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Cardiovascular System The cardiovascular system includes the heart, blood vessels (arteries and veins), and blood.

. Blood rich in oxygen, nutrients, & hormones moves thru vessels called arteries, which narrow to arterioles. Capillaries transport nourished blood to body cells & absorb waste products (CO2, urea, creatinine, ammonia) The deoxygenated blood returns to the circulation by the venules and veins to be eliminated by the lungs and kidneys with other waste products Blockage of vessels can inhibit blood flow. Heart The heart is composed of four chambers: the right and left atria and the right and left ventricles o The right atrium receives deoxygenated blood from the circulation o The right ventricle pumps blood thru the pulmonary artery to the lungs for gas exchange (CO2 for O2) o The left atrium receives oxygenated blood o The left ventricle pumps the blood into the aorta for systemic circulation. Myocardium, heart muscle that surrounds the ventricles and atria. o The ventricles are thick-walled (especially the left ventricle) to achieve the muscular force needed to pump blood to the pulmonary and systemic circulations. o The atria are thin-walled, have less pumping action, and serve as receptacles for blood from the circulation and lungs. Pericardium, a fibrous that covers the heart which protects it from injury and infection. Endocardium, a three-layered membrane that lines the inner part of the heart chambers. Four valves atrioventricular (tricuspid and mitral) and two semilunar (pulmonic and aortic) control blood flow between the atria and ventricles and between the ventricles and the pulmonary artery and the aorta. Two coronary arteries o Right coronary artery supplies blood to the right atrium and ventricle of the heart o Left coronary artery supplies blood to the left atrium and ventricle of the heart. o The left coronary artery divides near its origin to form the left circumflex artery and the anterior descending artery. o Blockage to one of these arteries can result in a myocardial infarction (MI), or heart attack. Conduction of Electrical Impulses Sinoatrial (SA) node, cardiac impulse originates in the posterior wall of the right atrium. o A.k.a. pacemaker, because it regulates the heartbeat (firing of cardiac impulses) o 60 to 80 beats/min in a normal adult. Atrioventricular (AV) node, located in the posterior right side of the interatrial septum o A.k.a. functional pacemaker, o It has a continuous tract of fibers called the bundle of His, or the AV bundle. o 40 to 60 beats/min in a normal adult o If the SA node fails, the AV node takes over, thus causing a slower heart rate. o The AV node sends impulses to the ventricles. These two conducting systems (SA node and AV node) can act independently of each other. The ventricle can contract independently 30 to 40 times per minute. Drugs that affect cardiac contraction are Ca, digitalis preparations, & quinidine and its related preparations. The autonomic nervous system (ANS) and the drugs that stimulate or inhibit it influence heart contractions. o The sympathetic nervous system and the drugs that stimulate it increase heart rate o The parasympathetic nervous system and the drugs that stimulate it decrease heart rate Regulation of Heart Rate and Blood Flow The heart beats approximately 60 to 80 bpm in an adult. As blood travels, resistance to blood flow develops and arterial pressure increases. The average systemic arterial pressure, a.k.a. blood pressure, is 120/80 mmHg. Arterial blood pressure is determined by peripheral resistance and cardiac output, the volume of blood expelled from the heart in 1 minute, which is calculated by multiplying the heart rate by the stroke volume: CO (Cardiac Output) = HR (Heart Rate) x SV (Stroke Volume)

The average cardiac output is 4 to 8 L/min. Stroke volume, amount of blood ejected from the left ventricle with each heart beat, is 70 ml/beat. Three factors determine the stroke volume: 1. Preload refers to the blood flow force that stretches the ventricle. However, o an increase in preload can increase stroke volume, a decrease in preload can decrease stroke volume 2. Contractility is the force of ventricular contraction 3. Afterload is the resistance to ventricular ejection of blood, which is caused by opposing pressures in the aorta and systemic circulation. o If afterload increases, stroke volume will decrease; if afterload decreases, stroke volume increase Specific drugs can increase or decrease preload and afterload, affecting both stroke volume and cardiac output. Most vasodilators decrease preload and afterload, thus decreasing arterial pressure and cardiac output. Circulation 1. Pulmonary circulation, the heart pumps deoxygenated blood from the right ventricle thru the pulmonary artery to the lungs o The artery carries blood that has a high [CO2] to the lungs o Oxygenated blood returns to the left atrium by the pulmonary vein. 2. Systemic or peripheral circulation, the heart pumps blood from the left ventricle to the aorta and into the general Circulation. o Arteries and arterioles carry blood to capillary beds. o Nutrients in the capillary blood are transferred to cells in exchange for waste products. o Blood returns to the heart through venules and veins. Blood Blood is composed of plasma, red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. o Plasma, made up of 90% water & 10% solutes, constitutes 55% of the total blood volume o The solutes in plasma include glucose, protein, lipids, amino acids, electrolytes, minerals, lactic and pyruvic acids, hormones, enzymes, oxygen, and carbon dioxide. The major function of blood is to provide nutrients and oxygen to body cells. Most of the oxygen is carried on the hemoglobin of RBCs. WBCs are the major defense mechanism of the body and act by engulfing microorganisms; o They also produce antibodies. The platelets are large cells that cause blood to coagulate. RBCs have a life span of approximately 120 days; WBCs have a life span of only 2 to 24 hours. Heart Failure Digitalis preparations is known for their effectiveness in treating heart failure (HF), a.k.a. (CF) & (CHF) HF or pump failure is when the heart muscle (myocardium) weakens and enlarges, and it loses its ability to pump blood thru the heart & into the systemic circulation. CHF is when compensatory mechanisms fail and the peripheral and lung tissues are congested The causes of HF include chronic hypertension, myocardial infarction (MI), coronary artery disease (CAD), valvular heart disease, congenital heart disease, and the aging heart. HF can be left-sided or right-sided. o Left-sided HF occurs when the left ventricle does not contract sufficiently to pump the blood returned from the lungs and left atrium out through the aorta into the peripheral circulation This causes excessive amounts of blood to back up into the lung tissue. Usually the client has shortness of breath (SOB) and dyspnea. o Right-sided HF occurs when the heart does not sufficiently pump the blood returned into the right atrium from the systemic circulation. The blood & its constituents are backed up into peripheral tissues, causing peripheral edema. One type of heart failure can lead to the other. Myocardial hypertrophy resulting in cardiomegaly (increased heart size) can be a major problem associated with progressive heart failure.

Physiology of Heart Failure There is an increase in preload & afterload. An increase in preload results from an increase in blood in the ventricle at the end of diastole, caused by a pathologic increase in the elasticity of the ventricular walls associated with a weakened heart. An increased afterload, there is an increased pressure in the ventricular wall caused by increased resistance in the aorta which must be over-come to open the aortic valve so blood can be injected into the circulation. HF is classified in stages according to its severity. Stages Characteristics According to Stages
1 (A) 2 (B) 3 (C) 4(D) High risk for HF without symptoms or structural heart disease Some level of cardiac changes, e.g., decreased ejection fraction without symptoms of heart failure. Structural heart disease with symptoms of HF, i.e., fatigue, shortness of breath, edema, and decrease in physical activity Severe structural heart disease and marked symptoms of heart failure at rest.

Pharmacologic Measure to Treat Heart Failure First-line drugs used to treat acute heart failure include inotropic agents (dopamine & dobutamine) and phosphodiesterase inhibitors (inamrinone (a.k.a. amrinone) & milrinone [Primacor]). Secondary drugs used to treat acute heart failure are natural cardiac glycosides (a.k.a. digitalis glycosides) o They are found in a plant called Digitalis o They inhibit the Na/K pump, resulting in an increase in intracellular Na. This increase leads to an influx of Ca, causing the cardiac muscle fibers to contract more efficiently o Digitalis preparations like digoxin have three effects on heart muscle: 1. a positive inotropic action (increases myocardial contraction stroke volume) 2. a negative chronotropic action (decreases heart rate) 3. a negative dromotropic action (decreases conduction of the heart cells) o The increase in myocardial contractility increases cardiac, peripheral, and kidney function by increasing cardiac output, decreasing preload, improving blood flow to the periphery & kidneys, decreasing edema, and increasing fluid excretion. As a result, fluid retention in the lung and extremities is decreased. o Digoxin does not prolong life. It acts by increasing the force & velocity of myocardial systolic contraction o Cardiac glycosides are also used to correct: Atrial fibrillation, cardiac dysrhythmia with rapid uncoordinated contractions of atrial myocardium Atrial flutter, cardiac dysrhythmia with rapid contractions of 200 to 300 beats per minute [bpm] This is accomplished by the negative chronotropic effects (decreases heart rate) and negative dromotropic effects (decreases conduction through the atrioventricular [AV] node) o Digoxin does not convert atrial fibrillation to normal heart rhythm. o For management of atrial fibrillation, a Ca channel blocker (verapamil [Calan]) may be prescribed. o To prevent thromboemboli resulting from atrial fibrillation, warfarin (Coumadin) is prescribed concurrently with other drug therapy Other drugs prescribed for heart failure include diuretics. Beta blockers, ACE inhibitors, angiotensinreceptor blockers (ARBs), calcium channel blockers, & vasodilators. Nonpharmacologic Measures to Treat Heart Failure The client should limit salt intake to 2 g daily, which is approximately 1 teaspoon. Alcohol intake should be either decreased to one drink per day or completely avoided, because excessive alcohol use can lead to cardiomyopathy. Smoking should be avoided, because it deprives the heart of oxygen (O2). Obesity increases cardiovascular problems; thus obese clients should decrease fat and caloric intake. o Mild exercise such as walking or bicycling is recommended. Laboratory Tests Atrial Natriuretic Hormone (ANH) or Peptide (ANP) Reference value: 20-77 pg/ml; 20-77 ng/l (SI units). An elevated ANH or ANP may confirm HF. ANH is secreted from the atria of the heart and acts as an antagonist to rennin and aldosterone o Its released during expansion of the atrium, produces vasodilatation, increases glomerular filtration rate

Brain Natriuretic Peptide (BNP) Reference values: Desired value: less than 100 pg/ml; positive value: greater than 100 pg/ml The BNP test aids in the diagnoses of HF Diagnosing HF is difficult in persons with lung disease who are experiencing dyspnea and in obese or elderly BNP is higher than 100 pg/ml in women > 65 years old. An 80-year-old womans BNP may be 160 pg/ml. With HF, the BNP is as high as 400 pg/ml. BNP is considered a more sensitive test than ANP for diagnosing HF Digoxin Pharmacokinetics
The absorption rate of digoxin in oral tablet is > 70%, 90% in liquid form, & 90% to 100% in capsule form. The protein-binding power for digoxin is low, t is 36 hrs. Because of its long t , drug accumulation can occur. Side effects should be closely monitored to detect digitalis toxicity. Clients should be aware of the SE and report to the doc. 30% of digoxin is metabolized by the liver, 70% is secreted by the kidneys mostly unchanged. Kidney dysfunction can affect the excretion of digoxin. Thyroid dysfunction can alter the metabolism of cardiac glycosides. o For clients with hypothyroidism, the dose of digoxin should be decreased; o For clients with hyperthyroidism, the dose may need to be increased. Digitoxin is a potent cardiac glycoside that has a very long t & is highly protein-bound: it is seldom prescribed. The names digoxin & digitoxin are very similar, so the client should take the same brand of digoxin to avoid unnecessary SE or adverse reactions. In clients with a failing heart, cardiac glycosides increase myocardial contraction, which increases cardiac output and improves circulation and tissue perfusion. Because these drugs decrease conduction thru the AV node, the heart rate decreases. The therapeutic serum level is 0.5-2.0 ng/ml for digoxin. To treat HF, the lower serum therapeutic levels should be obtained To treat atrial flutter or fibrillation, the higher therapeutic serum levels are required. Of these two drugs, digoxin is more frequently used. It can be administered orally or IV. Drug interaction with digitalis preparations can cause digitalis toxicity. Many of the potent diuretics, i.e. fiirosemide (Lasix) and hydrochlorothiazide (HydroDlURLL), promote the loss of K The resultant hypokalemia increases the effect of digoxin at its myocardial ceil site of action, resulting in digitalis toxicity. Cortisone preparations taken systemically promote Na retention and K excretion and can also cause hypokalemia. Clients who take digoxin along with a K-wasting diuretic or a cortisone drug should consume foods rich in K or take K supplements to avoid hypokalemia & digitalis toxicity. Antacids can decrease digitalis absorption if taken at the same time. To prevent this problem, doses should be staggered.

