Pharmacology CASE STUDY
Order Description
Here is the instruction for this assignment: Participate in the discussion by asking a question, providing a statement of clarification, providing a point of view with a rationale, challenging an aspect of the discussion, or indicating a relationship between one or more lines of reasoning in the discussion. Just write one paragraph for peer # 1 and one paragraph for peer # 2 . Two references one for peer # 1 and one for peer # 2
Discussion Question 1 This question is for Peer # 1 and Peer # 2
Discussion Question 1
Diuretics have long been a part of drug therapy and are found in products consumed everyday.
• What is the role of diuretics in modern medicine?
• What are the basic processes of kidney filtration?
• What are the actions of carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics, thiazide diuretics, and spironolactone?
• What are the associated toxicities of the above mentioned diuretics?
• Thiazide diuretics are considered first-line therapy for hypertension. What are the advantages and disadvantages of this therapy?
Justify your answers using examples and reasoning. Comment on the postings of at least two peers.
peer # 1 Thomas
Diuretics are used in the management of fluid and electrolyte balances in the body in treating multiple disorders such as hypertension, congestive heart failure (CHF), pulmonary edema, acute renal failure, cirrhosis, hyperkalemia, glaucoma, and increased intracranial pressure. The diuretics are typically divided into five groups; carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics, thiazides, and potassium sparing diuretics. Through differing processes, they act on portions of the renal tubules extending from the glomerulus to the end of the collecting duct.
The basic filtration processes of the kidney begin with the collection of fluid, bicarbonate (HCO3-), sodium (Na+), chloride (Cl-), potassium (K+) , and other organic solutes in the glomeruli (Grossman& Porth, 2014). The process then moves to the nephron which courses through the cortex and medulla. The nephron includes seven segments; the proximal convoluted tubule (PCT), the proximal straight tubule, the Loop of Henle consisting the thin descending limb, the thin ascending limb, and the thick ascending limb, the distal convoluted tubule, and the collecting tubule (Edmunds & Mayhew, 2014). The concentration of ions, the actions of enzymes, and hormones, specifically, the antidiuretic hormone (ADH) and the parathyroid hormone (PTH) control the influx and efflux of ions and thus water across membranes controlling the rate of diuresis. Diuretics act directly and indirectly on these processes to enhance diuresis.
Normally up to 75% of the filtered Na+ is reabsorbed through the walls of the proximal tubules that involves a Na+/H+ exchanger that is maintained by the actions of carbonic anhydrase on H2CO3. Carbonic anhydrase inhibitors were the first of the pharmacological agents to be produced. They act in the proximal convoluted tubules (PCT) to decrease Na+ and HCO3- resorption and increase diuresis (Katzung, Masters,& Trevor, 2012). They are highly effective, achieving almost 90% inhibition of HCO3- resorption capacity in the PCT. However, HCO3- and thus Na+ resorption at more distal points in the renal tubule reduce its effectiveness by nearly 50% (Katzung, Masters, & Trevor, 2012). Increasing the excretion of HCO2- decreases the pH in the system in resulting in a metabolic acidosis that will remain as long as the drug is administered. Increased excretion of phosphorus and calcium is a byproduct of inhibition of carbonic anhydrase increasing the potential for formation of renal stones. Increased K+ excretion also occurs due to interruptions in movements of Na+ and may require the addition of potassium supplements or a potassium-sparing diuretic.
Osmotic diuretics work primarily in the proximal tubule and the descending (thin) limb of the Loop of Henle. Opposing the action of ADH, they present non-reabsorbable solutes, which inhibit the reabsorption of water via osmotic forces (Katzung et al., 2012). They do not inhibit the resorption of Na+ and therefore over time may lead to hypernatremia. Osmotics are most frequently administered intravenously or via ophthalmic drops because of very poor absorption after oral dosage. They act throughout the body to promote the movement of fluid from intracellular to extracellular spaces. They are used most frequently with increased intracranial pressure, increased intraocular pressure, or for the rapid removal of renal toxins (Edmunds & Mayhew, 2014). The drug must be used with caution in patients with CHF and pulmonary edema because it increases extracellular volume; prolonged use may result in dehydration, hyperkalemia, and hypernatremia. Patients with chronic renal failure may experience hyponatremia when mannitol is not excreted and continues to act centrally (Katzung et al., 2012).
