Problem+Set+4

Problem Set #4 (Dr. Sheng; PSW481) Date of submission: 11/06/2009

A. Quiz on textbook reading and prerequisite coursework

(1) Is there any difference between the two double bonds indicated by dot lines? (Belfiore, Dufresne, Johnson, Ndungi, Smith, and Nguyen)

The double bonds are C=C and C=O. There is a difference between the two double bonds. Oxygen is more electronegative than carbon and will pull electron density away from the carbon atom. This gives the C=O bond polarity with a slight negative charge at the oxygen atom and a slight positive charge at the carbon atom. This would make the C=C bond more stable.

(2) The key structure shared by the carbonic anhydrase inhibitors mentioned in Chapter 27, Foye’s is a. Acetyl group c. Ketone group d. Sulfinyl group e. Aldehyde group
 * b. Sulfamoyl group**

(3) What is the lead for the development of angiotensin II receptor blockers (i.e. Losartan)? (Badavas, Davis, Jorgensen, Nelson, Pratt, and Vakil)
 * S-8308 shares three common structural features with angiotensin II.**

(4) Which of the following statements for G-protein-coupled receptors is wrong? a. N-terminal is responsible for ligand binding. b. C-terminal is responsible for interaction with G protein. c. Most of them have seven TM segments. d. For the protease-activated GPCR, its C-terminal segment can be cleaved by its ligand in order to be activated.

(5) IP3 is responsible for a. Opening of Na+ channels b. Opening of K+ channels d. Influx of extracellular Ca++
 * c. Intracellular Ca++ release**

(6) Which type of ion channels is responsible for the arrow-indicated curve? (Badr, Dean, Judge, George, Quinlan, and Verma)

b. K+ channels c. Na+ channels d. Cl- channels
 * a. Ca++ channels**

(7) In the reaction below, HSO4- acts as a HSO4- +H2O ⇋ H3O+ + SO42- b. Base c. both of a and b d. None of a and b Please justify your choice (Bagas, Diec, Kahura, Nguyen, Rodrigues, and Vu)
 * a. Acid**

HSO4- in this reaction would be an acid. Acids are proton donors. HSO4- is donating a proton to water yielding H3O+ and SO42-.

B. Explain the meaning of LogP and pKa and their relevance to the compound’s water solubility (Ackley, Bell, Faraj, Keeler, Ngang, and Sweatt)

LogP is the log of the partition coefficient for a molecule. Experimentally, the partition coefficient is the ratio of concentration of drug in octanol to that in water. A Log P can be calculated by adding all the pie values of each organic functional group. Log P is a measure of the solubility characteristics of the entire molecule. Values >0.5 are water insoluble and values <0.5 are water soluble. pKa is the pH at which a specific substituent will lose a H+. pKa=pH +log[(acid form)/(base form)] Above the pKa acids will be neutral and below the pKa bases will be neutral. Neutral compounds will be less water soluble than ionized or charged compounds.

C. Case studies from Foye’s Textbook: Case #1 (Page 767, Foye’s, 6th ed.)

“BB is a 58-year-old divorced woman who owns her own travel agency. She has a family history of alcoholism, and that, coupled with the social nature and constant pressures of her job, led BB to become an alcoholic. Five years ago, BB was diagnosed with diabetes, and since then, she has joined Alcoholics Anonymous and been successful in controlling her drinking. Her diabetes is under control with glyburide (5 mg daily with Breakfast). Lately, however, she has experienced a loss of energy and difficulty breathing on her daily walk uptown to her office. In addition, BB often wakes during the night frightened by a sense that she has stopped breathing and finds it necessary to prop herself up with a couple of pillows to get a good night’s sleep. On physical examination, her physician notices a tender abdomen reveals cardiomegaly. A diagonisis of mild congestive heart failure was made, and BB was prescribed captopril (25 mg, t.i.d) and advised to control salt intake and to continue her normal exercise routine. On a follow-up visit to her physician, BB’s symptoms have moderated, but she complains of an irritating cough and rash, that her medication makes everything taste like rust, and that her lips feel like they have silicon implants. BB’s physician wants to change her medication, and you have the following choices available. What do you think?”