Pharmacodynamics

Drug Interactions

Digitalis (Digoxin) Toxicity Overdose or accumulation of digoxin causes digitalis toxicity. Signs & symptoms: anorexia, diarrhea, nausea and vomiting, bradycardia (pulse rate < 60 bpm), premature ventricular contractions, cardiac dysrhythmias, headaches, malaise, blurred vision, visual illusions (white, green, yellow halos around objects), confusion, and delirium. Older adults are more prone to toxicity. Cardio toxicity is a serious adverse reaction; ventricular dysrhythmias result. Three cardiac-altered functions can contribute to digoxin-induced ventricular dysrhythmias: 1. Suppression of AV conduction 2. Increased automaticity 3. A decreased refractory period in ventricular muscle Antidysrhythmics phenytoin & lidocaine are effective in treating digoxin-induced ventricular dysrhythmias Antidote for Cardiac/Digitalis Glycosides Digoxin immune Fab (ovine, Digibind) may be given to treat severe digitalis toxicity. o It binds with digoxin to be excreted in urine; thus digoxin is unable to bind at the cellular site of action. Signs & symptoms of digoxin toxicity should be reported promptly to the doc. Instruct client how to check the apical pulse rate before taking digoxin and to call the doc for pulse rate less than 60 bpm or irregular pulse. Serum digoxin levels should be closely monitored. Digitalis toxicity may result in first-degree, second-degree, or complete heart block.

Herbal Alert: Cardiac Glycosides: Digoxin Ginseng may falsely elevate digoxin levels. St Johns wort decreases absorption of digoxin and thus decreases serum digoxin level. Psyllium (Metamucil) may decrease digoxin absorption. Hawthorn may increase the effect of digoxin. Licorice can potentiate the effect of digoxin. o It promotes hypokalemia, which increases the effect of digoxin. It may cause digitalis toxicity. Aloe may increase the risk of digitalis toxicity. o It increases K loss, which increases the effect of digoxin. Ma-huang or ephedra increases the risk of digitalis toxicity Goldenseal may decrease the effects of cardiac glycolsides and increase the effects of antidysrhythmics. Phosphodiesterase Inhibitors Positive inotropic drug group given to treat acute HF or when theres no response to the use of other agents They inhibit the enzyme phosphodiesterase, promoting a positive inotropic response & vasodilation The two drugs in this group are inamrinone lactate (Inocor) and milrinone lactate (Primacor). o These drugs increase stroke volume and cardiac output and promote vasodilation. o They are administered IV for no longer than 48 to 72 hours. Severe cardiac dysrhythmias might result from the use of phosphodiesterase inhibitors, so the clients electrocardiogram (ECG) and cardiac status should be closely monitored. Other Agents Used to Treat Heart Failure 1. Vasodilators They decrease venous blood return to the heart; thus there is a decrease in cardiac filling, ventricular stretching (preload), and oxygen demand on the heart. The arteriolar dilators act in three ways 1) to reduce cardiac afterload, which increases cardiac output 2) to dilate the arterioles of the kidneys, which improves renal perfusion and increases fluid loss 3) to improve circulation to the skeletal muscles 2. Angiotensin-converting enzyme (ACE) inhibitors They dilate venules and arterioles, improving renal blood flow and decreasing blood fluid volume. They also moderately decrease the release of aldosterone, which in turn reduces Na and fluid retention. They can increase K levels, so serum K levels should be monitored, especially if K-sparing diuretics (e.g., spironolactone [Aldactone]) are being taken concomitantly. 3. Angiotensin II receptor antagonists (blockers) i.e. valsartan (Diovan) and candesartan (Atacand) are for HF clients who cannot tolerate an ACE inhibitor 4. Diuretics (thiazides, furosemide) First-line drug treatment for reducing fluid volume & are frequently prescribed with digoxin/other agents. 5. Spironolactone (Aldactone) A potassium-sparing diuretic used in treating moderate to severe HF Spironolactone blocks the production of aldosterone o Aldosterone secretions are increased in HF o This promotes body loss of K & Mg needed by the heart and increases Na & water retention.. Spironolactone improves heart rate variability and decreases myocardial fibrosis. The recommended dose is 12.5 to 25 mg per day. Hyperkalemia is rare unless the client is receiving 50 mg daily and has renal insufficiency. However, the serum potassium level should be closely monitored. 6. Beta-blockers Certain beta-blockers are contraindicated for clients with HF, because they reduces cardiac contractility However, with chronic heart failure certain beta-blockers (carvedilol [Coreg] & metoprolol tartrate [Toprol-XL]) improve cardiac performance Other beta-blockers are not recommended for clients with class IV heart failure

7. Nesiritide (Natrecor) Its an ANP hormone that inhibits antidiuretic hormone (ADH) by increasing urine Na loss. It promotes vasodilation, natriuresis, and diuresis. It is useful for those who have acute decompensated HF with dyspnea at rest / with little physical exertion. 8. BiDil A combination of hydralazine (for blood pressure) and isosorbide dinitrate (a dilator to relieve heart pain) for treating HF in African Americans. Antianginal Drugs They are used to treat angina pectoris (acute cardiac pain caused by inadequate blood flow to the myocardium due to either plaque occlusions within or spasms of the coronary arteries). With decreased blood flow there is a decrease in O2 to the myocardium, which results in pain. Anginal pain is described as tightness, pressure in the center of the chest, and radiating down the left arm. Referred pain felt in the neck and left arm commonly occurs with severe angina pectoris. Anginal attacks may lead to myocardial infarction (Ml), or heart attack; usually lasts for a few minutes. Stress tests, echocardiogram, cardiac profile laboratory tests, and cardiac catheterization may be needed to determine the degree of blockage in the coronary arteries. Types of Angina Pectoris The frequency of angina pain depends on many factors, including the type of angina. There are three types of angina: 1. Classic (stable): Occurs with stress or exertion 2. Unstable (preinfarction): Occurs frequently over the course of a day with progressive severity 3. Variant (Prinzmetal, vasospastic): Occurs during rest The first two types are caused by a narrowing or partial occlusion of the coronary arteries Variant angina is caused by vessel spasm (vasospasm). It is common for a client to have both classic and variant angina. Unstable angina indicates an impending MI; it is an emergency that needs immediate medical intervention. Nonpharmacologic Measures to Control Angina Avoid heavy meals, smoking, extremes in weather changes, strenuous exercise, and emotional upset. Proper nutrition, moderate exercise (only after consulting with a doc), adequate rest & relaxation techniques Types of Antianginal Drugs They increase blood flow either by increasing O2 supply or by decreasing O2 demand by the myocardium. Nitrates reduce venous tone, which decreases the workload of the heart and promotes vasodilation. Beta-blockers and calcium channel blockers decrease the workload of the heart and decrease O2 demands. With unstable angina, immediate medical care is necessary. o Nitrates are usually given subQ and IV p.r.n.. o If the heart pain continues, a beta block is given IV, and o If the client is unable to tolerate beta blockers, a calcium blocker may be substituted.
Drug Group Nitrates Beta-Blockers Ca Channel Blockers Variant (Vasospastic) Angina Relaxation of coronary arteries, which decreases vasospasms and increases O2 supply Not effective Relaxation of coronary arteries, which decreases vasospasms and increases O2 supply Classic (Stable) Angina Dilation of veins, which decreases preload and decreases O 2 demand Decreases heart rate and contractility, which decreases O2 demand Dilation of arterioles, which decreases afterload and de- creases 02 demand. Verapamil and diltiazem decrease heart rate & contractility.

1. Nitrates They affect coronary arteries and blood vessels in the venous circulation. They cause generalized vascular & coronary vasodilation, thus increasing blood flow thru the coronary arteries to the myocardial cells. This group of drugs reduces myocardial ischemia but can cause hypotension The sublingual (SL) nitroglycerin tablet, absorbed under the tongue The average dose is 0.4 mg or gr 1/150 q 5 minutes for a total of 3 doses. o The effects last for 10 minutes

o It decomposes when exposed to heat & light, so they should be kept in airtight glass screw-cap tops non-childproof containers. o This facilitates emergency use by older adults who may have reduced manual dexterity and are experiencing an anginal attack. After a dose of nitroglycerin, the client may experience dizziness, faintness, or headache as a result of the peripheral vasodilation. If pain persists, the client should immediately call for medical assistance Its not swallowed, because it undergoes 1st pass metabolism by the liver, which decreases its effectiveness. Instead, it is readily absorbed into the circulation through the SL vessels. Nitroglycerin is also available in topical (ointment, transdermal patch), buccal extended-release tablet, oral extended-release capsule and tablet, aerosol spray (inhalation), and IV Isosorbide dinitrate (Isordil, Sorbitrate) can be administered in SL tablet form and is also available as chewable tablets, immediate-release tablets, and sustained-release tablets and capsules. Isosorbide mononitrate (Monoket, Imdur) can be given in immediate-release & sustained-release tablet Pharmacokinetics
SL Nitroglycerin is absorbed immediately into the internal jugular vein & the right atrium. 40%-50% of nitrates absorbed thru the GI tract are inactivated by liver metabolism (1 st pass metabolism in the liver). Nitro-Bid ointment and Transderm-Nitro patch is absorbed slowly thru the skin. It is excreted primarily in the urine Nitroglycerin acts directly on the smooth muscle of blood vessels, causing relaxation and dilation. o It decreases cardiac preload and afterload and reduces myocardial O 2 demand. o With dilation of the veins, there is less blood return to the heart, o With dilation of the arteries, there is less vasoconstriction and resistance. With SL & IV use, the onset of action is rapid (1-3 minutes); it is slower with the transdermal method (30-60 minutes). The duration of action of the transdermal nitroglycerin patch is 24 hours; o Apply once a day and its removed nightly to allow for an 8-12-hour nitrate-free interval. It is necessary to avoid tolerance associated with uninterrupted use or continued dosage increases of nitrate preparations Nitro-Bid ointment is effective for only 6 to 8 hours; it must be reapplied 3 4x a day. Headaches may become less frequent with continued use. Otherwise, Acetaminophen may provide some relief. Other SE are hypotension, dizziness, weakness, and faintness. When nitroglycerin ointment or transdermal Patches are discontinued, the dose should be tapered over several weeks to prevent the rebound effect of severe pain caused by myocardial ischemia Reflex tachycardia may occur if its given too rapidly o The heart rate increases greatly because of overcompensation of the cardiovascular system Beta-blockers, calcium channel blockers, vasodilators alcohol can enhance the hypotensive effect of nitrates. IV nitroglycerin may antagonize the effects of heparin.

