Angina and Antianginal Drugs 

Drug classes and list:VASODILATORS (VENODILATORS)

Nitrates:isosorbide dinitratenitroglycerin

  Ca2+ channel blockers:dihydropyridines (DHPs): amlodipine, nifedipinediltiazemverapamil

 

-ADRENERGIC RECEPTOR BLOCKERS:(without intrinsic sympathomimetic activity (ISA))

non-selective (1, 2): propranololselective (1): metoprolol, atenolol

  Carvedilol (see HF drug list) - looks promising

OTHERS: Anti-inflammatory drugs (ACE-I)Antiplatelet drugs (aspirin, clopidogrel)Lipid lowering drugsLate sodium channel blocker (e.g.,

ranolazine)If (sodium leak channel) blocker (ivabradine)

Amy J Davidoff '09

Classification andpathophysiologyof ischemic heart disease

Brenner Fig 11-1

O2 extraction is near maximal even at rest

O2 supply regulated by vascular resistance:

Local factors (e.g., adenosine, bradykinin, prostaglandins, NO)

Sherwood Fig 9-32

Angina myocardial O2 supply( coronary blood flow)

O2 demand( work)

<

Figure 21-4 Phasic flow of blood through the coronary capillaries of left ventricle

Guyton & Hall Fig 21-3

Coronary Blood Flow

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)

Martini Fig 20-10

Normal Restricted circulation

The Hurst's The Heart, 8th ed

Brenner Fig. 11-2

Fill in desired therapeutic effects (and drugs classes) which would benefit an angina patient

(with stable coronary artery disease (CAD))

When oxygen supply does not meet demandischemia LV dysfunction, pain, arrhythmias

Drug classes: Nitrates (NO) CCB BB

VASODILATORS

Strategies to treat angina

Improve coronary blood flow and/or Decrease myocardial oxygen demand

BLOCKERSDecrease cardiac work (reduce HR and contractility)

Improve coronary perfusion - directlyDecrease cardiac work – either on arterial side (red Afterload, or preload by venodilating dec venous return)

(reduce preload and/or afterload)

Nitrates (low doses)

(high doses)

Ca2+ channelblockers

cardiac work

Dilate veins systemic preload

Dilate arterioles

coronaries

systemic

myocardial O2 supply

TPR

TPR BP sympatheticactivity

contractilityHR

workO2 demand

blockers Ca2+ channelblockers

Reflexes affecting heart

(DHPs have little/no effects on heart muscle)

Do not combine verapamil and blockers

Venous vasodilatation

Preload

Coronary vasodilatation

Myocardial perfusion

Arterial vasodilatation

Afterload

Pulmonary congestionVentricular sizeVentricular wall stressMVO2

NITRATESHEMODYNAMIC EFFECTS

AHA website 2003

Shunting from ischemic area because already maximally dialyzed

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, hypotensiontolerance develops after 24 hours continuous use(prevented by 8-12h nitrate-free interval)

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

Kojda et al. Mol Pharm 53:547-554, 1998

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)

Isosorbide mononitrate is the active metabolite

Brenner Fig 11-4

Brenner Fig 11-3

Avoid using nitratesand Viagra

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)

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

Ca2+ channel blockersSite of action dependent on tissue selectivity

•Verapamilmost cardiac selective (nodal cells and myocytes)

•Diltiazemintermediate selectivity (SA node and vascular)

•Dihydropyridines (DHPs)most vascular selective

All have coronary vasodilatory effects (improve blood flow)

DHPsPredominantly cause vasodilation: peripherally reduce TPR (~afterload) and cardiac work coronary vasodilation increase blood flow

AmlodipineLong acting duration (days), T1/2 ~40hrsNo effects on HR, nodal conduction, myocardial contractilityReflex tachycardia, arrhythmias

Nifedipine*Short acting duration (hours), T1/2 ~3hrs

*ultra-short acting nifedipine may precipitate failureMay depress myocardial contractility a littleReflex tachycardia, arrhythmias

Why?

Verapamil and DiltiazemDuration (hours)Undergo significant first-pass hepatic metabolismUsed 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

VerapamilSlows A-V conduction and decreases myocardial contractility

DiltiazemMore selective for SA nodal cells than AV

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 anginanot 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

-Adrenergic Receptor Blockers

Non-selective: 1-, 2-blockerpropranolol

pindolol (partial agonist (ISA))rarely used ever, not indicated for

angina

Selective: 1-blockermetoprolol, atenolol1-, 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

Less effective in blacks, use with caution in elderly (may CO too much), Asians may be more sensitive (may need to lower dose)

Opie Fig 1-10, 1997

more lipophilic more hydrophilic

Propranolol• 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 also include drowsiness. Why?

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)

• 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

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)

Metoprolol & Atenolol

Metoprolol• Duration (hours) – similar to propranolol• Higher bioavailability and slightly less lipophilic than

propranolol• Indicated for heart failure (MERIT-HF study)

Strategies for Combination Therapy

Nitrates & -blockersnitrates reduce venous return (preload) -blockers prevent sympathetic reflex

(decrease HR and cardiac work)

DHPs & -blockersDHPs reduce TPR-blockers prevent sympathetic reflex

Nitrates & DHPs (maybe diltiazem)nitrates reduce preloadCa2+ channel blockers reduce TPR (afterload)

Nitrates, -blockers & DHPsnitrates reduce preloadCa2+ channel blockers reduce TPR-blockers prevent sympathetic reflex

From Golan et al. Principles of pharmacology: The pathophysiologic basis of drug therapy 2008

antiplatelet drugs(inhibit platelet aggregation)

Antiplatelet and thrombolytic drugs covered in heme.

(UA/NSTEMI)

(STEMI)

atherosclerosis diabetes

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

AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other

Atherosclerotic Vascular Disease: 2006 UpdateCirculation 2006;113:2363-2372 and J Am Coll Cardiol 2006;47:2130-2139

Guidelines are available on the Web sites of the AHA (www.americanheart.org) and the ACC (www.acc.org)

Components of Secondary PreventionCigarette 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

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)