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Antihypertensive Drugs
Hypertension is defined as sustained, reproducible increase in blood pressure. Generally, diastolic values greater than 90 mm Hg and/or systolic values greater than 140 mm Hg warrant a diagnosis of hypertension. If untreated, hypertension leads to serious problems such as stroke, renal failure, and problems in several other physiologic systems. Although the cause of hypertension is discernible in a small percentage of patients, the majority of hypertensive individuals are classified as having essential hypertension, which means that the cause of their elevated blood pressure is unknown. Fortunately, several types of drugs are currently available to adequately control blood pressure in essential hypertension. Drugs such as diuretics, sympatholytics (alpha blockers, beta blockers, etc.), vasodilators, angiotensin converting enzyme inhibitors, and calcium channel blockers have all been used in treating hypertension. These agents are usually prescribed according to a stepped-care protocol, where therapy is initiated with one drug, and subsequent agents are added as required. Rehabilitation specialists should be aware of the potential side effects of these drugs. Physical therapists and occupational therapists assume an important role in making patients aware of the sequelae of hypertension, and therapists should actively encourage patients to comply with pharmacologic and nonpharmacologic methods of lowering blood pressure. Due to the prevalence of hypertension, however, many patients receiving therapy for other problems will also be taking antihypertensive drugs, so knowledge of the pharmacology of these agents is essential. Drug Therapy Several major categories of drugs exist for the treatment of essential hypertension. These categories include diuretics, sympatholytic drugs, vasodilators, angiotensin-converting enzyme inhibitors, and calcium channel blockers. The primary sites of action and effects of each category are summarized in the table below.

Diuretics Diuretics - increase the formation and excretion of urine. These drugs are used as antihypertensive agents because of their ability to increase the renal excretion of water and sodium, thus decreasing the volume of fluid within the vascular system. Hence, diuretics have been a mainstay in the treatment of hypertension for many years, and they remain one of the primary methods for treating this condition in a large number of people. Classifications of Diuretics Thiazide Diuretics - These drugs act primarily on the early portion of the distal tubule of the nephron, where they inhibit sodium reabsorption, creating an osmotic force that also retains more water in the nephron. Since more sodium and water are passed through the nephron, where they will ultimately be excreted from the body, a diuretic effect is produced. Thiazides are the most frequently used type of diuretic for hypertension. Loop Diuretics - These drugs act primarily on the ascending limb of the loop of Henle (hence the term loop diuretic). They exert their diuretic effect by inhibiting the reabsorption of sodium and chloride from the nephron, thereby preventing the reabsorption of the water that follows these electrolytes. Potassium-Sparing Diuretics - Several different drugs with diuretic properties are classified as potassium-sparing because they are able to prevent the secretion of potassium into the distal tubule. Normally, a sodium-potassium exchange occurs in the distal tubule, where sodium is reabsorbed and potassium is secreted. Although these agents do not produce a diuretic effect to the same extent as the loop and thiazide diuretics, potassiumsparing drugs have the advantage of reducing potassium loss and thus preventing hypokalemia.

Sympatholytic Drugs Drugs that interfere with sympathetic discharge should be valuable as antihypertensive agents. These sympatholytic drugs can be classified according to where and how they interrupt sympathetic activity. Sympatholytic drugs used to treat hypertension include betaadrenergic blockers, alpha-adrenergic blockers, presynaptic adrenergic neurotransmitter depletors, centrally acting drugs, and ganglionic blockers . Beta Blockers - exert their primary effect on the heart, where they decrease heart rate and force myocardial contraction. In hypertensive patients, these drugs lower blood pressure by slowing down the heart and reducing cardiac output. Alpha Blockers - Drugs that block the alpha-1adrenergic receptor on vascular smooth muscle will promote a decrease in vascular resistance. In a sense, alpha blockers act directly on the tissues that ultimately mediate the increased blood pressurethat is, the peripheral vasculature. Presynaptic Adrenergic Inhibitors - Drugs that inhibit the release of norepinephrine from the presynaptic terminals of peripheral adrenergic. In either case, depletion of norepinephrine from the presynaptic terminal decreases sympathetic-mediated excitation of the heart and peripheral vasculature, resulting in decreased blood pressure. Centrally Acting Agents - Centrally acting sympatholytics are characterized as agonists and offers a rather unique approach to hypertension because these drugs limit sympathetic activity at the source (brainstem vasomotor center) rather than at the periphery (cardiovascular neuroeffector junction). Ganglionic Blockers - Drugs that block synaptic transmission at autonomic ganglia will dramatically and effectively reduce blood pressure by decreasing systemic sympathetic activity. These agents are essentially nicotinic cholinergic antagonists, which block transmission at the junction between presynaptic and postsynaptic neurons in sympathetic and parasympathetic pathways.