Pharmacodynamics

Side Effects and Adverse Effects


Drug Interactions

2. Beta-blockers Beta-adrenergic blockers block the beta1 and beta2 receptor sites. They decrease the effects of SNS by blocking the action of catecholamine, epinephrine, & norepinephrine o Thereby decreasing the heart rate and blood pressure They are used as antianginal, antidysrhythmic, and antihypertensive drugs. They are effective as antianginal because by decreasing the heart rate & myocardial contractility, reduce the need for O2 consumption and consequently reduce anginal pain These drugs are most useful for classic (stable) angina. Nonselective beta-blockers [propranolol (Inderal), nadolol (Corgard) & pindolol (Visken)] decrease the heart rate and can cause bronchoconstriction Cardio-selective beta-blockers act on beta1 receptor, thus decrease heart rate but avoid bronchoconstriction o Examples of selective beta-blockers are atenolol (Tenormin) & metoprolol (Lopressor, Toprol-XL) o Selective beta-blockers are the group of choice for controlling angina pectoris. Beta-blockers should not be abruptly discontinued. The dose should be tapered over a specified number of days to avoid reflex tachycardia and recurrence of anginal pain. Clients who have decreased heart rate & BP, have 2nd or 3rd degree AV block shouldnt take beta-blockers.

Pharmacokinetics
Beta-blockers are well absorbed PO. Propranolol (Inderal) s t of is 3- 6 hrs; atenolol (Tenormin)s t is 6-7 hrs; metoprolol (Lopressor)s t is 3-7 hrs. Propranolol & metoprolol are metabolized & excreted by the liver. Half an oral dose of atenolol is absorbed from the GI tract, the remainder excreted unchanged in feces 85% of an IV dose is excreted in urine within 24 hours. Because beta-blockers decrease the force of myocardial contraction, O 2 demand by the myocardium is reduced, and the client can tolerate increased exercise with less O2requirement. Beta-blockers tend to be more effective for classic (stable) angina. The onset of action of the nonselectrive propranolol is 30 mins, its peak action occurs in 1-1.5 hrs, duration of action 4-12 hrs The onset of action of the cardioselective atenolol is 60 mins, its peak action occurs in 2-4 hrs, duration of action is 24 hrs; The onset of action of the cardioselective metoprolol is 15 mins, and the duration of action is 6-12 hrs. Both nonselective and selective beta-blockers cause a decrease in heart rate and blood pressure For the nonselective beta-blockers, bronchospasm, behavioral or psychotic response, and impotence (with use of Inderal) are potential adverse reactions. Vital signs need to be closely monitored in the early stages of beta-blocker therapy. When discontinuing use, the dosage should be tapered for 1 or 2 weeks to prevent a rebound effect like reflex tachycardia or life-threatening cardiac dysrhythmias.

Pharmacodynamics

Side Effects & Adverse Reactions

3. Calcium Channel Blockers They are the treatment of stable & variant angina pectoris, certain dysrhythmias, and hypertension. Calcium activates myocardial contraction, increasing the workload of the heart and the need for more O2. Calcium blockers relax coronary artery spasm (variant angina) and relax peripheral arterioles (stable angina), decreasing cardiac O2 demand. o Decrease cardiac contractility (negative inotropic effect that relaxes smooth muscle), decrease afterload, decrease peripheral resistance, reduce the workload of the heart, thus decrease O2 demand Calcium channel blockers achieve their effect in controlling variant (vasospastic) angina by relaxing coronary arteries and in controlling classic (stable) angina by decreasing O2 demand. Pharmacokinetics
Verapamil (Caian), nifedipine (Procardia), dfltiazem (Cardizem) have been effectively used for the long-term treatment 80%-90% are absorbed thru the GI mucosa. However, 1st pass metabolism by the liver decreases the availability of free circulating drug, and only 20% of verapamil, 45% to 65% of diltiazem, and 35% to 40% of nifedipine are bioavailable. All three drugs are highly protein-bound (80%-90%), and their t is 2-6 hrs. Other calcium blockers are nicardipine HCI (Cardene), amlodipine (Norvasc), bephdil HCI (Vascor), felodipine (Plendil), and nisoldipine (Sular). All are high protein-bound (> 95%). Nicardipine has the shortest t at 5 hours. Bephdil is used for angina pectoris. Bradycardia is a common problem with the use of verapamil. Nifedipine promotes vasodilation of the coronary & peripheral vessels, and hypotension can result. The onset of action is 10 mins for verapamil and 30 mins for nifedipine and diltiazem. Verapamils duration of action is 3-7 hrs when give PO & 2 hrs when given IV Nifedipine and diltiazems duration of action is 6 to 8 hours. Headache, hypotension (more common with nifedipine and less common with diltiazem), dizziness, & flushing of the skin. Reflex tachycardia can occur as a result of hypotension. Calcium blockers can cause changes in liver and kidney function, and serum liver enzymes should be checked periodically. Calcium blockers are frequently given with other antianginal drugs such as nitrates to prevent angina. Immediate-release Nifedipine (10-and 20- mg capsules), has been associated with an increased incidence of sudden cardiac death, especially when prescribed in high doses for outpatients o This is not true of the sustained-release preparations (Procardia XL, Adalat CC). o For this reason, immediate-release nifedipine is prescribed only prn in the hospital setting for acute rises in BP

Pharmacodynamics

Side Effects and Adverse Effects

Antidysrhythmic Drugs Cardiac Dysrhythmias Any deviation from the normal rate or pattern of the heartbeat: bradycardia / tachycardia / irregular. Dysrhythmia (disturbed heart rhythm) & arrhythmia (absence of heart rhythm) are used interchangeably, The ECG identifies the type of dysrhythmia. o P wave reflects atrial activation o P-R interval indicates AV conduction time o QRS complex indicates ventricular depolarization o T wave reflects ventricular repolarization, return of cell membrane, resting after depolarization o Q-T interval reflects ventricular action potential duration. Atrial dysrhythmias prevent proper filling of the ventricles & decrease cardiac output by . Ventricular dysrhythmias, the ineffective filling of the ventricle results in decreased/absent cardiac output, are life-threatening Ventricular fibrillation is likely to occur with ventricular tachycardia followed by death. o Cardiopulmonary resuscitation (CPR) is necessary to treat these clients. Cardiac dysrhythmias can result from MI, hypoxia, hypercapnia, thyroid disease, coronary artery disease, cardiac surgery, excess catecholamine, or electrolyte imbalance. Cardiac Action Potentials Electrolyte transfer occurs thru the cardiac muscle cell membrane. When Na and Ca enter the cardiac cell, depolarization (myocardial contraction) occurs. o Na enters rapidly to start the depolarization, and Ca enters later to maintain it. o Calcium influx leads to an increased release of intracellular Ca from the sarcoplasmic reticulum, resulting in cardiac contraction. o In the presence of myocardial ischemia, the contraction can be irregular. Cardiac action potentials are transient depolarization followed by repolarization of myocardial cells. There are five phases. 1. Phase 0 is the rapid depolarization caused by an influx of sodium ions. 2. Phase 1 is initial repolarization, which coincides with termination of sodium ion influx. 3. Phase 2 is the plateau and is characterized by the influx of calcium ions, which prolong the action potential and promote atrial and ventricular muscle contraction. 4. Phase 3 is rapid repolarization caused by influx of potassium ions. 5. Phase 4 is the resting membrane potential between heart beats. o It is normally flat in ventricular muscle, but begins to rise in the cells of the SA node as they slowly depolarize toward the threshold potential just be4 depolarization occurs, initiating the next heartbeat. Types of Antidysrhythmic Drugs The desired action of antidysrhythmic (antiarrhythmic) drugs is to restore the cardiac rhythm to normal The antidysrhythmics are grouped into four classes: 1. Class I: Sodium Channel Blockers A Na channel blocker decreases Na influx into cardiac cells. They decreased conduction velocity in cardiac tissues; suppression of automaticity, which decreases the likelihood of ectopic foci; increased recovery time (repolarization/refractory period). There are three subgroups of sodium channel blockers: a) IA slows conduction and prolongs repolarization (quinidine, procainamide, disopyramide) b) IB slows conduction and shortens repolarization (lidocaine; mexiletine HCl, tocainide) c) IC prolongs conduction with little to no effect on repolarization (flecainide) Lidocaine was used as a local anesthetic and has antidysrhythmic properties as well. o Used to treat acute ventricular dysrhythmias. o It slows conduction velocity and decreases action potential amplitude. o Onset of action (IV) is rapid. of lidocaine reaches the general circulation. o A bolus of lidocaine is short-lived.

2. Class II: Beta-Blockers Beta-blockers decrease conduction velocity, automaticity, and recovery time (refractory period). Beta-blockers are more frequently prescribed for dysrhythmias than sodium channel blockers. Propranolol (Inderal), acebutolol (Sectral), esmolol (Brevibloc), sotalol (Betapace). 3. Class III: Drugs That Prolong Repolarization They prolong repolarization & are used in emergency treatment of ventricular dysrhythmias when other antidysrhythmics are ineffective. They increase the refractory period & prolong the action potential duration (cardiac cell activity). Bretylium (Bretylol) and amiodarone (Cordarone) 4. Class IV: Calcium Channel Blockers Verapamil [Calan, Isoptin] and diltiazem [Cardizem] Verapamil is a slow calcium channel blocker that blocks calcium influx, thereby decreasing the excitability and contractility (negative inotropic) of the myocardium. o It increases the refractory period of the AV node, which decreases ventricular response. Verapamil is contraindicated for clients with AV block or heart failure. Pharmacokinetics
The cardioselective beta drug acebutolol (Sectral) is well absorbed in the GI tract. It is metabolized in the liver to active metabolites; 50% to 60% of the drug is eliminated in the bile via feces, and 30% to 40% is excreted in the urine. The half-life for the drug is 3 to 4 hours, but the t for the metabolites is 8-13 hours

Pharmacodynamics
Acebutolol is prescribed for ventricular dysrhythmias as well as for angina pectoris and hypertension. As an antidysrhythmic drug; the onset of action is 1 hour; peak time is 4 to 6 hours, and duration of action is 10 hours. To treat hypertension, the duration of action is 20 to 24 hours. Quinidine, side effects (e.g., nausea. vomiting, diarrhea, confusion, and hypotension) o It can also cause heart block & neurologic & psychiatric symptoms. o Procainamide causes less cardiac depression than quinidine Lidocaine can cause cardiovascular depression, bradycardia, hypotension, seizures, blurred vision, double vision, dizziness, lightheadedness, and confusion. o It is contraindicated in clients with advanced AV block; caution in clients with liver disorder and heart failure o Mexiletine & tocainide have side effects similar to lidocaine. o They are contraindicated for use in clients with cardiogenic shock or in those with 2nd - or 3rd -degree heart block. Beta-blockers can cause bradycardia and hypotension. Bretyhum and amiodarone can cause nausea, vomiting, hypotension, and neurologic problems. Calcium blockers can cause nausea, vomiting, hypotension, and bradycardia. Antidysrhythmic drug is initiated during continuous cardiac monitoring of the clients heart rhythm in a hospital setting.