The Loop of Henle has the highest capacity for the reabsorption of sodium within the renal tubules. Loop diuretics selectively inhibit the resorption of NaCl in the thick ascending limb of the Loop of Henle by inhibiting the luminal sodium, potassium, two chloride (NKCC) transporter (Katzung et al., 2012). The alterations in action potentials within the lumen also result in the excretion of Ca++ and Mg++. Prolonged use may result in hypomagnesemia but rarely hypocalcemia due to its reabsorption in the distal tubule induced by the parathyroid hormone. Potential toxicities from prolonged use include hypokalemic metabolic acidosis, hyperuricemia which may precipitate an attack of gout, ototoxicity, and hypovolemia (Edmunds & Mayhew, 2014).
The thiazide diuretics act in the DCT to inhibit the NaCl transporter and thus increase diuresis. Since only 3% to 5% of the sodium filtered in the glomeruli is reabsorbed via the DCT and sodium is further reabsorbed in the collecting tubule and duct thiazides are not very effective diuretics when large volumes must be excreted, i.e. CHF and pulmonary edema (Katzung et al., 2012). An important advantage in the use of thiazide diuretics is the fact that they enhance the reabsorption of Ca++ thus reducing the opportunity for the formation of urinary calculi. Long-term use of thiazides results in a decrease in peripheral vascular resistance, a poorly understood effect (Edmunds & Mayhew, 2014). Toxicities with prolonged use include hypokalemic metabolic acidosis, hyperuricemia, elevated serum levels of cholesterol and LDL. Patients with diabetes or abnormal glucose tolerance tests may experience hyperglycemia due to impaired release of insulin (Katzung et al., 2012).
Spironolactone is the most popular of the potassium-sparing agents. They prevent the secretion of K+ by antagonizing the effects of aldosterone in the collecting tubes. Katzung states that in the case of spironolactone inhibition occurs by direct pharmacologic antagonism of mineralocorticoid receptors (Katzung et al., 2012, p. 261). Potassium-sparing diuretics are rarely used as the sole therapy because prolonged use may result in hyperkalemia. Spironolactone is a synthetic steroid; use in men may result in gynecomastia, impotence, and rarely BPH (Katzung et al., 2012).
The Eighth Joint National Committee (JNC 8) (2013) recommends selection from four drug classes, ACE inhibitors, ARBs, CCB, and or diuretics, for initial therapy in nonblack populations based on a review of random controlled trials (RCTs) (James et al., 2014). In black populations, CCBs or thiazide-type diuretics are recommended for initial therapy. JNC 7 guidelines recommended thiazide-type diuretics for initial therapy for the majority of patients without compelling indications for another class of drugs. However, thiazide-type diuretics remain the most frequently prescribed therapy for the initial therapy for hypertension.
The advantages of thiazide diuretic therapy begin with cost; HCTZ in generic form is the least expensive of all the diuretics. In addition to providing effective reduction of blood pressures, the thiazides provide greater protection against coronary heart disease and non-fatal MIs than the potassium sparing diuretics according to the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (Madhur, 2014). ALLHAT is “a long-term multicenter trial conducted on a large group of participants ages 55 and older with Stage 1 or 2 hypertension and at least on other cardiovascular disease (CVD) risk factor” (“NIH: National Heart Lung & Blood Institute,” n.d., screen 1). Thiazides also reduce Ca++ excretion and may be helpful in preventing the formation of urinary stones in patients with idiopathic hypercalciuria (Madhur, 2014). Long-term use of thiazides has also shown to provide some protection from osteoporotic fractures, reducing the incidence of hip fractures in patients taking thiazides by as much as 20 percent (Madhur, 2014).
The adverse effects of thiazide use have been shown to be dose related in most cases. Initial studies of HCTZ used dosages over 50 mg per day with patients experiencing hyperkalemia, hyperuricemia, hyperglycemia, and sudden death (Madhur, 2014). Recommendations from the ALLHAT trials include; dosage no greater than 50 mg per day and preferably no more than 25 mg per day. For all thiazides, the recommendations are that dosages begin at the lowest possible level, increases be incremental, use preparations with the shortest half-lives and dose twice daily if necessary. A disadvantage of twice daily dosage is the development of nocturia and hence sleep disturbances.
References
ALLHAT: Information for health professionals: Quick reference for health care providers. (n.d.). Retrieved from
http://www.nhlbi.nih.gov/health/allhat/qckref.htm
Edmunds, M. W., & Mayhew, M. S. (2014). Pharmacology for the primary care provider (4 ed.). St Louis, MO: Elsevier Mosby.
Grossman, S. C., & Porth, C. M. (2014). Porth’s pathophysiology: Concepts of Altered Health States (9 ed.). Philadelphia, PA: Wolters
Kluwer Health| Lippincott Williams & Wilkins.
