Antihypertensive and Diuretic Agents PDF

Summary

These notes cover the different types of antihypertensive and diuretic agents, their mechanisms of action in the body, and their relevance in cardiovascular disease management. This document provides an overview of the physiology and treatment strategies, with particular focus on the various roles of diuretics and their use in managing hypertension.

Full Transcript

Introduction Hypertension is the most common CV disease Definition: either a sustained SBP of greater than 130 mm Hg or a sustained DBP of greater than 80 mm Hg HTN can lead to cerebrovascular accidents (strokes), CHF, MI, and renal damage The incidence of morbidit...

Introduction Hypertension is the most common CV disease Definition: either a sustained SBP of greater than 130 mm Hg or a sustained DBP of greater than 80 mm Hg HTN can lead to cerebrovascular accidents (strokes), CHF, MI, and renal damage The incidence of morbidity and mortality significantly decreases when HTN is diagnosed early and is properly treated Hypertension Definition Introduction High-normal BP is intended to identify individuals who could benefit from lifestyle interventions and who would receive pharmacological treatment if compelling indications are present. Individuals identified with confirmed hypertension (grade 1 and grade 2) should receive appropriate pharmacological treatment Etiology of HTN I. Essential or primary hypertension – Accounts for ˃90% of cases – No single identifiable cause (idiopathic) – It is usually caused by a combination of several (multifactorial) abnormalities – A number of factors increase the risk of developing essential HTN: age, genetics, environment (e.g. stress, sodium intake, alcohol), weight, and race Etiology of HTN II. Secondary hypertension – Account for 10-15% of cases – Secondary to a known organic disease, such as renovascular disease or pheochromocytoma – Correction of the underlying disease may result in a fall in BP Determinants of Arterial Pressure Mean Arterial Pressure = Cardiac output X Peripheral resistance Heart Contractility Filling Arteriolar Rate Pressure Diameter Blood Volume Venous Tone Normal regulation of blood pressure BP is maintained by moment-to-moment regulation at four anatomic sites: arterioles, postcapillary venules (capacitance vessels), heart, & the kidney The function of these four control sites is controlled/coordinated mainly by two overlapping control mechanisms: a) The baroreflexes, which are mediated by the sympathetic nervous system b) The renin-angiotensin-aldosterone system Treatment Aims The aim of therapy is straightforward: 1) Reduction of blood pressure to within the normal range 2) Reduction of CV and renal mortality & morbidity Antihypertensive agents Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both All antihypertensive agents act at one or more of four anatomic control (arterioles, postcapillary venules, heart, & the kidney) and produce their effects by interfering with normal mechanisms of blood pressure regulation Treatment strategies It is important to match antihypertensive drugs to the particular patient Certain subsets of the hypertensive population respond better to one class of drug than they do to another: – Black patients respond well to diuretics and calcium-channel blockers, but therapy with β-blockers or ACE inhibitors is often less effective – Calcium-channel blockers, ACE inhibitors, and diuretics are favored for treatment of hypertension in the elderly, whereas β-blockers and α- antagonists are less well tolerated. HTN may coexist with other diseases that can be aggravated by some of the antihypertensive drugs. Examples?? Antihypertensive agents Antihypertensive agents can be categorized according to the principal regulatory site or mechanism on which they act: 1. Diuretics 2. Direct vasodilators 3. Sympathoplegic agents 4. Agents that block production or action of angiotensin I. Diuretics Introduction The main function of kidneys is to maintain the constancy of the 'interior environment' by: – eliminating waste products – regulating the volume, – regulating electrolyte content – And by regulating pH of the extracellular fluid Kidney is main organ by which drugs are eliminated. – In the presence of renal failure dose must be adjusted Drugs that alter the renal function (diuretics) are crucial for the management of cardiovascular disease Diuretics A "diuretic" is an agent that increases urine volume A “ natriuretic” is an agent that causes an increase in renal sodium excretion – …….as they almost always also increase water excretion they are also called diuretic Each kidney consists of an outer cortex, an inner medulla and a hollow pelvis, which empties into the ureter The functional unit of the kidney is the nephron, of which there are approximately 1.4 ∞ 106 in each kidney, with considerable variation between individuals and an age-related decline Normal regulation of fluid & electrolytes by the kidney ~20% of the blood plasma entering the kidneys is filtered from the glomerular capillaries into the Bowman's capsule All the low-molecular-weight (low Mwt) constituents of plasma appear in the filtrate including glucose, sodium bicarbonate (NaHCO3), amino acids (a.a), & electrolytes (Na+ , K+ , and Cl-), while albumin and larger proteins are retained in the blood The kidney regulates the ionic composition and volume of urine by: – the active reabsorption or secretion of ions and/or the passive reabsorption of water …… ……at five functional zones along the nephron—namely, the proximal convoluted tubule, the descending loop of Henle, the ascending loop of Henle, the distal convoluted tubule, and the collecting tubule Diuretics HOW THEY ACT?? These agents act as: I. Inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in the nephron. As a result, Na+ and other ions, such as Cl -, enter the urine in greater than normal amounts along with water, which is carried passively to maintain osmotic equilibrium. Diuretics thus increase the volume of urine and often change its pH as well as the ionic composition of the urine and blood Diuretics II. Osmotic diuretics that prevent water reabsorption III. Aldosterone