THE PHARMACOLOGIST

Vitamin D Boosts Calcium Potency: See Link For Interesting Article

2011-09-22T10:56:00.001-04:00

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

STUDENT QUESTION

2011-09-20T14:32:00.002-04:00

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

2011-09-20T07:10:00.001-04:00

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

Osteoporosis-Related Drugs

2011-09-15T17:49:00.001-04:00

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

2011-09-14T18:21:00.001-04:00

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

2011-09-13T19:02:00.000-04:00

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?

2011-09-08T19:47:00.000-04:00

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?

2011-09-08T18:59:00.001-04:00

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

2011-09-08T18:00:00.000-04:00

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

2011-09-08T07:18:00.000-04:00

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

2011-09-08T07:11:00.000-04:00

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

2011-04-29T05:25:00.000-04:00

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?

Adrenergic Agonists (Chapter 9) and Alpha Blockers (Chapter 10)

2011-04-20T09:00:00.001-04:00

Based on material presented today on the chalkboard.

1. Pharmacology of dopamine. How is it administered? What is its receptor affinity profile in the ANS? Explain the therapeutic uses of dopamine in the ANS. What is a potential serious adverse effect of dopamine? Does dopamine cross the blood brain barrier? How is the pharmacologic action of dopamine terminated? Which CYP450 metabolizes it?

2. Pharmacology of epinephrine. How is it administered? What is its receptor affinity profile in the ANS? What is the consequence of activating these kinds of receptors? Explain the therapeutic uses of epinephrine. Adverse effects? Does epinephrine cross the blood brain barrier? How is the pharmacologic action of epinephrine terminated? Which CYP450 metabolizes it? Why can't this drug be given orally? Should this drug be used in someone with narrow angle glaucoma? Why not?

3. Pharmacology of norepinephrine. How is it administered? What is its receptor affinity profile in the ANS? What is the consequence of activating these kinds of receptors? Explain the therapeutic uses of norepinephrine. Does this drug work as a bronchodilator? Why not? Adverse effects? Does norepinephrine cross the blood brain barrier? How is the pharmacologic action of norepinephrine terminated? Which CYP450 metabolizes it? Why can't this drug be given orally?

4. Pharmacology of albuterol. How is it administered (hint: three common ways)? What is its receptor affinity profile in the ANS? Explain the therapeutic uses of albuterol. Does this drug work as a bronchodilator? Why? Adverse effects? How is the pharmacologic action of albuterol terminated? Is it a catechol? Is it a substrate for COMT? What is its half life compared to epinephrine? Compared to salmeterol? Why is albuterol effective against bronchitis? Isn't bronchitis an inflammatory condition? Which patients should not take albuterol? Is it metabolized by COMT? MAO? the CYP450 system?

ALPHA BLOCKERS:

5. Know the receptor-specificities and therapeutic uses of the following alpha-adrenergic blockers (don’t forget about men with BPH):
phenoxybenzamine, prazosin, and tamsulosin.

Which receptor is blocked by yohimbine? Is it a well understood drug? Might it have efficiacy in people with sexual dysfunction? Is it still being investigated?

7. Back to alpha1. Pharmacology of phenoxybenzamine. List the therapeutic uses of phenoxybenzamine. Is it a reversible or an irreversible inhibitor of alpha1 receptor? Why does it work against pheochromocytoma? Why does it work to relieve the symptoms of BPH? Adverse effects? Is it considered long acting or short acting?

8. Pharmacology of prazosin. List the therapeutic uses of prazosin. Is it a reversible or an irreversible inhibitor of alpha1 receptor? Why does it work against hypertension? Why does it work to relieve the symptoms of BPH? Adverse effects? Is it considered long acting or short acting?

Pharmacology of terazosin(ter AY zoe sin). List the therapeutic uses of terazosin. Is it a reversible or an irreversible inhibitor of alpha1 receptor? Why does it work against hypertension? Why does it work to relieve the symptoms of BPH? Adverse effects? Is it considered long acting or short acting?

