Anti-hypertensive drugs - Essay Example

? Anti-Hypertensive Drugs 07-11-11 Anti-Hypertensive Drugs Introduction: “Hypertension is usually defined as a systolic pressure above 140 mm Hg and a diastolic pressure above 90 mm Hg.” (KODA-KIMBLE, M. A.2006). Hypertension is a common and a serious cardiovascular disorder, which if left untreated increases the incidence of other disorders including coronary thrombosis, stroke, and renal failure. The risk of hypertension increases with the advancement of age. The principle cause of stroke is hypertension because increased blood pressure causes hypertrophy and other changes in the vasculature of the left ventricle. Furthermore, hypertension increases the risk of coronary artery disease and renal failure. The risk of both fatal and non-fatal cardiovascular diseases increases with an increase in systolic and diastolic blood pressure. A systolic blood pressure of greater than 210 mm Hg and a diastolic blood pressure of higher than 120 mm Hg causes endothelial injury and endothelial thickness due to increased proliferation of cells in tunica intima of the blood vessels. These changes cause a further rise in blood pressure and promote ischemic tissue damage in vital organs. (RANG, H. P., & DALE, M. M.2012). The two main types of hypertension are secondary hypertension and malignant hypertension. Hypertension in which the direct cause is known is termed as secondary hypertension. While on the other hand, malignant hypertension is described as the condition in which the diastolic pressure has a value of above 130 mm Hg. In secondary hypertension, if the direct reason causing the increase in blood pressure is medically treated then immediately the blood pressure falls to normal. However, in malignant hypertension the case is not so straight forward. In most cases, malignant hypertension is very dangerous and if not treated appropriately, is fatal. Secondary hypertension develops slowly and in most cases is asymptomatic. Therefore, secondary hypertension is termed as a “silent killer”. While on the other hand, malignant hypertension has a rapid developmental phase which is associated with severe symptoms and requires immediate medical attention. (KODA-KIMBLE, M. A.2006). In certain cases of hypertension, the cause is known and such cases are treatable through surgery such as phaeochromocytoma but in majority of cases the cause of hypertension is not known and these are classified under the category of essential hypertension. Some of the early features helpful in diagnosing hypertension are increased cardiac output and increased peripheral resistance. Blood pressure and kidney function have a strong correlation, the significance of which is exhibited when a hypotensive individual receives a kidney from a normotensive individual. Soon after transplantation, the hypertensive patient shows a speedy recovery and his blood pressure continues to stay within the normal range. Hypertension is a direct consequence of raised peripheral resistance which ultimately leads to hypertrophy of left ventricle. The increase in peripheral vascular resistance induces numerous changes in the vasculature and function of vital organs and thus it needs to be corrected in order to prevent further damage to the cardiovascular system. (RANG, H. P., & DALE, M. M.2012). The sympathetic nervous system, rennin angiotensin aldosterone mechanism and tonically active endothelium derived autocoids, are the main systems which work in coordination to ensure that blood pressure remains within a narrow range in a normal individual. Drastic changes in blood pressure produce life threatening consequences such as hemorrhage and coma. Hypertension if left untreated causes severe damage to the human body such as retinal hemorrhages and arteriolar occlusion. However, if hypertension is treated properly by undergoing anti-hypertensivess therapy along with life style modification, the morbidity and the rate of mortality due to cardiovascular diseases is reduced by several degrees. (GOODMAN et al 1996). The administration of anti-hypertensive drugs is not the only way to treat hypertension. Most health care practitioners advise their patients to modify their lifestyles in an effort to reduce the dependence on anti-hypertensive drugs. Life style modification is particularly very important in patients with preexisting impaired renal function. Lifestyle changes such as regular cardio exercises and balanced diet are necessary in order to increase the efficacy of anti-hypertensive drugs. In majority of cases, hypertensive individuals are sensitive to salt so a reduction in salt intake is necessary to prevent further disease progress. Dietary Approaches to Stop Hypertension Diet is an effective dietary