Myocardial ischemia is a result of?
Increased myocardial work and/or decreased myocardial oxygen supply
Acute coronary syndrome is an umbrella term which covers clinical conditions such as:
*unstable angina
*non-Q wave MI (NSTEMI)
*Q-wave MI (STEMI)
Angina pectoris is usually associated with:
Large single to multivesel atherosclerotic CAD, coronary artery vasopasm, or both
Risk factors for developing atherosclerosis
*dyslipidemia
*family history of premature MI or sudden death
*cigarette smoking
*hypertension
*DM
*Obesity
*Physical Inactivity
*Males older than 45yo
Prognosis of anginal symptoms is mainly determined by what?
*Extent/severity of underlying CAD
*Extent of LV systolic dysfunction
*Presence/severity of ischemia during exercise
What are the major determinants of myocardial oxygen demand?
*heart rate
*contractility
*left ventricular systolic wall tension
Rate of rise in the intraventricular pressure during isovolumetric contraction
Myocardial Contractility
What is myocardial contractility influenced by?
*Autonomic nervous system
*Heart rate
*Blood cacium level
*Temperature
Systolic wall tension is directly related to?
ventricular systolic pressure and ventricular wall radius
Reducing systolic blood pressure does what to the afterload, decreasing oxygen demand?
reduces the afterload
What is myocardial oxygen supply determined by?
*coronary blood fow
*oxygen carrying capacity of the blood
When does myocardial ischemia develop?
When narrowing of the epicardial vessels by vasopasm or atherosclerosis results in high enough resistance to restrict coronary blood flow
What are the factors that affect coronary blood flow?
*Duration of systole
*Coronary vascular resistance
What is coronary vascular resistance determined by?
*metabolic control
*autoregulation
*extravascular compressive forces
*humoral and neural factors
Angina in which the frequency, severity, duration of symptoms, and time of day have not changed over the previous 2 months
Chronic stable angina
How does angina classically present?
*substernal discomfort that radiates to the neck and left arm
*pressure, heaviness, fullness, squeezing, burning, aching, gas, anxiety
*gradual onset
*lasts a few minutes
*relieved by rest or nitroglycerin
A long duration of anginal discomfort implies what?
*severe ischemia
*coronary spasm
*unstable angina
*impending MI
Functional classification of angina pectoris
*Class I - symptoms occur with unusual activity with minimal or no functional impairment
*Class II - symptoms occur with prolonged activity with mild functional impairment
*Class III - symptoms occur with usual ADL's with moderate functional impairment
*Class IV - symptoms occur at rest with severe functional impairment
How is silent myocardial ischemia detected?
exercise ECG testing (asymptomatic St-segment depression)
The incidence of MI, sudden cardiac death, Prinzmetal's angina, and myocardial ischemia associated with stable angina is higher at what time of day?
Morning
What are some factors that may provoke angina episodes?
*physical exercise
*emotions (anger, excitement, anxiety)
*exposure to cold, heat, or humidity
*meals
*sex
Abnormal ECG findings in patients with chronic stable angina
*ST-segment depression
*T-wave inversion
*ST-segment elevation in patients with Prinzmetal's angina
What is the initial therapy in the absence of contraindications in patients with chronic stable angina with or without prior MI?
Beta-Blockers
What should be used in all patients with chronic stable angina with CAD who also have diabetes and/or LV systolic dysfunction?
ACE-Inhibitor
What can be used when beta-blockers are contraindicated for initial therapy?
Long-acting calcium antagonists or long-acting nitrates
*can also be combined with beta-blockers when initial treatment with beta-blockers alone is not successful
Antiplatelet Agents
*Aspirin
*Ticlopidine (Ticlid)
*Clopidogrel (Plavix)
*Prasugrel (Effient)
*Dipyridamole (Persantine)
MOA of aspirin
*Inhibits cyclo-oxygenase preventing synthesis of thromboxane A-2
*decreased platelet release and aggregation
In patients with unstable angina, what does aspirin do?
Decreases the short and long-term risks of fatal and nonfatal MI
What should be used in all patients with acute or chronic ischemic heart disease with or without symptoms in the absence of contraindications?
Aspirin
MOA of Ticlopidine (Ticlid)
*inhibits platelet aggregation induced by ADP and low concentrations of thrombin, collagen, thromboxane A2, and platelet activating factor
What has ticlopidine (ticlid) been used for?
secondary prevention of stroke and MI and prevention of stent closure and graft occlusion
What limits the use of ticlopidine (ticlid)?
