Antihypertensive Drugs PDF

Antihypertensive Drugs § ACE inhibitors act in the lungs to prevent ACE from converting angiotensin I to angiotensin II, a powerful vasoconstrictor and stimulator of aldosterone release. § This action leads to a decrease in blood pressure and in aldosterone secretion, with a resultant slig...

Antihypertensive Drugs § ACE inhibitors act in the lungs to prevent ACE from converting angiotensin I to angiotensin II, a powerful vasoconstrictor and stimulator of aldosterone release. § This action leads to a decrease in blood pressure and in aldosterone secretion, with a resultant slight increase in serum potassium and a loss of serum sodium and fluid. § Pharmacokinetics § All the ACE inhibitors are administered orally. Enalapril also has the advantage of parenteral use (enalaprilat). § These drugs are well absorbed, widely distributed, metabolized in the liver, and excreted in the urine and feces. § There is a risk of decreased antihypertensive effects if taken with nonsteroidal anti-inflammatory drugs; patients should be monitored. § They should be taken on an empty stomach 1 hour before or 2 hours after meals to improve absorption. § Contraindications and Cautions § ACE inhibitors are contraindicated with impaired renal function, which could be exacerbated by the effects of this drug in decreasing renal blood flow, pregnancy and during lactation because of potential decrease in milk production and effects on the neonate. § Caution should be used in patients with heart failure because the change in hemodynamics could be detrimental in some cases and in those with volume depletion, which could be exacerbated by the drug effects. § Adverse Effects § Reflex tachycardia, chest pain, angina, heart failure, and cardiac arrhythmias. § GI irritation, dry cough (common), ulcers, constipation, and liver injury. § Renal insufficiency, renal failure, proteinuria and hyperkalemia. § Rash, alopecia, dermatitis, and photosensitivity. § The ARBs selectively bind with the angiotensin II receptors in vascular smooth muscle and in the adrenal cortex to block vasoconstriction and the release of aldosterone. § These actions block the blood pressure–raising effects of the renin–angiotensin system and lower blood pressure. § They are indicated to be used alone or in combination therapy for the treatment of hypertension and for the treatment of heart failure in patients who are intolerant to ACE inhibitors. § Recently, they were also found to slow the progression of renal disease in patients with hypertension and type 2 diabetes. § Pharmacokinetics § These agents are all given orally. § They are well absorbed and undergo metabolism in the liver by the cytochrome P450 system. They are excreted in feces and in urine. § Contraindications and Cautions § The ARBs are contraindicated during pregnancy and during lactation § Caution should be used in the presence of hepatic or renal dysfunction, which could alter the metabolism and excretion of these drugs, and with hypovolemia, because of the blocking of potentially life-saving compensatory mechanisms. § Adverse Effects § They commonly associated with headache, dizziness, syncope, and weakness, which could be associated with drops in blood pressure; hypotension and hyperkalemia. § GI complaints, including diarrhea, abdominal pain, nausea, dry mouth, and tooth pain. § Symptoms of upper respiratory tract infections and cough § Rash, dry skin, and alopecia. § Calcium channel blockers inhibit the movement of calcium ions across the membranes of myocardial and arterial muscle cells, altering the action potential and blocking muscle cell contraction. § This effect depresses myocardial contractility, slows cardiac impulse formation in the conductive tissues, and relaxes and dilates arteries, causing a fall in blood pressure and a decrease in venous return. § Pharmacokinetics § Calcium channel blockers are given orally and are generally well absorbed, metabolized in the liver, and excreted in the urine. § Nicardipine and clevidipine are available in an intravenous form for short-term use when oral administration is not feasible. § Contraindications and Cautions § These drugs are contraindicated in patients with heart block or sick sinus syndrome, which could be exacerbated by the conduction-slowing effects of these drugs; and with renal or hepatic dysfunction, which could alter the metabolism and excretion of these drugs. § These drugs should not be used during pregnancy unless the benefit to the mother clearly outweighs any potential risk to the fetus § Adverse Effects § CNS effects include dizziness, light-headedness, headache, and fatigue. § GI problems include nausea and hepatic injury related to direct toxic effects on hepatic cells. § CV effects include hypotension, bradycardia, peripheral edema, and heart block. § Skin flushing and rash may also occur. § Most of the vasodilators are reserved for use in severe hypertension or