plan which is known to show drastic anti-hypertensive effects when practiced in combination with drugs. (RANG, H. P., & DALE, M. M.2012). Risk Factors: Some of the major risk factors which increase the incidence of hypertension are smoking, age, obesity, diabetes, unhealthy lifestyle such as no physical activity and unbalanced diet, and excessive alcohol consumption. However, individuals who have a family history of cardiovascular diseases are more susceptible to hypertension. (KODA-KIMBLE, M. A.2006). Principles of Drug therapies in managing hypertension: Most anti hypertensive drugs decrease blood pressure by causing vasodilatation. The lumen of the arterial blood vessels is increased in response to such drugs and thus blood pressure falls because peripheral resistance to blood flow is reduced. There are four classes of drugs that are classified under the category of vasodilating drugs and are as follows: i. Adrenergic antagonist drugs ii. Anti adrenergic blocking drugs iii. Calcium channel blocking drugs iv. Vasodilating drugs Another class of anti-hypertensive drugs is diuretics. As the name implies, diuretics decrease blood pressure by increasing the excretion of salt and water in urine. Diuretics are of various types and are named according to the precise location of their site of action in the kidney. ACE inhibitors are another class of anti-hypertensive drugs which reduce blood pressure by antagonizing the mechanism of renin-angiotensin-aldosterone system. Certain drugs such as losartan and candesartan are very effective in reducing blood pressure and are classified as AT1 antagonists. Other classes of anti-hypertensive drugs include Ca2+ antagonists, ?-Adrenoceptor antagonist and ?1-Adrenoceptor antagonists. (RANG, H. P., & DALE, M. M.2012). Diuretics: Diuretics mediate their therapeutic effects primarily by increasing the excretion of Na+ along with water. The increased excretion of Na+ is achieved by reducing the reabsorption of Na+ and Cl- from the glomerular filtrate. Thus, inevitably water loss is also increased automatically in response to increased natriuresis. There are two ways through which increased natriuresis and increased diuretic effect can be achieved which are as follows: i. Directly affecting the activity of the nephron cells ii. Acting indirectly by altering the composition and osmotic balance of the glomerular filtrate Usually, a large proportion of salt and water that passes as the glomerular filtrate through the renal tubules is reabsorbed thus the small reduction in reabsorption by the action of diuretics either directly or indirectly is enough for causing a significant increase in natriuresis followed by increased production of dilute urine. (RANG, H. P., & DALE, M. M.2012). Loop diuretics: The loop diuretics mediate their therapeutic action by exerting their potent diuretic effecton the loop of Henle. The loop diuretics act as powerful agents which modify the fluid and electrolyte balance of the glomerular filtrate. The loop diuretics are also known as “High ceiling diuretics” because they have a potent diuretic effect which is several folds higher than the other diuretics. Furosemide is the most potent diuretic and is the drug of choice in the management of moderate to severe hypertension. (ASCHENBRENNER et al 2002). Loop diuretics act on thick ascending limb of Loop of henle, which plays an important role in reabsorbing salts from the tubular fluid. The ascending limb of Loop of Henle has a low permeability to water, and therefore does not play a significant role in water reabsorption. The major function of thick ascending limb is to reabsorb 20-30% of Na+ from the tubular fluid. The low permeability of ascending limb to water is due to the presence of tight junctions which prevent the passage of water. This prevention of water reabsorption is an important factor in the maintenance of an osmotic gradient in the luminal cells. Therefore, the reabsorption of NaCl from the tubular fluid lowers the osmotic concentration of tubular fluid. Conversely, the interstitial fluid of the medulla becomes hypertonic. Therefore, the thick ascending limb forms an ideal pharmacological target in clinical management of hypertension ranging from moderate to severe cases. However, all loop diuretics induce hypokelemia and thus should be administered with caution in patients who have a history of impaired renal function. (RANG, H. P., & DALE, M. M.2012). Furosemide: Furosemide is an anti-hypertensive drug that belongs to the class of diuretics and a sub class of loop diuretics. Furosemide can increase Na+ excretion by 15-25% and thus it is one of the most powerful diuretics. Most physicians describe the action of loop diuretics by a phrase “torrential urine flow” which