (Reduced Symptoms) – Decreases Mortality (Prolongs life) – Only Non-ISA

Beta Blockers and Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Beta Blockers and Heart Failure • • • Particular Effects – Decreased Heart Rate – Decreased Contractility – Decreased Afterload – Increased Preload – Increased Stroke Volume via Preload Net Effect – Increased Cardiac Output Place in Therapy – Stage B, C (myocardial damage present) – Improves Morbidity

B1

Renin Targets for Mixed Alpha/Beta Blockers Baroreflex Preload Afterload

CNS I-1 α 2

Vagus Nerve ANP Aldosterone NO

B1 + M2 -

Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

• • • Targets for Mixed Alpha/Beta Blockers Alpha 1 Blockade – Peripheral Vasodilation by inhibition of Gq Signaling pathway • Additional Reduced Afterload – Place In therapy • Heart Failure in particular – Examples • Carvedilol (alpha-1, beta 1/2) • Labetalol (alpha-1, beta 1/2) Alpha 2 Blockade – CNS Inhibition the inhibition of the baroreflex • Inhibits sympathetic increases in blood pressure – PNS inhibition of the negative feedback on vagal cardiac stimulation Alpha 2 Agonists – Stimulates Negative feedback on Beta 1 neurons controlling Heart Rate • Enhances Beta Blockade – Celiprolol (alpha-2 agonist, beta-1 blockade)

Non-DHP CCB Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Non-DHP CCB Targets • • • • Use dependent tissue selectivity – Binds to the open state of the channel – The more often the channel opens, the more drug exposure and therefore the more tissue “selective” – Peripheral vasodilation present, but not as strong as with DHP CCB Cardioselective Verapamil Diltiazem

Non-DHP CCB and Hypertension • • First line monotherapy, with a few restrictions BP Reductions primarily due to decreased heart rate and contractility reducing cardiac output

Non-DHP CCB and Ischemic Heart Disease • • • • • • Reduces Contractility Reduces Heart Rate Second line behind Beta Blockers for symptom relief Not strongly supported to improve prognosis First line for vasospastic Angina Use with extreme caution in combination with beta blockers due to risk of AV Block

Non-DHP CCB and Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Non-DHP CCB and Heart Failure • • • • • • Specific Effects – Decreased Contractility – – Decreased Conductivity Decreased Automaticity Net Effects – Decreased cardiac output Increases Edema via peripheral vasodilation, a major no-no for HF patients Place in Therapy Contraindicated in Systolic Heart Failure (most common kind of Heart Failure) Should be discontinued by Stage C Heart failure, even with compelling indications

Digitalis Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Digitalis Targets • • • Increases cardiac contractility by increasing calcium levels – Cellular target is Sodium Potassium ATPase which is loosely coupled with Sodium Calcium Exchanger Sympatholytic suppression of Renin Angiotensin System Increases Parasympathetic Vagal Tone – Reduces Preload – Reduces Heart Rate

Digitalis And Hypertension • • Neutral Effects on Blood Pressure …Move along, nothing to see here

Digitalis And Ischemic Heart Disease • • The improved cardiac function of Digitalis glycoside is only present in the hypertrophied heart. Mason, D. Digitalis and Angina Pectoris. Chest 1973;64;415-416

Digitalis And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Digitalis And Heart Failure • • • • Heart Failure is the only real use… Specific Effects – Increased Contractility dominates – – Decreased Preload Decreased Heart Rate Net Effect – Increased Cardiac Output Symptom management only – No improvement in mortality – Although RADIANCE and PROVED demonstrated worsening outcomes when Digitalis was discontinued

Aldosterone Antagonists Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP

B1 + M2 -

Preload Afterload NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Aldosterone Antagonists Targets • • • Blocks Collagen deposition (fibrosis) in the myocardium Minor Potassium sparing diuresis by blocking sodium reabsorption in the distal convoluted tubules and collecting ducts (potassium sparing) Examples – Spironolactone – Eplerenone

Aldosterone Antagonists And Hypertension • • Minor blood pressure effects due to diuresis Side effects limit efficacy – Gynecomastia in men due to testosterone production antagonism

Aldosterone Antagonists And Ischemic Heart Disease • Where’s the MOA?

