Angina and Antianginal Drugs Drug classes and list: VASODILATORS (VENODILATORS) Nitrates: isosorbide dinitrate nitroglycerin   Ca2+ channel blockers: dihydropyridines (DHPs): amlodipine, nifedipine diltiazem verapamil   -ADRENERGIC RECEPTOR BLOCKERS: (without intrinsic sympathomimetic activity (ISA)) non-selective (1, 2): propranolol selective (1): metoprolol, atenolol   Carvedilol (see HF drug list) - looks promising OTHERS: Anti-inflammatory drugs (ACE-I) Antiplatelet drugs (aspirin, clopidogrel) Lipid lowering drugs Late sodium channel blocker (e.g., ranolazine) If (sodium leak channel) blocker (ivabradine) Amy J Davidoff '09

of ischemic heart disease Classification and pathophysiology of ischemic heart disease Typical – athero and limited blood flow. Variant – vasospasm. Both have different type of therapy. Understand the different types and you can predict which class of drug to use. Brenner Fig 11-1

< Angina myocardial O2 supply ( coronary blood flow) O2 demand ( work) < Angina O2 extraction is near maximal even at rest O2 supply regulated by vascular resistance: Local factors (e.g., adenosine, bradykinin, prostaglandins, NO) In order to enhance O2 delivery you need to inc blood flow. Sherwood Fig 9-32

Coronary Blood Flow Dependent on: Aortic diastolic pressure Guyton & Hall Fig 21-3 Dependent on: Aortic diastolic pressure Collateral blood flow Arterial diameter (radius) Epicardial-endocardial flow (subendo. arteries constrict more with ventricular contraction,  particularly susceptible to ischemia) Figure 21-4 Phasic flow of blood through the coronary capillaries of left ventricle 4

Restricted circulation Normal Restricted circulation Martini Fig 20-10 The Hurst's The Heart, 8th ed

(with stable coronary artery disease (CAD)) Fill in desired therapeutic effects (and drugs classes) which would benefit an angina patient (with stable coronary artery disease (CAD)) Drug classes: Nitrates (NO) CCB BB Coronary vasculature composed of: large, proximal epicardial vessels (more frequent site of atheroma formation) small, distal endocardial vessels (regulate intrinsic, local vasotone to metabolites) Want to decrease demand and/or increase supply. O2 exctraction is near 100% in heart at nl. When oxygen supply does not meet demand ischemia  LV dysfunction, pain, arrhythmias Brenner Fig. 11-2 6

Strategies to treat angina Improve coronary blood flow and/or Decrease myocardial oxygen demand VASODILATORS Improve coronary perfusion - directly Decrease cardiac work – either on arterial side (red Afterload, or preload by venodilating dec venous return) (reduce preload and/or afterload)  BLOCKERS Decrease cardiac work (reduce HR and contractility)

 cardiac work Dilate veins systemic  preload Dilate arterioles coronaries  myocardial O2 supply  TPR Ca2+ channel blockers Nitrates (low doses) (high doses) Notes: from Paul Massion thesis: ACh induces a strong NO production in macrovascular EC but only weakly in microvascular EC. EDHF plays a backup role in microarteriolar vessels, such that one needs high doses of NO to affect peripheral resistance CCB will dilate coronaries and some peripheral arterials Nitrates – at low doses have more effect on venous side, higher doses more on arterial side

Reflexes affecting heart  TPR  BP sympathetic activity contractility HR work O2 demand  blockers Ca2+ channel blockers Don’t forget reflexes that occur if you lower/raise too quickly. BB – inhibit symp aspect of refelx, CCB inhibit contractility and inc in HR. Verapamil – CCB Don’t combine b/c verapamil is highly selective for the heart. Would be hitting heart twice. Would cause too much cardiodepression. Do not combine verapamil and  blockers (DHPs have little/no effects on heart muscle)