Side Effects and Adverse Effects

Diuretics Diuretics are used for two main purposes: 1) To decrease hypertension (lower blood pressure) 2) To decrease edema (peripheral and pulmonary) in heart failure (HF) and renal or liver disorders. Diuretics produce increased urine flow (diuresis) by inhibiting Na & water reabsorption from kidney tubules. Most Na and water reabsorption occurs throughout the renal tubular segments The first process for urine formation: q 1.5 hrs ECF goes thru the kidneys (glomeruli) for cleansing; o Small particles (electrolytes, drugs, glucose, and waste products) are filtered in the glomeruli. o Larger products (protein & blood cells) are not filtered thru renal function, they remain in the circulation. o Sodium and water are the largest filtrate substances. 99% of the filtered Na that passes thru the glomeruli is reabsorbed. 50% to 55% of Na reabsorption occurs in the proximal tubules, 35% to 40% in the loop of Henle, 5% to 10% in the distal tubules, and < 3% in the collecting tubules. Diuretics that act on the tubules closest to the glomeruli have the greatest effect in causing natriuresis o Ex: osmotic diuretic mannitol. Diuretics have an antihypertensive effect cuz they promote Na & water loss by blocking Na & Cl reabsorption.

o This causes a decrease in fluid volume, lowering blood pressure. o With fluid loss, edema decreases, but if Na is retained, water is also retained, & blood pressure increases. Many diuretics cause the loss of other electrolytes, including K, Mg, Cl, and bicarbonate. Potassium-wasting diuretics promote K excretion; Potassium-sparing diuretics promote K retention 1. Thiazide and Thiazide-Like Thiazide acts on the distal convoluted renal tubule to promote Na, Cl and water excretion. Thiazide is used to treat hypertension and peripheral edema; its not effective for immediate diuresis and should not be used to promote fluid loss in clients with severe renal dysfunction. If the client has renal disorder & creatinine clearance is < 30 ml/min, the effectiveness is greatly Thiazides cause a loss of Na, K, and Mg, but they promote Ca reabsorption. o Hypercalcemia may result and the condition can be hazardous to the client who is digitalized or has cancer that causes hypercalcemia. Thiazides affect glucose tolerance, so hyperglycemia can also occur. o Laboratory test results (e.g., electrolytes, glucose) need to be monitored. Drug dosages for hypertension and edema are similar Chlorothiazide, hydrochlorothiazide o Hydrochlorothiazide has been combined with selected ACE inhibitors, beta-blockers, alphablockers, angiotensin II blockers, and centrally acting sympatholytics to control hypertension. Pharmacokinetics
Thiazides are well absorbed from the GI tract. Hydrochlorothiazide has a moderate protein-binding power. The half-life of thiazide drugs is longer than that of the loop diuretics. Therefore, thiazides should be administered in the morning to avoid nocturia (night time urination) and sleep interruption. Thiazides act directly on arterioles to cause vasodilation, which lower BP; they promote NaCl & water excretion, resulting in a decrease in vascular fluid volume and a concomitant decrease in cardiac output and BP. The onset of action of hydrochlorothiazide occurs within 2 hrs. Peak concentration times are long (3-6 hrs). Thiazides are divided into three groups, according to their duration of action: o Short-acting (duration < 12 hrs), intermediate-acting (duration 12 to 24 hrs), and long-acting (duration > 24 hrs). Side effects and adverse reactions of thiazides include electrolyte imbalances (hypokalemia, hypercalcemia, hypomagnesemia, & bicarbonate loss), hyperglycemia, hyperuricemia (elevated serum uric acid level), and hyperlipidemia. Signs and symptoms of hypokalemia should be assessed; serum K levels must be closely monitored. o K supplements are frequently needed. Serum Ca & uric acid levels should be checked because thiazides block Ca & uric acid excretion. Thiazides affect the metabolism of carbs; hyperglycemia can result especially in clients with high blood sugar levels. Thiazides can increase serum cholesterol, LDL, and triglyceride levels. A drug may be ordered to lower blood lipids. Other side effects include dizziness, headaches, nausea, vomiting, constipation, urticaria (rare), and blood dyscrasias(rare) Thiazides are contraindicated for use in renal failure. Symptoms of severe kidney impairment or shutdown include oliguria (decrease in urine output), elevated blood urea nitrogen (BUN), and elevated serum creatinine.

Pharmacodynamics

Side Effects and Adverse Effects


Contraindications Drug Interactions


The most serious drug interaction occurs with digoxin. Thiazides can cause hypokalemia, which enhances the action of digoxin, and digitalis toxicity can occur. o Potassium supplements are frequently prescribed, and serum potassium levels are monitored. Thiazides also induce hypercalcemia, which enhances the action of digoxin, resulting in possible digitalis toxicity Signs and symptoms of digitalis toxicity (bradycardia, nausea, vomiting, and visual changes) should be reported. Thiazides enhance the action of lithium, and lithium toxicity can occur; they potentiate the action of other antihypertensive Serum Chemistry Abnormalities Associated with Thiazides Serum Chemistry Abnormal Results Blood Lipids Potassium, 3.5-5-3 mEq/l Hypokalemia. Potassium is excreted from the distal renal tubule. Magnesium, 1.8-3.0 mg/dl Hypomagnesemia. Potassium and sodium loss prompt magnesium loss. Calcium, 4.5-5.5 mEq/1 Hypercalcemia. Thiazides may block calcium excretion. Cholesterol:< 200 mg/dl Chloride, 95-105 mEq/1 Hypochloremia. Sodium and potassium losses produce chloride loss, LDL: < 100 mg/dl Bicarbonate, 24-28 mEq/1 Minimal bicarbonate loss from proximal tubule. Triglyceride: 10-190 mg/dl Uric acid, 2.8-8.0 mg/dl Hyperuricemia (elevated uric acid). Thiazides can block uric acid excretion. Blood sugar, 70-110 mg/dl Hyperglycemia. increase fasting blood sugar levels and those of prediabetic

2. Loop or High-Ceiling This diuretics act on the thick ascending loop of Henle to inhibit Cl transport of Na into the circulation (inhibit passive reabsorption of Na). Na & water are lost, together with K, Ca, and Mg. Loop diuretics can affect blood sugar and increase uric acid levels. Drugs in this group are extremely potent and cause marked depletion of water and electrolytes. o This high diuretic potential is the reason they are often called high-ceiling diuretics. The effects of loop diuretics are dose-related (increasing the dose increases the effect and responses). More potent than thiazides for promoting diuresis (inhibiting reabsorption of Na 3x more effectively) less effective as antihypertensive agents. Loop diuretics should not be prescribed if a thiazide could alleviate body fluid excess. If furosemide (Lasix) alone is not effective in removing body fluid, a thiazide may be added o However, Lasix should never be combined with another loop diuretic. o Lasix is usually administered PO in the morning or IV when the clients condition warrants immediate removal of body fluid, Ex: in cases of acute HF or pulmonary edema. Loop diuretics can increase renal blood flow up to 40%. Lasix is a frequently prescribed diuretic for clients whose creatinine clearance is < 30 ml/min and those with end-stage renal disease. This group of diuretics causes excretion of calcium, unlike thiazides, which inhibit calcium loss. Ethacrynic acid (Edecrin), furosemide (Lasix), bumetanide (Bumex) Bumex is more potent than Lasix on a per mg-for-mg basis. They are derivatives of sulfonamides. Edecrin, a phenoxyacetic acid derivative, is a seldom-chosen loop diuretic. o It is usually reserved for clients allergic to sulfa drugs. Pharmacokinetics
Loop diuretics are rapidly absorbed by the GI tract. They are highly protein bound with t that vary from 30 min-1.5 hrs Loop diuretics compete for protein-binding sites with other highly protein-bound drugs. Loop diuretics have a great saluretic (Na-Cl losing) or natriuretic (Na-losing) effect and can cause rapid diuresis, decreasing vascular fluid volume and causing a decrease in cardiac output and blood Pressure. Because furosemide is a more potent diuretic than thiazide diuretics, it causes a vasodilatory effect; thus renal blood flow increases before diuresis. Furosemide is used when other conservative measures, such as Na restriction and use of less potent diuretics, fail. The onset of action of loop diuretics occurs within 30-60 minutes. The onset of action for IV furosemide is 5 minutes. Duration of action is shorter than that of the thiazides. Side effects of loop diuretics are fluid & electrolyte imbalances (i.e. hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, and hypochloremia. o Hypochloremic metabolic alkalosis may result, which can worsen hypokalemia. Orthostatic hypotension can occur. Thrombocytopenia, skin disturbances, and transient deafness are rarely seen. Prolonged use of loop diuretics could cause thiamine deficiency. The major drug interaction is with digitalis preparations. If the client takes digoxin with a loop diuretic, digitalis toxicity can result. o Hypokalemia enhances the action of digoxin and increases the risk of digitalis toxicity. o The client needs K replacement with food or supplements. o Serum K levels should be closely monitored, especially when the client is taking high dosages of loop diuretics.

Pharmacodynamics

Side Effects and Adverse Effects


Drug Interactions

3. Osmotic Osmotic diuretics increase the osmolality & Na reabsorption in the proximal tubule & loop of Henle Na, Cl, K (to a lesser degree), and water are excreted. Its used to prevent kidney failure, to decrease ICP (cerebral edema), to decrease IOP (glaucoma). Mannitol is used in emergency situations (ICP & IOR). o It can be used with cisplatin & carboplatin in cancer chemotherapy to induce a frank diuresis and decreased side effects of treatment. Diuresis occurs within 1-3 hrs after IV administration Side Effects and Adverse Effects of Mannitol: F & E imbalance, pulmonary edema from rapid shift of fluids, nausea,
vomiting, tachycardia from rapid fluid loss, and acidosis. Crystallization in the vial may occur when the drug is exposed to a low temp. The vial should be warmed to dissolve the crystals. Do NOT use the IV infusion if crystals are present and have not been dissolved. Extreme caution to clients with HD and HF, stop immediately if s/he develops Heart/renal failure

4. Carbonic Anhydrase Inhibitor Acetazolamide, dichlorphenamide ethoxzolamide, & methazolamidc block the action of the carbonic anhydrase enzyme (needed to maintain the bodys acid-base balance [H & bicarbonate ion]) Inhibition of this enzyme causes increased sodium, potassium, and bicarbonate excretion. With prolonged use, metabolic acidosis can occur. This group of drugs is used primarily to decrease IOP in clients with open-angle (chronic) glaucoma, diuresis, management of epilepsy, and treatment of high altitude or acute mountain sickness Also used for client in metabolic alkalosis who needs a diuretic Carbonic anhydrase inhibitors may be alternated with a loop diuretic. Side Effects and Adverse Effects
F & E imbalance, metabolic acidosis, nausea, vomiting, anorexia, confusion, orthostatic hypotension, and crystalluria. Hemolytic anemia and renal calculi can occur. These drugs are contraindicated during the first trimester of pregnancy.