antagonists IV. Carbonic anhydrase inhibitor The major clinical uses of diuretics are in: – managing disorders involving abnormal fluid retention (edema) – or treating hypertension in which their diuretic action causes a decreased blood volume, leading to reduced blood pressure Principles important for understanding effects of diuretics Interference with Na+ reabsorption at one nephron site interferes with other renal functions linked to it It also leads to increased Na+ reabsorption at other sites Increased flow and Na+ delivery to distal nephron stimulates K + (and H +) secretion Principles important for understanding effects of diuretics The magnitude of the diuretic effect depends on the amount of Na+ reaching that site The effects of the diuretic agents are predictable from a knowledge of the function of the segment of the nephron in which they act The efficacy of the different classes of diuretics varies considerably Diuretic actions at different nephron sites can produce synergism Diuretics Diuretics alone often provide adequate treatment for mild or moderate essential HTN Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke, MI, and CHF, all of which can cause mortality Diuretics are used in combination with sympathoplegic and vasodilator drugs to reverse Na+ and H2O retention observed with other antihypertensive agents Loop or high ceiling diuretics Agents: Bumetanide, furosemide (Prototype), torsemide, & ethacrynic acid Their major action on the thick ascending limb (TAL) of the loop of Henle Loop diuretics are the most powerful diuretics, capable of causing the excretion of 15-25% of filtered Na+ Loop diuretics mechanism of action I. Loop diuretics inhibit luminal Na+/K +/2Cl– transporter in the TAL of Henle's loop II. Loop diuretics induce expression and synthesis PGE2, which blunts both Na+ reabsorption in the TAL of Henle's loop and ADH-mediated water transport in collecting tubules III. Loop diuretics increases renal blood flow via prostaglandin actions on kidney vasculature & reduce pulmonary congestion and left ventricular filling pressures in heart failure before measurable increase in urinary output Blocked by loop diuretics Loop diuretics Diuretic Response 1. Increase in the urinary excretion of Na+ and Cl - owing to blockade of Na+/K +/2Cl– transporter 2. Increase the excretion of Mg2+ and Ca2+ : – Lumen-positive potential that comes from K+ recycling is diminished, which normally drives divalent cation reabsorption in the loop (Do they cause hypomagnesimia and hypocalcemia?) 3. Increase the excretion of K+ and H+ due to increased delivery of Na+ to the distal tubule Loop diuretics Pharmacokinetics Loop diuretics are administered orally or parenterally. They are rapidly absorbed They are eliminated by the kidney by glomerular filtration and tubular secretion Their duration of action is relatively brief: furosemide is 2–3 hours and torsemide is 4–6 hours Half-life depends on renal function Loop diuretics Clinical uses 1. Edematous conditions: DOC (Drug of Choice) for reducing the acute pulmonary edema of heart failure 2. Hypertension: Loop diuretics (e.g. furosemide) are used in moderate, severe, and malignant hypertension 3. Severe hypercalcemia 4. Hyperkalemia 5. Acute Renal Failure 6. Anion overdose (bromide, fluoride, and iodide) Loop diuretics Adverse effects 1. Hypokalemic Metabolic Alkalosis By inhibiting salt reabsorption in the TAL, loop diuretics increase delivery of sodium to the collecting duct This increased delivery results in significant K+ wasting and excretion of proton (H+) by the duct, causing hypokalemic alkalosis This toxicity can be reversed by K + replacement and correction of hypovolemia Loop diuretics Adverse effects 2. Ototoxicity Loop diuretics occasionally cause dose-related hearing loss usually reversible Most common in patients with diminished renal function or those receiving other ototoxic agents (such as aminoglycoside antibiotics) 3. Acute hypovolemia Loop diuretics can cause a severe and rapid reduction in blood volume, with the possibility of hypotension, shock, and cardiac arrhythmias. Loop diuretics Adverse effects 4. Hyperuricemia Due to hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule May be prevented by using lower doses to avoid development of hypovolemia 5. Hypomagnesemia Magnesium depletion is a predictable consequence of the chronic use of loop agents and occurs most often in patients with dietary magnesium deficiency Can be reversed by administration of oral Mg2+ preparations Loop diuretics Adverse effects 6. Allergic & Other Reactions All loop diuretics, with the exception of ethacrynic acid, are sulfonamides ……skin rash, eosinophilia, and less often, interstitial nephritis are occasional reversible ADEs of these drugs Contraindication: Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare Thiazide Diuretics Agents: hydrochlorothiazide, chlorothiazide, metolazone, chlorthalidone, & indapamide Thiazides inhibit Na+ & Cl- reabsorption from the luminal side of epithelial cells in the distal convoluted tubules (DCT) by blocking the Na+/Cl– cotransporter (NCC) Thiazide Diuretics All thiazides affect the distal tubule (DCT) ***All have equal maximum diuretic effects, differing only in potency (expressed on a per milligram basis) Thiazide diuretics are only moderately efficacious (i.e., maximum excretion of filtered load of Na+ is only 5-10%) because approximately 90% of the filtered Na+ load is reabsorbed before reaching the DCT Blocked by thiazide diuretics Thiazides diuretics Thiazide diuretics enhance Ca2+ reabsorption: – In the DCT, lowering of intracellular Na+ by thiazide- induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane, and increases overall reabsorption of Ca2+ – In the PCT, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption Thiazide diuretics Pharmacokinetics All thiazides can be administered orally, but there are differences in their metabolism Chlorothiazide is the only thiazide available for parenteral administration Plasma protein binding varies considerably among thiazide diuretics All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system

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