Vitamin D Boosts Calcium Potency: See Link For Interesting Article

http://www.sciencenews.org/?_kk=science/view/generic/id/6775/title/Food_for_Thought__Vitamin_D_Boosts_Calcium_Potency

STUDENT QUESTION

Q. I heard that triphasic COCs can cause mood changes more than other types. Is it true? Why?

Answer: Here's what I could find:

taken from: J. Bancroft, D. Sanders, P. Warner and N. Loudon, The effects of oral contraceptives on mood and sexuality: a comparison of triphasic and combined preparations. J Psychosom Obstet Gynaecol, 7 (1997), pp. 1–8.

"OCs may also aggravate the “vulnerability factor”; in a comparison of triphasic and monophasic OCs, women with a tendency to premenstrual mood change showed more negative mood on the triphasic pill, usually occurring during mid cycle."

The why part is harder to answer. Any ideas?

Website with information pertaining to contraceptives and breast feeding

http://www.kellymom.com/health/meds/birthcontrol.html#sideeffects

Osteoporosis-Related Drugs

REQUIRED READING: AGENTS THAT AFFECT BONE MINERAL HOMEOSTASIS
Katzung’s Basic and Clinical Pharmacology
11th edition
Chapter 42

After attending the lecture and reading the textbook, you should be able to answer these questions.

1. Is osteoporosis a condition that disturbs the structural support of the body? What are the three major body organs involved in calcium and phosphate homeostasis? What is the normal range of calcium in the blood?

2. What is parathyroid hormone (PTH)? Which glands of the body secrete PTH? What is the physiological effect of PTH? How many amino acids are in PTH? Is the secretion of PTH inversely related to plasma Ca++ levels? What hormone in the body has the opposite effect of PTH? What physiological effect is achieved with prolonged, chronic, exposure to PTH? How does that differ from intermittent exposures to PTH?

3. Describe the PTH receptor. Is it a nuclear receptor? What 2nd messenger accumulates within the cell following activation of the receptor? Does PTH stimulate the activity of many proteins? Does it inhibit the activity of other proteins? Pretty cool, eh? (PS. No need to memorize that list. But one should realize that PTH can both stimulate and inhibit the functions of unique gene products.)

4. What vitamin is required for PTH to exhibit its full spectrum of action? Describe the relevant steps in the conversion of 7-dehydrocholesterol to vitamin D3 and metabolism of D3 to 1,25(OH)2D3 (calcitriol). What do you suspect could happen to calcitriol biosynthesis in a patient with renal failure?

5. What is hypocalcemia? What are the pharmacotherapeutic options available to treat HYPOcalcemia?

6. What is osteoporosis? What pharmacotherapetic options are available to treat this disease? Which of these agents are hormonal? Which of them are non hormonal?

7. Draw the general structure of the nitrogen-containing bisphosphonates. What is FPPS? What is the therapeutic mechanism of action of the bisphosphonates? Are these agents well-absorbed after oral administration? Are there dietary factors that can influence the absorption of these agents?

8. What are the FDA-labeled indications for alendronate? What is the mechanism of action of alendronate? Does the bioavailability of this drug? Describe the Phase I and Phase II metabolism of alendronate. What are the common adverse effects associated with this drug? What are some rare but serious adverse effects associated with this drug? Is alendronate given as an oral administration? As an intramuscular administration? As an inhalational administration?

9. What are the clinical indications for risedronate? Is it given orally? Intramuscularly? Intravenously? What are its chief adverse effects?

10. What are the clinical indications for ibandronate? Is it given orally? Intramuscularly? Intravenously? What are its chief adverse effects? Daily? Yearly? Monthly? Weekly?

11. What are some contraindications to the bisphosphonates?

12. Any relevant drug drug interactions with bisphosphonates?

13. What are the clinical indications for zoledronic acid? Is it given orally? Intramuscularly? Intravenously? What are its chief adverse effects? Why do you think that esophageal toxicity not on this list?

14. Why is salmon calcitonin the preferred agent to human calcitonin? How does the drug work? What is it used for? Is the preferred route of administration oral dosing? Why or why not? What are the common adverse effects of calcitonin?

15. Raloxifene is important in osteoporosis. Why? How does it work? In breast and uterus, how does raloxifene work? What about in the bone? Is it an agonist or an antagonist of estrogen receptors? Is it well absorbed after oral administration? What is its bioavailability? Why the big difference in absorption vs. bioavailabilty? What is the predominant Phase II conjugate of raloxifene? What is its elimination half-life? What are some precautions and adverse effects associated with this drug?