Vasodilators Drugs that directly vasodilate the peripheral vasculature will produce an antihypertensive effect by decreasing peripheral vascular resistance. Vasodilators are believed to inhibit smooth-muscle contraction by increasing the intracellular production of second messengers such as cyclic guanosine monophosphate, thus leading to vasodilation. Inhibition of the Renin-Angiotensin System The renin-angiotensin system involves several endogenous components that help regulate vascular tone in various organs and tissues. Renin is an enzyme produced primarily in the kidneys. When blood pressure falls, renin is released from the kidneys into the systemic circulation. Angiotensinogen is a peptide that is produced by the liver and circulates continually in the bloodstream. Calcium Channel Blockers Drugs that selectively block calcium entry into vascular smooth-muscle cells were originally developed to treat certain forms of angina pectoris and cardiac arrhythmias. Calcium appears to play a role in activating the contractile element in smooth muscle much in the same way that calcium initiates actin-myosin interaction in skeletal muscle cells. Drugs that block calcium entry into vascular smooth muscle will inhibit the contractile process, leading to vasodilation and decreased vascular resistance.

Angina Pectoris
Angina pectoris is pain that occurs in the chest region during ischemic heart disease. Attacks of angina pectoris begin suddenly and are often described as a sensation of intense compression and tightness in the retrosternal region, with pain sometimes radiating to the jaw or left arm. In many patients, episodes of angina pectoris are precipitated by physical exertion. Some forms of angina, however, may occur spontaneously even when the patient is at rest or asleep. Pain in the chest region, or angina pectoris, is a common symptom of ischemic heart disease. Anginal pain usually occurs because of an imbalance between myocardial oxygen supply and myocardial oxygen demand. Organic nitrates, beta blockers, and calcium channel blockers are the primary drugs used to treat angina pectoris. Organic nitrates and beta blockers primarily exert their effects by decreasing myocardial oxygen demand, whereas calcium channel blockers primarily increase myocardial oxygen supply. Several forms of angina pectoris can be identified, and specific types of antianginal drugs are used alone or in combination with each other to treat or prevent various forms of angina. Rehabilitation specialists must be aware of any patients who have angina pectoris and the possibility of patients having an anginal attack during a therapy session. Therapists should also be cognizant of what drugs are being taken to control the patients angina, as well as any side effects that may influence certain rehabilitation procedures.

Drugs Used to Treat Angina Pectoris Three drug groups are typically used to treat the symptoms of angina pectoris: organic nitrates, beta blockers, and calcium channel blockers. These drugs exert various effects that help restore or maintain the balance between myocardial oxygen supply and myocardial oxygen demand. Organic Nitrates Organic nitrates consist of drugs such as nitroglycerin, isosorbide dinitrate, and isosorbide. The ability of these agents to dilate vascular smooth muscle is well established. Nitrates are actually drug precursors (prodrugs) that become activated when they are converted to nitric oxide within vascular smooth muscle. Nitrates can also dilate the coronary arteries to some extent; these drugs are documented to have an increase in coronary artery flow. Specific Agents Nitroglycerin (Nitro-Bid, Nitrostat, Nitro-Dur, many others) - In addition to being used as a powerful explosive, nitroglycerin is perhaps the most well known antianginal drug. The explosive nature of this agent is rendered inactive by diluting it with lactose, alcohol, or propylene glycol. Nitroglycerin is administered for both the prevention and treatment of anginal attacks and is available in oral, buccal, sublingual, and transdermal forms Isosorbide Dinitrate - Like nitroglycerin, isosorbide dinitrate is used for the treatment of acute episodes of angina as well as for the prevention of anginal attacks. The antianginal and hemodynamic effects last longer with isosorbide dinitrate, however, so this drug is often classified as a long-acting nitrate.For acute attacks, isosorbide dinitrate is administered sublingually, buccally, or by chewable tablets. For prevention of angina, oral tablets are usually given. Isosorbide Mononitrate - This drug is another long-acting nitrate that is similar in structure and function to isosorbide dinitrate. It is typically given orally for prevention of anginal attacks. Amyl Nitrite - This drug is supplied in small ampules that can be broken open to inhale during acute anginal attacks. Absorption of the drug through the nasal membranes causes peripheral vasodilation and decreased cardiac preload and afterload. Clinical use of inhaled amyl nitrite is very limited, however, and this type of antianginal treatment has generally been replaced by safer and more convenient methods of nitrate administration (e.g., nitroglycerin patches).

