Problem+Set+2

Problem Set #2 (Dr. Sheng; PSW481) Date of submission: 11/04/2009

A. MCQs (1) Which of the following is NOT a result of diuretics usages? a. increase of excretion of electrolytes such as sodium b. increase of excretion of amino acid c. increase of excretion of water d. increase of excretion of glucose e**. both b and d**

(2) The acting site of carbonic anhydrase inhibitors is (Badavas, Davis, Jorgensen, Nelson, Pratt, and Vakil )
 * B - The Proximal Convoluted Tubule**

(3) Fill out the blank areas (Badr, Dean, Judge, George, Quinlan, and Verma) Classes of diuretics Acting sites MOA Therapeutic uses Adverse effects 2) increases medullary blood flow to decrease medullary blood flow to decrease medullary hypertonicity and reduce Na and water reabsorption 3) sodium and H2O reabsorption decreases because of reduced hypertonicity and elevated urinary flow rate. || # prophylaxis of ARF -competitive inhibition of aldosterone -blockage of sodium channel at the luminal membrane || # edema from hyper-aldosteronism
 * **Class of Diuretics** || **Acting Sites** || **MOA** || **Therapeutic Uses** || **Adverse Effects** ||
 * osmotics || # proximal tubule
 * 1) loop of henle
 * 2) collecting duct || 1) osmotic effect decreases Na and H2O reabsorption
 * 1) reduces high intracranial and intraocular pressure || # expansion of ECF volume
 * 2) alteration of blood Na levels ||
 * loop or high ceiling diuretics || # thick ascending limb || -inhibition of the Na/K/2Cl transport system || # hypertension
 * 1) edema || # hypokalemia
 * 2) fluid and electrolyte imbalances
 * 3) hyperuricemia
 * 4) increased serum lipid levels
 * 5) ototoxicity
 * 6) GI effects ||
 * K-sparing diuretics || # distal tubule
 * 1) collecting duct || -inhibition of the Na and water reabsorption by:
 * 1) edema due to liver cirrhosis || # hyperkalemia
 * 2) GI disturbances
 * 3) PUD
 * 4) gynecomastia
 * 5) decreased libido
 * 6) impotence ||

(4). Compare the Na+/Cl- and Na+/K+/2Cl- transport systems in terms of tissue distribution, physiological function, and interaction with diuretics. (Bagas, Diec, Kahura, Nguyen, Rodrigues, and Vu) The Na+/Cl- transport system is a symporter located in the apical membrane of the distal tubule that brings both Na+ and Cl- from the ultrafiltrate into the cell in response the Na+ gradient set up by the Na+/K+/ATP transporter. The Na+/K+/2Cl- transport system is a symporter located in the apical membrane of the thick ascending limb of the loop of Henle. This transporter moves 1 Na+, 2 Cl-, and 1 K+ from the ultrafiltrate into the cell in response to the Na+ gradient set up by the Na+/K+/ATP transporter. Loop diuretics, or Na-K-2Cl symport inhibitors, inhibit the Na+/K+/2Cl- transport system to stop the reabsorption of Na+ and water in the thick ascending limb. Thiazide diuretics, or Na-Cl symport inhibitors, inhibit the Na+/Cl- transport system to stop the reabsorption of Na+ and water in the distal tubule.

(5) Why does the urine of patients with prolonged use of carbonic anhydrase inhibitor diuretics become alkaline? (Ackley, Bell, Faraj, Keeler, Ngang, and Sweatt) Carbonic anhydrase (CA) inhibitors block the reabsorption of Na and HCO3- from the ultrafiltrate via proximal tubule epithelial cells. Approximately 35% of filtered HCO3- that is filtered at the glomerulus remains in the ultrafiltrate to be excreted. CA inhibitors also inhibit the secretion of titratable acids and NH4+ into the ultrafiltrate in the collecting duct. Both of these factors, increase in excretion of HCO3- in the urine and decrease in the excretion of acid and NH4+, cause the pH of the urine to rise rapidly to ~pH 8 (alkaline).