16. What are the clinical uses of calcitriol? What are some of its proposed mechanisms of action in the relief of osteoporosis? Is calcitriol absorbed well via oral administration? Compare and contrast the physiological actions of PTH and calcitriol.

17. What is teriparatide? What are its FDA-labeled indications? What is one of the rare but serious adverse effects associated with this drug? Will it be administered orally? Why or why not?

THE GONADAL HORMONES AND INHIBITORS

REQUIRED READING: THE GONADAL HORMONES AND INHIBITORS
Katzung’s Basic and Clinical Pharmacology
11th edition
Chapter 40

Infertility- know the mechanism of action, route of administration, most common adverse effects, any rare but serious adverse effects, efficacy rates (in other words, are these drugs effective?), risk of multiple gestation, risks to the developing baby (if any), risk of ovarian hyperstimulation syndrome, etc… pertaining to clomiphene, aromatase inhibitors, FSH, LH, GnRH, bromocriptine and corifollitropin alpha.


HRT and menopause
1. What is menopause? What are the symptoms associated with menopause that have found to be alleviated by estrogen?

2. How might the adverse effect of post-menopausal bleeding be controlled in women taking estrogen replacement? What is a serious potential cause of postmenopausal bleeding not related to estrogen pharmacotherapy?

3.. Aside from postmenopausal bleeding, what other adverse effects can occur in patients taking estrogen replacement therapy? How can adverse effects like nausea and breast tenderness be managed? Does E+P HRT increase the risk of certain diseases? What are those diseases? Do these diseases appear in all women taking estrogen? Is the endometrium particularly sensitive to unopposed estrogen toxicity? What happens to the risk of endometrial cancer in patients taking estrogen and progesterone combination therapy?

Hormonal Contraception

1. What happens to the release of LH and FSH by the pituitary when plasma levels of both estrogen and progesterone are high?

2. What two types of agents do combination oral contraceptives (OCs) contain? For most OCs, what is the standard dosing regimen? Of 28 tablets, how many are “active” and how many are “inert?” What happens during the seven days of “inert” tablets? Is the choice of combo OC universal? Or is it patient-specific? How should the doses be decided?

3. What are the proposed mechanisms of action for the combination oral contraceptives? How about for the progestin-only OCs? What types of products are available?

4. Comment on some of the interesting adverse effects relating to transdermal administration or administration via vaginal ring.

5. Compared to estradiol, what are the chief pharmacokinetic advantages (half-life, bioavailability, protein binding) for ethinyl estradiol? How is the compound eliminated from the body?

6. What is the major metabolite of the synthetic progestins? Is that metabolite active or inactive? How are progestins eliminated from the body? Compared to progesterone, what are the chief pharmacokinetic advantages (half-life, bioavailability, protein binding) for norethindrone?

7. With respect to the combination OCs, does either drug alter the pharmacokinetics of the other?

8. What is the difference between monophasic, biphasic, and triphasic OCs? Why are withdrawal- bleeding periods, on average, shorter for loestrin 24 Fe than with other combo OCs?

9. Long-duration contraception with progesterone-only agents can be achieved using parenteral routes of administration such as implantable or intramuscular preps. Which agent is available as a subcutaneous implant? As an i.m. injection? Why are progestin-only contraceptive tablets a possible option for nursing mothers? Are menstrual irregularities commonly observed in women taking progesterone-only OCs? Do women on oral progestin-only tablets need to take them every day? Or do they take 21 active pills and 7 inactive pills each month?

10. (SEE slides) What are the pharmacological effects of the combination oral contraceptives on: the ovaries, the uterus, the breast, the blood, the liver, the skin, the cardiovascular system, and the metabolism of lipids and carbohydrates?

11. In which patients are the oral contraceptives contraindicated. Why? What are some of the common and rare but serious adverse effects associated with the OCs?

12. What possible drug-drug interactions can be predicted in patients taking oral contraceptives and antibiotics? In patients taking oral contraceptives and inducers of CYP450s (eg. Rifampin)?

13. What is so unique about drospirenone? Does is have antiandrogenic activity? Does it have antimineralocorticoid activity? Should women with renal failure take an oral contraceptive that contains drospirenone?

