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Coronary Artery Disease, Myocardial Ischemia and Myocardial Infarction and continuums that do what?
1. Impairs pumping ability of the heart by depriving the heart muscle of blood-borne oxygen and nutrients.
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Imbalances between supply and demand occur from what?
- 1. Tachycardia
- 2. Exercise
- 3. HTN
- 4. valvular disease
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Ischemic Heart Disease begins with CAD primarily from atherosclerosis, slide One:
- 1. Dyslipidemia, HTN, Tobacco use, DM, Obesity, Sedentary lifestyle, nontraditional factors..
- 2. Atherosclerotic plaques can grow to occlude blood flow (leads to stable angina or effort related) or can rupture/ulcerate leading to thrombus formation (acute coronary syndromes, unstable angina, myocardial infarction).
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Angina Pectoris; Determinant of myocardial oxygen demand what are they:
- 1. Wall Stress from; (1) Intraventricular Pressure (2) Ventricular Radius (volume) (3) Wall Thickness
- 2. Heart Rate
- 3. Contractility
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Angina Pectrois; What are the Determinants of myocardial oxygen supply;
- 1. Perfusion Pressure (AoDBP)
- 2. Duration of diastole
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Angina Pectrois; What are the Determinants of vascular tone?
- 1. cGMP (improves relaxation)
- 2. Ca++ (modulates myosin light chain kinase)
- 3. resting Membrane potential (at or below increases excitability)
- 4. cAMP (improves relaxation/inactivity)
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What are the three class of treatment for Angina Pectoris?
- 1. Organic Nitrates - (improve fuel flow, decrease demand)
- 2. Calcium channel blockers - (Decrease Demand)
- 3. Beta Blockers - (Decrease demand)
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What is the Pharmacokinetics of Nitrates / Nitrites?
- 1. Liver
- - Organic nitrate reductase
- 2. Bioavailability
- - Per oral route, only 10-20%
- - Therefore, nitroglycerine and isosorbide dintrate given SL to bypass liver.
- - Isosorbide mononitrate for oral use, 100% bioavialability
- 3. Excretion
- - After glucuronidation, largely by kidneys
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Pharmacodynamics; What is the mechanism of action in smooth muscle for Nitrates / Nitrites?
- 1. Drug activated by release of nitric oxide via ALDH2
- 2. Free nitrite ion released, converted to nitric oxide
- 3. Combines with guanylyl cyclase, increases cGMP
- 4. Increased cGMP increases smooth m. relaxation
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What are the organ system effects, vascular smooth muscle, of Nitrates / Nitrites?
- 1. Arterial relaxation
- 2. Venous relaxation
- 3. Vein relaxation greater than arterial
- 4. marked vein relaxation
- 5. Increased venous capacitance
- 6. Decreased Ventricular Load
- 7. Studies suggest redistribution of coronary flow from normal to ischemic tissue
- 8. Weak negative inotropic effect via nitric oxide
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What are the acute adverse effects of Nitrates / Nitrites?
- 1. Orthostatic hypotension
- 2. Tachycardia (Autonomic Response)
- 3. HA (Nitrates contraindicated in increase ICP)
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Tolerance of nitrates / nitrites will cause what?
- 1. Tachyphylaxis with long acting preparations (oral/TD)
- May be result of decreased NO release
- Systemic compensation (Sympathetic discharge, salt and water retention over (time)
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Mechanism of clinical effects: Nitrate effects in angina of effort is what?
- 1. Nitrate effects in angina of effort
- 2. Decreased venous return,
- 3. decreased intracardiac volume,
- 4. decreased wall tension=Decreased myocardial oxygen demand
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Mechanism of clinical effects: Nitrate effects in Variant Angina is what?
- 1. Nitrate effects in Variant angina
- 2. Relax smooth m. of epicardial coronary arteries,
- 3. thus relieving CA spasm
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Mechanism of clinical effects: Nitrate effects in Unstable Angina is what?
- 1. Nitrate effects of Unstable angina
- 2. Thought to be from increased epicardial CA diameter and decreased myocardial oxygen demand
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Name some beneficial effects of nitrates in the treatment of angina
- 1. Decreased ventricular volume
- 2. Decreased arterial pressure
- 3. Decreased ejection time
- will all result in decreased myocardial oxygen requirement
- 4. Vasodilation of epicardial coronary arteries
- will result in relief of coronary artery spasm
- 5. Increased collateral flow
- will improve perfusion to ischemic myocardium
- 6. Decreased left ventricular diastolic pressure
- Will result in improved subendocardial perfusion
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Name some deleterious effects of nitrates in the treatment of angina
- 1. Reflex tachycardia
- will result in myocardial oxygen requirement
- 2. reflex increase in contractility
- 3. decreased diastolic perfusion time due to tachycardia
- will result in decreased coronary perfusion
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What is the Pharacokinetics of calcium channel blockers?