hypertensive emergencies. § The vasodilators act directly on vascular smooth muscle to cause muscle relaxation, leading to vasodilation and drop in blood pressure. § They do not block the reflex tachycardia that occurs when blood pressure drops. § Pharmacokinetics § Nitroprusside is used intravenously; hydralazine is available for oral, intravenous, and intramuscular use; and minoxidil is available as an oral agent only. § These drugs are rapidly absorbed and widely distributed. They are metabolized in the liver and primarily excreted in urine. § Contraindications and Cautions § The vasodilators are contraindicated in patients with any condition that could be exacerbated by a sudden fall in blood pressure, such as cerebral insufficiency. § Caution should be used in patients with peripheral vascular disease, CAD, heart failure, or tachycardia, all of which could be exacerbated by the fall in blood pressure. § These drugs are also contraindicated with pregnancy unless the benefit to the mother clearly outweighs the potential risk § Adverse Effects § Dizziness, anxiety, and headache; reflex tachycardia, heart failure, chest pain, and edema; skin rash and lesions (abnormal hair growth with minoxidil); and GI upset, nausea, and vomiting. § Cyanide toxicity (dyspnea, headache, vomiting, dizziness, ataxia, loss of consciousness, imperceptible pulse, absent reflexes, dilated pupils, pink color, distant heart sounds, and shallow breathing) may occur with nitroprusside, which is metabolized to cyanide and also suppresses iodine uptake and can cause hypothyroidism. Diuretic Agents § Diuretics are drugs that increase the excretion of sodium and water from the kidney; they affect blood sodium levels and blood volume. § Diuretics are very important for the treatment of hypertension. These drugs are often the first agents tried in mild hypertension. § Although these drugs increase urination and can disturb electrolyte and acid–base balances, they are usually tolerated well by most patients. § Diuretic agents used to treat hypertension include the following: § Thiazide and thiazide-like diuretics: chlorothiazide, hydrochlorothiazide, methyclothiazide, chlorthalidone, indapamide and metolazone § Potassium-sparing diuretics: amiloride, spironolactone and triamterene Renin Inhibitor § Aliskiren directly inhibits renin, leading to decreased plasma renin activity and inhibiting the conversion of angiotensinogen to angiotensin I. § This inhibition of the renin–angiotensin–aldosterone system leads to decreased blood pressure, decreased aldosterone release, and decreased sodium reabsorption. § It is slowly absorbed from the GI tract, with peak levels in 3 hours. It is metabolized in the liver, with a half-life of 24 hours, and is excreted in the urine. § Because it blocks the renin–angiotensin system and aldosterone will not be stimulated to be released, there is a risk of hyperkalemia. § Although it is generally well tolerated, cases of angioedema with respiratory involvement have been reported in patients using this drug. § Avoid in pregnant and lactating women. Sympathetic Nervous System Blockers 1. Beta-blockers block vasoconstriction, decrease heart rate, decrease cardiac muscle contraction, and tend to increase blood flow to the kidneys, leading to a decrease in the release of renin. § These drugs have many adverse effects and are not recommended for all people. § They are often used as monotherapy in step 2 treatment, and in some patients, they control blood pressure adequately. § Beta-blockers used to treat hypertension include the following agents: § Acebutolol, Atenolol, Betaxolol, Bisoprolol, Metoprolol, Nadolol, Nebivolol, Propranolol and Timolol. 2. Alpha- and beta-blockers are useful in conjunction with other agents and tend to be somewhat more powerful, blocking all of the receptors in the sympathetic system. § Patients often complain of fatigue, loss of libido, inability to sleep, and GI and genitourinary disturbances. § Alpha- and beta-blockers used to treat hypertension include the following agents: Carvedilol and Labetalol. 3. Alpha-adrenergic blockers inhibit the postsynaptic alpha1-adrenergic receptors, decreasing sympathetic tone in the vasculature and causing vasodilation, which leads to a lowering of blood pressure. § Associated with reflex tachycardia that occurs when blood pressure decreases. § They have limited usefulness in essential hypertension because of the associated adverse effects. 4. Alpha1-blockers are used to treat hypertension because of their ability to block the postsynaptic alpha1-receptor sites. This decreases vascular tone and promotes vasodilation, leading to a fall in blood pressure. § Alpha1-blockers used to treat hypertension include the following agents: Doxazosin, Prazosin and Terazosin. 