5. Potassium-Sparing Diuretics They act primarily in the collecting duct renal tubules and late distal tubule to promote Na & water excretion and K retention. They are weaker than thiazides & loop diuretics; used as mild diuretics or in combination with another diuretic (hydrochlorothiazide or antihypertensive drugs). Do Not take K supplement when K sparing diuretic is being used The serum K should be monitored when the client continuously takes a potassium-sparing diuretic. o If the serum K level is < 5.3 mEq/L, discontinue k sparing diuretics & restrict foods high in K The drugs interfere with the Na/K pump controlled by the mineralocorticoid hormone aldosterone Spironolactone (Aldactone), aldosterone antagonist, inhibit Na/K pump Aldactone is often use by clients with cardiac disorders because of its K retaining effect, so the heart rate is more regular, and the possibility of myocardial fibrosis is decreased. The effects of Aldactone may take 48 hrs. Amiloride (Midamor) and eplerenone (Inspra) are effective as antihypertensive agents. Triamterene (Dyrenium) is useful in the treatment of edema caused by HF or cirrhosis of the liver. Low doses of Aldactone and Inspa are effective for chronic HF; Aldactone, Midamor, Dyrenium, and Inspra should not be taken with ACE inhibitors and angiotensin II receptor blockers (ARBs), because they can also increase serum potassium levels. K paring diuretics are usually combined with a K wasting diuretic (hydrochlorothiazide/loop diuretic) o This combination of diuretics intensifies the diuretic effect & prevents K loss. o Common combination: spironolactone & hydrochlorothiazide (Aldactazide); amiloride & hydrochlorothiazide (Moduretic); triamterene & hydrochlorothiazide (Dyazide, Maxzide). Side Effects and Adverse Effects
GI disturbances (anorexia, nausea, vomiting, diarrhea, and numbness and tingling of the hands and feet) The main side effect is hyperkalemia. Caution must be used when giving K sparing diuretics to a client with poor renal function, because the kidneys excrete 80% to 90% of K. Urine output should be at least 600 ml per day. Clients should not use K supplements while taking K sparing diuretics, unless the serum K level is tow. If a K sparing diuretic is given with antihypertensive ACE inhibitors, hyperkalemia could become severe or lifethreatening because both drugs retain potassium. Monitoring serum K levels is essential.

The thiazide, loop or high-ceiling, and potassium-sparing diuretics are most frequently prescribed for hypertension and for edema associated with HF. Except for those in the potassium-sparing group, all diuretics are potassium-wasting. Combination of K wasting and K sparing drugs is primarily for the treatment of hypertension. Combinations have an additive effect in reducing blood pressure Herbal Alert: Diuretics: Aloe with K wasting diuretic such as a thiazide can decrease the serum K level hypokalemia Uva ursi may increase the effects of diuretics. It may cause electrolyte imbalance. Gingko may increase blood pressure when taken with thiazide diuretics. Licorice can increase potassium loss hypokalemia

Hypotension Ototoxicity Skin disturbances Photosensitivity Hypovolemia Hypo-K, Mg, Ca, Cl, & hyponatremia hyperglycemia Hyperuricemia Elevated BUN & creatinine Thrombocytopenia, leucopenia Elevated lipids

Physiologic and Laboratory Changes Associated with Loop Diuretics Postural (orthostatic) hypotension can result because of ECFV deficit. It is more common with use of ethacrynic acid. Diuretics in other categories are not considered ototoxic. Caution: Avoid taking a loop diuretic with a drug that can be ototoxic, such as an aminoglycoside. Pruritus, urticaria, exfoliative dermatitis, and purpura may occur in clients who allergic to the drug or when taking the loop diuretic in high doses over a long period. When exposed to sun/sunlamp for a long time severe sunburn could result. Use sun block & avoid long sun exposure Excess extracellular fluid is lost through increased urine excretion. Potassium, magnesium, sodium, calcium, & chloride are lost from the body from increased urine excretion. Chloride, is attached to the cations potassium & sodium; thus chloride is lost along with potassium and sodium. Increased glycogenosis may contribute to an elevated blood sugar level. Clients with diabetes should closely monitor their blood glucose levels when taking a loop diuretic. elevated uric acid levels are common in clients susceptible to gout. These elevations may result from ECFV loss. Hemoconcentration can cause elevated BUN and creatinine levels, which are reversible when fluid volume returns to normal levels. Decreases in platelet and white blood cell counts are rare, but they should be closely monitored. Decrease HDL & increase LDL. Clients with elevated cholesterol levels should have their levels of HDL and LDL checked. Regardless of the lipid effects, loop diuretics are useful for clients with serious fluid retention caused by a cardiac condition such as HF.

Antihypertensive Hypertension Hypertension is an increase in blood pressure that > 140 mmHg / > 90 mmHg Contributing factors include: 1) A family history of hypertension 5) Obesity 2) Hyperlipidemia 6) Aging 3) African American background 7) Stress 4) Diabetes 8) Excessive smoking and alcohol ingestion. Essential hypertension is the most common type (90%) Secondary hypertension are related to renal and endocrine disorders (10%) Selected Regulators of Blood Pressure The kidneys and blood vessels strive to regulate and maintain a normal blood pressure. The kidneys regulate blood pressure via the rennin-angiotensin-aldosterone system. o Renin (from the renal cells) stimulates production of angiotensin II (a potent vasoeonstrictor) release of aldosterone (adrenal hormone that promotes Na retention and thereby water retention). o Retention of Na and water causes fluid volume to increase, elevating blood pressure The baroreceptors in aorta & carotid sinus, the vasomotor center in medulla assist in the regulation of BP Catecholamines such as norepinephrine & epinephrine increase BP thru vasoconstriction activity. Other hormones that contribute to blood pressure regulation are the antidiuretic hormone (ADH), atrial natriuretic peptide (hormone) (ANP), and brain natriuretic peptide (BNP). ADH is produced by the hypothalamus and is stored and released by the posterior pituitary gland (neurohypophysis). It stimulates the kidneys to conserve & retain water when there is a fluid volume deficit. o When there is a fluid overload, ADH secretion is inhibited, and the kidneys then excrete more water. Physiologic Risk Factors A diet with excess fat & carbohydrates can increase blood Pressure. Carbohydrate intake can affect sympathetic nervous activity. Alcohol increase rennin secretions, causing the production of angiotensin II. Obesity affects the sympathetic & cardiovascular systems by increasing cardiac output, stroke volume, and left-ventricular filling. Normally weight loss can decrease hypertension, as can mild to moderate sodium restriction.

Cultural Responses to Antihypertensive Agents African Americans are more likely to develop hypertension at an earlier age & higher mortality rate from hypertension than white Americans. African American clients have a low-renin hypertension so they only respond to beta-adrenergic blockers & angiotensin-converting enzyme (ACE) inhibitors combined with a diuretic OR alpha1 blockers & Ca blockers White clients usually have high-renin hypertension and respond well to all antihypertensive agents. Asian Americans are 2x as sensitive as whites to beta-blockers and other antihypertensives. o A reduction in antihypertensive dosing is needed. American Indians have a reduced or lower response to beta-blockers compared with whites. Monitoring blood pressure and drug dosing should be an ongoing assessment for these cultural groups. Hypertension in Older Adults By the age of 65, 26% of males & 30% of females are hypertensive. Between 65 and 75 years of age 30% of males & 45% of females are hypertensive. Both systolic & diastolic hypertension is associated with increased cardiovascular morbidity and mortality. One of the side effects of antihypertensive agents in older adults, especially frail or institutionalized persons, is orthostatic hypotension; drug dose may need to be decreased or another antihypertensive drug used. Older adults with hypertension should be instructed to modify their lifestyle activities (e.g. restricting dietary Na to 2.4 g (2400 mg) daily, avoiding tobacco, and losing weight if obese). Nonpharmacologic Control of Hypertension Nonpharmacologic ways to decrease blood pressure include: 1. stress-reduction techniques 3. salt restriction 2. exercise (increases high-density 4. decreased alcohol ingestion lipoproteins [HDL]) 5. weight reduction If systolic pressure is >140 mmHg or hypertension cannot be controlled by nonpharmacologic means, antihypertensive drugs are prescribed. Nonpharmacologic methods should be combined with antihypertensive drugs to control hypertension. Guidelines for Hypertension Prehypertension SBP 120 to 139 / DBP 80 to 89 Stage 1Hypertension 140/90 - 159/99 Stage 2 Hypertension is greater than 160/100. SBP is more important than DBP as a CVD risk for clients > 50 years. According to the JNC 7, if the BP is greater than 20/10 mmHg above goal, drug regimen should be started. CVD risk doubles with each increase of 20/10 mmHg, starting at 115/75 mmHg Pharmacologic Control of Hypertension Reduction of other cardiovascular risk factors and the use of fewer drugs (i.e., substituting instead of adding drugs) at the lowest effective doses are emphasized. After a client has taken an antihypertensive drug for a year, the drug dose & its effect should be evaluated. Under the current guidelines [JNC 7] there three classifications for defining an elevated SBP; 1. Prehypertension, SBP 120 to 139 1. Stage3, SBP 180 to 200 2. Stage 1, SBP 140 to 160 2. Stage 4, SBP > 200 As a result of staging, the stepped-care hypertension approach to treatment was developed. o It included a single drug stepped up to multiple drugs, depending upon severity of disease When SBP is stage 1 or 2 and DBP is normal or prehypertensive, the staging would be assigned according to SBP and would be known as isolated systolic hypertension, or 1 or 2 1SH o If SBP is stage 2 & DBP is < 90 mmHg, the staging will be 2 isolated systolic hypertension (2 ISH) Most clients may need two or more antihypertensive drugs to achieve goal blood pressure. A thiazide diuretic may be the first antihypertensive drug prescribed. Antihypertensive drugs, used either singly/in combination with other drugs, are classified into 6 categories:

1. Diuretics Diuretics promote Na depletion, which decreases ECF volume. Diuretics are effective as first-line drugs for treating mild hypertension. o i.e. Hydrochlorothiazide (HydroDIURIL) Many antihypertensive drugs can cause fluid retention; therefore diuretics are often administered together with antihypertensive agents. Thiazide diuretics should not be used for pt w/ renal insufficiency [creatinine clearance < 30 ml/min] Loop diuretics [fiirosemide (Lasix)] are recommended, because they do not depress renal blood flow. Diuretics are not used if hypertension is the result of renin-angiotensin-aldosterone system involvement, because they tend to elevate the serum renin level. Instead of a single thiazide, combination of K wasting & K sparing diuretics cause less K excretion Thiazides can be combined with other antihypertensive drugs to increase their effectiveness. ACE inhibitors increase serum K level, so combined w/ thiazide diuretic, serum K loss is minimized. 2. Sympatholytics (sympathetic depressants) 1) Beta-Adrenergic Blockers (Beta Blockers) Used as antihypertensive or in combination with a diuretic; as antianginals; as antidysrhythmics Beta (1 & 2)-adrenergic blockers reduce cardiac output by diminishing the SNS response to decrease basal sympathetic tone. o With continued use, vascular resistance is diminished, and blood pressure is lowered. Beta-blockers reduce heart rate, contractility, and renin release. There is a greater hypotensive response in clients with higher renin levels. African American hypertensive pt do not respond well to beta-blockers for control of hypertension o Instead, hypertension can be controlled by combining beta-blockers with diuretics. Nonselective beta-blockers [i.e. propranolol (Inderal)] inhibit beta1 (heart) & beta2 (bronchial) o Heart rate slows (BP decreases secondary to the decrease in heart rate), and bronchoconstriction occurs because of unopposed parasympathetic tone Cardioselective beta-blockers are preferred, they act mainly on the beta1 o Acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol (Zebeta), and metoprolol (Lopressor) are cardioselective beta-blockers that block beta1 receptors. o Only atenolol demonstrated true protection from bronchoconstriction. Other cardioselective beta-blockers were only partially effective. In clients with preexisting bronchospasms / other pulmonary disease, beta-blockers, even cardioselective, should be used with caution. Considered as contraindication A nonselective propranolol (Inderal) should not be given to a client with COPD Beta-blockers should not be used by clients with 2nd- or 3rd -degree atrioventricular (AV) block or sinus bradycardia. Pharmacokinetics
Metoprolol is well absorbed from the GI tract, its half- life is short and its protein-binding power is low. Cardioselective beta-adrenergic blockers block beta1 receptors, thereby decreasing heart rate 7 BP. The nonselective beta-blockers block beta1 & beta2 receptors, which can result in bronchial constriction. Beta-blockers cross the placental barrier and are excreted in breast milk. The onset of action of oral beta-blockers is 30 minutes, the duration of action is 6-12 hours. When beta-blockers are administered IV, the onset of action is immediate, peak time is 20 minutes, & duration of action is 4-10 hours. SE: decreased pulse rate, decreased BP, and (with nonselective beta blockers) bronchospasm. Beta-blockers should not be abruptly discontinued, because rebound hypertension, angina, dysrhythmias, &MI can result. Beta-blockers can cause insomnia, depression, nightmares, and sexual dysfunction. Nonselective beta-blockers inhibit the livers ability to convert glycogen to glucose in response to hypoglycemia, so beta-blockers should be used with caution in clients with diabetes mellitus. In addition, the depression of heart rate masks the symptom (tachycardia) of hypotension

Pharmacodynamics

Side Effects and Adverse Effects


2) Centrally Acting Alpha2 agonists They decrease the sympathetic response from the brainstem to the peripheral vessels. They stimulate the alpha2 receptors, decreases sympathetic activity, increases vagus activity, decreases cardiac output, and decreases serum epinephrine, norepinephrine, and renin release. All these actions result in reduced peripheral vascular resistance & increased vasodilation. This group of drugs has minimal effects on cardiac output and blood flow to the kidneys. Beta-blockers are not given with this group, because accentuation of bradycardia during therapy and rebound hypertension on discontinuing therapy can occur. Methyldopa, clonidine, guanabenz, and guanfacine. High doses of methyldopa & clonidine can cause Na & water retention, theyre often administered with diuretics Clonidine is available in transdermal that provides a 7-day duration of action. o Transdermal patches are replaced every 7 days and may be left on while bathing. o Skin irritations have occur Guanfacine has a long half-life and usually is taken once a day. Side Effects and Adverse Effects
Drowsiness, dry mouth, dizziness, and bradycardia. Methyldopa should not be used in clients with impaired liver function, serum liver enzymes should be monitored Do NOT abruptly discontinue because a rebound hypertensive crisis can result. If the drug needs to be stopped immediately, another antihypertensive drug is prescribed to avoid rebound hypertensive symptoms (e.g., restlessness, tachycardia, tremors, headache, and increased blood pressure). Rebound hypertension is less likely to occur with guanabenz & guanfacine The nurse should emphasize the need to take the medication as prescribed. This group of drugs can cause Na and water retention, resulting in peripheral edema. o A diuretic may be ordered with methyldopa or clonidine to decrease water and sodium retention (edema). Clients who are pregnant or contemplating pregnancy should avoid clonidine. Methyldopa is frequently used to treat chronic or pregnancy-induced hypertension; o However, it crosses the placental barrier, and small amounts may enter the breast milk of a lactating client.

3) Alpha-Adrenergic Blockers They cause vasodilation & decreased BP, and they help maintain the renal blood flow rate Alpha-blockers are useful in treating hypertension in clients with lipid abnormalities. They decrease the VLDL & the LDL that are responsible for the buildup of fatty plaques in the arteries (atherosclerosis). In addition, they increase HDL levels Alpha-blockers are safe for clients with diabetes, because they do not affect glucose metabolism They also do not affect respiratory function The selective alpha1-drenergic blockers (prazosin, terazosin, doxazosin) are used mainly to reduce BP & can be used to treat benign prostatic hypertrophy (BPH). Terazosin & doxazosin have longer t than prazosin, and they are normally given once a day. Prazosin taken with alcohol/other antihypertensives, the hypotensive state is intensified These drugs, like the centrally acting alpha2 agonists, cause Na and water retention with edema; o Therefore diuretics are given to decrease fluid accumulation in the extremities. The more potent alpha-blockers (phentolamine, phenoxybenzamine, tolazoline) are used primarily for hypertensive crisis and severe hypertension resulting from catecholaminesecreting tumors of the adrenal medulla (pheochromocytomas). Pharmacokinetics
Prazosin is absorbed thru the Gl tract, but a large portion of prazosin is lost during hepatic first-pass metabolism. The t is short, so the drug should be administered two times a day. Prazosin is highly protein- bound, with other highly protein-bound drugs, pt should be assessed for adverse react. Selective alpha-adrenergic blockers dilate arterioles & venules, decreasing peripheral resistance and lowering BP. With prazosin, the heart rate is only slightly increased, whereas with non selective alpha-blockers such as phentolamine and tolazoline, the BP is greatly reduced, and reflex tachycardia can occur. Nonselective alpha-blockers are more effective for acute hypertension; Selective alpha-blockers are more useful for long-term essential hypertension.

Pharmacodynamics

Side Effects and Adverse Effects


SE of prazosin, doxazosin, and terazosin: Orthostatic hypotension (dizziness, faintness, light- headedness, increased heart rate, which may occur with first dose), nausea, drowsiness, nasal congestion caused by vasodilation, edema, and weight gain. SE of phentolamine: hypotension, reflex tachycardia caused by the severe decrease in blood pressure, nasal congestion caused by vasodilation, and GI disturbances. Peripheral edema is intensified when prazosin and an anti-inflammatory drug are taken daily. Nitroglycerin taken for angina lowers blood pressure. If prazosin is taken with nitroglycerin, syncope (faintness) caused by a decrease in blood pressure can occur.

Drug Interactions

4) Adrenergic Neuron Blockers (Peripherally acting Sympatholytics) They block norepinephrine release from the sympathetic nerve endings, causing a decrease in norepinephrine release that result in a lowering of blood pressure. There is a decrease in both cardiac output and peripheral vascular resistance. Reserpine, guanethidine, and guanadrel are used to control severe hypertension. The adrenergic neuron blockers are considered the last choices for treatment of chronic hypertension, because these drugs can cause orthostatic (postural) hypotension. o the client should rise slowly from a reclining or sitting position Reserpine may cause vivid dreams, nightmares, and suicidal intention. The drugs in this group can cause sodium and water retention. o Diuretic can be added to decrease peripheral edema. 5) Alpha1 & Alpha2 Adrenergic Blockers Labetalol (Normodyne) & carteolol (Cartrol) Blocking the alpha1- receptor causes vasodilation, decreasing resistance to blood flow, BP The effect on the alpha-receptor is stronger than the effect on the beta-receptor; therefore BP is lowered and pulse rate is moderately decreased. By blocking the cardiac beta1-receptor, both heart rate and AV contractility are decreased. Large doses of alpha-/beta-blockers can block beta2 receptors, thus increasing airway resistance o Clients who have severe asthma should not take large doses of labetalol or carteolol. SE: orthostatic hypotension, Gl disturbances, nervousness, dry mouth, and fatigue. o Large doses of labetalol or carteolol may cause AV heart block. 3. Direct-Acting Arteriolar Vasodilators They act by relaxing the smooth muscles of the arteries blood vessels, causing vasodilation. Vasodilators increase in blood flow to the brain & kidneys, BP deceases, & Na and water are retained peripheral edema. o Diuretics can be given with a direct acting vasodilator to decrease the edema. Hydralazine & minoxidil are for moderate-severe hypertension. These two drugs o They cause little orthostatic hypotension, because of the minimum dilation of the arterioles. o However, reflex tachycardia & release of renin can occur secondary to vasodilation & BP. o Beta-blockers are frequently prescribed with arteriolar vasodilators to decrease the heart rate; This counteracts the effect of reflex tachycardia. Ntroprusside & diazoxide are prescribed for acute hypertensive emergency. o These two drugs are very potent vasodilators that rapidly decrease blood pressure o Nitroprusside acts on both arterial & venous vessels; diazoxide acts on arterial vessels only. Side Effects and Adverse Effects
Hydralazine can cause tachycardia, palpitations, edema, nasal congestion, headache, dizziness, GI bleeding, lupus-like symptoms, and neurologic symptoms (tingling, numbness). Minoxidil has similar SE, as well as tachycardia, edema, & excess hair growth. It can precipitate an angina attack. Nitroprusside & diazoxide can cause reflex tachycardia, palpitations, restlessness, agitation, nausea, and confusion. Diazoxide can cause hyperglycemia, because the drug inhibits insulin release from the beta cells of the pancreas.