signifies that Furosemide causes excessive production of urine. The therapeutic effect of furosemide is directly related to its plasma concentration thus, when oral dose potency is changed, there is an immediate change in therapeutic activity of the drug at the luminal membrane of thick ascending limb of nephron. (RANG, H. P., & DALE, M. M.2012). Pharmacotherapeutics: Furosemide is available by the brand name of Lasix and is marketed by Sanofi-Aventis. Furosemide is a powerful diuretic that is not only the drug of choice in treating hypertension but is also preferred in the management of peripheral edema due to Congestive Heart Failure and nephrotic diseases. Due to its capability of not causing a reduction in the Glomerular Filtration Rate, Furosemide is preferred over Thiazide Diuretics in patients with preexisting renal disease. Many researchers and health care practitioners believe that Furosemide when used in combination with Metolazone is extremely beneficial in the treatment of heart failure. The synergistic effect of both drugs increase sodium excretion by mediating their effects in different parts of the nephron. (ASCHENBRENNER et al 2002). Pharmacodynamics: Furosemide mediates its powerful diuretic effect by acting on the thick ascending limb of the loop of Henle and causes the inhibition of a carrier known as Na+/K+/2Cl-, located in the luminal membrane. Furosemide binds with the chlorine binding site on the carrier and thereby inhibits its activity. The mechanism of action of Furosemide does not involve the inhibition of aldosterone and carbonic anhydrase. Thus, the therapeutic effects are a result of drug action on only the loop of Henle. In addition, the drug also acts as a non competitive antagonist at GABA-A receptor. Furosemide mediates vasodilation in addition to its diuretic effect, when administered intravenously in patients with pulmonary edema induced by acute heart failure. The precise mechanism of action through which Furosemide mediates its vascular actions has not been clearly defined up till now. However, certain possible mechanism of actions has been put forward in an attempt to describe vasodilation caused by intravenous administration of Furosemide, which include; reducing the responsiveness of vessels to vasoconstrictors such as angiotensin II and nor-epinephrine, increasing the production of vasodilators such as prostaglandins, reducing the production of ouabain-like natriuretic hormone which leads to decreased vasoconstriction by opening potassium channels in cell membrane of constricted arteries. Furosemide leads to increased loss of H+ and K+ by increasing the delivery of Na+ to the distal convoluted tubule of the nephron. As Furosemide has no significant effect on increasing the excretion of HCO3-, its plasma concentration rises, as increased water loss reduces the total plasma volume. The increased HCO3- plasma concentration leads to metabolic alkalosis. Furosemide when administered orally easily crosses the gastrointestinal tract membrane and enters the bloodstream. However, Furosemide is administered intravenously in certain cases such as acute pulmonary edema. Intravenous route is preferred over oral route in patients of congestive heart failure because of impaired absorptive property of the intestinal tract. The therapeutic activity of furosemide is direct proportional to its dose. Therefore, greater the dose administered greater the diuretic effect is observed. (RANG, H. P., & DALE, M. M.2012). Pharmacokinetics: Furosemide is administrated orally, intravenously and intramuscularly. After oral administration, Furosemide acts within one hour. However, following IV administration, it acts within 10 to 30 minutes. The drug has a duration of action of approximately 2 hours. After administration, 95% of the drug bounds to plasma proteins, which is responsible for its prolonged effect. (MACDOUGALL, M. L.1977). The drug is metabolized by the liver and is excreted by the kidneys. (ASCHENBRENNER et al 2002).Due to the strong bonding of Furosemide to plasma proteins, the drug does not easily passes into the glomerular filtrate. Thus, the drug reaches the luminal membrane through secretion by the proximal convoluted tubule through the mechanism of organic acid transport and mediates its diuretic effects in the thick ascending limb. In patients with nephrotic syndrome, Furosemide binds to albumin present in the tubular fluid and thus becomes unavailable at its target site i.e. the thick ascending limb of the loop of Henle. Thus, patients of nephrotic syndrome are resistant to loop diuretics. The proportion of Furosemide that is not eliminated in urine is metabolized by being glucuronidated. Furosemide has a plasma half-life of 90 minutes. However, the plasma