5. Alpha2-agonists stimulate the alpha2-receptors in the CNS and inhibit the cardiovascular centers, leading to a decrease in sympathetic outflow from the CNS and a resultant drop in blood pressure. § These drugs are associated with many adverse CNS and GI effects, as well as cardiac dysrhythmias. § Alpha2-blockers used to treat hypertension include the following agents: Clonidine and Methyldopa. Antianginal Agents § CAD involves changes in the coronary vessels that promote atheromas (tumors), which narrow the coronary arteries and decrease their elasticity and responsiveness to normal stimuli. § Angina pectoris occurs when the narrowed vessels cannot accommodate the myocardial demand for oxygen. § Stable angina occurs when the heart muscle is perfused adequately except during exertion or increased demand. Unstable or preinfarction angina occurs when the vessels are so narrow that the myocardial cells are deprived of sufficient oxygen even at rest. § Prinzmetal angina is a spasm of a coronary vessel that decreases the flow of blood through the narrowed lumen. § When a coronary vessel is completely occluded, the cells that depend on that vessel for oxygen become ischemic, then necrotic, and die. The result is known as an MI. § These drugs can work to improve blood delivery to the heart muscle in one of two ways: § (1) by dilating blood vessels (i.e., increasing the supply of oxygen) or § (2) by decreasing the work of the heart (i.e., decreasing the demand for oxygen). § Nitrates, beta-adrenergic blockers, and calcium channel blockers are used to treat angina. § In 2006, a new class of drugs, the piperazineacetamides, was introduced to treat chronic angina. § The nitrates relax and dilate veins, arteries, and capillaries, allowing increased blood flow through the vessels and lowering systemic blood pressure because of a drop in resistance. § The main effect of nitrates, however, seems to be related to the drop in blood pressure that occurs. § The vasodilation causes blood to pool in veins and capillaries, decreasing preload, while the relaxation of the vessels decreases afterload. The combination of these effects greatly reduces the cardiac workload and the demand for oxygen, thus bringing the supply and-demand ratio back into balance. § Nitrates are available in many forms that vary in time of onset and duration of action. Fast-acting nitrates are used to treat acute anginal attacks. Slower-acting nitrates are used to prevent anginal attacks from occurring. § Pharmacokinetics § Nitroglycerin is available as a sublingual tablet, a translingual spray, an intravenous solution (for bolus injection or infusion), a transdermal patch, a topical ointment or paste, or a transmucosal agent. § It can be carried with the patient, who then can use it when the need arises. § Amyl nitrate is supplied as a capsule that is broken and waved under the patient’s nose for inhalation. The administration is somewhat awkward for the patient to use by himself or herself. It usually requires another person to administer it properly. § Isosorbide dinitrate and isosorbide mononitrate are available in oral form. § Nitrates are very rapidly absorbed, metabolized in the liver, and excreted in urine. § Contraindications and Cautions § Contraindicated in the following conditions: severe anemia because the decrease in cardiac output could be detrimental in a patient who already has a decreased ability to deliver oxygen because of a low RBCs count; head trauma or cerebral hemorrhage because the relaxation of cerebral vessels could cause intracranial bleeding; and pregnancy or lactation. § Caution should be used in patients with hepatic or renal disease, also is required for patients with hypotension, hypovolemia, and conditions that limit cardiac output § Adverse Effects § CNS effects include headache, dizziness, and weakness. § GI symptoms can include nausea, vomiting, and incontinence. § CV problems include hypotension, which can be severe and must be monitored; reflex tachycardia that occurs when blood pressure falls; syncope; and angina, which could be exacerbated by the hypotension and changes in cardiac output § Skin related effects include flushing, pallor, and increased perspiration. With the transdermal preparation, there is a risk of contact dermatitis and local hypersensitivity reactions. § DDI: Patients should not combine nitrates with sildenafil, tadalafil, or vardenafil, drugs used to treat erectile dysfunction, because serious hypotension and cardiovascular events could occur. § Beta-blockers are used in the treatment of angina to help restore the balance between supply of oxygen and demand for oxygen. § Beta-blockers prevent the activation of sympathetic receptors, which normally would increase heart rate, increase blood pressure, and increase cardiac contraction. § All of these actions would increase the demand for oxygen; blocking these actions decreases the demand for oxygen. § Calcium channel blockers block muscle contraction in smooth muscle and decrease the heart’s workload, relax vasospasm in Prinzmetal angina, and possibly block the