(6) What do “E” and “Z” mean in chemical nomenclature [i.e. (E)-2-butene; (Z)-2-butene]? What about “R” and “S” [i.e. R-indacrinone; S-indacrinone]? What about “D” and “L” [i.e. D-glucose; L-glucose]? (Balkhi, Dion, Kammermayer, Nguyen, Roth, and Walden) E and Z describe the stereochemistry of double bonds based on priority of substituents. If the two groups of highest priority are on the same side of the double bond, the structure is Z. This is also known as cis. If they are on opposite sides, the structure is labeled E. This is also known as trans.

Chiral centers are labeled R or S according to which substituents have the highest priority. When the center is oriented so that the lowest-priority of the 4 substituents is pointed away, and the priority of the remaining 3 substituents decreases in a clockwise direction, you have the R enantiomer. If the priority of the remaining 3 substituents decreases in a counter clockwise direction, you have the S enantiomer.

//Enantiomers can also be named by the direction in which they rotate the plane of polarized light. D- enantiomers rotate polarized light in a clockwise manner (dextrorotatory) and L- enantiomers rotate polarized light in a counter clockwise manner (levorotatory).//

B. Describe the adverse effects of potassium sparing diuretics and how do they occur? (Basmadjian, Donnelly, Karki, Nwafor, Safo, and Wallace) Adverse effects associated with the potassium-sparing diuretic amiloride can include nausea, vomitting, diarrhea, and headache. Adverse effects associated with triamterene include nausea, vomitting, leg cramps and dizziness. Both can cause hyperkalemia if the dose is significant. Potassium-sparing diuretics are also known as Na channel inhibitors, causing a small increase in NaCl excretion. They are often used for offsetting the effects of other diuretics that cause an increase in potassium excretion.

C. Compare triamerterene with spironolactone structurally and functionally? (Bello, Dowjat, Kaur, Obiakwata, Sallout, and Wilson)

Spironolactone is structurally similar to aldosterone (a mineralocorticoid). Triamterene is not similar to aldosterone, but its activity is retained if an amine group is replaced with a lower alkylamine group. Fuinctionally Spironolactone is a competative aldosterone inhibitor. It binds to the mineralocorticoid receptor which prevents aldosterone from binding →prevents the reabsorbtion of sodium, chloride, and water at the distal tubule and collecting duct. Triamterene interferes with the cation exchang by blocking the luminal sodium duct→blocks the reasorbtion of sodium and inhibits the secretion of potassium at the distal tubule and collecting duct.

D. Is H2O a diuretic? If yes, discuss the mechanism of action? (Adabie, Bou-Mitri, Finke, Kibazo, O'Connor, and Taylor) Consumption of water will increase the amount of urine output as well as inhibiting ADH, which encompasses the definition of a diuretic. However, therapeutically speaking we use a diuretic to decrease the amount of water in the body so taking in more water would be counterproductive.

E. Is glucose a diuretic? If yes, discuss the mechanisms of action? (Bhalodia, El-Zoghbi, Kazinich, Odumuko, Seth, and Wong) Yes, Glucose is a diuretic. It is highly water soluble and increases osmotic pressure within the lumen, which allows water to enter the tubule. So glucose exerts its action as an osmotic diuretic. Since water is not being reabsorbed, this leads to diuresis, therefore increasing the excretion of water and electrolytes which leads to an increase in urine volume.

F. Why are osmotic diuretics not considered to be primary diuretics for edema? (Blagg, Enwonwu, Kebulu, O'Halloran, Shah, and Wood) "Due to the fact that they can increase extracellular fluid volume they are inappropriate as diuretics for the treatment of edema." "Osmotics MOA is to inhibit the re-absorption of water and maintain urine flow. Osmotics have an adverse effect of possibly causing expansion of the extracellular volume. Since a patient with edema already has excess volume in their extracellular compartments, this would not be the primary choice of diuretics; but rather contraindicated in their condition."