Compound 1 Compound 2

Compound 3 - Olmesartan Compound 4 - Losartan Mechanism of action of compounds 3 and 4 :they block the angiotensin II receptor, thus reversing and preventing the effects of angiotensin II. They are used for treatment of hypertension and nephropathy in patients with DM2

1. Briefly discuss how ACE inhibitors were developed. (Balkhi, Dion, Kammermayer, Nguyen, Roth, and Walden) ACE inhibitors were originally developed from the venom of a poisonous Brazilian snake.

2. What are the diagnoses for this patient? Identify the therapeutic problem(s) in which the pharmacist’s intervention may benefit the patient. Why was captopril prescribed? (Basmadjian, Donnelly, Karki, Nwafor, Safo, and Wallace) The patients diagnoses is congestive heart failure. Captopril is an ACEI which will increase the bradykinin level that, in turn stimulate prostaglandin biosynthesis. This will lead to vasodialation of the blood vessels and reduce the work or the heart.

3. Discuss the MOA of glyburide and why it is given 5 mg daily with breakfast. (Bello, Dowjat, Kaur, Obiakwata, Sallout, and Wilson) The hypoglycemic action of glyburide is due to stimulation of pancreatic islet cells, which results in an increase in insulin secretion. Sulfonylureas are believed to bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, thereby reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. The drug is not effective in the absence of functioning beta-cells, as occurs in diabetes mellitus type 1, or when the number of viable beta-cells is low, as occurs in severe cases of diabetes mellitus type 2.

Prolonged administration of glyburide also produces extrapancreatic effects that contribute to its hypoglycemic activity. These effects include reduction of basal hepatic glucose production and an enhanced peripheral sensitivity to insulin secondary to an increase in insulin receptors or to changes in the events that follow insulin-receptor binding. The relative importance of each of these actions to the overall therapeutic effect of the drug will vary among oral antidiabetic agents and from patient to patient, which may account for the variability in potency among these drugs. Like glipizide, glyburide exhibits mild diuretic actions but does not affect uric acid concentrations

4. On the follow-up visit, why does BB’s physician want to change her medication? (Adabie, Bou-Mitri;Finke, Kibazo, O'Connor, and Taylor) BB is having an allergic reaction to the sulfhydryl component of the medication (taste disturbances and rash) as well as the symptomatic dry cough associated with this class of drugs.

5. Name compounds 1 and 2. Discuss their MOA and therapeutic uses. (Bhalodia, El-Zoghbi, Kazinich, Odumuko, Seth, and Wong) strucure # 1 = lisinopril, structure # 2 = enalapril. they are used for HTN, Heart failure, left ventricular dysfunction. MOA- it is an ACEI. It blocks conversion of angiotensin I to angiotensi II, which is vasoconstrictor. It converts into angiotensin II (1-7) peptide which a vasodilator and reduces a blood pressure.

6. Identify the key chemical functional groups that determine the pharmacological activity and pharmaceutical properties of compounds 1 and 2. What is/are the major difference(s) between Compounds 1 and 2? (Blagg, Enwonwu, Kebulu, O'Halloran, Shah, and Wood) __Compound 1:__ has **n-butylamine** (lysine) side chain. This produces a compound which does not require prodrug for oral activity. __Compound 2:__ has **a methyl group**; the addition of a methyl group mimics amino side chain (alanine). This enhances activity but only marginally. The major difference between compound 1 and 2 is that __compound 2__ contains the carbon atom directly adjacent to the carboxylic acid (-OCH2CH3). This carbon acts as part of a ring system and provides some __steric hinderence to conjugation__.

7. Name Compounds 3 and 4. What are they MOA and therapeutic uses? (Blomgren, Erickson, Khodadadian, Opoku, Mensah, Sargent, Shateva, and Xhai) Compound 4 is losartan, an ARB. This blocks angiotensin II from binding its receptors, preventing it from causing vasoconstriction. It is used for hypertension.