Pharmacology of doxazosin. List the therapeutic uses of doxazosin Is it a reversible or an irreversible inhibitor of alpha1 receptor? Why does it work against hypertension? Why does it work to relieve the symptoms of BPH? Adverse effects? Is it considered long acting or short acting?

What do we mean by the term "non-selective alpha1 inhibitor." Does that mean there is more than one type of alpha1 receptor? Why is the alpha 1a subtype important to BPH?

Chapter 9: Adrenergic Agonists

2011-04-20T06:41:00.000-04:00

Required Readings:
Katzung, 11th edition- Chapter 9

1. Discuss the effect of sympathetic stimulation in each of these target organs: eye, heart, blood vessels, bronchial smooth muscle, the GI tract, the genitourinary tract, the skin, the liver, the kidneys, and the adipose tissue. In each of these organs or tissues, which receptors mediate the responses? (REVIEW QUESTION FROM CHAPTER 6)

2. Describe the location, the structural features (ie. Ligand-gated vs. G-protein coupled) and the postreceptor mechanisms of the three major types of beta-adrenergic receptors. (REVIEW QUESTION FROM Chapter 6)

3. Describe the location, the structural features (ie. Ligand-gated vs. G-protein coupled) and the postreceptor mechanisms of the two major types of alpha-adrenergic receptors. (REVIEW QUESTION FROM CHAPTER 6)

4. List all of the potential fates of norepinephrine after release from the adrenergic synapse. Make sure to describe things like, postsynaptic receptor activation, presynaptic receptor activation, uptake 1, uptake 2, re-packaging of NE, degradative enzymes (MAO-A; COMT).

5. What is the mechanism of action of amphetamine drugs?

6. What is the mechanism of action of cocaine?

7. With respect to amphetamines and cocaine, what happens to synaptic levels of norepinephrine?

8. With respect to alpha and beta receptors, what are the receptor affinity profiles for epinephrine? Norepinephrine? Isoproterenol?

9. Where are the alpha1 receptors located? Presynaptically? Postsynaptically? What second messenger(s) is (are) used by this receptor? What is the effector enzyme activated? Can you name two agonists of this receptor? Is phenylephrine an agonist of alpha1 receptors? Is prazosin an antagonist of alpha1 receptors?

10. Where are the alpha2 receptors located? Presynaptically? Postsynaptically? What second messenger(s) is (are) used by this receptor? What is the effector enzyme activated? Is clonidine an agonist of alpha2 receptors? Is prazosin an antagonist of alpha2 receptors?

11. Activation of all three subtypes, beta1, beta2 and beta3 results in activation of adenylyl cyclase and increased intracellular accumulation of cAMP. What G-protein is involved in this process? What effector enzyme?

12. In what way are the dopamine receptors (D1 specifically) part of the autonomic nervous system? What G-protein are they coupled to? What is the net effect of D1-receptor acvtivation? Do levels of cAMP within the cell increase or decrease?

13. In general, how would you define ‘sympathomimetic’ and what are these kinds of drugs used for?

14. What are the major effects of sympathomimetics on the pulmonary system? Use epinephrine as an example.

16. What is the difference among these types of sympathomimetics: direct-acting, indirect-acting, mixed-acting? List one example of each type.

17. Know the receptor-specificities and therapeutic uses of the following sympathomimetics:
Epinephrine, norepinephrine, isoproterenol, dopamine, dobutamine, phenylephrine, clonidine, metoproterenol, albuterol, ritodrine, terbutaline, amphetamine, and ephedrine.

18. adverse effect(s) of dobutamine? what happens after 1 week of continuous therapy with dobutamnine? Aside from B1, what other receptors can be activated by dobutamine (albeit to a lesser extent)?

19. adverse effects of ephedrine? (List both ANS effects and CNS effects). Contraindications of ephedrine? What is pseudoephedrine? Is ephedrine metabolized by COMT? What is ephedra and why was it banned?