Beta-Adrenergic Blockers By antagonizing beta-1 receptors on the myocardium, beta blockers tend to decrease the heart rate and force of myocardial contraction, thus producing an obvious decrease in the work that the heart must perform and a decrease in myocardial oxygen demand. Beta blockers help maintain an appropriate balance between myocardial oxygen supply and demand by preventing an increase in myocardial oxygen demand. Consequently, beta blockers are given to certain patients with angina to limit the oxygen demands of the heart. This prophylactic administration prevents the onset of an anginal attack.

Calcium Channel Blockers These drugs block the entry of calcium into vascular smooth muscle. In vascular smooth muscle, calcium ions facilitate contraction by initiating actin-myosin interaction. Calcium channel blockers decrease the entry of calcium into vascular smooth-muscle cells, thus causing relaxation and vasodilation. Consequently, a primary role of calcium channel blockers in angina pectoris is to directly increase coronary blood flow, thus increasing myocardial oxygen supply. Specific Agents Bepridil (Vascor). Bepridil is a nonselective calcium channel blocker that inhibits calcium influx into vascular smooth muscle and cardiac striated muscle.D ecreases heart rate (negative chronotropic effect) and cardiac contractility (negative inotropic effect) through an inhibitory effect on the myocardium. Diltiazem (Cardizem, Dilacor) - Like the other calcium channel blockers, diltiazem is able to vasodilate the coronary arteries and the peripheral vasculature. Diltiazem also produces some depression of electrical conduction in the sinoatrial and atrioventricular nodes, an effect that may cause slight bradycardia. This bradycardia can be worsened by beta blockers or in patients with myocardial conduction problems, and diltiazem should probably be avoided in these individuals Nifedipine (Adalat, Procardia) and Other Dihydropyridines - Nifedipine and similar drugs are members of the dihydropyridine class of calcium channel blockers. This class is distinguished by drugs with an -ipine suffix, including felodipine (Plendil), isradipine (DynaCirc), and nicardipine (Cardene). These drugs are relatively selective for vascular smooth muscle as compared to cardiac striated muscle, and they vasodilate the coronary arteries and peripheral vasculature without exerting any direct effects on cardiac excitability or contractility. Verapamil (Calan, Isoptin) - Verapamil has been used to treat angina because of its ability to vasodilate the coronary vessels. Verapamil, however, seems to be moderately effective compared to the other antianginal drugs, and verapamil also depresses myocardial excitability and decreases heart rate. Because of its negative effects on cardiac excitation, verapamil is probably more useful in controlling certain cardiac arrhythmias.