proliferation of the damaged endothelium in coronary vessels. § Patients on calcium channel blockers need to be monitored for signs of decreased cardiac output and response, including slow heart rate, hypotension, dizziness, and headache. § The newest drug approved for the treatment of angina is the piperazineacetamide agent ranolazine. § The mechanism of action of this drug is not understood. It prolongs QT intervals, does not slow heart rate or blood pressure, but decreases myocardial workload, bringing the supply and demand for oxygen back into balance. § It is rapidly absorbed, reaching peak levels in 2 to 5 hours. It is metabolized in the liver with a half-life of 7 hours and is excreted in urine and feces. § Ranolazine is contraindicated with preexisting prolonged QT interval or in combination with drugs that would prolong QT intervals; and with hepatic impairment and lactation. Caution should be used with pregnancy or renal impairment. § Dizziness, headache, nausea, and constipation are the most commonly experienced adverse effects. Cardiotonic Agents § Cardiotonic (inotropic) drugs affect the intracellular calcium levels in the heart muscle, leading to increased contractility. § This increase in contraction strength leads to increased cardiac output, which causes increased renal blood flow and increased urine production. § Increased renal blood flow decreases renin release, interfering with the effects of the renin–angiotensin–aldosterone system, and increases urine output, leading to decreased blood volume § The cardiac glycosides were originally derived from the foxglove or digitalis plant. § Digoxin increases intracellular calcium and allows more calcium to enter myocardial cells during depolarization, causing the following effects: § Increased force of myocardial contraction (a positive inotropic effect) § Increased cardiac output and renal perfusion (which has a diuretic effect, increasing urine output and decreasing blood volume while decreasing renin release and activation of the renin–angiotensin–aldosterone system) § Slowed heart rate, owing to slowing of the rate of cellular repolarization (a negative chronotropic effect) § Decreased conduction velocity through the atrioventricular (AV) node § Digoxin is indicated for the treatment of heart failure (HF), atrial flutter, atrial fibrillation, and paroxysmal atrial tachycardia. § Digoxin has a very narrow margin of safety (meaning that the therapeutic dose is very close to the toxic dose), so extreme care must be taken when using this drug § Pharmacokinetics § Digoxin is available for oral and parenteral administration. The drug has a rapid onset of action and rapid absorption. It is widely distributed throughout the body. § Digoxin is primarily excreted unchanged in the urine. Because of this, caution should be exercised in the presence of renal impairment because the drug may not be excreted and could accumulate, causing toxicity. § Contraindications and Cautions § Digoxin is contraindicated in the following conditions: § Ventricular tachycardia or fibrillation, which are potentially fatal arrhythmias and should be treated with other drugs; § Heart block or sick sinus syndrome, which could be made worse by slowing of conduction through the AV node; § Acute MI because the increase in force of contraction could cause more muscle damage and infarct; § Electrolyte abnormalities (e.g., increased calcium, decreased potassium, decreased magnesium), which could alter the action potential and change the effects of the drug. § Adverse Effects § The adverse effects most frequently seen with the cardiac glycosides include headache, weakness, drowsiness, and vision changes (a yellow halo around objects is often reported). § GI upset and anorexia also commonly occur. § Arrhythmias may develop because the glycosides affect the action potential and conduction system of the heart. § Digoxin toxicity is a serious syndrome that can occur when digoxin levels are too high. The patient may present with anorexia, nausea, vomiting, malaise, depression, irregular heart rhythms including heart block, atrial arrhythmias, and ventricular tachycardia. This can be a life-threatening situation. § A digoxin antidote, digoxin immune Fab, has been developed to rapidly treat digoxin toxicity. § DDI § There is a risk of increased therapeutic effects and toxic effects of digoxin if it is taken with verapamil, amiodarone, quinidine, quinine, erythromycin, tetracycline, or cyclosporine. § The risk of cardiac arrhythmias could increase if these drugs are taken with potassium-losing diuretics. § Absorption of oral digoxin may be decreased if it is taken with cholestyramine, charcoal, colestipol, antacids, bleomycin, cyclophosphamide, or methotrexate. Antiarrhythmic Agents § Arrhythmias (also called dysrhythmias) are disruptions in the normal rate or rhythm of the heart. § The cardiac conduction system determines the heart’s rate and rhythm. The