20. Please make sure to do the assigned reading for today’s lecture.

STUDENT QUESTION: How is succinylcholine usually given?

2011-04-20T03:33:00.000-04:00

It is usually given IV. A summary of the dosing protocol can be found at the link below:

http://www.globalrph.com/succinylcholine_dilution.htm

STUDENT QUESTION: Is oxybutynin safe to use in pregnancy?

2011-04-20T03:24:00.000-04:00

Oxybutynin has been assigned to FDA pregnancy category B by the FDA. Animal reproductive studies have failed to reveal evidence of impaired fertility or fetotoxicity. There are no controlled data in human pregnancy. Therefore, oxybutynin is only recommended for use during pregnancy when benefit outweighs risk.

Chapter 8 Material: Cholinergic Antagonists

2011-04-15T07:00:00.000-04:00

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

1. There are three broad types of anticholinergic drugs. Can you name them?

2. What is atropine? Scopolamine? What is the classic description of atropine poisoning?

3. What is the approximate dissociation constant (Kd) for atropine at M1, M2, and M3 receptors? What about pirenzapine? Which of the two is considered M1-selective? Which of the two (atropine or pirenzapine) has a higher affinity for M1 receptors? Can you draw the structures of atropine? scopolamine? Pirenzapine? Talk about pirenzapine and peptic ulcers. Does atropine heal peptic ulcers?

4. What kinds of diseases/disorders are treated clinically with anticholinergics?

5. What is the mechanism of action of atropine and scopolamine?

6. There are potency differences between scopolamine and atropine. Explain.

7. What effect(s) do antimuscarinincs have in the eye? Should they be given to patients with glaucoma? Why not? What is mydriasis? Why are such agents sometimes called ‘bella-donna’ alkaloids?

8. What effect(s) do antimuscarinics have on the GI tract? The genitourinary tract? The lungs? What is enuresis? What effect(s) do antimuscarinics have on most glandular secretions?

9. Draw a graph depicting the effects of topical scopolamine drops on pupil diameter (mm) and accommodation (diopters) in the normal human eye (See Figure 8-3 in text). Note the extremely slow recovery.

10. List at least 5 antimuscarinic drugs used in ophthalmology and indicate the duration of their effect. How many days does the effect of atropine persist? Scopolamine? What are the adverse effects and contraindications of atropine? Scopolamine?

11. Aside from autonomic effects, what other effects can scopolamine have in patients? (Amnesia? Preventing motion sickness?) What does ‘prophylactic’ mean? [NOTE THAT DRAMAMINE, also known as dimenhydrinate, is a first-generation anti-histamine with anticholinergic action and anti-motion sickness activity]. Both scopolamine and dimenhydrinate are less effective against an episode of motion sickness already present.

12. What is ipratropium? Is it well-absorbed? How does it work? Against what disorders is it used?

13. What is propantheline used for? Is it well-absorbed? What is glycopyrrolate used for? Do you think it is well-absorbed? (See Figure 8-2).

14. NICOTINE- Depending on the dose, it first stimulates autonomic ganglia and then blocks the ganglia. Explain.

15. What is mecamylamine? Trimethaphan? What are some PK differences between the two? Which of these two is likely to be better absorbed? To be given iv? What receptor is blocked by agents like mecamylamine and trimethaphan?

16. What is the difference between depolarizing and nondepolarizing skeletal muscle blockers? Provide examples of each type.

17. Describe the metabolism of tubocurarine. Is it given orally? Parenterally?

18. Is succinylcholine a depolarizing skeletal muscle blocker? What is its main therapeutic use? What are the major potential adverse effects of succinylcholine? What is a laryngoscope?

STUDENT QUESTION: Can marijuana be used to treat glaucoma?