half-life of the drug is longer in patients with renal failure. (RANG, H. P., & DALE, M. M.2012). In pregnant females, Furosemide crosses the placenta and is also excreted in breast milk. (ASCHENBRENNER et al 2002). Dose: Furosemide has an initial intravenous dose of 20-40 mg. However, if no therapeutic effects are observed, the dose is increased to 80, 160 or in severe cases to 250 mg. According to registry data, the therapeutic activity of furosemide is reduced in patients who receive dose higher than 160 mg. However, certain heart failure patients are resistant to loop diuretics and such patients are given an IV infusion of 3-4 mg/hour. (THOMPSON, P. L.1997). Clinical Pharmacology: Furosemide is used in the treatment of hypertension in individuals with preexisting impaired renal function. Furosemide is also used in the treatment of hypercalcaemia. In addition, the drug is used in the management of salt and water overload in cases of acute pulmonary edema, chronic heart failure and liver cirrhosis, nephrotic syndrome and renal failure. (RANG, H. P., & DALE, M. M.2012). Adverse Effects: Most of the adverse effects of Furosemide occur as a result of fluid and electrolyte imbalance. In most instances, electrolyte imbalance cases such as hyponatremia, hypokalemia, hypochloridemia and hypocalcemia, occur within the first two weeks of the therapy. Furosemide causes metabolic alkalosis due to excessive loss of H+. (OLSON, J. M.2006). A large dose of Furosemide significantly decreases the volume of blood returning to the heart which causes a 20% decrease in the cardiac output. In certain individuals, Furosemide causes orthostatic hypotension, vertigo and dizziness. (LAURENCE et al 1997). Moreover, Furosemide may also cause severe dehydration due to the loss of excessive water in urine. In addition, Furosemide also causes severe reduction blood volume which leads to circulatory collapse. On the other hand, Furosemide administration in elderly individuals increases the incidence of vascular thrombosis and embolism. (PAW et al 2002). Dehydration caused by Furosemide has certain warning signs which include dry mouth, thirst, anorexia, lethargy, weakness, drowsiness, restlessness, muscle pains, hypotension, oliguria, tachycardia, and arrhythmia and muscle fatigue. (WRIGHT, H. N. G.1936). Due to excessive diuresis occurring after Furosemide administration, cardiac output decreases which lead to decreased renal perfusion and thus BUN levels and serum creatinine levels rise significantly. In patients with hepatic cirrhosis and encephalopathy and ascites, Furosemide administration increases the chances of hepatic encephalopathy and coma due to excessive electrolyte shifts. Furosemide therapy in patients with Gout, may lead to problems associated with hyperuricemia. Another adverse effect of Furosemide therapy is ototoxicity. The incidence of ototoxicity increases when the drug is administered intravenously due to high bioavailability. Some of the signs that indicate ototoxicity are tinnitus, vertigo, and medium and high hearing loss. The duration of ototoxicity is about 1 to 12 hours but in certain individuals its duration may be as long as 24 hours. However, ototoxicity causes permanent damage such as complete loss of hearing. The inhibition of Na-K-Cl active co transport system is the reason why Furosemide causes ototoxicity. The co transport system in the kidney has an isoform transporter in the inner ear which is also inhibited along with the inhibition of the transporter in the kidney, thus causing deafness and damage to the inner ear. Another adverse effect related to Furosemide therapy is allergy and hypersensitivity. Rash and acute interstitial nephritis are the most common hypersensitivity responses to Furosemide administration. Most of the allergic responses to Furosemide are similar to those that occur with the administration of sulphonamide drugs. Adverse effects of Furosemide in CNS are paresthesia, xanthopsia, blurred vision and fever. While adverse effects of GI tract are constipation, diarrhea, cramping, pancreatitis, jaundice, and ischemic hepatitis. Hematologic adverse effects of Furosemide are leucopenia, anemia, thrombocytopenia, and agranulocytosis. Other adverse effects of Furosemide administration include urinary bladder spasm, dermatologic photosensitivity, and increased blood glucose concentration. In addition, it has been observed that Furosemide causes a rise in blood low density lipo protein, cholesterol, and triglyceride concentration. On the other hand, patients of SLE exhibit disease exacerbations on receiving Furosemide therapy. (ASCHENBRENNER et al 2002). Contraindications and Precautions: Furosemide is contraindicated in patients who are allergic to sulpha drugs