property by which the cardiac cells generate an action potential internally to stimulate the cardiac muscle without other stimulation is known as automaticity. § Electrolyte disturbances, decreases in the oxygen delivered to the cells, structural damage in the conduction pathway, drug effects, acidosis, or the accumulation of waste products can trigger arrhythmias. § Changes in the heart rate, uncoordinated heart muscle contractions, or blocks that alter the movement of impulses through the system can disrupt heart rhythm. § Arrhythmias change the mechanics of blood circulation (hemodynamics), which can interrupt delivery of blood to the brain, other tissues, and the heart. § Antiarrhythmics affect the action potential of the cardiac cells by altering their automaticity, conductivity, or both. § Because of this effect, antiarrhythmic drugs can also produce new arrhythmias- that is, they are proarrhythmic. § Antiarrhythmics are used in emergency situations when the hemodynamics arising from the patient’s arrhythmia are severe and could potentially be fatal. § Class I antiarrhythmics are drugs that block the sodium channels in the cell membrane during an action potential. These drugs are further broken down into three subclasses, reflecting the manner in which their blockage of sodium channels affects the action potential. § Class Ia drugs depress phase 0 of the action potential and prolong the duration of the action potential. § Class Ib drugs depress phase 0 somewhat and actually shorten the duration of the action potential. § Class Ic drugs markedly depress phase 0, with a resultant extreme slowing of conduction, but have little effect on the duration of the action potential. § These drugs preferable in conditions such as tachycardia, in which the sodium gates are open frequently. § Pharmacokinetics § These drugs are widely distributed after injection or after rapid absorption through the gastrointestinal (GI) tract. They undergo extensive hepatic metabolism and are excreted in urine. § Contraindications and Cautions § Class I antiarrhythmics are contraindicated in patients with bradycardia or heart block unless an artificial pacemaker is in place, because changes in conduction could lead to complete heart block; with heart failure (HF), hypotension, or shock, which could be exacerbated by effects on the action potential; and with electrolyte disturbances, which could alter the effectiveness of these drugs. § Caution should be used in patients with renal or hepatic dysfunction. § Adverse effects § CNS effects can include dizziness, drowsiness, fatigue, twitching, mouth numbness, slurred speech, vision changes, and tremors that can progress to convulsions. § GI symptoms include changes in taste, nausea, and vomiting. § CV effects include the proarrhythmic effects that lead to the development of arrhythmias (including heart blocks), hypotension, vasodilation, and the potential for cardiac arrest. § Respiratory depression progressing to respiratory arrest can also occur. § The class II antiarrhythmics are beta-adrenergic blockers that block beta-receptors, causing a depression of phase 4 of the action potential. § They competitively block beta-receptor sites in the heart and kidneys. The result is a decrease in heart rate, cardiac excitability, and cardiac output, a slowing of conduction through the AV node, and a decrease in the release of renin. § These effects stabilize excitable cardiac tissue and decrease blood pressure, which decreases the heart’s workload and may further stabilize hypoxic cardiac tissue. § These drugs are indicated for the treatment of supraventricular tachycardia and premature ventricular contraction. § The class III antiarrhythmics block potassium channels and slow the outward movement of potassium during phase 3 of the action potential, prolonging it. § All of these drugs are proarrhythmic and have the potential of inducing arrhythmias. § Although amiodarone has been associated with such serious and even fatal toxic reactions, it is named the drug of choice for treating ventricular fibrillation or pulseless ventricular tachycardia in cardiac arrest situations. § Pharmacokinetics § These drugs are well absorbed after oral administration and are immediately available after IV administration and widely distributed. § Absorption of sotalol is decreased by the presence of food. They are metabolized in the liver and excreted in urine. § Contraindications and Cautions § Ibutilide and dofetilide should not be used in the presence of AV block, which could be exacerbated by the drug. § Because sotalol is known to be proarrhythmic, patients should be monitored very closely at the initiation of therapy and periodically during therapy. § Caution should be used with all of these drugs in the presence of shock, hypotension, or respiratory depression; with a prolonged QT interval, which could worsen due to the depressive effects on action potentials; and with renal