2011-04-14T02:08:00.000-04:00

There are data to support a use for marijuana in this setting. However, far more efficacious drugs, with fewer side effects, are available. See the attached link for more info:

http://books.nap.edu/openbook.php?record_id=9586&page=124

-Dr Billack

Chapter 7 Material: Cholinergic Agonists

2011-04-13T16:00:00.002-04:00

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

1. What are the major groups of cholinoceptor-activating drugs, receptors, and target tissues? (See Fig. 7-1 from Textbook). What is the difference between a reversible acetlycholinesterase inhibitor and an irreversible cholinesterase inhibitor? Provide 5 examples of direct-acting choline esters. Are they well absorbed? Why not? Are carbamic acid, carbachol, and bethanechol more or less sensitive to hydrolysis by acetylcholinesterase than acetylcholine? What is the pharmacological effect of the beta-methyl groups on methacholine and bethanechol? Which of the choline esters are able to activate both nicotinic and muscarinic receptors? What are the major clinical uses of the choline esters?

2. Discuss the effect of parasympathetic stimulation in each of these target organs: eye, heart, blood vessels, bronchial smooth muscle, the GI tract, the genitourinary tract, the skin, the liver, the kidneys, and the adipose tissue. In each of these organs or tissues, which receptors mediate the responses?

3. What are some of the pharmacological properties of the choline esters? Which ones are mostly-muscarinic? What is pilocarpine? How does that work? (see notes from blackboard) What is its mechanism of action? Why is that drug given topically rather than orally? What other pharmacologic options are out there for the treatment of glaucoma?

4. Discuss the physiology of the eyes. Why is the ciliary body important? Muscarinic agonists and AchE inhibitors reduce intraocular pressure (IOP) by contracting the ciliary body and enhancing fluid outflow. Explain. Beta-adrenergic blockers may also reduce secretion of aqueous humor by the ciliary epithelium. Explain.

5. List one reversible, short-acting, AchE inhibitor.

6. List three reversible, longer-acting, AchE inhibitors. Which one is likely to be better-absorbed, neostigmine or physostigmine?

7. List three irreversible AchE inhibitors.

8. What is meant when we say that the irreversibly-bound AchE has ‘aged?’ What are organophosphates? What is pralidoxime? What is 2-PAM? How does it (2-PAM) work? What are some of the signs and symptoms of cholinergic poisoning?

9. With respect to absorption, what difference exists between reversible, charged, species like neostigmine and irreversible, noncharged, species like parathion?

10. What are the typical uses for the indirectly-acting cholinergic agonists? What is myasthenia gravis? Is it a disorder of the Autonomic Nervous System? Somatic Nervous System? What is the rationale for using cholinomimetic agents to treat this disease?

11. What is echothiophate? Is it used clinically? What is sarin? Is it used clinically?

12. What are the signs of muscarinic excess? What about CNS effects? What about peripheral effects? Why is cholinergic excess life-threatening if untreated?

13. What are the therapeutic uses and durations of action of: edrophonium, neostigmine, physostigmine and echothiophate (See Table 7-4 in textbook)?

14. With respect to nicotinic acetylcholine receptors, what is ‘depolarizing blockade?’

15. (from the chalkboard). What is the clinical indication for nicotine? What is the mechanism of action of nicotine? What are the effects of nicotine upon: adrenal medulla, cardiac muscle, vasculature, and the GI tract? major side effects of nicotine? How is nicotine metabolized?

16. (from the chalkboard). What is the clinical indication for pilocarpine? What is the mechanism of action of this drug? What are the effects of pilocarpine upon: the eyes? salivary glands?

17. What other classes of drugs are used to treat glaucoma?

Chapter 6: Autonomic Nervous System (cont). and Chapter 7: Cholinergic Drugs

2011-04-08T06:02:00.000-04:00

After today's lecture you should be able to answer the following:

1. Discuss the effect of sympathetic stimulation in each of these target organs: eye, heart, blood vessels, bronchial smooth muscle, the GI tract, the genitourinary tract, the skin, the liver, the kidneys, and the adipose tissue. In each of these organs or tissues, which receptors mediate the responses?

2. Discuss the effect if parasympathetic stimulation in each of these target organs: eye, heart, blood vessels, bronchial smooth muscle, the GI tract, the genitourinary tract, the skin, the liver, the kidneys, and the adipose tissue. In each of these organs or tissues, which receptors mediate the responses?