NITRATES HEMODYNAMIC EFFECTS Venous vasodilatation Preload Coronary vasodilatation Myocardial perfusion Arterial vasodilatation Afterload Pulmonary congestion Ventricular size Ventricular wall stress MVO2 Treatment of Heart Failure. Nitrates: Hemodynamic effects At therapeutic doses, nitrates produce venodilatation that reduces systemic and pulmonary venous resistances. As a consequence, right atrial pressure, pulmonary capillary pressure, and LVEDP decrease. The preload reduction improves the signs of pulmonary congestion and decreases myocardial wall tension and ventricular size, which in turn reduce oxygen consumption. With higher doses, nitrates produce arterial vasodilatation that decreases peripheral vascular resistance and mean arterial pressure, leading to a decrease in afterload, and thereby reduce oxygen consumption. This arterial vasodilatation increases cardiac output, counteracting the possible reduction caused by the reduction in preload caused by venodilatation. The overall effect on cardiac output depends on the LVEDP; when LVEDP is high, nitrates increase cardiac output, while when it is normal nitrates can decrease cardiac output. Nitrates can also produce coronary vasodilatation, as much through reducing preload as through a direct effect on the vascular endothelium. This vasodilatation can decrease the mechanical compression of subendocardial vessels and increases blood flow at this level. Additionally, nitrates reduce coronary vascular tone, overcoming vasospasm. By reducing preload you reduce all of the other factors in box – reduces how hard ht has to work. Also cause vasodilation which inc myocardial perfusion. More NO will not improve blood flow to ischemic area, but will improve collateral blood flow to ischemic area. The area is already dialyzed b/c of local factors. Can also get arterial vasodilation – ht doesn’t have to work so hard. Shunting from ischemic area because already maximally dialyzed AHA website 2003

Nitroglycerin Sublingual, oral, transdermal, buccal (IV preparations : Sodium nitroprusside (SNP), used in surgeries - potential risk of cyanide toxicity) Onset and duration (dependent on route of administration) Effective for treating or preventing effort (stable), variant and unstable angina Side effects: reflex tachycardia, hypotension tolerance develops after 24 hours continuous use (prevented by 8-12h nitrate-free interval) Too much venodilation (preload) will compromise arterial pressure.

Isosorbide dinitrate (mononitrate) Sublingual, oral Onset and duration (dependent on route of administration) (slower than nitroglycerin) Tx or prevent angina Reflex tachycardia, hypotension Tolerance develops All the nitrates preferentially dilate large veins  preload   cardiac work and O2 demand Vasodilation via release of NO from endothelial cells Tolerance may be due to development of mitochondrial reactive oxygen species (ROS), which can inactivate nitrate reductase, resulting in inhibition of NO vasodilatory effects

Proposed mechanism for preferential effects on venous side (compared to arterial side), regarding potency Preferential venodilation may be due to: Duration of exposure diminishes response (tolerance) Less endogenous NO in the veins (therefore veins more responsive than arteries) Don’t need to know details on this. Arterial side is already presenting with tolerance due to endogenous NO. Venous will be more responsive to exogenous NO. Kojda et al. Mol Pharm 53:547-554, 1998

Isosorbide mononitrate is the active metabolite Brenner Fig 11-4

Avoid using nitrates and Viagra Brenner Fig 11-3 Endothelial cells produce NO and it diffuses into vascular smooth muscle cells. Phosphatase – inhibits contraction NO leads to cGMP – relaxation. cAMP also inhibits MLC kinase to cause relaxation (contraction in heart) Epi – B2 – adenyl cyclase – cAMP – vasodilation NE – A1 – PLC – IP3 – Ca2 release – vasoconstriction - DAG – activates PLC – opens Ca2+ channels A1 and B2 will be on different cells. L-type Ca2+ channels on smooth muscle cell. Can get contraction by opening them, or promote relaxation by blocking them. Nitrates and viagra (enzyme – increases cGMP) – if combined with nitrates could cause too much vasodilation and impair venous return – could precipitate an infarct Brenner Fig 11-3

Calcium Channel Blockers (Antagonists) Inhibit inward calcium flux (through L-type channels) Decrease myocardial and vascular smooth muscle contraction Slow AV conduction and SA rate Decrease afterload, contractility, heart rate, and improve myocardial blood flow Agents differ in these activities No adverse effects on lipid profiles (whereas B-blockers have adverse effects) All Ca channels (drugs) in vasc system target L-type.

Indications for Calcium Channel Blockers Useful in stable and variant/vasospastic angina (not unstable angina) Used to manage (prevent) angina (not treat attack) Effort angina refractory to beta-blockers Patients intolerant to beta-blockers and nitrates Useful for 24 hour protection (vs nitrates) “add on”, not monotherapy Not unstable – won’t do much if there is a clot. Not to treat attack b/c they have slow onset. Not first line, but used if refractory to BB

Ca2+ channel blockers Site of action dependent on tissue selectivity Verapamil most cardiac selective (nodal cells and myocytes) Diltiazem intermediate selectivity (SA node and vascular) Dihydropyridines (DHPs) most vascular selective All have coronary vasodilatory effects (improve blood flow) 3 classes: many dihydrop.. Dit > than Ver for SA nodal cell. Verapamil greater chance for AV block.