James, P. A., Oparil, S., Carter, B. L., Cushman, W. C., Dennison-Himmelfarb, C., Handler, J., Ortiz, E. (2014). Evidence-based guideline for
the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee
(JNC 8). Journal of the American Medical Association, 311(5), 507-520. http://dx.doi.org/10.1001/jama.2013.284427
Katzung, B. G., Masters, S. B., & Trevor, A. J. (2012). Basic & clinical pharmacology (12 ed.). New York, NY: McGraw Hill.
Madhur, M. S. (2014). Hypertension. Retrieved from http://emedicine.medscape.com/article/241381-overview
peer # 2 Felicia
What is the role of diuretics in modern medicine?
The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. The discovery of these drug groups arose largely by chance, yet each has dramatically influenced the treatment of congestive cardiac failure and arterial hypertension. The central role which diuretics have had in the management of both edema and hypertension hinges on their ability to induce a net renal excretion of solute and water by selective interference with either active or passive ion transport processes in different segments of the nephron. The continued antihypertensive action of diuretics is characterized by a reduction in plasma volume and extracellular fluid (ECF) volume that lasts for as long as the diuretic is given. The mechanism of this effect remains unclear but may involve autoregulatory reactions that leave cardiac output unaltered but maintain a sustained reduction in total peripheral resistance. ACE inhibitors also lower blood pressure by decreasing total peripheral resistance, leaving cardiac output, plasma volume and ECF volume unchanged. The detailed way these haemodynamic changes are achieved remains unknown but inhibition of converting enzyme present not only in the kidney but also in many extrarenal tissue sites, appears important. In both hypertension and cardiac failure, however, the kidney acts as a key target organ for ACE inhibitors. The increased renal vascular resistance and inappropriate renal salt excretion are reversed with enhanced renal blood flow and saluresis. Both angiotensin II (AII) and vasopressin-mediated contraction of glomerular mesangial cells is inhibited, making glomerular filtration more efficient. Reduced aldosterone secondary to blockade of AII formation contributes to saluresis whilst encouraging positive potassium balance. ACE inhibition also impairs breakdown of kinins which may contribute to intrarenal and peripheral vasodilation either on their own or via release of prostaglandins and other vasoactive substances. The hypotensive actions of diuretics are potentiated by ACE inhibition primarily through blockade of AII formation and prevention of secondary aldosteronism. In combination, these drugs permit low doses to be used because of their synergistic effects. Caution has to be exercised whenever ACE inhibition is used, without and especially with diuretics, in the management of renovascular hypertension and other low-perfusion states. In these circumstances, AII plays an important autoregulatory role in preserving glomerular filtration through an increase in post-glomerular resistance.
What are the basic processes of kidney filtration?
There are four basic processes in the formation of urine starting with plasma. Filtration is the mass movement of water and solutes from plasma to the renal tubule that occurs in the renal corpuscle. About 20% of the plasma volume passing through the glomerulus at any given time is filtered. This means that about 180 liters of fluid are filtered by the kidneys every day. Thus, the entire plasma volume (about 3 liters) is filtered 60 times a day! Filtration is primarily driven by hydraulic pressure (blood pressure) in the capillaries of the glomerulus. Note that the kidneys filter much more fluid than the amount of urine that is actually excreted (about 1.5 liters per day). This is essential for the kidneys to rapidly remove waste and toxins from the plasma efficiently.
Reabsorption is the movement of water and solutes from the tubule back into the plasma. Reabsorption of water and specific solutes occurs to varying degrees over the entire length of the renal tubule. Bulk reabsorption, which is not under hormonal control, occurs largely in the proximal tubule. Over 70% the filtrate is reabsorbed here. In addition, many important solutes (glucose, amino acids, bicarbonate) are actively transported out of the proximal tubule such that their concentrations are normally extremely low in the remaining fluid. Further bulk reabsorption of sodium occurs in the loop of Henle. Regulated reabsorption, in which hormones control the rate of transport of sodium and water depending on systemic conditions, takes place in the distal tubule and collecting duct.
Secretion
Even after filtration has occured, the tubules continue to secrete additional substances into the tubular fluid. This enhances the kidney’s ability to eliminate certain wastes and toxins. It is also essential to regulation of plasma potassium concentrations and pH. (See Fluid and electrolyte balance).
Excretion is what goes into the urine, the end result of the above three processes. Although the original concentration of a substance in the tubule fluid may initially be close to that of plasma, subsequent reabsorption and/or secretion can dramatically alter the final concentration in the urine. The amount of a particular substance that is excreted is determined by the formula:
amount excreted = amount filtered – amount reabsorbed + amount secreted
What are the actions of carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics, thiazide diuretics, and spironolactone?