4. Angiotensin Converting Enzyme (ACE) Inhibitors They inhibit the formation of angiotensin II (vasoconstrictor) and block the release of aldosterone. o Aldosterone promotes Na retention and K excretion. o When aldosterone is blocked, Na is excreted along with water, and K is retained. ACE inhibitors cause little change in cardiac output/heart rate, and they lower peripheral resistance. ACE inhibitors can be used in clients who have high serum renin levels. African Americans & older adults do not respond to ACE inhibitors unless combine with a diuretic, ACE inhibitors should not be given during pregnancy, because they reduce placental blood flow. Renal insufficiency clients, reduction of the drug dose (except fosinopril [Monopril]), is necessary. ACE inhibitors should be administered with food (except moexipril [Univasc]) ACE inhibitors are used primarily to treat hypertension; some are also effective in treating HF. The following drugs can be used for first-line antihypertensive therapy, but thiazide diuretics are recommended by the JNC 7 o Benazepril (Lotensin) o fosinopril (Monopril) o perindopril (Aceon) o captopril (Capoten) o lisinopril (prinivil, Zestril) o quinapril [accupril] o enalapril maleate (Vasotec) o moexipril (Univasc) o ramipril (Altace) o trandolanril (Marik) Side Effects and Adverse Effects
SE: constant, irritated cough, nausea, vomiting, diarrhea, headache, dizziness, fatigue, insomnia, hyperkalemia, and tachycardia. Adverse effects are first-dose hypotension and hyperkalemia. o First-dose hypotension results because of the vasodilating effect, more common in clients also taking diuretics. ACE inhibitors should not be given during pregnancy; harm to the fetus due to reduction in placental blood flow. ACE inhibitors should not be taken with potassium-sparing diuretics such as spironolactone (Aldactone) or salt substitutes that contain potassium, because of the risk of hyperkalemia (serum potassium excess)

Contraindications

5. Angiotensin II receptor blockers (ARBs) They prevent the release of aldosterone (sodium-retaining hormone), similar to ACE inhibitors They act on the renin-angiotensin-aldosterone system (RAAS). The difference between ARBs & ACE inhibitors is that o ARBS block angiotensin II from the AT1 receptors found in tissues o ACE inhibitors inhibit the angiotensin-converting enzyme in the formation of angiotensin II. o ARBS do not cause the constant, irritated cough ACE inhibitors can. Like ACE inhibitors, ARBs should not be taken during pregnancy The ARBs cause vasodilation & decrease peripheral resistance The following agents block the vasoconstrictor effects of angiotensin II at the receptor site o losartan (Cozaar) o irbesartan (Avapro) o olmesartan medoxomil (Benicar) o valsartan (Diovan) o candesartan cilexetil (Atacand) o telmisartan (Micardis) o eprosartan (Teveten) The combination of losartan K & hydrochlorothiazide tablets and valsartan & hydrochlorothiazide tablets should not cause serum potassium excess or loss. ARBs may be used as a first-line treatment for hypertension. Pharmacokinetics
Losartan (Cozaar) is prescribed primarily to manage hypertension. The combination drug Hyzaar contains losartan potassium + a low dose of hydrochlorothiazide. o It is rapidly absorbed in the Gl tract and undergoes first-pass metabolism in the liver to form active metabolites. o It is highly protein-bound and should not be given during pregnancy, especially the second and third trimester. o The t is 1.2-2 hours, and the t of the metabolite is 6 -9 hours. o The drug is excreted in urine and feces. Losartan potassium is a potent vasodilator; blocks the binding of angiotensin II to the AT 1 receptors Its peak time is 6 hours, and it has a long duration of action: 24 hours. Like ACE inhibitors, the ARBS are less effective for treating hypertension in African Americans & may cause angioedema; ARBS can be taken with or without food and are suitable for clients with mild hepatic insufficiency.

Pharmacodynamics

6. Direct Renin Inhibitor Aliskiren (Tekturna) binds with renin reduce angiotensin I, angiotensin II, & aldosterone levels It is effective for mild & moderate hypertension. Aliskiren can be used alone or with another antihypertensive agent. It has an additive effect in reducing BP when combined with a thiazide diuretic or an ARB. 7. Calcium channel blockers (calcium antagonists, calcium blockers) Slow Ca channels are found in the myocardium and vascular smooth muscle (VSM) cells. Free Ca increases muscle contractility, peripheral resistance, and blood pressure. Ca channel blockers block the Ca channel in the VSM, promoting vasodilation. The large central arteries are not as sensitive to Ca blockers as coronary & cerebral arteries and the peripheral vessels. Calcium blockers are highly protein-bound but have a short half-life. Slow-release preparations decrease frequency of administration. 3 groups of calcium blockers: 1. Verapamil (Calan) is used to treat chronic hypertension, angina pectoris, & cardiac dysrhythmia o Verapamil & diltiazem act on the arterioles & the heart. 2. Dihydropyridines consist of seven drugs; six of these are used to control hypertension. o Amlodipine (Norvasc) o Isradipine (DynaCirc) o Nifedipine (Procardia) o Felodipine (Plendu) o Nicardipine HCL o Nisoldipine (Sular, Nisocor) (Cardene, Cardene SR) Almodipine is used to prevent ischemic brain injury due to vasospasm that often accompanies subarachnoid hemorrhage. Nifedipine (Procardia) decreases BP in older adults & in those with low serum renin values Nifedipine, in its immediate-release form (10- & 20-mg capsules) is associated with an incidence of sudden cardiac death, especially when prescribed for outpatients at high doses. o This is not true of the sustained-release preparations (i.e., Procardia XL, Adalat CC). o For this reason, immediate-release nifedipine is prescribed for acute rises in blood pressure only on an as needed basis in the hospital setting. 3. Benzodiazepines: diltiazem HCl (Cardvzem, Cardizem CD or SR) Like the vasodilators, Ca channel blockers can cause reflex tachycardia; o it is more prevalent with nifedipine -blockers are not prescribe with Ca blockers, because both decrease myocardium contractility Calcium blockers lower blood pressure better in African Americans than drugs in other categories Pharmacokinetics
Amlodipine (Norvasc), like other calcium blockers, is highly protein-bound. It is gradually absorbed via the Gl tract. Because the half-life of amlodipine is longer than other calcium blockers, it is taken once a day Amlodipine may be used alone or with other antihypertensive drugs. Peripheral edema may occur because of its vasodilator effect, so pts with edema may need to take another type of antihypertensive drug. This drug has a long duration of action, so it is prescribed only once a day. Amlodipine may be combined with the ACE inhibitor benazepril, forming Lotrel. SE & AR: Flush, headache, dizziness, ankle edema, bradycardia, and AV block.

Pharmacodynamics

Herbal Alert: Antihypertensives Ma-huang and ephedra decrease or counteract the effect of antihypertensive drugs. When taken with betablockers, hypertension may continue or increase Ephedra increases hypertension when taken with beta-blockers Black cohosh increases the hypotensive effect of antihypertensive drugs. Hawthorn may increase the effects of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. Licorice antagonizes the effects of antihypertensive drugs. Goldenseal may increase the effects of antihypertensives Parsley may increase the cause of hypotension when taken with an antihypertensive drug.

Anticoagulants, Antiplatelets, and Thrombolytics Pathophysiology: Thrombus Formation Thrombosis is the formation of a clot in an arterial/venous vessel. a) Arterial clots are made up of both white & red clots with the white clots (platelets) initiating the process, followed by fibrin formation and the trapping of RBCs in the fibrin mesh. b) Vein clots are from platelet aggregation with fibrin that attaches to RBC. o Both types of thrombus can be dislodged from the vessel & become an embolus (blood clot moving through the blood stream) Arterial thrombus could be caused by blood stasis (because of decreased circulation), platelet aggregation on the blood vessel wall, or blood coagulation. o Platelets do not stick together unless there is a break in the endothelial lining of a blood vessel. o When platelets adhere to the broken surface of an endothelial lining, they synthesize thromboxane A2 [a product of prostaglandins and a potent stimulus for platelet aggregation (clumping of platelet cells)]. o Glycoprotein IIb/IlIa, GP IIb/IIIa, platelet receptor that binds fibrinogen promotes platelet aggregation Thromboxane A2 & adenosine diphosphate (ADP) increase the activation of this receptor. o As the thrombus inhibits blood flow, fibrin, platelets, & RBCs surround the clot, clots size & structure o As the clot occludes the blood vessel, tissue ischemia occurs. Venous thrombus develops because of slow blood flow. The venous clot can occur rapidly. o Small pieces of the venous clot can detach & travel to the pulmonary artery the lung. o Inadequate oxygenation and gas exchange in the lungs result Oral & parenteral anticoagulants (warfarin & heaprin) prevent venous thrombosis Antiplatelet drugs act to prevent arterial thrombosis. Both groups of drugs suppress thrombosis Anticoagulant It is used to inhibit clot formation. They do not dissolve clots that have already formed, but rather act prophylactically to prevent new clots from forming. It is used in pt with venous & aterial vessel disorders that put them at high risk for dot formation. Venous problems: deep vein thrombosis (DVT) and pulmonary embolism Arterial problems: coronary thrombosis (MI), artificial heart valves, cerebro-vascular accidents (CVA/stroke) A. Heparin It is anticoagulant, administered PO/parenterally ([subQ] & [IV]). A natural substance in liver that prevents clot formation; used in blood transfusions to prevent clotting It is indicated for rapid anticoagulant effect when a thrombosis occurs because of a DVT, pulmonary embolism (PE), or an evolving stroke Heparin is used in open heart surgery to prevent blood from clotting and in the critically ill client with disseminated intravascular coagulation (DIC). o DIC occurs when fibrin clots from within the vascular system, causing excess bleeding. o However, the primary use of heparin is to prevent venous thrombosis, which can lead to pulmonary embolism or stroke. Heparin combines with antithrombin III, which accelerates the anticoagulant reactions o By inhibiting the action of thrombin, conversion of fibrinogenfibrin does not occur and the formation of a fibrin clot is prevented Heparin is poorly absorbed thru the GI mucosa, and much is destroyed by heparinase, a liver enzyme. Because heparin is poorly absorbed PO, it is given subQ for prophylaxis or IV to treat acute thrombosis. o It can be administered as an IV bolus or in IV fluid for continuous infusion. Heparin prolongs Partial thromboplastin time (PTT) & activated partial thromboplastin time (aPTT) o Laboratory tests to detect deficiencies of certain clotting factors, used to monitor heparin therapy. Heparin can decrease the platelet count, causing thrombocytopenia. o If hemorrhage occurs during heparin therapy, anticoagulant antagonist IV protamine sulfate is given Protamine can be an anticoagulant. In the presence of heparin, its an antagonist to reverse heparin. Before discontinuing heparin, oral therapy with warfarin therapy is begun.

