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Pharmacology II Test 1
Blumenthal - antianginals
40
Pharmacology
01/08/2013

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Cards

Term

Learning Objectives

(4)

Definition

Know the major classes of drugs used to treat angina and their clinically important mechanisms of action
Know the major contraindications, toxicities, and drug interactions of each class of antianginal drugs
Know the drugs of choice for treating different forms of angina
Know which antianginal drug combinations are beneficial and which are ill-advised

 

Term

Angina Pectoris

(4)

Definition

  •      Angina pectoris is the principle symptom of ischemic heart disease
  •      The condition is characterized by a sudden, severe substernal pressure, ‘squeezing’, or ‘strangulation’
    •     Angina derives from the Latin angere“to choke or throttle”, and Greek ankhon“a strangling”
    •     Angina was first described in 1772 by the English physician William Heberden in twenty patients who suffered from "a painful and most disagreeable sensation in the breast, which seems as if it would extinguish life, if it were to increase or to continue." Such patients, he wrote, "are seized while they are walking (more especially if it be uphill, and soon after eating); but the moment they stand still, all this uneasiness vanishes.”
Term

Myocardial Oxygen Economics: 

Supply and Demand

(5)

Definition

The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels
–This imbalance may be due to:
»a decrease in myocardial oxygen delivery (O2 supply)
»an increase in myocardial oxygen demand (O2 demand)
»or a combination of both

Diagram on pg #4

Term

Stable Angina

(7)

Definition

Stable angina is also known as:
–Exertional angina
–Typical or classic angina
–Angina of effort
–Atherosclerotic angina
•The underlying pathology is usually atherosclerosis (reduced oxygen supply) giving rise to ischemia under conditions where the work load on the heart increases (increased oxygen demand)
•Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating

Term

Unstable Angina

(7)

Definition

Unstable angina is also known as:
–Preinfarction angina
–Crescendo angina
–Angina at rest
•Associated with a change in the character, frequency, and duration of angina in patients with stable angina, and episodes of angina at rest
•Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm (reduced oxygen supply)
•May be associated with myocardial infarction (acute coronary syndrome); a prompt and accurate diagnosis is important for timely initiation of appropriate therapies

Term

Vasospastic Angina

(6)

Definition

Vasospastic angina is also referred to as:
–Variant angina
–Prinzmetal's angina
•Caused by transient vasospasm of the coronary vessels (reduced oxygen supply)
•Usually associated with underlying atheromas
•Chest pain may develop at rest

Term

History of Anti-Anginal Drugs

(5)

Definition

Amyl nitrate and nitroglycerin were found to provide transient relief of angina in the mid-to-late 1800s
•Subsequently many other vasodilators were introduced for the treatment of angina, but double-blinded clinical trials showed many were no better than placebo
–Some of the first studies of the placebo effect were carried out in patients with angina
•Beta-adrenergic blockers and calcium channel blockers were developed during the early 1960’s and are now also widely used in the prophylactic therapy of angina
•Ranolazine, an inhibitor of late sodium current (late Ina) and  the first new drug for angina in  more than 20 years, was approved by the FDA in 2006

Term

Pharmacology of Anti-Anginal Agents

Classes

(5)

 

Definition

Four major classes of agents are used individually or in combination to treat angina:

  • Organic nitrates / nitrovasodilators
  • calcium Cgannel Blockers
  • Beta-adrenergnic Blockers
  • Late Sodium Current Inhibitors

Term

Pharmacology of Anti-Anginal Agents

Organic nitrates / nitrovasodilators

(2)

Definition
  • Vasodilate coronary arteries
  • Reduce preload and afterload
Term

Pharmacology of Anti-Anginal Agents

Calcium Channel Blockers 

(3)

Definition
  • Vasodilate Coronary arteries
  • Reduce afterload
  • Non-dihydropyridines (verapamil and diltiazem) also decrease heart rate and contractility
Term

Pharmacology of Anti-Anginal Agents

Beta-adrenergic blockers

(3)

Definition
  • Decrease HR and contractility
  • Decrease afterload secondary to a decrease in CO
  • Improve myocardial perfusion secondary to a decrease in HR
Term

Pharmacology of Anti-Anginal Agents

Late sodium current inhibitors

(2)

Definition
  • Refuces myocardial oxygen consumption during diastole
  • No hemodynamic effects
Term

Stages for treatment of myocardial ischemia

(3)

Definition

 

•Antianginal therapies attempt to restore a balance between myocardial O2 supply and O2 demand
•Some agents such as calcium channel blockers can have effects on decreasing O2 demand and increasing O2 supply
•Not shown is the novel antianginal agent, ranolazine, which has no appreciable effect on hemodynamics (heart rate, contractility, blood pressure, or venous return)- it acts by improving cardiac diastolic function