DHPs Predominantly cause vasodilation: peripherally  reduce TPR (~afterload) and cardiac work coronary vasodilation  increase blood flow Amlodipine Long acting duration (days), T1/2 ~40hrs No effects on HR, nodal conduction, myocardial contractility Reflex tachycardia, arrhythmias Nifedipine* Short acting duration (hours), T1/2 ~3hrs *ultra-short acting nifedipine may precipitate failure May depress myocardial contractility a little Why? Nifedipine – greater chance for reflex tachycardia b/c it is rapid onset and short acting.

Verapamil and Diltiazem Duration (hours) Undergo significant first-pass hepatic metabolism Used for stable or variant angina (also used for certain arrhythmias) Usually contraindicated for ventricular dysfunction particularly verapamil (e.g., heart failure) Decreases cardiac work  O2 demand Verapamil Slows A-V conduction and decreases myocardial contractility Diltiazem More selective for SA nodal cells than AV Verapamil – contraind for vent dysf – slowing through sa node, can interfere with contractility. Can work on vent cells themselves. Toxicities are extensions of their therapeutic effects

Choice of Tx in Chronic Stable Angina ASA, lipid therapy (target LDL = <100mg/dL), ACEI Short-acting NTG Beta-blockers Reduce mortality post-MI and in HTN Calcium channel blockers (except rapid release nifedipine – b/c reflex tachycardia) Rapid release forms may increase morbidity May be preferred over long-acting nitrates (lack of tolerance) Long-acting Nitrates No effect on mortality with MI or CAD Tolerance Combination therapy before declaration of treatment failure Circulation 2003,107:149

Important Drug Interactions with Ca2+ Blockers CYP 3A4 inhibitors (e.g., grapefruit juice) and amlodipine/felodipine These DHPs are normally extensively metabolized Amlodipine, verapamil, diltiazem and cyclosporin Decreased cyclosporin metabolism with blockers Verapamil and digoxin (cardiac glycoside) Both slow A-V conduction (don’t combine them) Verapamil and -blockers (don’t combine) Too much cardiodepression

-BLOCKERS IN ANGINA Used to manage typical angina not effective for variant angina Cardiac work (HR and SV)  O2 demand May improve O2 delivery by prolonging diastole (HR) Long-term BP because of renin release (via 1 blocking) Other indications: Use immediately after acute MI (improves survival) Heart failure patients may benefit because of reduced myocardial ‘remodeling’ Also used for certain arrhythmias, hypertension Long term effects less on cardiac side and more on renin/angio/aldos system.

-Adrenergic Receptor Blockers Non-selective: 1-, 2-blocker propranolol pindolol (partial agonist (ISA)) rarely used ever, not indicated for angina Selective: 1-blocker metoprolol, atenolol COMET (Lancet 2003) compared carvedilol with short-acting metoprolol carvedilol had reduced mortality associated with MIs, but it is unclear whether this would also be indicated if the comparison was made with long-acting metoprolol (Opie 2004) 1-, 2- and 1- blockers: (discussed later) carvedilol, labetalol some indications for angina (not yet FDA approved) and HF

All -blockers are competitive inhibitors Vary in lipophilicity, bioavailability, metabolism (i.e., pharmokinetics) Some have unfavorable effects on lipids Clinical problems with abrupt withdrawal because of receptor up-regulation - make more receptors/low concentration Contraindications/precautions with Significant AV block, severe unstable LV failure, HR<50, SBP<90, asthma Adrenergic receptors are sensitive to up/down regulation – concentration of ligand. Can anticipate a withdrawal response if they have been on for a while. Selectivity is a relative term based on concentration. If high, can affect other receptors as well. Less effective in blacks, use with caution in elderly (may CO too much), Asians may be more sensitive (may need to lower dose)

more lipophilic more hydrophilic Opie Fig 1-10, 1997 Some by liver, some by kidney. If liver – lipophilic – cross barriers in liver cells/ can also cross BBB – cause drowsiness Kidney – hydrophilic – filtered or secreted by kidney b/c of solubility. more lipophilic more hydrophilic Opie Fig 1-10, 1997