G. Cases from Foye’s Textbook: Case #1(Page 735, Foye’s, 6th ed.) “BD is a 67 year-old man who was admitted with a complaint of shortness of breath that has increased over the last few months. He also indicated that he has recently gained more than 12 pounds without changing his eating or exercise habits and that he often has trouble breathing when climbing stairs at home. Physical examination reveals signs and symptoms consistent with both right-sided (systemic edema, hepatomegaly, neck vein distension) and left-sided (weakness, fatigue, rales, cyanosis) heart failure. A diagnosis of congestive heart failure (CHF) is established, and a decision is made to limit sodium intake (low sodium diet) and to initiate oral therapy with digitalis. A diuretic also will be added.” 1. Use your patho-physiological knowledge to explain why the patient gains 12+ pounds? (Blomgren, Erickson, Khodadadian, Opoku, Mensah, Sargent, Shateva, and Xhai)


 * According to Foye's, page 724, "Decreased cardiac function can result in decreased perfusion of all organs and limbs and an accumulation of edema fluid in the extremities". This patient had gained weight due to water retention resulting from CHF. In CHF the heart is not ejecting blood efficiently. Therefore blood in the venous circulation is backing up and edema results from the increased venous pressure.**

2. Use your patho-physiological knowledge to explain why systemic edema, hepatomegaly, neck vein distension occurred and why weakness, fatigue, rales, cyanosis occurred in this case. Are these enough to establish a diagnosis of CHF? Can these also occur in other diseases? (Addo, Bui, Finneran, Kothari, Pang, and Urbach)

· Left-sided heart failure signs and symptoms are: o Weakness and fatigue: Weakness and fatigue occur because the left-side of the heart supplies the muscles with oxygen. Without enough oxygen to the muscles, they will not have enough energy. o Rales: Rales (or crackles) heart initially in the lung bases, and when severe, throughout the lung fields suggest the development of pulmonary edema, because the left-side of the heart is unable to pump all the blood coming from the right-side of the heart and it is trapped at the lungs. o Cyanosis: Suggests severe hypoxemia because not enough oxygen is getting to the rest of the body, a late sign of extremely severe pulmonary edema. · Right-sided heart failure signs and symptoms are: o Systemic edema: Congestion of the systemic capillaries because the right-side of the heart is unable to pump the deoxygenated blood from the body into the lungs, so there is an accumulation of blood in the systemic circulation. o Hepatomegaly: Caused by significant liver congestion, resulting in impaired liver function, causes the liver to swell. o Neck vein distension: Occurs because of the extra fluid in the systemic circulation, causing veins to distend · These can occur in other diseases individually, but not with all the signs and symptoms together. All the signs and symptoms are indicative of congestive heart failure. Referenced from pathophysiology lecture.

3. Why does the physician decide to limit the patient’s sodium intake and why digitalis and a diuretic were prescribed? (Bourque, Fiore, Khorassani, Orock, Shim, and Youkhanna) The physician orders a low sodium diet in order to limit the retention of water in the patient. He orders the diuretic to promote fluid excretion which will improve the systemic edema. Digitalis is ordered because it is a first line agent in the treatment of CHF. Digitalis will increase the intracellular concentration of sodium, so it is also a good idea to have a low sodium diet for this reason.

4. Which diuretics would be appropriate to use in this patient and why? (Boyce, Fredette, Kum, Padron, Shindo, and Zbikowski)
 * A loop diuretic is a better choice since it will provide quicker, more robust diuresis compared to a thiazide diuretic. The textbook on p.735 also mentions that a loop diuretic also has direct effects on the pulmonary venous system to relieve his pulmonary symptoms due to his left-side CHF (weakness, fatigue, rales, cyanosis).

5. Does BD have normal liver and kidney function? Please justify your answer. (Alhammad, Caron, Fletcher, Lalinde, Piehler, and Valder) BD does not have normal liver function because he has hepatomegaly which will impair the liver's ability to function properly. He does not have normal renal function because he is retaining water. CHF will decrease cardiac output which will cause a decrease in renal perfusion leading to abnormal renal function.

6. How is the patient’s liver function relevant to diuretic therapy? (Boyd, Gandhi, Lally, Paige, and Shoemaker)

The liver is responsible for the metabolism of many drugs through the CYP450 enzymes. Patients with decreased liver function are at risk for poor metabolism of drugs which could lead to drug accumulation in the body. Drug accumulation of diuretics could lead to severe hypotension. Below are some examples of diuretic therapy being affected by decreased liver function: Carbonic Anhydrase Inhibitors-induces alkaline of the urine decreasing ammonium excretion and causing hyperammonemia and hepatic encephalopathy in patients with cirrhosis. Loop diuretics -overzealous use is dangerous in hepatic cirrhosis KSparing Diuretics- patient's with liver disease can have impaired metabolism of triamterene and spironolactone.(From Basis of Clinical Pharmacology)