• • • Aldosterone Antagonists And Heart Failure Decrease in Preload due to decreased blood pressure Real benefit is the inhibition of myocardial fibrosis 25mg QD with no titration

Peripheral Vascular Agents 1. Dihydropyridine CCB (DHP-CCB) 2. Nitrates 3. Hydralazine 4. Phosphodiesterase Inhibitors (PDE) 5. Alpha 1 Antagonists 6. Phentolamine

DHP-CCB Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

DHP-CCB Targets • • State Dependent Binding – Bind to the inactive state of the channel – The less active the tissue, the greater selectivity for the tissue Arterial vascular smooth muscle relaxation – Reducing Afterload – Some Baroreflex triggering

DHP-CCB and Hypertension • • • First line monotherapy Preferred over Non-DHP for patients with HF Preferred over Non-DHP for patients taking BB

DHP-CCB and Ischemic Heart Disease • • • • Reduces Afterload Second line after Beta Blockers Improves morbidity only – Mortality benefit not adequately demonstrated Preferred in patients with HF over Non-DHP

DHP-CCB and Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

DHP-CCB and Heart Failure • • • • Reduces Afterload Minor effects on Contractility, Heart Rate, and Conductivity Net effect is a reduction of cardiac output Increases Edema via peripheral vasodilation, a major no-no for HF patients

Nitrate Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Nitrate Targets • • Peripheral Vasodiation by promoting Nitric Oxide Release 1. Veins 2. Arteries 3. Arterioles Decrease Preload

Nitrate And Hypertension • Not particularly helpful

Nitrate And Ischemic Heart Disease • • Short acting first line for Angina Attacks Long acing second line after Beta Blockers for Symptom Relief

Nitrate And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Nitrates And Heart Failure • • • Decreases Preload Not for monotherapy Combine with Hydralazine (as BiDil), indicated in State C Heart Failure – More on that next…

Hydralazine Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Hydralazine Targets • • • • MOA not well understood May affect calcium mobilization May increase Nitric oxide production Arterial vasodilation – Generally triggers baroreflex – Reduces Afterload

Hydralazine And Hypertension • • May be used for refractory hypertension Baroreflex limits use

Hydralazine And Ischemic Heart Disease • No data for use…

Hydralazine And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Hydralazine And Heart Failure • Combination of Hydralazine and Isosorbide Dinitrate (BiDil) – Hydralazine decreases Afterload – Nitrate decreases Preload – Combination Decreases mortality and hospitalizations – Mechanism not well understood

PDE Inhibitor Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

PDE Inhibitor Targets • • • • Increases cGMP levels Increases Contractility (Inotropy) – Increases Calcium Influx – Increases Calcium release from the SR via RyR channels Peripheral vasodiation by inhibition of smooth muscle contractions – That means decreased Afterload – Some decrease in Preload secondary to afterload reductions, but that’s standard stuff Rapid Resistance develops with continuous use

PDE Inhibitors And Hypertension • No data for use…

• PDE Inhibitors And Ischemic Heart Disease Mechanistic support not there

PDE Inhibitors And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

PDE Inhibitors And Heart Failure • • • • Specific Effects – Increased Contractility – Decreased Afterload Net effect – Increased Cardiac Output Clinical data – No demonstrated benefits over Digitalis – – Increased mortality Increased Arrhythmia – Rapid Tolerance Place in therapy – Some suggest there use for acute decompensated heart failure, but no clear support

Alpha 1 Antagonist Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP

B1 + M2 -

Preload Afterload NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

• • • Alpha 1 Antagonist Targets & Place in Therapy Inhibition of sympathetic simulation of vascular smooth muscle – That means reduced Afterload!

Really use for BPH, not CVD – But has some synergistic effects for people with BPH and CVD – – Reduced BP Reduced Afterload & increased Cardiac Output Examples – Prazosin – Doxazosin – Terazosin – Tamsulosin

Renal Agents 1. ACE Inhibitors 2. Angiotensin 2 Inhibitors (ARBs) 3. Diuretics i.

Carbonic Anhydrase Inhibitors ii. Loop iii. Thiazide Diuretics iv. Aldosterone Antagonists v. Potassium Sparing Diuretics

ACE Inhibitor Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

ACE Inhibitor Targets • • • • • Inhibition of Angiotensin Converting Enzyme – Inhibition of the conversion of Angiotensin I to Angiotensin II – Inhibition of the Degredation of Bradykinins – Cough Peripheral Vasodilation – ATII causes peripheral vasoconstriction Reduced GFR – ATII preferential activity on Efferent arterioles Reduced Antidiuretic Hormone (ADH) Production – Reduced fluid volume Reduced Aldosterone Production – Reduced fluid volume

ACE Inhibitor And Hypertension • • First line Monotherapy May synergistic effects with nephropathy, diabetes, kidney diease, MI, and HF