14. What happens to the risk of endometrial cancer in patients taking estrogen + progesterone oral contraceptives? Risk of ovarian cancer? Risk of breast cancer? Risk of cervical cancer?

STUDENT QUESTION

Student Question: Does the nausea associated with Byetta subside with time?

Student Answer:
I researched the question I asked in class about Byetta inducing nausea and if it would subside after a while of treatment. I looked on Micromedex and found this:

"Nausea has tended to occur early (first few days), generally subsiding after a week of treatment (Nielsen & Baron, 2003)."

Note that the answer was provided by the same student. GOOD JOB! That is the beginning of true scholarship! BTW, glad to hear that the nausea subsides.

Metformin for Type 1?

Interesting link. Stay tuned.
http://www.diabetesmine.com/2010/01/metformin-for-type-1-diabetes-really-why.html

Student Question: Does sorbitol get absorbed in the diabetic patient?

Taken from:

http://www.healthytipsdirectory.com/anti-aging/benefits-of-prune-juice-and-good-health/

"The content of sorbitol in prune juice is amazingly high. The sugar is a complex polysaccharide, meaning that it’s an extended chain of sugar-like molecules. When ingested, it tends to absorb a lot of water and stays in gut. In fact, because it’s not absorbed in the same way as glucose, sorbitol is often used as a sweetener that is calorie free."

PLEASE DO NOT WORRY ABOUT THE QUESTION ABOUT A DNA MICROARRAY CHIP

Students,

Since I did not have the time to go into this technology, you will not be held responsible for it. Here is a creative link which does talk about it (DNA microarrays) in general terms.



-Dr. Billack
http://www.bio.davidson.edu/courses/genomics/chip/chip.html

Diabetes Lecture Review Questions

REQUIRED READING: PANCREATIC HORMONES AND ANTI-DIABETIC DRUGS
Katzung’s Basic and Clinical Pharmacology
11th edition
Chapter 41, pp. 727-751

After this lecture, you should be able to answer the following:

1. What are the differences between Type 1 and Type 2 diabetes mellitus? What are some of the complications of diabetes mellitus? What are pancreatic islets? What types of islet cells make insulin? Islet amyloid polypeptide (IAPP)? Glucagon? Note: Be very comfortable with the slide dealing with glucose homeostasis and the effects of insulin.

2. What is preproinsulin? Proinsulin? Insulin?

3. Insulin receptor… made up of two alpha and two beta subunits. Alpha domains bind insulin. Beta domains have tyrosine kinase activity (able to put PO4 2- groups on tyrosine residues of protein substrates). Insulin binds… the Beta subunits of the insulin receptor are phosphorylated (auto phosphorylation)… this results in phosphorylation of IRS-1 (insulin receptor substrate 1) and Shc .. let’s just consider the events after that as “cell signaling” which results in mitogenesis, glycogen synthesis, lipid (triglyceride) synthesis and membrane trafficking of GLUCOSE TRANSPORTER 4 (in skeletal muscle and adipose tissue)

4. What is ketoacidosis? Can you smell acetone on the breath of severe Type 1 diabetics? Yes… because excess acetyl-CoA is being made into acetone and related compounds rather than being used to feed into the TCA cycle to make energy. KETONE BODIES (like acetone) are acidic and acidify the blood.. this can lead to diabetic ketoacidosis and coma.

5. GLUT2 is used by beta cells of the pancreas to determine whether or not to secrete insulin. NOTE: ALL TISSUES HAVE GLUT1.. be comfortable with the table listing the different GLUT transporters. Concentrate on the transporter, its tissue location, and its function.

6. Understand the role of Glucose intake through GLUT2 in beta cells… ATP production… closure of ATP-gated Potassium channels.. influx of calcium and release of insulin as the proposed mechanism of insulin release.

7. What happens to GLUT4 transporters when insulin levels rise. Where are they normally… where do they go? What happens to these transporters when insulin levels in blood decrease? Do GLUT4 transporters stay in the cell membrane? or do they return home.. back to the cytoplasm where they are contained in vesicles?

8. What are some of the metabolic effects of insulin on the liver? On the skeletal muscle? On fat cells?

9. What are the four major types of insulin preparations available? Is insulin administered orally? Why not? Does it have a long half-life?

10. Using these terms…. Hexamers… dimers… monomers…. Two amino acid change.. insulin…. Lispro…decreased hydrogen binding of insulin with itself… Explain to your study partner or a complete stranger who is willing to listen why lispro is rapid acting.