7. Following 6 weeks on his low-salt diet and drug therapy, this patient’s condition seems to be greatly improved. His serum potassium levels, however, have decreased from 4.2 to 3.1 mEq/L (normal value, 3.8-5.6 mEq/L). What caused the patient’s serum potassium levels to decrease over time? Why is this change a concern and what can be done to remedy this problem? (Alqahtani, Chaudhari, Foreman, Lauze, Poku, and Varieur) Loop and Thiazide diuretics are not useful with low salt diet and cause excessive loss of K+ ions. Hypokalemia alone can lead to the development of cardiac arrhythmias. Hypokalemia can be prevented by the use of potassium sparing diuretics or potassium supplements.

8 . If the patient’s CHF was mild but his renal function was already impaired (glomerular filtration rate [GFR], 25 mL/min, how would you select a diuretic for him? (Broek, Gemma, Le, Park, and Simonds)

= Some diuretics reach their site of action via GF. Thus, if renal function is impaired and GFR is reduced, we need to consider if GF is necessary for the drug to reach the site of action. Thiazide diuretics reach their site of action via GF. Thus, a thiazide should not be selected for this patient. Instead, a loop diuretic which reaches its site of action via active secretion could be used. =

Case #2 (Page 736, Foye’s textbook) “You often eat your lunch with your favorite grandma, who is 85 years old and generally in good health except for infrequent bouts of gout. During the last few years when you meet with her, you have noticed that she has been gaining weight around her middle and that her legs and ankle seem to be puffy. During your most recent lunch date, grandma shares with you a problem she has been having at night. It doesn’t happen every night, but every now and then she wakes gasping for air, which requires her to get out of bed and open the window to get relief. She has taken to propping herself up using two or three pillows to get back to sleep. The next day, you accompany grandma to the family doctor, who based on physical examination and a chest radiograph makes a diagnosis of mild CHF (Class II, New York Heart Association [NYHA] Functional Classification). A recommendation is made to limit sodium intake, institute a regimen of exercise and initiate diuretic therapy to remove pulmonary and pedal edema fluid, and decrease the workload on grandma’s heart. The physician knows you are a pharmacy student who likes medicinal chemistry and asks you to make an appropriate choice from compound 1 to 4.” 1. Identify the therapeutic problem(s) in which the pharmacist’s intervention may benefit the patient (Adebogun, Buabeng, Goldenberg, Lee, Park, and Singh)

Compound 2 = Thiazide - *Drug of choice* Preferred drug for mild CHP to remove edema fluid and help improve pulmonary symptoms related to failing heart without dramatic imbalances in extracellular volume and electrolyte levels. Compound 3 = Osmotic (Mannitol) - ** **would not be effective at mobilizing edema fluid and will expand expand extracellular fluid, which would worsen the workload on the heart.**
 * Compound 1 = Carbonic Anhydrase Inhibitor (Acetazolamide) - weak diuretic and would not provide adequate diuresis to effectively reduce the workload on the heart.
 * Compound 4 = Loop (Furosemide) - Preferred only for moderate to severe CHF to efficaciously remove edema fluid and improve pulmonary symptoms. However, will cause more dramatic extracellular volume and electrolyte imbalances.**

(Foye's pg. 735)

2. Why did the patient have to grasp air in the mid of night? (Afolayan, Cabral, Goodrich, Lee, Patel, and Snell)


 * Grandma is lying down when she sleeps. This causes the pulmonary edema to spread out over a large surface area of her lungs. The edema causes a barrier to gas exchange at the alveoli. It is much like drowning. The decrease in gas exchange leads to decreased oxygen in the body. The tissues become hypoxic causing an increased work on the heart. This increased work happens because the heart must pump more blood to the tissues to try to make up for the small amount of oxygen coming in (more blood cells passing by = more surface area with available oxygen). The increased work on the heart increases grandma’s work of breathing because the heart is now demanding more oxygen to keep pumping at an increased work. The lungs can’t get enough oxygen with half their surface area covered by fluid so they tell the brain to wake grandma up gasping for air. She stands up and the fluid drains down to the bottom of her lungs taking up less surface area.**