Cardiac Arrhythmias
An arrhythmia can be broadly defined as any significant deviation from normal cardiac rhythm. Various problems in the origination and conduction of electrical activity in the heart can lead to distinct types of arrhythmias. If untreated, disturbances in normal cardiac rhythm result in impaired cardiac pumping ability, and certain arrhythmias are associated with cerebrovascular accidents, cardiac failure, and other sequelae that can be fatal. Fortunately, a variety of drugs are available to help establish and maintain normal cardiac rhythm. Drugs affecting acetylcholine-mediated responses are classified as cholinergic stimulants and anticholinergic drugs. Cholinergic stimulants increase cholinergic activity by binding to the acetylcholine receptor and activating the receptor (direct-acting stimulants) or by inhibiting the acetylcholinesterase enzyme, thus allowing more acetylcholine to remain active at the cholinergic synapse (indirect-acting stimulants). Anticholinergic drugs inhibit cholinergic activity by acting as competitive antagonists; that is, they bind to the cholinergic receptor but do not activate it. Cholinergic stimulants and anticholinergic drugs affect many tissues in the body and are used to treat a variety of clinical problems. Cholinergic stimulants are often administered to increase gastrointestinal and urinary bladder tone, to treat conditions such as glaucoma, myasthenia gravis, and Alzheimer disease, and to reverse the neuromuscular blockade produced by curarelike drugs. Anticholinergic drugs are used principally to decrease gastrointestinal motility and secretions, and to decrease the symptoms of Parkinson disease, but they may also be used to treat problems in several other physiologic systems. Because of the ability of cholinergic stimulants and anticholinergic drugs to affect different tissues, these drugs may be associated with a number of side effects. Considering the diverse clinical applications of cholinergic stimulants and anticholinergics, physical therapists and occupational therapists may frequently encounter patients taking these drugs. Rehabilitation specialists should be aware of the rationale for drug administration as well as possible side effects of cholinergic stimulants and anticholinergic agents. Classification of Antiarrhythmic Drugs Drugs used to treat cardiac arrhythmias are traditionally placed in one of four distinct classes according to their mechanism of action. The classification system has been criticized somewhat because it has several limitations, including the fact that certain drugs may have characteristics from more than one class, and that certain drugs with antiarrhythmic properties (e.g., digitalis) do not fit into this system. Class I: Sodium Channel Blockers Class I antiarrhythmic drugs are essentially sodium channel blockers. These drugs bind to membrane sodium channels in various excitable tissues, including myocardial cells. In cardiac tissues, class I drugs normalize the rate of sodium entry into cardiac tissues and thereby help control cardiac excitation and conduction. Class IA. Drugs in this group are similar in that they produce a moderate slowing of phase 0 depolarization and a moderate slowing of action potential propagation throughout the myocardium. Class IA agents include quinidine, procainamide, and disopyramide; these drugs are used to treat a variety of arrhythmias originating in the ventricles or atria. Class IB. These drugs display a minimal ability to slow phase 0 depolarization, and produce a minimal slowing of cardiac conduction. In contrast to IA drugs, class IB drugs usually shorten cardiac repolarization; that is, the effective refractory period is decreased. Class IB drugs include lidocaine, mexiletine, and moricizine. These drugs are primarily used to treat ventricular arrhythmias such as ventricular tachycardia and premature ventricular contractions (PVCs). Class IC. These drugs produce both a marked decrease in the rate of phase 0 depolarization and a marked slowing of cardiac conduction. They have little effect on repolarization. Class IC drugs include flecainide and propafenone, and appear to be best suited to treat ventricular arrhythmias such as ventricular tachycardia and PVCs. Class II: Beta Blockers Drugs that block beta-1 receptors on the myocardium are one of the mainstays in arrhythmia treatment. Beta blockers are effective because they decrease the excitatory effects of the sympathetic nervous system and related catecholamines (norepinephrine and epinephrine) on the heart. This effect typically decreases cardiac automaticity and prolongs the effective refractory period, thus slowing heart rate. Beta blockers also slow down conduction through the myocardium, and are especially useful in controlling function of the atrioventricular node. Hence, these drugs are most effective in treating atrial tachycardias such as atrial fibrillation. Some ventricular arrhythmias may also respond to treatment with beta blockers. Class III: Drugs That Prolong Repolarization Class III agents delay repolarization of cardiac cells, which prolongs the effective refractory period of the cardiac action potential. This delay lengthens the time interval before a subsequent action potential can be initiated, thus slowing and stabilizing the heart rate. The effects of class III drugs are complex, but their ability to lengthen the cardiac action potential is most likely mediated by inhibition of