3. Describe the location, the structural features (ie. are they G-protein coupled?) and the postreceptor mechanisms of the three major types of muscarinic acetylcholine receptors.

4. Describe the location, the structural features (ie. are they G-protein coupled?) and the postreceptor mechanisms of the three major types of beta-adrenergic receptors.

5. Describe the location, the structural features (ie. are they G-protein coupled?) and the postreceptor mechanisms of the two major types of alpha-adrenergic receptors.

6. Describe the physiology and the pharmacologically-relevant aspects of the cholinergic synapse. Start from choline. Don’t forget about VAMPs and SNAPs and voltage-gated calcium channels. How do hemicholinium drugs work? How does vesamicol work? How does botulinum toxin work? What is acetylcholinesterase?

7. Describe the physiology and the pharmacologically-relevant aspects of the adrenergic synapse. Don’t forget about VMAT and reuptake 1 and 2. Start from tyrosine. Know how each of the following drugs work: metyrosine, reserpine, bretylium, guanethidine. What is the overall effect of NE levels in the synapse in response to cocaine?

8. List four drugs that are cholinoceptor-activating. List three drugs that are cholinesterase inhibiting.

9. Where are the cholinergic systems in the body found? Talk about acetylcholine receptors. Are there well known-antagonists? What are they? What is the difference in the neuronal-type versus the muscle-type of nicotinic receptors?

10. What are the intracellular events mediated by the muscarinic receptors? Which G-proteins are they coupled to?

11. What are the major groups of cholinoceptor-activating drugs, receptors, and target tissues? (See Fig. 7-1 from Textbook). What is the difference between a reversible acetlycholinesterase inhibitor and an irreversible cholinesterase inhibitor? Provide 5 examples of direct-acting choline esters. Are they well absorbed? Why not? Of the five, which is most likely to be absorbed? Are carbamic acid, carbachol, and bethanechol more or less sensitive to hydrolysis by acetylcholinesterase than acetylcholine? What is the pharmacological effect of the beta-methyl groups on methacholine and bethanechol? Which of the choline esters are able to activate both nicotinic and muscarinic receptors? What are the major clinical uses of the choline esters?

12. Please make sure to do the assigned reading for today’s lecture.

Chapter 6: Intro to the Autonomic Nervous System

2011-04-08T06:00:00.001-04:00

Required Readings:
Katzung, 11th edition- Chapters 6/7

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

1. Describe the organization of the autonomic nervous system to your study partner. Is it an efferent system? Is it part of the Peripheral Nervous system? What are the three branches of the autonomic nervous system?

2. What is a synapse? In your answer, refer to things like…. Presynaptic cell, postsynaptic cell, synaptic cleft. In the next lecture, we will discuss 'synapse-relevant' issues such as voltage-gated calcium channels, vesicles, exocytosis, and degradative enzymes.

3. Describe the anatomy of the sympathetic nervous system. Is the ganglion close to the spinal cord? Far away from the spinal cord? What is a ganglion? Is the preganglionic fiber longer or shorter than the postganglionic fiber? What tissues are innervated by the sympathetic nervous system? Why is the adrenalla medulla sometimes called a ‘modified sympathetic ganglion?’ In sympathetic ganglia, what neurotransmitter is released by the preganglionic axon terminal? What receptor on the surface of the postganglionic cell is activated by that neurotransmitter? Is that receptor a ligand-gated ion channel? What ion can cross that channel? What transmitter(s) are released by the postganglionic axon terminus? The is the consequence of that transmitter being released onto a target cell?

4. What do we mean when we say ‘the viscera?’

5. Describe the anatomy of the parasympathetic nervous system. Is the ganglion close to the spinal cord? Far away from the spinal cord? Is the preganglionic fiber longer or shorter than the postganglionic fiber? What tissues are innervated by the parasympathetic nervous system? In the parasympathetic ganglia, what neurotransmitter is released by the preganglionic axon terminal? What receptor on the surface of the postganglionic cell is activated by that neurotransmitter? Is that receptor a ligand-gated ion channel? What ion can cross that channel? What transmitter(s) are released by the postganglionic axon terminus? To what kinds of receptors can these transmitters bind to and activate in target organs?