The potential for neutropenia and thrombotic thrombocytopenia purpura (TTP)
MOA of Clopidogrel (Plavix)
*Prevents ADP-mediated activation of platelets by blocking the activation of the glycoprotein IIb/IIIa complex
In a trial in patients with previous MI, stroke, or symptomatic peripheral disease, was clopidogrel or aspirin more effective?
Clopidogrel
MOA of Prasugrel (Effient)
*Prevents ADP mediated activation of platelets by blocking the activation of the glycoprotein IIb/IIIa complex
What is Prasugrel (Effient) indicated for?
reduction of thrombolic events in patients with acute coronary syndrome (ACS) who are managed with percutaneous coronary intervention
MOA of Dipyridamole (Persnatine)
*has vasodilatory effects on coronary resistance vessels and antithrombotic effects
*causes vasodilation via increased plasma adenosine
Why is it recommened that dipyridamole not be used as an antiplatelet agent in patients with stable angina?
Can enhance exercise induced myocardial ischemia
Beta Blockers (Examples)
Propanolol, metoprolol, atenolol, acebutolol, pindolol, nadolol, timolol, betaxolol, bisoprolol, carteolol, penbutolol, esmolol (IV)
*carvedilol and labetolol
MOA of beta blockers
*competitively inhibit the binding of catecholamines to the beta-adrenergic receptors
What does stimulation of Beta 1 receptors cause?
increased heart rate, accelerated AV nodal conduction, increased myocardial contractility
What are the beneficial effects of beta blockers in angina?
*reduction in heart rate which reduces cardiac work and decreases oxygen demand
*slowing of heart rate also prolongs diastolic filling leading to improved oxygen supply
*reduction of myocardial contractility and arterial blood pressure which reduces oxygen demand
*reduce frequency of angina episodes, improve exercise tolerance, and decrease need for NTG
Nonselective beta blockers should be avoided in patients with?
obstructive lung disease, asthma, poor circulation, and diabetes
Beta blockers with partial agonist activity may be detrimental in what patients?
Patients with rest angina or post MI
*may not decrease heart rate and blood pressure at rest
Why are beta blockers frequently combined with nitrates?
To attenuate the potential for reflex tachycardia caused by increased sympathetic tone from nitrates
Adverse effects of beta blockers
*sinus bradycardia and sinus arrest
*AV block
*Reduced LV function
*Fatigue
*Bronchoconstriction
*Depression
*Nightmares
*Sexual dysfunction
*Intensification of insulin-induced hypoglycemia
Patients with what should avoid using beta blockers?
*bradyarrhythmias
*AV conduction disturbances
*asthma, COPD, CHF, DM
*peripheral vascular disease
ACE Inhibitors (Examples)
Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, Trandolapril
All CAD patients who also have diabetes and/or LV systolic dysfunction should receive what?
ACE inhibitor
MOA of Ace-Inhibitors
*Suppress renin-angiotensin aldosterone system
*decrease the formation for angiotensin II and decrease the degredation of bradykinin
Adverse Effects of ACE-Inhibitors
*Dry cough, angioedema, dizziness, hypotension, rash
*Hyperkalemia, neutropenia, proteinuria, renal function impairment
Angiotensin II Receptor Antagonists (ARBs)
Candesartan, Eprosartan, Irbesartan, Losartan, Telmisartan, Valsartan
MOA of Angiotensin II Receptor Antagonists
*Block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues
Adverse reactions of angiotensin II receptor antagonists
*much lower incidence of cough, angioedema, and dizziness
*higher incidence of URTI, hypotension, renal function impairment, hyperkalemia
*fetal and neonatal morbidity and death when administered to pregnant women
What is nitrate tolerance?
A decreased pharmacologic response in the presence of continuously or frequently administered nitrates
How is nitrate tolerance prevented?
Provide a 10-12 hour daily nitrate-free interval with chronic dosing (usually at night except in patients with nocturnal angina)
Adverse effects of nitrates
Headache, lightheadedness, dizziness, facial flushing, hypotension, reflex tachycardia
Drug Interactions with Nitroglycerin
*Viagara use within 24 hours
*Cialis use within 48 hours
*Levitra use within 48 hours
*These drugs exaggerate and prolong NTG mediated vasodilation
What is sublingual nitroglycerin used for?
Management of acute episodes of angina and prophylaxis of an expected anginal episode
Why does sublingual aerosol spray nitroglycerin have some benefits over sublingual tablet nitroglycerin?
Shelf life of 3 years and no rigid storage conditions
What can increase the absorption of nitroglycerin transdermal patches?