or hepatic disease. § Adverse Effects § Nausea, vomiting, and GI distress; weakness and dizziness; and hypotension, HF, and arrhythmia are common. § Amiodarone has been associated with a potentially fatal liver toxicity, ocular abnormalities, and the development of very serious cardiac arrhythmias. § The class IV antiarrhythmics block the movement of calcium ions across the cell membrane, depressing the generation of action potentials and delaying phases 1 and 2 of repolarization, which slows automaticity and conduction. § Adenosine is another antiarrhythmic agent that is used to convert supraventricular tachycardia to sinus rhythm if vagal maneuvers have been ineffective. § It is preferred in this case for two reasons: (1) It has a very short duration of action (about15 seconds), after which it is picked up by circulating red blood cells and cleared through the liver, (2) it is associated with very few adverse effects (headache, flushing, and dyspnea of short duration). § This drug slows conduction through the AV node, prolongs the refractory period, and decreases automaticity in the AV node. § It is given IV with continuous monitoring of the patient. § Digoxin is also used at times to treat arrhythmias. § This drug slows calcium from leaving the cell, prolonging the action potential and slowing conduction and heart rate. § Digoxin is effective in the treatment of atrial arrhythmias. § The drug exerts a positive inotropic effect, leading to increased cardiac output, which increases perfusion of the coronary arteries and may eliminate the cause of some arrhythmias as hypoxia is resolved and waste products are removed more effectively. § Dronedarone has properties of all four classes of antiarrhythmics. § It is used to reduce the risk of hospitalization in patients with paroxysmal or persistent AF of flutter who have risks factors for cardiovascular disease and who are in sinus rhythm or are scheduled to be converted to sinus rhythm. § It is an oral drug that is taken twice a day. § Many drug– drug interactions have been associated with the drug. Grapefruit juice should be avoided while taking this drug. § The most common adverse effects seen with dronedarone are HF, prolonged QT interval, nausea, diarrhea, and rash. § C/I: It should never be used during pregnancy because it has been associated with fetal abnormalities. Drugs affecting clot formation § Disorders that are directly related to the clotting process include thromboembolic disorders, in which too much clotting can lead to emboli and occlusion of blood vessels. § Drugs that affect clot formation include antiplatelet drugs, which alter platelet aggregation and the formation of the platelet plug; anticoagulants, which interfere with the clotting cascade and thrombin formation; and thrombolytic agents, which break down the thrombus or clot that has been formed by stimulating the plasmin system. § Antiplatelet agents decrease the formation of the platelet plug by decreasing the responsiveness of the platelets to stimuli that would cause them to stick and aggregate on a vessel wall. § The antiplatelet agents inhibit platelet adhesion and aggregation by blocking receptor sites on the platelet membrane, preventing platelet–platelet interaction or the interaction of platelets with other clotting chemicals. § Pharmacokinetics § Abciximab, eptifibatide, and tirofiban are administered intravenously (IV). Antiplatelet agents that are administered orally include anagrelide, aspirin, cilostazol, clopidogrel, ticagrelor, and ticlopidine. Dipyridamole is used orally or as an IV agent. § These drugs are generally well absorbed and highly bound to plasma proteins. They are metabolized in the liver and excreted in urine, and they tend to enter breast milk. § Contraindications and Cautions § Caution should be used in the following conditions: the presence of any known bleeding disorder because of the risk of excessive blood loss; recent surgery because of the risk of increased bleeding in unhealed vessels; and closed head injuries because of the risk of bleeding from the injured vessels in the brain. § Anagrelide should be used with caution with any history of thrombocytopenia because it decreases the production of platelets in the bone marrow. § Adverse Effects § The most common adverse effect seen with these drugs is bleeding, which often occurs as increased bruising and bleeding while brushing the teeth. § Other common problems include headache, dizziness, and weakness. § Nausea and gastrointestinal (GI) distress may occur because of direct irritating effects of the oral drug on the GI tract. § Anticoagulants are drugs that interfere with the normal coagulation process by interfering with the clotting cascade and thrombin formation. § Warfarin, an oral drug in this class, causes a decrease in the production of vitamin K–dependent clotting factors in the liver. The eventual effect is a depletion of these clotting factors and a