Diagram on pg #10

Term

Organic Nitrates / Nitrovasodilators

(7)

Definition

Includes nitroglycerin, isosorbidedinitrate (ISDN), isosorbidemononitrate (ISMN), amyl nitrite
•All of these agents are enzymatically converted to nitric oxide (NO) in the target tissues (“NO donors”)
–NO is a very short-lived endogenous mediator of smooth muscle contraction and neurotransmission
•Veins and larger arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects in these vessels
•NO activates a cytosolic form of guanylatecyclase in smooth muscle
–Activated guanylatecyclase catalyzes the formation of cGMP which activates cGMP-dependent protein kinase
–Activation of this kinase results in phosphorylation of several proteins that reduce intracellular calcium and hyperpolarize the plasma membrane causing vascular smooth muscle relaxation

Term

Effects of Nitrovasodilators

Peripheral vasodilation:

Definition

 
–Dilation of veins predominates over that of arterioles (i.e., more effects on preload than afterload)
 

Term

Effects of Nitrovasodilators

Increased coronary blood flow:

(5)

Definition

–Large epicardial coronary arteries are dilated without impairing autoregulation in small coronary vessels
–Collateral flow may be increased
–Decreased preload improves subendocardial perfusion
–Although organic nitrates can relax vasospastic coronary arteries, they have little or no effect on total coronary blood flow in patients with typical angina due to atherosclerosis
–Dilation of coronary arteries can paradoxically result in aggravation of angina - a phenomenon known as “coronary steal”
Term

Effects of Nitrovasodilators

Inhibition of platelet function:

Definition
 
–May contribute to their effectiveness in the treatment of unstable angina
Term

Pharmacokinetic Properties of Organic Nitrates

(4)

Definition

Hepatic first-pass metabolism is high and oral bioavailability is low for nitroglycerin (GTN) and isosorbidedinitrate (ISDN)
–Sublingual or transdermal administration of these agents avoids the first-pass effect
•Isosorbidemononitrate (5-ISMN) is not subject to first-pass metabolism and is 100% available after oral administration
•Hepatic blood flow and disease can affect the pharmacokinetics of GTN and ISDN
• Table on Pg 13***

Term

Oragnic Nitrates Routes of Administration

(4)

Definition

Amyl nitrate is a gas at room temperatures and can be administered by inhalation
–Rapid onset, short duration (3-5 min)
•GTN and ISDN have a rapid onset of action (1-3 min) when administered sublingually, but the short duration of action (20-30 min) is not suitable for maintenance therapy
•IV nitrogylcerin can be used to treat severe recurrent unstable angina

Slowly absorbed preparations of nitrovasodilators (oral, buccal, transdermal) can be used to provide prolonged prophylaxis against angina (3-10 hrs), but can lead to tolerance (tachyphylaxis

Term

Tolerance and Dependence with Nitrovasodilators

(6)

Definition

Continuous or frequent exposure to nitrovasodilators can lead to the development of complete tolerance
–Transdermal GTN may provide therapeutic levels of drug for 24 hours or more, but efficacy only lasts 8-10 hrs
–Nitrate-free periods of at least 8 hrs (e.g., overnight) are recommended to avoid or reduce tachyphylaxis
•The mechanism of tolerance is not completely understood but appears to relate to impairment of the enzymes involved in converting the nitrates to NO, or impairment of the enzyme that produces cGMP
•Industrial (occupational) exposure to organic nitrates has been associated with “Monday disease” (headaches and dizziness) and physical dependence manifest by variant angina occurring 1-2 days after withdrawal (“weekend angina”); even myocardial infarction

 

–No evidence that dependence occurs in normal therapy, even with high doses

Term

Adverse Effects of Nitrovasodilators

(8)

Definition

The major acute adverse effects of nitrovasodilators are due to excessive vasodilation
–Severe throbbing headache
–Orthostatic hypotension
–Tachycardia
–Dizziness
–Flushing
–Syncope
•Organic nitrates are contraindicated in patients with elevated intracranial pressure

Term

Nitrovasodilators: Drug Interactions

(6)

Definition

All of the PDE-5 inhibitors are contraindicated in patients taking nitrovasodilators
•Sildenafil (Viagra) and other PDE-5 inhibitors (vardenafil (Levitra), tadalafil (Cialis)) used to treat erectile dysfunction can potentiate the actions of nitrovasodilators because they inhibit the breakdown of cGMP in vascular smooth muscle
•This potentiation can result in severe hypotension
•Sildenafil should not be taken within 6 hours of taking a nitrovasodilator; long-acting PDE5 inhibitors such as tadalafil may require >24 hours
–Fluids and a-adrenergic agonists may be needed in patients who inadvertently combine a PDE5 inhibitor and nitrate