Propranolol Side effects also include drowsiness. Why? Non-selective blocks both 1-AR and 2 –AR Duration (hours) – same as metoprolol, shorter than atenolol Low bioavailability because of 1st pass hepatic metabolism (highly lipid soluble) MSA (membrane stabilizing activity) local anesthetic effects Side effects include: Slight TPR (sympathetic reflex), -AR intact  Bronchconstriction (via 2 blocking)  Renal blood flow (because CO) therefore, Na+, H2O retention (may need to add a diuretic) May prevent response to hypoglycemia (via 2 blocking) and mask symptoms of hypoglycemia (e.g., tachycardia, sweating) care with diabetics (especially type 1) May alter serum lipid levels ( VLDL and  HDL) Reduced CO – decreased firing of baroreceptors – inc symp response – won’t do too much to heart b/c of BB, but will increase peripheral resistance b/c BB don’t block A1 in periphery. Reduction in renal flow – starts renin system – inc Na and H2O – need diuretic. Side effects also include drowsiness. Why?

Metoprolol & Atenolol Metoprolol Atenolol Both selective 1-AR blockers = “cardioselective” Avoid bronchospasms Avoid masking hypoglycemia Both (-)renin (good effect), but may also  renal blood flow via CO (like propranolol), therefore may need to add diuretic Metoprolol Duration (hours) – similar to propranolol Higher bioavailability and slightly less lipophilic than propranolol Indicated for heart failure (MERIT-HF study) Atenolol Much less lipophilic, therefore Less CNS effects (e.g., drowsiness) but may not have cardioprotective effects like metoprolol Longer durations of action (longer half-live)

Strategies for Combination Therapy Nitrates & -blockers nitrates reduce venous return (preload) -blockers prevent sympathetic reflex (decrease HR and cardiac work) DHPs & -blockers DHPs reduce TPR -blockers prevent sympathetic reflex Nitrates & DHPs (maybe diltiazem) nitrates reduce preload Ca2+ channel blockers reduce TPR (afterload) Nitrates, -blockers & DHPs nitrates reduce preload Ca2+ channel blockers reduce TPR -blockers prevent sympathetic reflex

atherosclerosis diabetes (STEMI) (UA/NSTEMI) antiplatelet drugs (inhibit platelet aggregation) Depressed ST segment infers ischemia Elevated ST segment infers MI Antiplatelet and thrombolytic drugs covered in heme. From Golan et al. Principles of pharmacology: The pathophysiologic basis of drug therapy 2008

In addition to aspirin: Note: In addition to aspirin: Clopidogrel or glycoprotein IIb-IIIa antagonists (antiplatelet agents) is recommended for acute coronary syndromes and subsequent to percutaneous coronary intervention New drug for stable angina: Ranolazine (ra noe' la zeen) used in combination with nitrate, BB or CCB (symptom prevention, not relief) mechanism in question (probably a late sodium channel blocker) Medical Letter June 2006; Circulation 2006; 113:2462-2472

Choice of Tx in Chronic Stable Angina ASA, lipid therapy (target LDL = <100mg/dL), ACEI Short-acting NTG Beta-blockers Reduce mortality post-MI and in HTN Calcium channel blockers (except rapid release nifedipine) Rapid release forms may increase morbidity May be preferred over long-acting nitrates (lack of tolerance) Long-acting Nitrates No effect on mortality with MI or CAD Tolerance Combination therapy before declaration of treatment failure Circulation 2003,107:149

Components of Secondary Prevention AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2006 Update Circulation 2006;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139 Components of Secondary Prevention Cigarette smoking cessation Blood pressure control Lipid management to goal Physical activity Weight management to goal Diabetes management to goal Antiplatelet agents / anticoagulants Renin angiotensin aldosterone system blockers Beta blockers Influenza vaccination Guidelines are available on the Web sites of the AHA (www.americanheart.org) and the ACC (www.acc.org)

Lipid-lowering Therapy (discussed later) Goal = LDL <100mg/dL; perhaps as low as 70 Diet/exercise HMG CoA reductase inhibitors (statins): atorvastatin, lovastatin, pravastatin, simvastatin Interfere with hepatic cholesterol production Stabilize, lead to regression of coronary atherosclerotic plaques Anti-inflammatory Treating osteoporosis 20-30% reduction in mortality and coronary events (Treatment Guidelines – Medical Records February 2008)