11. What effect does having zinc and acetate in the insulin preparation have on its abosorption? In other words.. what makes insulin intermediate- or long-acting?
More zinc favors more insulin in crystalline form which translates into slower absorption.

12. Protamine can be combined with regular insulin to make intermediate-acting insulin preparations. WHY does that work in slowing down absorption of regular insulin? This kind of intermediate-acting insulin is designated as NPH insulin.

13. Please be very familiar with the tables listing the different types of insulin preparations. Focus on the type.. the time to peak effect.. and the duration of action.

14. Is hypoglycemia the most common side effect of insulin therapy? Are all type 1 diabetics treated with insulin replacement? Is type 1 the result of beta pancreatic cell destruction?

15. What are the clinical indications for pramlintide? What are its chief pharmacological actions? What are its most relevant ADME parameters? Is there a boxed warning associated with this drug? What’s that all about?

16. Would you use sulfonylureas in Type 1 or Type 2 patients?? Think about the role of the beta cell in the action of these drugs,-- the answer is Type 2. Type 1s have low (or no) beta cells and hence little insulin to release.

17. Where do the sulfonylureas act? (inhibit the ATP-dependent K+ channel of beta cells). Be able to identify sulfonylureas such as first generation and second generation: NOTE: These drugs can induce hypoglycemia…..nausea, diarrhea & vomiting.
The following link is interesting: http://www.mja.com.au/public/issues/180_02_190104/vei10508_fm.html
It provides some case studies and things to think about in patients using sulfonylureas.
Please read the article. It’s not required… but suggested.

18. Meglitinides cause insulin release from beta cells. Two major meglitinides- repaglinide & nateglinide. How do they work? adverse effects? Receptor binding sites?

19. Do biguanides such as phenformin and metformin increase glucose uptake into skeletal muscle? (YES) What is lactic acidosis and is it related to metformin use, especially in patients with liver disease, renal impairment and cardiopulmonary insufficiency?

20. Understand the relationship of rosiglitazone and the receptor for PPARgamma (peroxisome proliferators activated receptor- gamma).
Rosiglitazone can activate PPARgamma receptor, a nuclear receptor which regulates expression of insulin-responsive genes involved in the control of glucose production, transport and utilization.

21. Chromium… understand that it may be involved in glucose tolerance and may help patients with type 2.

22. Alpha-glucosidase inhibitors. HOW DO THEY WORK? Inhibit break down of oligosaccharides to monosaccharides in the intestine by inhibiting alpha-glucosidase. Acarbose is one drug that belongs to this class. Flatulence, diarrhea and abdominal pain are COMMONLY seen in patients taking acarbose.

23. Glucagon is the physiological antagonist to insulin made by alpha cells of the pancreatic islet. Is glucagon often elevated in patients with Type 2 diabetes?

24. How does exenatide work? Adverse effects? Receptor binding sites.

25. Incretin mimetics. Adverse effects? Mechanism of action?

26. DPP-IV inhibitors. Adverse effects? Mechanism of action?

Thyroid Lecture Review Questions

REQUIRED READING: THYROID AND ANTI-THYROID DRUGS
Katzung’s Basic and Clinical Pharmacology
11th edition
Chapter 38, pp. 665-680.


After this lecture, you should be able to answer the following:

1. What is the chemical name for the three hormones secreted by the thyroid gland? Can you draw the structures of T3? T4? Where do the ‘iodides’ come from? Are they synthesized by the body? Are they derived from the diet? What is the RDA of iodide in the diet?

2. Describe the biosynthesis of thyroid hormones. Make sure to use terms like iodide trapping, thyroidal peroxidase, tyrosine, MIT, DIT, thyroglobulin, proteolysis of thyroglobulin. What is the ratio of T4 to T3 on thyroglobulin? Which of these is released to a higher degree from the thyroid gland? Which of the two is the more active hormone? How is T4 converted to T3 in the periphery?

3. What are the two chemical activities of thyroidal peroxidase? Compared to T4 and T3, what is the biological activity of rT3? What is the half life of T4? T3? Describe the possible metabolic fates of T4 after it is released from the thyroid gland. Describe the relationship among the thyroid gland, the hypothalamus, and the pituitary gland.

4. What are the relevant ADME pharmacokinetic parameters of T3 and T4? For example, which is better absorbed? Are there factors that can affect absorption? Which has the longer half-life?