or are suffering from anuria. (CRAIG et al 2004). The drug is also contraindicated in patients who are hypersensitive to Furosemide. Loop diuretics should be administered with caution in patients of lupus erythematosus. The drug should also be administered with caution in patients who have an impaired renal function. Furosemide is classified as a pregnancy category C drug. (ASCHENBRENNER et al 2002). Pregnancy and Lactation: Animal studies reveal teratogenic effects of furosemide during pregnancy. (KAMIENSKI et al 2006). Growth retardation, slow spinal bone development, impaired kidney function are some of the effects revealed by animal studies. Therefore, furosemide should not be administered in pregnant females because it is capable of easily crossing the placental barrier. Moreover, Furosemide is excreted in breast milk therefore the drug should not be used by nursing females. (WOLFE et al 1999). Drug Interactions: The administration of Furosemide with food significantly decreases the bioavailability and the degree of diuresis.The therapeutic activity of Furosemide is reduced to 50%,when concomitantly administered with Phenytoin. The reduction in the diuretic response of Furosemide is primarily due to decreased absorption of the drug through the GI tract. The concomitant administration of potassium wasting drugs such as licorice and carbenoxolone potentiates the hypokalemic effects of Furosemide. In hypertensive patients with preexisting impaired renal function, the natriuretic and kaliuretic effect of Furosemide is reduced when co administered with Piroxicam. In patients of hormone-refractory prostate cancer, co administration of Furosemide with Suramin reduces the plasma clearance of Suramin by 36%. The concurrent administration of Furosemide with Theophylline increases its steady state concentration. When thiazide derivatives and Furosemide are administrated in combination for the management of severe and resistant hypertension, leads to further impairment of renal function.The precise reason for this deterioration of renal function is not known. The use of Vancomycin and Furosemide in combination causes a reduction in serum concentration of Vancomycin. The prothrombin time is changed without a change in the plasma concentration of warfarin is mediated when Furosemide is administered in patients who are undergoing warfarin therapy. The Furosemide’s diuretic induced depletion of volume is the reason for reduced anticoagulant effect of warfarin. (ARONSON, J. K.2009). The chances of Furosemide’s ototoxicity are greatly increased when administered in combination with amino glycosides. On the other hand, the hypokalemic affects of Furosemide increases the chances of digoxin toxicity without significantly increasing the plasma concentration of digoxin. The use of ACE inhibitors in combination with Furosemide causes first dose postural hypotension. In addition, the concomitant administration of Furosemide and beta blockers such as propranolol increases the plasma concentration of beta blockers. Furosemide administration with corticosteroids causes increased excretion of potassium in urine and therefore results in hypokalemia. Some of the effects of using Furosemide in combination with chloral hydrates are hypotension, hot flashes, and transient diaphoresis, tachycardia and weakness. The use of Furosemide and Class III anti arrthymics in combination, increases the risk of fatal cardiac toxicity. The risk of cardio toxicity s greatly increased when Furosemide is used in combination with droperidol. The effectiveness of Furosemide is reduced when used along with germanium and ginseng. Increased plasma clearance has been observed in patients receiving concomitant doses of hydralazine and Furosemide. Licorice administration reduces the therapeutic activity and increases the hypokalemic effect of furosemide. The chance of lithium toxicity is increased when used together with furosemide because it causes an increase in plasma lithium levels. Furosemide antagonizes the therapeutic effects of non-polarizing muscle relaxants therefore, co administration should be avoided. The therapeutic response of furosemide is altered significantly when administered in combination with ma huang and yohimbine. Charcoal is a potent antidote for furosemide overdose because it decreases GI tract absorption of furosemide up to several folds. The risk of furosemide ototoxicity is increased when administered in combination with cisplatin. The co administration of sulphonylureas and furosemide should be carefully monitored because of increased risk of hyperglycemia. Clofibrate increases the therapeutic activity of furosemide and thus causes increased diuresis. 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