Exercise and high temperatures
MOA of calcium channel blockers
*inhibit movement of calcium ions across the cell membrane decreasing the contraction of cardiac and vascular smooth muscle cells and depresses impulse formation and conduction velocity
Dihydropyridine calcium channel blockers
Nifedipine, Nimodipine, Amlodipine, Felodipine, Isradapine, Nicardipine, Nisoldipine
Effects of calcium channel blockers
*Decrease coronary vascular resistance
*Increase epicardial coronary artery size
*decrease systemic vascular resistance
*decrease myocardial contractility
*slow sinus and AV nodal conduction
What adverse reactions occur commonly in patients treated with verapamil and diltiazem?
Depression of myocardial contractility, bradycardia, and AV block
Verapamil and Diltiazem should be used with caution in what patients?
Patients with CHF or in combination with beta-blockers
What effect does Ranolazine have on heart rate and blood pressure?
It has antianginal effects without reducing heart rate or blood pressure
Ranolazine is contraindicated with what medications?
*CYP3A inducers (Rifampin, rifabutin, rifapentine, phenoarbital, phenytoin, carbamezapine, St.John's Wort)
*CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, nefazadone, ritonavir, indinavir)
Adverse reactions of Ranolazine
Bradyarrhythmia, hypotension, peripheral edema, prolonged QT interval, N/V,constipation, dizziness, headache
Four areas in the management of chronic stable angina pectoris
*Correction/treatment of all modifiable cardiovascular risk factors
*Alteration in lifestyle
*Drug therapy
*Revascularization therapy (PTCA or CABG) in patients where medical therapy is not effective in reducing the number of anginal attacks or with underlying severe CAD
What drug is recommended in stable angina and has been shown to reduce the risk of first MI?
Aspirin
What medication should be used in patients with chronic stable angina who cannot take beta blockers?
Calcium channel blocker
What medications are often used with nitrates to prevent angina during the nitrate-free interval?
Beta Blockers and Calcium channel blockers
Why should diltiazem and verapamil be used with caution with beta blockers?
slowing of the AV nodal conduction and decreasing contractility
Myocardial ischemia associated with coronary artery vasospasm and not necessarily associated with atheroscleoritic CAD
Variant Angina or Prinzmetal's angina
Decreased myocardial oxygen supply in variant angina is due to?
narrowing of a large coronary vessel
What is used for chronic prophylaxis of variant angina?
Calcium channel blockers or long acting nitrates with nitrate free period during the day
Combination therapy with what 2 CCBs have shown effective in variant angina but with increased adverse drug effects?
Diltiazem and Nifedipine
Why should beta blockers be avoided in patients with variant angina?
exacerbation of coronary artery vasospasm
How does unstable angina usually present?
*rest angina over 20 minutes in duration
*new onset angina which occurs with minimal exertion
*angina with increasing frequency/duration
What does an ECG of a patient with unstable angina usually show?
ST Segment changes
*elevation with STEMI
*depression with UA/NSTEMI
What 3 processes contribute to the decreased myocardial oxygen supply with unstable angina?
*progression of atherosclerosis
*platelet aggregation
*thrombus formation
When a patient is admitted to the hospital for acute coronary syndrome, what does standard medical therapy usually consist of?
*Aspirin
*Beta blocker
*Anticoagulant therapy
*GP IIb/IIIa inhibitor
*Thienopyridine (Clopidogrel)
What medication is recommended immediately for patients with unstable angina?
Aspirin (chew or swallow)
Why is Hirudin, a direct thrombin inhibitor, not indicated in unstable angina?
Incidence of intracranial hemorrhage
Why are thrombolytics not indicated in unstable angina?
Clinical studies have shown no beneficial effects
IV nitroglycerin is recommended for patients with unstable angina when?
Continuation of chest pain after 3 sublingual nitroglycerin tablets and initiation of beta blockers
When are calcium channel blockers indicated in patients with unstable angina?
When patietns are not controlled with optimal doses of nitrates and beta blockers or in patients with a known vasospastic component to their angina
Class I Recommendations for Anti-Ischemic Therapy
*Bed rest with continuous ECG monitoring
*Supplemental Oxygen
*SL NTG every 5 minutes up to 3 doses
*IV NTG in first 48 hours
*Oral BB therapy
*If BB contraindicated - nonDHP CCB
*ACE-I in patients with pulmonary congestion or LVEF under 40%
*ARB in patients intolerant of ACE-I and signs of HF or LVEF under 40%
*Discontinue any NSAIDs except for aspirin
Class I Antiplatelet therapy recommendations
*Aspirin given ASAP
*Clopidogrel if unable to take aspirin
*Proton pump inhibitor in patients with hx of GI bleed to minimize risk with aspirin or clopidogrel
*Clopidogrel or an IV GPIIb/IIIa inhibitor in addition to aspirin prior to angiography
*Clopidogrel and aspirin for at least 1 month up to 1 year