potassium efflux during repolarization. That is, these drugs limit the ability of potassium to leave the cell during phase 2 and 3 of the action potential, which prolongs repolarization and prevents the cell from firing another action potential too rapidly. Class III drugs are used to treat ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation, and supraventricular arrhythmias such as postoperative atrial fibrillation. Interest in using these drugs and developing new class III agents has increased recently because they affect both atrial and ventricular problems and are relatively safe compared to other agents such as the class I drugs. Class IV: Calcium Channel Blockers Class IV drugs have a selective ability to block calcium entry into myocardial and vascular smooth-muscle cells. These drugs inhibit calcium influx by binding to specific channels in the cell membrane. As discussed previously, calcium entry plays an important role in the generation of the cardiac action potential, especially during phase 2. By inhibiting calcium influx into myocardial cells, calcium channel blockers can alter the excitability and conduction of cardiac tissues. Calcium channel blockers decrease the rate of discharge of the SA node and inhibit conduction velocity through the AV node.5 These drugs are most successful in treating arrhythmias caused by atrial dysfunction, such as supraventricular tachycardia and atrial fibrillation.

Cardiac glycoside
Cardiac Glycosides have two prominent effects: Increased Contractility of the Heart The longer calcium stays in a cell, the harder and longer the contraction will be. Cardiac glycosides decrease the hearts ability to pump calcium out of the cardiac cell so we get increased contractility of the heart. This is known as an increased inotropic effect. This leads to an increase in cardiac output (greater contractility and duration) in a failing heart. Decreased AV Node Conduction The AV node is the gate. When you decrease AV node conduction, the gate stays closed longer and the amount of electrical activity going from the atrium to the ventricle decreases. This is known as adecreased chronotropic effect. This helps prevent atrial fibrillation from becoming ventricular fibrillation. Therapeutic Monitoring The lower end dose works on increasing contractility. The higher end dose works on decreasing AV node conduction. But the therapeutic index is very narrow so we dont have a lot of play with this. We must hold the dose if the apical pulse is <60: Nurses must always monitor the apical pulse of a patient before administering a cardiac glycoside. If its below 60, you must not give the medication. You must call the physician because the patient may be toxic. Why is the pulse rate so important with cardiac glycosides?

Quick reminder of P, QRS, T. P = atrial contraction QRS = for the most part, ventricles are contracting T = repolarization Since cardiac glycosides work on the AV node, as the dose increases the gate closes longer and longer. In 1st Degree AV block, the EKG would have a long PRinterval because the conduction decreased through the AVnode. This means wed have less QRS beats. This gives us a warning that if the apical pulse is less than 60, then we could be in 1st degree AV block. If you dont heed that warning, without getting into 2nd degree block, we could throw them into 3rd degree AV block. In 3rd degreeAV block, nothing is getting through that AV node. This is when the automaticity of the heart takes over which looks like pre-fibrillation. Serum drug levels: We monitor the serum drug levels because of the narrow therapeutic index. When you get lab results back, most medication blood levels come back as micrograms per deciliter (mcg/dL). Cardiac glycosides come back in nanograms per deciliter (10^9). Serum calcium: In phase 2 of the action potential, calcium is slowly entering the cell and this is when we have contraction. Too much calcium, hypercalcemia, will make the contraction too hard. Serum potassium: In phase 3 of the action potential, potassium exits the cell and we have repolarization, If a person doesnt have enough potassium, they cant recover. So even if a person is therapeutic with the serum drug level, but hypokalemic, its a big deal. Why would they be hypokalemic? Maybe because they are on a diuretic. EKG: We also monitor the EKG for reasons stated above.

Pharmacokinetics of Cardiac Glycosides Steady-state: If we give a person a drug orally, it goes through the intestinal tract, blood levels kick in, and when the kidneys kick in, we start eliminating the drug. We need to know the half-life of a drug because thats what the dose is based on. Before the drug blood level drops too much due to the half-life, we give another dose. The average blood level will increase every time we redose. After the 5th halflife, we reachsteady-state and this is the range we want to stay in permanently.