Low-Molecular-Weight Heparins (LMWH) They are derivatives of heparin to prevent venous thromboembolism. It is extracted thru depolymerization, have a lower risk of bleeding. o As a result frequent laboratory monitoring of APTT is not required Heparin prevents coagulation by combining with Antithrombin III to inactivate factor Xa and thrombin. o LMWH inactivates the Xa factor, but it is less able to inactivate thrombin. LMWHs: enoxaparin Na (Lovenox), dalteparin Na (Fragmin), danaparoid (Orgaran), tinzaparin Na (Innohep). danaparoid is refer to as LMW heparinoid drug because it does not have heparin in its structure Fondaparinux (Arixtra), use SubQ injection 1x daily. Categorized as a selective Factor Xa inhibitor LMWHs prevent DVT & acute pulmonary embolism after orthopedic or abdominal surgery. o Hip- & knee-replacement anticoagulant therapy often includes enoxaparin and danaparoid o Abdominal surgery, dalteparin. o Can be administered at home, because aPTT monitoring is not necessary, o They are given subQ 1-2/day, available in prefilled syringes with attached needles. o The pt/family member is taught how to administer the subQ injection in the abdomen. o The average treatment period lasts 7 to 14 days. o The LMWH is usually started in the hospital within 24 hours after surgery The t of LMWHs is 2-4x longer than heparin. Clients should not take antiplatelet drugs (i.e. aspirin) while taking LMWHs or heparin. LMWH overdose is rare; if bleeding occurs, protamine sulfate is the anticoagulant antagonist used. o The dosage for protamine sulfate is 1 mg of protamine for every 1 mg of LMWH given. The LMWHs are contraindicated for clients with strokes, peptic ulcers, and blood anomalies. These drugs should not be given to clients having eye, brain, or spinal surgery. Direct Thrombin Inhibitors: Parenteral Anticoagulants II They directly inhibit thrombin from converting fibrinogenfibrin. Aigatroban (Acova), bivalirudin (Angiomax), & lepirudin (Refludan) are given IV. o Bivalirudin binds with and inhibits free-flowing thrombin. Desirudin (Iprivask) is administered SubQ Oral Anticoagulant Warfarin (Coumadin) is the only oral anticoagulant prescribed. It inhibits hepatic synthesis of vitamin K, thus affecting the clotting factors II, VII, IX and X. It is used mainly to prevent thromboembolic conditions (i.e. thrombophlebitis, pulmonary embolism, and embolism formation caused by atrial fibrillation, which can lead to a stroke (CVA). It prolongs clotting time and are monitored by the prothrombin time (PT), a laboratory test that measures the time it takes blood to clot in the presence of certain clotting factors which warfarin affects. o This laboratory test is usually performed immediately before administering the next drug dose until the therapeutic level has been reached. o IINR, a laboratory test most frequently used to report PT results. o PT test are compared with an international reference standard and reported as the 1NR Normal INR is 1.3 to 2. Clients on warfarin therapy are maintained at an INR of 2 to 3. The desired INR for clients who have a mechanical heart valve or recurrent systemic embolism is 2.5 to 3.5, but the desired level could be as high as 4.5. Oral Anticoagulant Antagonists Bleeding occurs in about 10% of clients taking oral anticoagulants. Vitamin K1 (phytonadione) is an antagonist warfarin used for warfarin overdose or uncontrollable bleeding Usually 1-10 mg of vitamin K1 is given at once If it fails to control bleeding, then fresh whole blood or fresh-frozen plasma or platelets are generally given.

Pharmacokinetics
Heparin is poorly absorbed through the Gl mucosa, and much is destroyed by heparinase, a liver enzyme. Heparin is given parenterally, either SubQ for prophylactic anticoagulant therapy or IV bolus or continuous infusion for an immediate response. Warfarin, an oral anticoagulant, is well absorbed through the GI mucosa; food will delay but not inhibit absorption. High doses prolong the half- life. The half-life of warfarin is 0.5 to 3 days, in contrast to 1 to 2 hours for heparin. Because warfarin has a long half-life and is highly protein- bound, the drug can have cumulative effects. Bleeding can occur, especially if another highly protein-bound drug is administered together with warfarin. Kidney and liver disease prolong the half-life of both heparin and warfarin. Warfarin is metabolized to inactive metabolites that are excreted in urine and bile Heparin, administered for acute thromboembolic disorders, prevents thrombus formation and embolism. It has been effectively used to treat DIC, which causes multiple thrombi in small blood vessels. Warfarin is effective for long-term anticoagulant therapy. The PT level should be 1.5-2x the reference value , or INR 2-3 INR has effectively replaced the use of PT, because PT can vary from laboratory to laboratory and reagent to reagent. INR levels (3.5) are usually required for clients with prosthetic heart valves, cardiac valvular disease, and recurrent emboli. Heparin does not cross the placental barrier, unlike warfarin; warfarin use is not suggested during pregnancy IV heparin has a rapid onset; its peak time of action is reached in minutes, and its duration of action is short. o After an IV heaprin dose, the clients clotting time will return to normal in 2 to 6 hours. SubQ heparin is more slowly absorbed through the blood vessels in fatty tissue. Warfarin (Coumadin) has a long onset of action, peak concentration, and duration of action, so drug accumulation may occur. Bleeding (hemorrhage) is the major adverse effect of warfarin. Clients should be monitored closely for signs of bleeding (e.g., petechias ecchymosis, hematemesis). Laboratory testing of PT or INR should be scheduled at recommended intervals. Warfarin is highly protein-bound Aspirin, NSAIDs, anti-inflammatory drugs (sulfonamides, phenytoin, cimetidine (Tagamet), allopurinol) and oral hypoglycemic drugs for diabetes can displace warfarin from the protein-bound site, causing more free circulating o Acetaminophen (Tylenol) should be used instead of aspirin by clients taking warfarin. For frank bleeding resulting from excess free drug, parenteral vitamin K is given as a coagulant to decrease bleeding and promote clotting. However, caution must be used, because the prothrombin can remain depressed for prolonged periods.

Pharmacodynamics

Side Effects and Adverse Effects Drug Interactions


Antiplatelet Drugs Antiplatelets are used to prevent thrombosis in the arteries by suppressing platelet aggregation. o Heparin and warfarin prevent thrombosis in the veins. This drug therapy is mainly for prophylactic use in: 1. prevention of myocardial infarction or stroke for clients with familial history 2. pretention of a repeat myocardial infarction or stroke, 3. prevention of a stroke for clients having transient ischemic attacks (TlAs). Long-term, low-dose aspirin therapy is effective & inexpensive treatment for suppressing platelet aggregation; o Aspirin inhibits cyclooxygenase, an enzyme needed by platelets to synthesize thromboxane A2 (TxA2). For pt w/ familial history of stroke or myocardial infarction, the recommended dose is 81, 162, 325 mg/day. Aspirin therapy should be discontinued at least 7 days before surgery. Other antiplatelet drugs include dipyridamole (Peisantine), ticlopidine (Ticlid), clopidogrel (Plavix), anagrelide HCl (Agrylin), abciximab (ReoPro), eptifibatide (integrilin), and tirofiban (Aggrastat). Clopidogrel, dipyridamole, & ticlopidine are known as ADP antagonists affecting platelet aggregation. o Cilostazol (Pletal) inhibits platelet aggregation, a vasodilator that is used for intermittent claudication. o Clopidogrel (Plavix), an antiplatelet drug used after MI or stroke to prevent a 2nd event. It may be prescribed singly/with aspirin. Plavix and aspirin are more effective in inhibiting platelet aggregation than separate antiplatelet Abriximab, eptifibatide, & tirofiban are for acute coronary syndromes (unstable angina or nonQ wave myocardial infarction) and for preventing reocclusion of coronary arteries following percutaneous transluminal coronary angioplasty (PTCA); given before and after PTCA. o Abciximab, eptifibatide, and tirofiban are platelet glycoprotein (GP) IIb/ IIIa receptor antagonists. o The drug of choice for angioplasty is abciximab. o Following IV infusion, the antiplatelet effects for abciximab persist for 24 to 48 hours; for eptifibatide and tirofiban: 4 hours.

Herbal Alert: Antiplatelets: Dong quai, feverfew, garlic, and ginkgo interfere with platelet aggregation. When one of these herbs is taken with an antiplatelet drug such as aspirin, increased bleeding may occur. Pharmacokinetics
Cfopidogrel (Plavix) is rapidly absorbed and has a high protein-binding power The half-life is 8 hours; it is usually prescribed once a day. Excretion of the drug metabolite occurs equally in the urine and feces. Clopidogrel (plavix) prevents platelet aggregation by blocking the binding of ADP to the platelet ADP receptor. ADP- mediated activation of the glycoprotein (GP) IIb/IIIa complex inhibits platelet aggregation. Plavix prolongs bleeding time; therefore it should be discontinued for 7 days preceding surgery. The onset of action of Plavix is 1 to 2 hours, and its peak time is 2 to 3 hours. The drug should not be taken if the client has a bleeding peptic ulcer, any active bleeding, or intracranial hemorrhage.

Pharmacodynamics

Thrombolytics Thromboembolism (occlusion of an artery or vein caused by a thrombus or embolus) results in ischemia that causes necrosis of the tissue distal to the obstructed area. o It takes approximately 1 to 2 weeks for the blood clot to disintegrate by natural fibrinolytic mechanisms. Thrombolytic therapy: if a new thrombus or embolus can be dissolved more quickly, tissue necrosis is minimized, and blood flow to the area is reestablished faster Thrombolytics promote the fibrinolytic mechanism (converting plasminogen to plasmin, which destroys the fibrin in the blood clot). o The thrombus (blood clot) disintegrates when its given within 4 hours after an acute MI. o The need for cardiac bypass or coronary angioplasty can be evaluated soon after thrombolytic treatment. o Thrombolytic drug should be administered within 3 hours of a thrombolic stroke. o These drugs are also used for pulmonary embolism, DVT, noncoronary arterial occlusion from an acute thromboembolism, and thrombotic stroke. Streptokinase, urokinase, alteplase, reteplase (Retavase), and tenecteplase (TNKase). Streptokinase and urokinase are enzymes that promote the conversion of plasminogen to plasmin. Alteplase [a.k.a. tissue plasminogen activator (tPA)], is a clot-specific & binds to the fibrin surface of a clot, promoting the conversion of plasminogen to plasmin. o Plasmin, an enzyme, digests the fibrin in the clot & degrades fibrinogen, prothrombin, & other (fibrin breakdown). Streptokinase may cause hypotension when first administered. Drug dosage may need to be adjusted. Reteplase (Retavase), a derivative of tPA Anticoagulants & antiplatelet drugs increase the risk of hemorrhage; therefore they should be avoided until the thrombolytic effect has passed. o Find out whether the client has taken any of these drugs before seeking treatment. Pharmacokinetics
The commercial preparation of alteplase (tissue plasminogen activator (tPA) is identical to natural human tPA, the enzyme that converts plasminogen to plasmin. Alteplase is initially administered as an IV bolus, then infused over 30 minutes, then 60 minutes. A total dose of 100 mg is the recommended maximum; a larger dose could result in the risk of intracranial bleeding. The half-life of alteplase (tPA) is 5 minutes, shorter than the half-life of streptokinase. Alteplase costs about $2750, making it five times more expensive than streptokinase, but about the same as TNKase and reteplase. Allergic reactions to alteplase occur less frequently than to streptokinase, anistreplase, and urokinase. Afteplase is similar to natural human tissue plasminogen activator (tPA). It promotes thrombolysis by converting plasminogen to plasmin. Plasmin degrades fibrin, fibrinogen, and factors V, VIII, and XII. Alteplase does not induce hypotension as does streptokinase. Peak action of Alteplase is 5 to 10 minutes. The duration of action is 3 hours. Allergic reactions can complicate thrombolytic therapy. Anaphylaxis (vascular collapse) occurs more frequently with streptokinase than with the other thrombolytics. If the drugs are administered through an intracoronary catheter after myocardial infarction, reperfusion dysrhythmia or hemorrhagic infarction at the myocardial necrotic area can result. The major complication of thrombolytic drugs is hemorrhage. The antithrombolytic drug aminocaproic acid (Amicar) is used to stop bleeding by inhibiting plasminogen activation, which inhibits thrombolysis.

Pharmacodynamics

Side Effects and Adverse Effects