8. Identify the key chemical functional groups that determine the pharmacological activity and pharmaceutical properties of compounds 3 and 4. What is/are the major difference(s) between Compounds 3 and 4? (Addo, Bui, Finneran, Kothari, Pang, and Urbach) - Compounds 3 and 4 are ARBs (olmesartan, losartan). All commercially available ARBs are contains: (1) acidic group (carboxylic acid, phenyl tetrazole, or phenyl carboxylate), (2) in the biphenyl series, the tetrazole and carboxylate groups must be in the ortho position, (3) n-butyl group, (4) imidazole ring or an isosteric equivalent, (5) substitution can vary at the R position (carboxylic acid, hydroxymethyl group, a keton, or a benzimidazole ring). - The major differences between olmesartan and losartan are the different substituents coming off the imidazole ring (chloride, carbon chains, hydroxyl, etc.). - Foye's p. 754-755.

9. Discuss the roles of enzymatic reactions in vivo in determining the pharmacokinetic properties of these drugs. Name the enzymes. (Bourque, Fiore, Khorassani, Orock, Shim, and Youkhanna) Lorsartan is oxidized by the isozymes CYP2C9 and CYP3A4 to produce Exp-3174 the active metabolite that acts at the AT1 receptor located in the myocardial tissues, CNS, brain, vascular tissue, kidneys, lungs and liver. This metabolite is 10 to 40 fold more potent than losartan. The pharmacological effects of losartan are due to the combined effects of the parent drug and the active metabolite. No other member of the ARB's is converted to the active metabolite and are excreted almost entirely unchanged (80%).

10. How do you make your therapeutic decision? If the patient also takes rifampin for tuberculosis at the same time, does rifampin affect your decision making? (Boyce, Fredette, Kum, Padron, Shindo, and Zbikowski)


 * The patient should be taken off of the captopril due to the cough and angioedema, and also due to her allergy to sulfa. Rifampin is an inducer of CYP3A4. Rifampin is reported to decrease pharmacological effects of enalapril (compound 2) and losartan (compound 4) (Table 28.5 p.752). The compound 2 will not be appropriate. The compound 1, lisinopril, is reported to have the most severe chronic cough. Thus, it would not be appropriate for the patient. In order to improve her quality of life, ARBs will be more appropriate since they have milder ADR profiles without chronic cough. The compound 3 is olmesartan medoxomil and the compound 4 is losartan. On p.756, rifampin is reported to decrease the plasma levels of losartan and its active metabolite, EXP-3174. Thus, the compound 3, olmesartan medoxomil would be the best option for this patient.

11. How do you counsel this patient? (Alhammad, Caron, Fletcher, Lalinde, Piehler, and Valder) Olmesartan: can either be take with or without food, cannot take if pregnant, side effects are dizziness, gout, nausea, upper respiratory infection, take this medication regularly for it to be effective and can take a couple of weeks to start working. Case #2 (from the Principles of Medicinal Chemistry) “GM is a 38-year-old mildly obese black, diabetic male who is the CEO of a new and rapidly growing internet-based marketing firm. His hyperglycemia is being controlled moderately well with glipizide, although he has experienced a few hyperglycemic episodes over the past year. He suffered a mild MI several years ago, but is not currently on any cardiovascular medication. GM is happily married and the father of three young children. He seems interested in doing what he needs to do to stay healthy, but admits to being intensely focused on making a financial success of his business. He is finding less and less time for exercise, and regularly wines and dines clients at fancy restaurants. When he eats alone it is usually “on the run.” A social cigar smoker, he has recently experienced shortness of breath when jogging on the treadmill his wife bought him for his birthday and, once last week, he experienced transient chest pain while working out. He routinely takes OTC Tagamet-HB for lifestyle-induced “heartburn.” GM is now in your ambulatory clinic for his annual physical exam. Although he has tried to modify his diet and has lost 10 pounds since his last office visit, he is still 30 pounds overweight and admits to eating too much salt. His blood pressure had routinely been on the high end of normal, but now is overtly elevated (180/94). His blood lipid profile reveals HDL 40, LDL 120, and serum cholesterol 230. Renal and hepatic function tests are all within normal limits. The physician asks for your input on appropriate antihypertensive therapy. She wishes to begin with monotherapy, but is not opposed to combination therapy if you can provide scientifically sound justification for it. Consider the relative merits of the antihypertensive agents drawn above.”