Digoxin, the most common glycoside, has a half-life of 24 hours for those with normal kidney functions. It will take 5 days to reach a steady state concentration if we give them digoxin. In an emergency, this is unacceptable, so the other option we have is to give a loading dose. Loading Dose: A loading dose is typically given by IV instead of orally. So we give a dose that hopefully gets them up to the steady state faster. We calculate the dose based on their body weight, fat, etc but if we are wrong with that calculation, they could be toxic. So we give them half the loading dose, then 6 hours later we give a quarter of the loading dose and then 6 hours later we give another loading dose. So in 12 hours we can get the person to the steady state. Importance of Bioavailability of Digoxin You dont have to memorize the numbers, but understand the concept. Intravenous = 100% Intramuscular = 80% Tablet = 70% Sometimes youll see an order such: Digoxin 0.25mg p.o. daily. If unable to swallow, give dose IVP. Whats wrong with this order? Were dealing with a drug with a very narrow therapeutic index and if we do it through IV push, theyre going to get 100% of the drug instead of 70%. The physician has not specified the IVdosage! It would need to be reduced by at least 30%. Toxicities A-V Block (1st degree = delayed PR interval, 3rd degree = nothing getting through the AV node) Sinus bradycardia (apical pulse <60) Arrhythmias Yellow-green halo vision is a classical symptom patients may see around lights. This is a warning sign. CNS: Headaches, etc Toxicity Therapy Discontinue Cardiac Glycoside and talk to the doctor. Digoxin immune fab (Digibind) Correct hypokalemia: Administer potassium intravenously (not IV push but diluted in a bag) Therapeutic Uses We utilize cardiac glycosides such as digoxin during congestive heart failure and adjunct therapy for atrial fibrillation.

Thrombolysis
Thrombolytic agents: mechanism of action, indications, contraindications and side effects Thrombolytic agents are used to lyse already formed blood clots in clinical settings where ischemia may be fatal ( acute mycardial infarction, pulmonary embolism, ischemic stroke, and arterial thrombosis). Very precise indications rule the use of these drugs, which are not free from serious side effects ( bleeding). The image below shows how serine protease thrombin (also called activated factor II) converts fibrinogen tofibrin. Fibrin polymerizes and constitutes a mesh that acts as hemostatic clot (in conjunction with platelets) over a wounded site.

This plasmin meshwork can be cleaved by plasmin, which derives from an inactive precursor: plasminogen. Plasminogen can be activated by the tissue plasminogen activator (t-PA), which is released by endothelial cells.

As can be seen in the image, streptokinase acts by activating plasminogen conversion into plasmin, which promotes clot lysis. Since streptokinase is a protein obtained from Streptococci cultures, it is capable of eliciting antigenic responses in humans. The following animation integrates the concepts previously explained, showing how endothelial cells release t-PA.

Agent Streptokinase (Streptase) Urokinase Alteplase or Tissue plasminogen activator(trade names Retavase, Rapilysin) Anistreplase or Acylated plasminogen: streptokinase activator) Prourokinase or Single-chain urokinase plasminogen activator

Abbreviation SK UK t-PA

Source Streptococcal culture Renal cell culture Recombinant technology

APSAC SCU-PA

Streptococcal Renal cell culture

Pharmacological properties Streptokinase is a protein produced by Beta-hemolytic streptococci as a component of that organism tissue destroying machinery. There are two drawbacks for streptokinase therapy: Previous administration of the drug is a contraindication, because of the risk of anaphylaxis. The thrombolytic actions are relatively nonspecific and can result in systemic fibrinolysis. Since t-PA is produced by endothelial cells, it is nonantigenic and causes a more selective thrombolysis than streptokinase. Alteplase, the recombinant t-PA, is produced by recombinant DNA technology. It is effective in recanalizing occluded coronary arteries, limiting cardiac dysfunction and reducing mortality following an ST elevation myocardial infarction. At pharmacologic doses it can trigger a systemic lytic state and cause unwanted bleeding. A genetically engineered variant of t-PA. Tecneplase has a longer half life than t-PA which allows it to be administered as a single weight-based bolus. It has an increased half life than t-PA and increased specificity for fibrin. Its efficacy and adverse effect profile are similar to those of streptokinase and t-PA. Therapeutic considerations