prolongation of clotting times. § Dabigatran directly inhibits thrombin, which blocks the last step to clot formation. § Rivaroxaban is a factor Xa inhibitor that stops the coagulation cascade at early step. § Heparin, argatroban, and bivalirudin block the formation of thrombin from prothrombin. Patients may be started on heparin in the acute situation and then switched to the oral drug warfarin. § Fondaparinux is a newer anticoagulant. It inhibits factor Xa and blocks the clotting cascade to prevent clot formation. § Pharmacokinetics § Warfarin is readily absorbed through the GI tract, metabolized in the liver, and excreted in urine and feces. Warfarin’s onset of action is about 3 days; its effects last for 4 to 5 days. Because of the time delay, warfarin is not the drug of choice in an acute situation, but it is convenient and useful for prolonged effects. § Dabigatran has a rapid onset of action, peaking in 1 to 2 hours. It is excreted in the urine after being metabolized in the liver. § Rivaroxaban is also absorbed rapidly with peak effects in 2 to 4 hours. It is excreted in the urine and feces after being metabolized in the liver. Patients must use care in storing this dabigatran (in a dark, nonhumid environment) and in the original bottle and it is only stable for 60 days from the time the bottle if opened. § Desirudin and fondaparinux are absorbed quickly from subcutaneous sites and metabolized and excreted by the kidneys. § Bivalirudin is given IV and is excreted through the kidneys. § Heparin is the anticoagulant of choice if one is needed during lactation. Contraindications and Cautions § They also should not be used with any conditions that could be compromised by increased bleeding tendencies, including hemorrhagic disorders, recent trauma, spinal puncture, GI ulcers, recent surgery, intrauterine device placement, tuberculosis, presence of indwelling catheters, and threatened abortion. § Warfarin is contraindicated in pregnancy because fetal injury and death have occurred; in lactation, because of the potential risk to the baby; and in renal or hepatic disease, which could interfere with the metabolism and effectiveness of these drugs. § Adverse Effects § The most commonly encountered adverse effect of the anticoagulants is bleeding, ranging from bleeding gums with tooth brushing to severe internal hemorrhage. § Patients need teaching about administration, disposal of the syringes, and signs of bleeding to watch for. § Periodic blood tests will be needed to assess the effects of the drug on the body. The patient should also be monitored for warfarin overdose. § Warfarin has documented drug–drug interactions with a vast number of other drugs. It is a wise practice never to add or take away a drug from the regimen of a patient receiving warfarin without careful patient monitoring and adjustment of the warfarin dose to prevent serious adverse effects. § Thrombolytic agents break down the thrombus that has been formed by stimulating the plasmin system. This process is called clot resolution. § All of the drugs that are available for this purpose work to activate the natural anticlotting system—conversion of plasminogen to plasmin. The activation of this system breaks down fibrin threads and dissolves any formed clot. The thrombolytics are effective only if the patient has plasminogen in the plasma. § Pharmacokinetics § These drugs are given IV and are cleared from the body after liver metabolism. § Contraindications and Cautions § They should not be used with any condition that could be worsened by the dissolution of clots, including recent surgery, active internal bleeding, CVA within the last 2 months, aneurysm, obstetrical delivery, organ biopsy, recent serious GI bleeding, rupture of a noncompressible blood vessel, recent major trauma, known blood clotting defects, cerebrovascular disease, uncontrolled hypertension, and liver disease. § These drugs are also contraindicated in pregnancy. § Adverse Effects § The most common adverse effect associated with the use of thrombolytic agents is bleeding. Patients should be monitored closely for the occurrence of cardiac arrhythmias (with coronary reperfusion) and hypotension. § Low-Molecular-Weight Heparins: § These drugs inhibit thrombus and clot formation by blocking factors Xa and IIa. Because of the size and nature of the molecules, these drugs do not greatly affect thrombin, clotting, or the PT; therefore, they cause fewer systemic adverse effects. § These drugs are indicated for very specific uses in the prevention of clots and emboli formation after certain surgeries or prolonged bed rest. § Low-molecular-weight heparins include dalteparin, enoxaparin, and tinzaparin. § Summary § DVT: Deep Vein Thrombosis § PE: Pulmonary Embolism § Allowed in pregnancy: injectable heparin and injectable low molecular weight Heparins (SC) § C/I in pregnancy and lactation: oral warfarin § C/I in pregnancy: IV thrombolytic agents