STUDENT QUESTION: How does morphine-6-glucouronide, a supposed very polar Phase 2 metabolite, get into the brain?

2011-04-01T13:07:00.000-04:00

See the attached file for your answer... very interesting!

"Morphine 6-glucuronide and morphine 3-glucuronide as molecular chameleons with unexpected lipophilicity"

http://pubs.acs.org/doi/abs/10.1021/jm00108a005

Chapter 4: Biotransformation

2011-04-01T05:00:00.000-04:00

Required Readings:
Katzung, 11th edition- Chapter 4

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

1. The liver is tremendously important for the metabolism of drugs. In this regard, the role of the liver is to convert the drug into a more water-soluble compound. How does the liver fulfill this role? Explain.

2. Is lipophilicity a barrier to drug excretion? Why? How does lipophilicity relate to passive reabsorption by the renal tubular membranes?

3. What is the net effect of hepatic metabolism? In other words, are the hepatic metabolic reactions ‘inactivating’ or ‘activating?’ Are partially-active metabolites sometimes observed? What is a prodrug? Is it activated or inactivated by metabolism?

4. What are some characteristics of Phase I metabolic reactions? Within the hepatocytes, where do Phase I reactions occur? What do you mean by ‘microsomes?’ What is the fate of Phase I reaction products? Can some of them be polar enough to be excreted directly into the urine? What about those Phase I reaction products that are more polar than the parental drug, but not polar enough to go directly into the urine? What can then happen to those?

5. What are the characteristics of Phase II metabolism? What are the names of the polar endogenous molecules that can be conjugated to Phase I metabolites? What are the names of the specific enzymes that attach each of these conjugating molecules? Within the hepatocytes, where do Phase II reactions occur? What about glucuronidation? Where does that occur? What about sulfation? In the nucleus? The lysosome? Where?

6. Are most Phase II conjugates generally water-soluble, inactive, and rapidly excreted in the urine? Can you identify at least one drug which is an exception to this general rule?

7. What happens to high molecular weight Phase II conjugates? Do they get excreted by the kidney? What is the role of the gut flora in the enterohepatic recirculation of drugs such as morphine? Estrogen?

8. What is ‘first-pass’ metabolism? Provide examples of drugs that exhibit high ‘first-pass’ effects. Why is it that drugs like insulin or sympathomimetic catecholamines cannot be given orally?

9. Are there any drugs that can enter Phase II metabolism before Phase I? Can you name one such drug? (See Figure 4-2 in your text).

10. List five specific examples of Phase I metabolic reactions. Draw structures before and after.

11. What is a mixed-function oxidase? Where does the O2 go (O2=molecular oxygen)? What family of enzymes with mixed-function oxidase activity is intricately involved in Phase I metabolism? What is the 7-step reaction mechanism involved in the oxidation of substrates by these mixed-function oxidases? Where do the electrons come from? What coenzyme? Are both CYP450 and NADPH-Cytochrome P450 Reductase both microsomal enzymes?

12. List six specific examples of Phase II conjugation reactions. Let’s now focus on three of these reactions in a little more detail. Draw the structures before and after glucuronidation, sulfation, and glutathione conjugation reactions. Make sure to name the enzyme and to draw the endogenous reactant. (This question is somewhat related to question 5—see above). What is phosphoadenosylphosphosulfate (PAPS)? For which Phase II reaction is PAPS a cofactor?

13. Describe the biotransformation of acetaminophen. What happens when someone takes too much of this agent? What is CYP2E1? What is the predominant toxicity of acetaminophen? Why give a person who overdosed on acetaminophen a drug like N-acetylcysteine?