The thiazides act on the proximal portion of the distal convoluted tubule to inhibit sodium resorption and promote potassium excretion .Because the thiazides act on a different site of the renal tubule than other diuretics, they may be combined with a loop diuretic or potassium-sparing diuretic for treatment of refractory fluid retention. Adverse effects are electrolyte and fluid balance disturbances, similar to furosemide.
Spironolactone is used most frequently and is a competitive antagonist of aldosterone. Aldosterone is elevated in animals with congestive heart failure when the renin-angiotensin system is activated in response to hyponatremia, hyperkalemia, and reductions in blood pressure or cardiac output. Aldosterone is responsible for increasing sodium and chloride reabsorption and potassium and calcium excretion from renal tubules. Spironolactone competes with aldosterone at its receptor site, causing a mild diuresis and potassium retention. Spironolactone is well absorbed after administration PO, especially if given with food. It is highly protein bound (>90%) and extensively metabolized by the liver to the active metabolite, canrenone. It is primarily eliminated by the kidneys. The onset of action for spironolactone is slow, and effects do not peak for 2–3 days. Spironolactone is not recommended as monotherapy, but can be added to furosemide or thiazide therapy to treat refractory heart failure cases. Because of the potential for hyperkalemia, spironolactone should not be administered concurrently with potassium supplements or ACE inhibitors.
Carbonic anhydrase inhibitors act in the proximal tubule to noncompetitively and reversibly inhibit carbonic anhydrase, which decreases the formation of carbonic acid from carbon dioxide and water. Reduced formation of carbonic acid results in fewer hydrogen ions within proximal tubule cells. Because hydrogen ions are normally exchanged with sodium ions from the tubule lumen, more sodium is available to combine with urinary bicarbonate. Diuresis occurs when water is excreted with sodium bicarbonate. As bicarbonate is eliminated, systemic acidosis results. Because intracellular potassium can substitute for hydrogen ions in the sodium resorption step, carbonic anhydrase inhibitors also enhance potassium excretion.
What are the associated toxicities of the above mentioned diuretics?
• dry mouth
• thirst,
• weakness,
• lethargy
• drowsiness,
• restlessness,
• muscle pains or cramps,
• confusion,
• seizures
• muscular fatigue,
• hypotension
• oliguria
• tacycardia
• GI disturbances
Thiazide diuretics are considered first-line therapy for hypertension. What are the advantages and disadvantages of this therapy?
Advantages of Beta-A drenergic Blockers
Although the beta-blockers have many individual side effects, when compared to many other antihypertensive
drugs, they are remarkably free of a number of troublesome side effects that have bedeviled the treatment of hypertension for many years. The drowsiness, lethargy, and nasal congestion so common with methyldopa,” the interference with sexual function and postural hypotension frequently encountered with the adrenergic neurone blocking drugs.
Once-Daily Treatment.Thiazide diuretics may be administered on a once-daily basis, and there is now good evidence that most, if not
all, beta-adrenergic blocking drugs may be administered once daily for the treatment of hypertension. A further advantage of
the beta-blockers is the presence of bradycardia as an indicator of patient compliance. Treatment of Associated Conditions; angina pectoris, cardiac arrhythmias, and an anxiety’state are not uncommonly associated with hypertension, andeach will respond to treatment with beta-adrenergic blocking drugs and thusminimize the treatment regimen.
Disadvantages of Beta-Adrenergic Blockers
There are a number of predictable pharmacologic actions of beta-blockers: bradycardia, heart block, cardiac failure, bronchospasm, cold extremities, claudication, Raynaud’s phenomenon, diarrhea, fatigue, muscle cramps. weakness, dizziness, hallucinations, vivid dreams, andsleep disturbance. There is considerable individual variation in these effects, and careful patient selection will ensure that they do not occur too often. Withdrawal Effects. Sudden withdrawal of beta-blockers may result in cardiac
arrhythmias or an exacerbation of symptoms of ischemic heart disease, sometimes with the occurrence of myocardial infarction, the cardiovascular effects of beta-blocker withdrawal are not as striking as those of some other antihypertensive.Reference
Edmunds, M., & Mayhew, M. (2014). Pharmacology for the Primary Care Provider, 4th Edition. [VitalSource Bookshelf version]. Retrieved from http://digitalbookshelf.georgeuniversity.edu/books
Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions–parallels and contrasts. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3034317
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