Compound 1 Compound 2

Compound 3 1. Describe the therapeutic uses and mechanisms of action of glipizide and Tagamet-HB. (Boyd, Gandhi, Lally, Paige, and Shoemaker) Glipizide is used as an adjunct to diet for hyperglycemia in patients with type 2 diabetes. It is indicated when diet alone has been unsuccessful in correcting hyperglycemia. Furthermore, loss of blood glucose control on diet alone also may be transient, requiring only short-term administration of glipizide. Glipizide lowers blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. It also reduces basal hepatic glucose production and enhances peripheral sensitivity to insulin secondary to an increase in insulin receptors. (Drug Facts & Comparisons)

Tagamet-HB is used in the management of duodenal ulcer, treatment of GERD, erosive esophagitis, benign gastric ulcer, pathologic hypersecretory conditions, & prevention of upper GI bleeding. It reversibly and competitively blocks histamine at the H2 receptors, particularly in gastric parietal cells, inhibiting gastric acid secretion. (Drug Facts & Comparisons)

2. At the time he comes to the ambulatory clinic for his annual physical exam, what should the diagnoses be? What are the therapeutic problem(s) where the pharmacist’s intervention may benefit him? (Broek, Gemma, Le, Park, and Simonds) This patient is suffering from severe hypertension as evidenced by his elevated blood pressure of 180/94. He may also have hyperlipidemia as evidenced by his high lipid profile. The pharmacist could suggest a medication to combat the patient’s high blood pressure such as an ACE-I, ARB, or a calcium channel blocker. The pharmacist could also suggest medication for his hyperlipidemia. Finally, lifestyle modifications could be discussed with the patient. Therapeutic problems include: hypertension, diabetes, and hyperlipidemia.

3. Use your pathphysiology knowledge to explain why the patient experienced shortness of breath when jogging on the treadmill. (Alqahtani, Chaudhari, Foreman, Lauze, Poku, and Varieur) The patient experiences shortness of breath when jogging is due to decreased oxygen reaching to the organs due to decreased cardiac output.

4. What is his “heartburn” and why did he take Tagamet-HB? Should this be considered when you make your therapeutic decision? (Adebogun, Buabeng, Goldenberg, Lee, Park, and Singh)

GM's heartburn is postprandial heartburn. GM took Tagamet-HB to treat his GERD. Yes, it should be considered.

5. Give the generic name and drug class of compound 1. Describe its therapeutic uses and mechanism of action. (Afolayan, Cabral, Goodrich, Lee, Patel, and Snell)

6. Give the generic name and drug class of compound 2. Describe its therapeutic uses and mechanism of action. (Afrane, Cardoso, Gossiho, Libera, Patel, and Sok)

Generic Name: Losartan

Brand name: Cozaar

Therapeutic Class: Angiotensin Receptor Blocker Mechanism of Action: Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland).  Therapeutic Uses: COZAAR is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics. 

7. Give the generic name and drug class of compound 3. Describe its therapeutic uses and mechanism of action. (Al-Ruthia, Cormier, Friesen, Dillon, and Zamoiski) conversion of angiotensin-I to angiotensin-II. Inhibitors of ACE increase bradykinin levels that stimulate prostaglandin biosynthesis. Decreased angiotensin-II levels increase the release of renin and the production of angiotensin-I. Because the angiotensin converting enzyme is inhibited, angiotensin-I is shunted toward the production of angiotensin (1-7) and other peptides all leading to vasodilation and a decrease in blood pressure.
 * Generic name:** fosinopril (Brand: Monopril)
 * Therapeutic class:** ACE Inhibitor
 * Mechanism of Action:** ACE Inhibitors decrease the effects of the renin-angiotensin system by inhibiting the
 * Therapeutic uses:** Hypertension, Heart Failure

8. Besides these three drugs, what else can you suggest to the patient and her physician? (Akwari, Caron, Guan, Liu, Patel, and Stevenson)

We can give a beta blocker (such as metoprolol succinate) for his hypertension.