- 1. Orally active
- 2. High first pass effect
- 3. High plasma protein binding
- 4. verapamil and diltiazem also used IV
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What is the mechanism of action for calcium channel blockers
- 1. Bind to a1 subunits of L-type Ca++ channels. Allosteric difference b/n dihydropyridines and non dihydropyrodines
- 2. Bind to open and inactive channels, inside cell membrane
- 3. Can be affected by sympathomimetics (increase transmembrane flux of Ca++)
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What is the organ system effects of calcium channel blockers?
- 1. Smooth m.: Relaxation. Vascular smooth m. more sensitive.
- -Dihydropyridines more effective on vascular smooth m.
- 2. Cardiac m.:
- -Non dihydropyridines more effective on cardiac. Verpamil and diltiazem block tachycardias in SA and AV node more than dihydropyridines.
- 3. Skeletal m.: Not depressed.
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What is the Toxicity of Calcium channel blockers?Direct effect of their therapeutic actions
1. Cardiac depression (bradycardia, AV block, arrest, heart failure)
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2. Nifedipine (immediate acting) associated with increased incidence of MI in HTN patients. Should be avoided.
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3. Patients on β blockers more sensitive to cardiodepressant effects of Ca++ channel blockers.
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What are the mechanism of clinical effects for calcium channel blockers?
- 1. Decrease contractility
- 2. Decrease arterial and intra-ventricular pressure
- 3. Decrease SA & AV node conduction with verapamil and diltiazem. Less reflex tachycardia noted with non dihydropyridines, so choice agents for control of angina.
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Beta Blockers: Although not vasodilators may be used for angina of effort because it?
- 1. Decreased myocardial oxygen consumption
- Therapeutic effects r/t hemodynamic effects-
- -Decrease HR
- -Decrease BP
- -Decrease Contractility
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When treating Angina of effort what drugs may be used?
- 1. Long acting nitraes
- 2. Calcium channel blockers
- 3. beta blockers
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Long-acting nitrates, Ca++ channel blockers, or β blockers may be chosen.
- Choice depends on patient’s response.
- 1. HTN patients: Use Ca++ chanel or β blockers
- 2. Non HTN patients: long-acting nitrate appropriate
- 3. If monotherapy ineffective, add drug from different class.
- (See table 12-7)
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Nitates alone will:
- 1. reflex increase heart rate
- 2. decrease arterial pressure
- 3. decrease end diastolic volume
- 4. reflex increase contractility
- 5. decrease ejection time
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Beta blockers or calcium channel blockers will:
- 1. decrease increase heart rate
- 2. decrease arterial pressure
- 3. increase end diastolic volume
- 4. decreasee contractility
- 5. increase ejection time
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Combined Nitrates with Beta blockers or calcium channel blockers will:
- 1. decrease increase heart rate
- 2. decrease arterial pressure
- 3. none or decreased end diastolic volume
- 4. none contractility
- 5. none ejection time
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What does positive inotropic mean?
1. strengthens contraction
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what does negative inotropic mean?
1. weakens contraction
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what does positive chronotropic mean?
1. increase Heart rate
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What does negative chronotropic mean?
1. decrease heart rate
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What is the definition of CHF?
1. CO not sufficient to maintain tissue oxygen demands
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2. 50% Mortality within the first 5 years
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3. Systolic
- -Decreased contractility
- -Decreased ejection fraction
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4. Diastolic
- -Decreased elasticity
- -Decreased filling
- -Decreased stroke volume but can have a normal ejection fraction
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List the pathophysiologic mechanisms involved in CHF:
- 1. Primary insult
- 2. decreased cardiac performance
- 3. neurohormonal stimulation
- 4. release of renin/angiotensin, catecholamines, others
- 5. Vasoconstriction and increased vascular volume - increased after load -decreased cardiac performance
- 6. Increased preload
- 7. heart failure symptoms
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What are the goals for treatment of CHF?
- 1. Prevent further damage
- 2. Promote optimal function
- 3. Monitor closely for early intervention
- 4. Minimize episodes of acute decompensation
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5. Treat Co-morbid Exacerbating conditions
- -HTN, Hyperlipidemia, DM
- -Tobacco cessation
- 6. Self Monitoring
- -Nutrition
- -Symptoms
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What drug groups are used in Heart failure? Chronic heart failure
- 1. Diuretics
- 2. Aldosterone receptor antagonists
- 3. ACEI
- 4. ARBs
- 5. B Blockers
- 6. Cardiac Glycosides
- 7. Vasodilators
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What drug groups are used in Heart failure? Acute heart failure
- 1. Diuretics
- 2. Vasodilators
- 3. Beta Agonists
- 4. Bipyridines
- 5. Natriuretic Peptide
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Pharmacologic treatment for CHF
- 1. Diuretic
- 2. Aldosterone Antagonists
- 3. ACE Inhibitors
- 4. ARB
- 5. Beta Blockers
- 6. Cardiac glycosides
- 7. Vasodilators
- 8. Bipyridines
- 9. Natriuretic peptides
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Pharmacologic treatment for CHF: Diuretics, what is the purpose, specific meds and cautions?
- 1. Decrease venous pressure and preload>decrease NaCl/H2O retention>decrease edema>remodeling> increase pump efficiency, esp. in systolic failure.
- 2. Specific Meds:
- -Furosemide drug of choice in acute heart failure.