Agent Streptokinase

Indication ST elevation myocardial infarction.Arterial thrombosis. Deep vein thrombosis. Pulmonary embolism. Intra-arterial or intravenous catheter occlusion. Acute myocardial infarction.Acute cerebrovascular thrombosis. Pulmonary embolism. Central venous catheter occlusion Acute myocardial infarction

t-PA

Tenecteplase (TNK) and reteplase

Adverse effects common to all agents of the class: - Major bleeding. - Cardiac arrhythmias. - Cholesterol embolus syndrome. - Anaphylactoid reaction. - Cerebrovascular accident. - Intracraneal hemorrhage. Steptokinase adverse effects: - Non-cardiogenic pulmonary edema. - Hypotension. - Fever and shivering. - History of cerebrovascular hemorrhage at any time. - Nonhemorrhagic stroke or other cerebrovascular event within the past year. - Marked hypertension ( reliably determined systolic arterial pressure >180 mmHg and/or a diastolic pressure >110 mmHg) at any time during presentation. - Suspicion of aortic dissection. - Active internal bleeding (excluding menses). - Relative contraindications to thrombolytic therapy - Current use of anticoagulats (INR 2). - A recent (<2 weeks) invasive or surgical procedure or prolonged (10 min) cardiopulmonaty resuscitation . - Known bleeding diathesis. - Pregnancy. - Hemorrhagic ophthalmic condition. - Active peptic ulcer disease. - History of severe hypertension that is currently adequately controlled.

Antilipemic drugs
Antilipemic drugs are used to lower abnormally high blood levels of lipids, such as cholesterol, triglycerides, and phospholipids. The risk of developing CAD increases when serum lipid levels are elevated. Drugs are used in combination with lifestyle changes (such as proper diet, weight loss, and exercise) and treatment of an underlying disorder causing the lipid abnormality to help lower lipid levels. The classes of antilipemic drugs include: bile-sequestering drugs fibric acid derivatives 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors nicotinic acid cholesterol absorption inhibitors. Bile-sequestering drugs The bile-sequestering drugs are cholestyramine, colestipol, and colesevelam. These drugs are resins that remove excess bile acids from the fat deposits under the skin. Pharmacokinetics Bile-sequestering drugs arent absorbed from the GI tract. Instead, they remain in the intestine, where they combine with bile acids for about 5 hours. Eventually, theyre excreted in stool. Pharmacodynamics The bile-sequestering drugs lower blood levels of low-density lipoproteins (LDLs). These drugs combine with bile acids in the intestines to form an insoluble compound thats then excreted in stool. The decreasing level of bile acid in the gallbladder triggers the l iver to synthesize more bile acids from their precursor, cholesterol. Getting out of storage As cholesterol leaves the bloodstream and other storage areas to replace the lost bile acids, blood cholesterol levels decrease. Because the small intestine needs bile acids to emulsify lipids and form chylomicrons, absorption of all lipids and lipid-soluble drugs decreases until the bile acids are replaced. Pharmacotherapeutics Bile-sequestering drugs are the drugs of choice for treating type IIa hyperlipoproteinemia (familial hypercholesterolemia) when the patient cant lower his LDL levels through diet alone. Patients whose blood cholesterol levels place them at a severe risk of CAD will most likely require one of these drugs in addition to dietary changes. Drug interactions Bile-sequestering drugs produce the following drug interactions: They may bind with acidic drugs in the GI tract, decreasing their absorption and effectiveness. Acidic drugs likely to be affected include barbiturates, phenytoin, penicillins, cephalosporins, thyroid hormones, thyroid derivatives, and digoxin. Bile-sequestering drugs may decrease absorption of propranolol, tetracycline, furosemide, penicillin G, hydrochlorothiazide and gemfibrozil. Bile-sequestering drugs may reduce absorption of lipid-soluble vitamins, such as vitamins A, D, E, and K. Poor absorption of vitamin K can affect prothrombin times significantly, increasing the risk of bleeding. Warning! Adverse reactions to bile-sequestering drugs Short-term adverse reactions to these drugs are relatively mild. More severe reactions can result from long-term use. Adverse GI effects with long-term therapy include severe fecal impaction, vomiting, diarrhea, and hemorrhoid irritation. Rarely, peptic ulcers and bleeding, gallstones, and inflammation of the gallbladder may occur.