5. What is the net effect of an ‘activating’ mutation of the TSH receptor? Provide an example of an abnormal thyroid stimulating agent.

6. What happens to T4 when it enters the cell? What is 5’deiodinase? What kind of receptors are thyroid hormone receptors? For example, are they transmembrane spanning receptors? What other types of receptors are related to thyroid receptors? How is it that T3 causes cells to utilize ATP? What ATPase is induced by T3? Can T4 bind to T3 receptors?

7. What are the normal physiological effects of thyroid hormones? What happens to these effects in the hyperthyroid state? Remember to detail the effects of the hyperthyroid state on skin, eyes, cardiovascular system, respiratory, GI, CNS, musculoskeletal, renal, and hematopoietic systems as well as on metabolism. (See also Table 38-4 in your text for help).

8. What are ‘antithyroid agents?’ What are ‘goitrogens?’ How do the thioamides work to reduce the production of thyroid hormones by the thyroid gland? Can you describe three different thioamides that do this? Be sure to include relevant PK differences in your answer. Aside from inhibiting thyroidal peroxidase, what other enzyme is blocked by these agents (hint: it’s in the periphery). Discuss the pertinent pharmacokinetic properties of these thioamides. Do these agents have a fast or a slow onset of pharmacologic effect? What is the most common adverse reaction caused by these agents? What are some of the rare but serious adverse effects associated with these agents? Carbimazole is a prodrug? How does it work as an anti-thyroid agent? What are its most significant adverse effects? Based on its PK, would you recommend carbimazole over propylthiouracil in pregnancy? Why or why not?

9. What is Grave’s Disease? Is Grave’s Disease frequently associated with exophthalmus and swelling of the periorbital tissues?

10. What is ipodate? What is it’s mechanism of action? What are its most significant adverse effects?

11. What is the antithyroid mechanism of action of I-131 (radioactive iodine)? What is its half-life? Should it be used in pregnant patients? Why or why not?

12. What is the antithyroid mechanism of action of propranolol?

13. List three anion inhibitors of the Na+/I- transporter? Why do such agents have antithyroid activity?

14. How do iodides work to block thyroid function? What is the proposed mechanism of iodide’s antithyroid actions? Why might iodides be helpful in preoperative preparation for surgery?

15. How does guanethidine work as a potential anti-thyroid agent? Does it have direct effects on th thyroid gland?

16. What are some of the clinical manifestations of hypothyroidism? What is Hashimoto’s thyroiditis? What is ‘cretinism?’ What is ‘myxedema?’

17. Describe the types of synthetic and animal-derived thyroid hormones available for replacement therapy. What is the preparation of choice for thyroid replacement therapy?

How might drugs like lithium or amiodarone affect levels of T4 in the body (Hint: see Table 38-3).

18. What is ‘thyroid storm?’ What is the presenting syndrome? Which pharmacological agents can be used to treat thyroid storm? What is the rationale behind using each of those reagents?

19. Describe the functional domains of the thyroid hormone receptor? What is the mechanism of thyroid hormone action? Can genes be both activated or inhibited by thyroid hormone?

20. What is a microarray DNA chip?

B-adrenergic Receptor Antagonists

Leftover question from alpha antagonists:How is tamsulosin different from the other alpha1 inhibitors?

Required Readings:
Katzung, 11th edition- Chapter 10
1. Know the receptor-specificities and therapeutic uses of the following beta-adrenergic blockers:

metoprolol, propranolol, timolol

2. Which of the beta-blockers was found to increase the life span (by protecting the myocardium)?

3. Which of the beta-blockers above are nonselective B1 and B2-blockers? Which of these blockers are B1-selective? Which ones not only block beta receptors but also block alpha1 receptors?

4. Which of the beta-blockers above are short-acting? Long acting? Which of them do not possess local anesthetic activity?

5. Why do beta-blockers have therapeutic effects against hypertension? glaucoma? Hyperthyroidism? What is thyroid storm? Can these agents also work to reduce migraine headaches? To reduce bleeding from esophageal varices in patients with cirrhosis of the liver?

6. What are the adverse effects of beta-blockers?

7. What is the bioavailability of propranolol administered orally? administered intravenously?

8. Why do patients taking beta blockers need to be tapered off them? Why not just stop "cold turkey?"

9. What is the relationship of beta blockers and renin? Beta blockers and the CNS? Does propranolol trigger any adverse CNS effects?

10. What effect do beta blockers have on gluconeogenesis and glycongenolysis?