9. Describe the key chemical group(s) that determines the pharmacological activity and pharmaceutical properties of compound 1. (Alberding, Carr, Guillemette, Loring, Patel, and Stover) a. A substituted phenyl ring at the c4 position optimizes activity. b. Phenyl ring substitution is important for size and position rather than for electronic nature. Compounds with ortho or meta substitutions possess optimal activity. Compounds with electron withdrawing groups at the same positions have also demonstrated good activity. The ortho and meta substitutes provide sufficient bulk to "lock" the conformation of the compound. c. The 1,4-DHP ring is essential for activity. Substitution at the N1 position or the use of oxidized or reduced ring systems greatly decreases activity. d. Ester groups at the C3 and C5 are nonidentical, the C4 carbon becomes chiral, and stereoselectivity between the enantiomers is observed. f. With the exception of amlodipine, all 1,4-DHPs have C2 and C6 methyl groups. It was found that enhanced activity could be obtained by altering these groups.

10. Describe the key chemical group(s) that determines the pharmacological activity and pharmaceutical properties of compound 2. (Aleksiewicz, Casavant, Haibi, Manouchehrian, Patel, and Sultan)

There is an Ionized carboxylate with the same c-terminal carboxylate as the angiotensin 2. It has an imidizole ring with a side chain that has a His residue. There is also an N-butyl group that has the hydrocarbon side chain of Ile5

11. Describe the key chemical group(s) that determines the pharmacological activity and pharmaceutical properties of compound 3. (Anderson, DaCosta, Hannemann, McCarthy, and Raphael)

An N ring must be present that mimics the C-terminal carboxylate of ACE substrates. This N ring also increases the potency of the compound, and enhances the acidity of the carboxylic acid.. The phosphinic acid binds the zinc group, mimicing the peptide hydrolysis transition state. The acyloxy alkyl group allows better lipid solubility and improved bioavailability.

12. Make a therapeutic decision and counsel your patient. (Aletti, Charron, Hamidi, Marcus, Patel, and Sureja) -Initiate patient on appropriate low dose of lisinopril once daily. This will help reduce his high blood pressure by preventing conversion of angiotensin I to angiotensin II and blocking the vasoconstrictive effects of angiotensin II. Additionally ACEI are renoprotective in diabetics and are indicated in therapy. -Counsel the patient to continue exercising and to reduce his salt intake slowly. Encourage patient of TLC that will help to reduce his cholesterol, as this will help increase later morbity and mortality. Patient should be told to stop taking tagamet and to instead use Prilosec OTC,as omeprazole does not have as many drug interacts as cimetidine. Finally, counsel patient on expected side effects of ACEI: this drug may cause cough, rash, taste disturbances, headache, dizziness or fatigue. If any of these symptoms because severe or bothersome, contact your physician immediately. If you experience rash or swellling of the face, contact your physician immediately. ACEI may also cause hypotension, so if you experience any dizziness or fainting, also contact your physican as your medication dose many need to be adjusted.

13. Define and compare the following terms (Ali, Chau, Heinzelmann, Mathew, Patel, and Sylvestre) (a). Monotherapy and combination therapy
 * Monotherapy** = using a single drug to treat a disorder
 * Combination therapy** = using multiple agents to treat a clinical condition

(b). Pharmacological; pharmaceutical; pharmacokinetic; pharmacodynamic
 * Pharmacological** = pertaining to pharmacology - the properties and characteristics of a drug
 * Pharmaceutical** = a medicinal drug
 * Pharmacokinetics** = the relationship between a dose of a drug and its concentration in the body (what the body does to the drug)
 * Pharmacodynamics** = the relationship between the concentration of a drug and its response (what the drug does to the body)