- -Spironolactone, Eplerenone with ACE I decrease Morbidity/Mortality with Severe Disease
- -Start with Thiazide with mild disease, switching to loop as needed.
- 3. Cautions:
- -Monitor secondary K+ loss if concurrently taking digoxin
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Pharmacologic treatment for CHF: Ace Inhibitors, ARBs: Purpose
- 1. Purpose
- -Decrease Preload by decrease NaCl/H2O retention
- -Decrease Afterload
- -Decrease remodeling (thickening/dilation)
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2. ACE = Use appears to lead to specific decrease in Morbidity and Mortality in moderate and severe disease
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3. ACE = First line drug in LV disease with no edema
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4. ACE = First line tx with diuretic for chronic CHF
-NOT a substitute for digoxin
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5. All ACE are equally effective
6. If patient unable to tolerate ACEI, try ARB.
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Pharmacologic treatment for CHF: Beta Blocker:
- 1. Meds
- Studies show positive effect with use of bisoprolol, carvedilol and metoprolol
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2. Mechanism of Action
Used to prevent further injury by decreasing HR
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3. May need to use for months prior to seeing an effect
-Start low go slow
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Pharmacologic treatment for CHF: Cardiac Glycoside Digitalis-Digoxin
- 1. Purpose
- -Positive Inotropic
- -Negative Chronotropic
- 2. Pharmacodynamics/Mechanism of Action
- Mechanical:
- -Inhibit sodium pump (Na+/K+-ATPase transporter): Inc. intracellular Na+
- -Reduce Ca++ expulsion from Inc. intracellular Na+. Ca++ sequestered in SR.
- Electrical:
- -Direct- Dec. SA node rate, Dec. AV node conduction velocity/Inc. refractory period, Slight Dec. in refractory period in Purkinje system.
- -ECG: Increased PR interval and Decreased QT interval.
- 3. Pharmacokinetics
- -65-80% absorbed after po administration
- -2/3rd excreted: Not extensively metabolized.
- -Renal clearance proportional to Cr. clearance.
- -Half life 36-40 hours
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Cardiac Glycoside Digitalis-Digoxin: Side effects and Contraindicatons/cautons
- 1. Side effects
- -HR must be > 60/min to give
- -Arrhythmias with toxicity
- -Bradycardia/tachycardia
- 2. Contraindications/Cautions
- -Hyperkalemia decreases effects of digitalis, esp. toxic effects.
- -Hypercalcemia increases effect and risk of arrhythmia.
- -Hypomagnesaemia increases digitalis effects.
- -Take home message: Carefully evaluate serum electrolytes before/during digitalis therapy, monitor closely for digitalis-induced arrhythmias.
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Pharmacologic treatment for CHF: Vasodilators
- 1. Venodilator
- -Isosorbide
- -Decreases preload ventricular stretch
- -Antianginal
- 2. Arteriolar
- -Hydralazine
- -Decreased mortality when used with Isosorbide
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Pharmacologic treatment for CHF: bipyridines
- 1. Purpose
- -Positive Inotropic
- -Vasodilation
- 2. Meds
- -Inamrinone, milrinone – parenteral only
- 3. Mechanism of Action
- -Phosphodiesterase inhibitors, type 3.
- -Decrease cAMP breakdown
- -Moderate Ca++ flux
- 4. Side effects
- -Thrombocytopenia, hepatotoxic, arrhythmias
- 5. Indications
- -Emergency decompensation use only
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What is the treatment for Acute Decompensation Episodic Treatement?
- 1. Direct Vasodilator
- -Nitroprusside, nitroglycerin
- 2. Beta Adrenoceptor agonist
- -Dobutamine
- -Positive Ionotropic effect
- -Increase CO
- -Dopamine
- -Positive Ionotropic effect
- -Increase BP
- -Increase renal blood flow (?)
- 3. Bipyridines
- 4. Natriuretic Peptides
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Cardiac output =
1. heart rate x stroke volume
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Blood pressure = cardiac output x resistance
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Tie it together:
- 1. Cardiac Output = Heart Rate x Stroke Volume
- 2. The Acutely Failing Heart:
- Fix treatable cause if possible: AMI- PCI, thrombolytics, etc.
- 3. IV TX:
- -Unload: Diuretics- Furosemide
- -Augment: Beta Agonists- Dobutamine, Dopamine
- -Relax: Vasodilators- Na++ nitroprusside, nitroglycerin, nesiritide.
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Tie it together?
- 1. Cardiac Output = Heart Rate x Stroke Volume
- 2. The Chronically Failing Heart:
- 3. Class A (Prefailure- risk factors)
- -Control: Tx obesity, HTN, DM, hyperlipidemia
- 4. Class B (Class I- Symptoms with severe exercise)
- -Relax: ACEI/ARB
- -Slow: B Blocker
- -Unload: Diuretic
- 5. Class C (II/III- Symptoms with marked or mild exercise)
- -Same as B, Add:
- -Remodel: Ald. Agonist
- -Squeeze: Digoxin
- -Mo’ Relax: Hydralazine, nitrate
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