See the movie “Something’s Gotta Give” (Jack Nicholson & Diane Keaton

Term

Chemistry of Ca++ Channel Blockers

(4)

Definition

Three classes of Ca++ channel blockers are used to treat angina:
–Benzothiazepines:  Diltiazem
–Phenylalkylamines:  Verapamil
–Dihydropyridines:  Nifedipine, nimodipine, amlodipine, nicardipine, and many others

Term

Ca++ Channel Blockers:

Effects on Vascular Smooth Muscle

(7)

Definition

Ca++ channel blockers inhibit L-type (and/or T-type) voltage-dependent Ca++ channels
•Little or no effect on receptor-operated channels or on release of Ca++ from SR
•“Vascular selectivity” is seen with the Ca++ channel blockers
–Decreased intracellular Ca++ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure)
–Little or no effect of Ca++-channel blockers on venous beds  -> no effect on cardiac preload (ventricular filling pressure)
–Specific dihydropyridines may exhibit greater potencies in some vascular beds (e.g.- nimodipine more selective for cerebral blood vessels, nicardipine for coronary vessels)
–Little or no effect on nonvascular smooth muscle

Term

Ca++ Channel Blockers:

Effects on Cardiac Cells

(7)

Definition

Magnitude and pattern of cardiac effects depends on the class of Ca++ channel blocker (non-dihydropyridinevsdihydropyridine) and its site of action
•Negative inotropic effect (L-type channels in ventricular myocytes)
•Reduced inward movement of Ca++ during action potential plateau phase
–Dihydropyridines have very modest negative inotropic effect
•Negative chronotropic/dromotropic effects (L-type channels in nodes and conduction system)
–Verapamil, and diltiazem depress SA node and AV conduction
-- Dihydropyridines have minimal direct effects on SA node and AV conduction (but they can cause reflex tachycardia)
Term

Ca++ Channel Blockers:

Relative Cardiovascular effects

Definition
Table on pg#21****
Term

Desired Therapeutic effects of calcium Channel Blockers for Angina

(7)

Definition

Improved oxygen supply to ischemic myocardium
–Vasodilate coronary arteries
»Particularly useful in treating vasospastic angina
•Reduced myocardial oxygen demand
–Decrease afterload by dilating arterioles (no effect on preload)
–Non-dihydropyridines (verapamil and diltiazem) also lower heart rate and decrease contractility

 

*Note: Dihydropyridines may aggravate angina in some patients due to reflex increases in heart rate and contractility; these sympathetic effects can be prevented by co-administration of b-adrenergic blockers.

Term

Ca++ Channel Blockers:

Toxicities

(8)

Definition

Adverse effects are typically direct extensions of their therapeutic effects and are relatively rare
–Major adverse effects (non-dihydropyridines):
»Depression of contractility and exacerbation of heart failure
»AV block, bradycardia, and cardiac arrest
–Minor adverse effects
»Hypotension, dizziness, edema, flushing
•Patients with ventricular dysfunction, SA node or AV conduction disturbances, WPW syndrome, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem
•Immediate-release forms of dihydropyridines may increase mortality in patients with myocardial ischemia

Term

Ca++ Channel Blockers:

Drug Interactions

(7)

Definition

b-blockers in combination with verapamil or diltiazem
–Bradycardia, AV block, depression of LV function
•Some channel blockers (verapamil, diltiazem) can cause an increase in plasma digoxin levels
–AV block can also occur with concurrent treatment with channel blockers and digoxin because of direct and indirect increases in vagal tone
•Quinidine in combination with some calcium channel blockers
–Results in decreased clearance of both and an increased risk of bradycardia and AV nodal block
–Other antiarrhythmic drugs can also inhibit SA and AV node function and should be avoided

Term

β-Adrenergic Blockers in the Treatment of Angina

(2)

Definition

A variety of beta-adrenergic blockers are used in treating angina including propranolol, metoprolol, atenolol, nadolol, many others
•Though most beta-blockers do not cause coronary vasodilation like the nitrovasodilators or calcium channel blockers, beta-blockers are important in the treatment of angina because of their ability to decrease oxygen demand of the heart

Term

Desired Effects of Beta-blockers in the Treatment of Angina

(4)