3. Why did she have to prop herself up in order to get back to sleep? (Afrane, Cardoso, Gossiho, Libera, Patel, and Sok)


 * Her recently diagnosed congestive heart failure allowed for a redistribution of fluid, while sleeping, from the feet and legs, into the lungs and interfering with the exchange of oxygen. By propping herself up with pillows, some of that accumulated fluid redistributes away from the lungs so that she may breathe deep, allow oxygen to exchange properly and reach the tissues, and resume her ability to sleep.**

4. What is New York Heart Association [NYHA] Functional Classification? (Al-Ruthia, Cormier, Friesen, Dillon, and Zamoiski)


 * Class - Patient Symptoms:**
 * Class I (Mild)** - No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath).
 * Class II (Mild)** - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.
 * Class III (Moderate)** - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.
 * Class IV (Severe)** - Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

5. Identify and prioritize the patient-specific factors that must be considered to achieve the desired therapeutic outcomes (Akwari, Caron, Guan, Liu, Patel, and Stevenson) 1. pulmonary edema - top priority as this is the patient's chief complaint and affects quality of life 2. congestive heart failure - of second priority, although the therapy for this will also affect the first and third factor 3. pedal edema 4. gout

6. Name the drugs shown above. These four compounds, which also are listed on page 736, Foye’s Textbook, are belonging to which class of diuretics respectively? (Alberding, Carr, Guillemette, Loring, Patel, and Stover) Compound 1: Carbonic anhydrase inhibitor Compound 2: Thiazide Diuretic Compound 3: Osmotic diuretic Compound 4: Loop diuretic **
 * Answer:

​7. Evaluate the structure-activity relationship findings against the patient-specific factors and desired therapeutic outcomes, and make a therapeutic decision. (Aleksiewicz, Casavant, Haibi, Manouchehrian, Patel, and Sultan)


 * Compound 2, which is the Thiazide Diuretic has a sulfonamide group present at C-7, which is responsible for increased diuretic activity. Also, the Cl ion present at the C-6 position is a plus because it is an electron withdrawing group, increasing the effect of diuretics. The saturation of the double bond between C3 and C4 is known to increase diuretic activity 10X than if the bond between the group is unsaturated. Lastly, the CF3 substitution is more lipid soluble and thus would induce greater diuretic action than a water soluble substituted group. Since Grandma has a bout of pedal/peripheral edema, we would recommend the drug HCTZ.**

8. Counsel the patient. (Anderson, DaCosta, Hannemann, McCarthy, and Raphael)

Grandma, I would like to talk with you about this new medication. Do you have any allergies, or are you taking any other medications (including over the counter meds)? This medication is used to help with the swelling in your legs and difficulty breathing at night which are caused by your congestive heart failure. Take this medication by mouth with or without food, as directed by your doctor. Try not to take it within 4 hours of bedtime, because it may make you have to get up and urinate. This medication can cause dizziness, lightheadedness, headache, or blurred vision. Use this medication regularly, at the same time every day. If you miss a dose, do not double up on doses. If it is close to the next dose, simply skip the missed dose and resume taking the medication as usual. If you have any further questions about this medication, contact your pharmacist or doctor.

9. The treatment of one of the compounds appears to be reasonably effective in controlling your grandma’s blood pressure. However, plasma electrolytes reveal hypokalemia. Which compound has likely been used by your grandma’s cardiologist and, to restore the electrolyte imbalance, how is your grandma’s cardiologist going to contemplate a change in diuretic therapy? (Aletti, Charron, Hamidi, Marcus, Patel, and Sureja) -**Grandma was mostly likely initiated on compound 2 or 4 (thiazide or a loop), and given that her classification was at level II, compound 2 (thiazide) was used, as the potency of the loop diuretics was not required. To restore granny's electrolyte balance, cardiologist can initiate a low dose of a K+ sparing diuetic, as those are often used in combination with the thiazides to prevent hypokalemia. Triamterene/HCTZ is available in a generic combination formulation. If we had to chose from the listed compounds 1-4, acetazolamide would be the next best option, although its use as a diuretic is limited by decreased potency and the potential for acidosis.**