ACE Inhibitor And Ischemic Heart Disease • • Short Answer – Get them on and ACEI Long Answer – Strong evidence for improved prognosis in patient with Diabetes or any CVD (HTN, MI, HF) – Moderate evidence for all patients for improved prognosis

ACE Inhibitor And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

ACE Inhibitor And Heart Failure • • • • • Reduced Afterload Possible benefit of reduced aldosterone production & fibrosis Clinical data supporting reduction in Morbidity/Mortality Indicated for Stage A with any compelling indication (HTN, MI, Diabetes, etc) Indicated in all other stages

ARB Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP

B1 + M2 -

Preload Afterload NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

ARB Targets • • All ATII receptors – Theoretical benefit over ACEI, but not demonstrated – No effect on bradykinins Physiological effects – Peripheral vasodilation – Reduced GFR and arteriole vasodilation – Reduced ADH production – Reduced Aldosterone Production – Reduced fluid volume

ARB Place in therapy • Second line – ACEI have more data and are cheaper, so start with them

Carbonic Anhydrase Inhibitor Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP

B1 + M2 -

Preload Afterload NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Carbonic Anhydrase Inhibitors • • • Work in the proximal convoluted tubule Too much opportunity for later water reabsorption, not really used in CVD Not used much for diuresis, but used in Acid/Base Imbalances and Renal Failure

Loop Diuretic Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Loop Diuretic Targets • • • Inhibit Na, K, Ca, Mg Reabsorption in the Loop of Henle Powerful diuresis and volume reduction Decreased Afterload

Loop Diuretic And Hypertension • • Not used much for BP reduction May be useful in patients with Edema

• Loop Diuretic And Ischemic Heart Disease No mechanism, no indication

Loop Diuretic And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Loop Diuretic And Heart Failure • • Stage C,D Heart failure for management of fluid volume and Edema Symptom relief only

Thiazide Diuretic Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP

B1 + M2 -

Preload Afterload NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Thiazide Diuretic Targets • • Inhibition of Sodium/Cl reuptake – loosely coupled with Potassium excretion – Potassium Sparing – Moderate diuresis & afterload reduction Therapeutic value appears to be beyond diuresis

Thiazide Diuretic And Hypertension • Gold standard monotherapy

Thiazide Diuretic And Ischemic Heart Disease • Not particularly useful

Thiazide Diuretic And Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

Thiazide Diuretic And Heart Failure • • Provides some benefits due to decreased afterload Stage C generally requires loops for edema control

B1

Renin Potassium Sparing Diuretics Targets

I-1

Baroreflex

CNS α 2

Vagus Nerve Preload Afterload ANP Aldosterone NO

B1 + M2 -

Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

Potassium Sparing Diuretics Targets & place in therapy • • Inhibition of Sodium channels in the distal convoluted tubule and collecting duct – Modest Diuresis – Potassium Sparing Really just used as Add On therapy for Hypokalemia

I-1 Agonist Targets

B1

Renin

I-1

Baroreflex

CNS α 2

Vagus Nerve Aldosterone ANP Preload Afterload

B1 + M2 -

NO Conductivity ATII PG ADH/Vasopressin Na↑ HCO3↓ Na↑ K↓ Na Cl↑ + K↓ Na↑ Ca↑ Mg↑ K↑ Na↑ H2O

α 1 B2

I-1 Agonist Targets • Imidazoline-1 Receptor Agonists – Inhibits Renin Production • Reduced ADH • Reduced Aldosterone • Peripheral Vasodilation – Inhibits Sympathetic Vagal cardiac stimulation (sympathlytic) • Reduced heart Rate

I-1 Agonists and Hypertension • • Reduction in blood pressure No strong evidence, not part of guidelines yet

I-1 Agonists and Ischemic Heart Disease • • • Sympatholytic mechanism may have an indication No strong evidence yet Moxonidine

I-1 Agonists and Heart Failure

Contractility Heart Rate + + Cardiac Output Preload + Afterload Stroke Volume +

I-1 Agonists and Heart Failure • • Specific Effects – Reduced Heart Rate (decreasing Cardiac output) – Decreased Afterload (Increasing cardiac output) Net Effect… – Increased Mortality – MOXCON Trial stopped due to increased mortality of 54 deaths with Moxonidine vs 32 with placebo in over 950 patients in each arm.

Conclusions • • Mechanisms suggest potential indications – Cardiac output – Renin-Angiotensin System – Target Tissues Clinical data usually required to determine actual efficacy and safety – Balance of Cardiac Output parameters – MOXCON – BiDil