Definition

Reduced myocardial oxygen demand by reducing contractility and heart rate
–Reducing cardiac output also reduces afterload (independent of decreased vascular resistance)
–Some b-blockers can cause vasodilation directly or by acting as a-blockers (e.g., labetolol, carvedilol)
•Improved myocardial perfusion by slowing heart rate (more time spent in diastole)

Term

Adverse Effects, Contraindications and Drug Interactions of β-Blockers

(4)

Definition

May exacerbate symptoms in patients with moderate to severe heart failure
•Contraindicated in patients with asthma
•Should be used with caution in patients with diabetes since hypoglycemia-induced tachycardia can be blunted or blocked
•May depress contractility and heart rate and produce AV block in patients receiving non-dihydropyridine calcium channel blockers (i.e., verapamil and diltiazem), and other drugs that inhibit the SA and AV nodes (e.g., many antiarrhythmic drugs and digoxin)

Term

Ranolazine : Late Sodium Current Inhibitor

(7)

Definition

Ranolazine (Ranexa, piperazineacetamide) was approved in 2007 for treatment of chronic angina refractory to other treatments
–First new antianginal drug in more than 25 years
•Unique in that it has no hemodynamic effects (i.e., does not affect heart rate or blood pressure)
•Always used in combination with other antianginal agents
•Approved for use only in refractory cases of angina primarily due to concerns of safety
–Causes QT prolongation, but there is no evidence that it causes torsades de pointes
–Possible risk of testicular toxicity

Term

MOA of Ranolazine

(3)

Definition

Appears to be through inhibition of late sodium current (INa), which results in cardiac myocyte calcium overload by slowing the rate of myocardial calcium removal via the sodium-calcium exchanger. 
•The excess intracellular calcium ion increases contractile protein activation, giving rise to increased diastolic myocardial oxygen consumption, and reduced coronary perfusion due to reduced myocardial relaxation.
Diagram on Pg #29

Term
Combo Use Pg #30***
Definition
Term

Antianginal Combination Therapies

Good ones

(4)

Definition

 
–A dihydropyridine calcium channel blocker and a beta-blocker (coronary vasodilation, decreased afterload, lower heart rate, suppression of reflex tachycardia)
–A nitrovasodilator and a beta-blocker (coronary vasodilation, decreased preload, lower heart rate, suppression of reflex tachycardia)
–A nitrovasodilator and a non-dihydropyridine calcium channel blocker (coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia)

A nitrovasodilator, a dihydropyridine calcium channel blocker, and a beta-blocker (coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia)

Term

Antianginal Combination Therapies

Bad Ones

Definition

A beta-blocker and non-dihydropyridine calcium channel blocker (bradycardia, AV block, depressed LV function)

 

Term

Antianginal Therapeutic Considerations

(5)

Definition

The conditions that might lead to the development of angina (coronary artery disease) need to be considered in the overall treatment of patients with angina
–Thus, many patients with angina need to be treated for hypertension and hyperlipidemia, and low-dose aspirin or other antiplatelet agent to reduce the risk of myocardial infarction
•Modify risk factors associated with atherosclerosis (smoking, hypertension, hyperlidemia)
•Patients with stable angina who are refractory to drug therapy may require surgical revascularization (bypass graft) or angioplasty (PCI)
–Patients with vasospastic angina are not good candidates for these surgical procedures and are usually well-treated by calcium channel blockers

Term

Therapy of Unstable Angina

(6)

Definition

Unstable angina covers a broad range of clinical conditions
•Patients with a high risk of adverse outcomes (e.g., myocardial infarction or death) are considered to have acute coronary syndrome (ACS), an emergent condition that may require maximally tolerated doses of conventional antianginal drugs, and additional drugs and treatments including:
–Antiplatelet drugs (aspirin, platelet glycoprotein IIB/IIIA inhibitors, and/or platelet ADP antagonists)
–Thrombolytic drugs (tissue plasminogen activator, streptokinase, or similar fibrinolytic agent)
–Anticoagulants (heparins or one of the new oral anticoagulants)
–Surgical revascularization (coronary artery bypass graft-CABG) or angioplasty (percutaneous coronary intervention- PCI)

Term

Antianginal Key Concepts

(4)

Definition

Antianginal drugs act to restore balance between myocardial oxygen demand and supply
•The type of angina determines which antianginal drugs are likely to be most effective
•Antianginal drugs can often be used in combination for enhanced therapeutic benefit, but some combinations are ill-advised
•Patients with stable angina or unstable angina are at risk of myocardial infarction and should receive additional therapies (e.g., antiplatelet drugs, statins, antihypertensives) and life-style modifications to reduce risk of myocardial infarction