14. What do we mean by ‘rapid’ or ‘slow’ acetylators? Does genetics play a role in whether or not a patient will be a rapid or slow acetylator? Would it matter to a TB patient being treated with isoniazid if s/he was a ‘rapid’ or ‘slow’ acetylator? Why or why not?

15. What is a drug-drug interaction? Describe at least two hypothetical drug-drug interactions.

16. What is the primary extrahepatic site containing CYP450 enzymes? Are all drugs metabolized in that extrahepatic site? (NO! Most will be metabolized in the liver, but some drugs can be metabolized in the intestine. For ex., sympathomimietic catecholamines).

17. What are the major CYP450 isoforms used in drug metabolism by humans? Which of these CYP450 isoforms has been observed to be polymorphic? In other words, which of these isoforms exhibit ‘poor metabolizer/extensive metabolizer’ phenotypes. Which race/ethnicity has been shown to exhibit a large percentage of poor metabolizing ability via CYP2D6? CYP2C19?

18. With respect to CYP450s, what are some dietary factors that can affect drug metabolism?

19. Which of the CYP450s are induced by agents like carbamazepine? Phenobarbital? Phenytoin? Which of the CYP450s are inhibited by competitive inhibitors like cimetidine? Ketoconazole? Which CYP450 is inhibited by chloramphenicol in an irreversible manner? What are drugs like cimetidine, ketoconazole, and chloramphenicol used for? Might coadministration of a drug like ketoconazole with a drug like venlafaxine (a CYP3A4 substrate and antidepressant agent) result in a drug-drug interaction? Why?

20. Please make sure to do the assigned reading for today’s lecture.

Interesting Article About Albumin- NOT REQUIRED

2011-03-30T12:10:00.000-04:00

Here's an interesting article for the student who is curious about albumin:

http://www.nlm.nih.gov/medlineplus/ency/article/003480.htm

ENJOY!

-Dr Billack

STUDENT QUESTION: How does blocking the Na+/K+ ATPase lead to an increase in cardiac contractility?

2011-03-30T12:05:00.000-04:00

Answer:
(Obtained from Tintinalli's Emergency Medicine Chapter 174. Digitalis Glycosides written by William Dribben, Mark A. Kirk)

"Digitalis has a narrow therapeutic-toxic margin. Toxicity results from an exaggeration of its therapeutic actions. Digitalis binds to a specific receptor site on the cardiac cell membrane, inactivating the Na+K+ATPase pump. This pump concentrates sodium extracellularly and potassium intracellularly to maintain the electrochemical membrane potential vital to conduction tissues. When Na+K+ATPase is inhibited, the sodium-calcium exchanger removes accumulated intracellular sodium in exchange for calcium. This exchange increases sarcoplasmic calcium and is the mechanism thought to be responsible for the positive inotropic effect of digitalis. Inhibition of the Na+K+ATPase pump also results in an increase in extracellular potassium. Other potential mechanisms accounting for increased cytosolic calcium resulting in increased inotropic and/or toxic effects may be due to actions directly at calcium channels on the sarcoplasmic reticulum or via activation of the ryanodine receptor."

Did that help?

Chapter 3: Introduction to Pharmacokinetics

2011-03-30T06:19:00.000-04:00

Required Readings: Katzung, 11th edition- Chapter 3

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

1. What is ADME? Explain why understanding the ADME of a drug is relevant to therapeutics. Why is the ‘standard dose’ of a drug not suitable for all patients?

2. What is ‘clearance?’ What is ‘the volume of distribution?’ What does it mean if a drug has a high Vd? Low Vd? How is Vd related to half-life? What are some factors that can affect the Vd of a drug?

3. Draw a graph showing the drug concentrations in blood after a single injection of a drug at time zero. Make sure to indicate the distribution phase and the elimination phase. Correctly label each axis.

4. Discuss the elimination of drugs by the kidney. Explain the nephron and where drugs can enter the nephron. Under normal circumstances, do drugs bound to plasma proteins enter into the nephron?

5. What kinds of factors can alter the clearance of a drug? Explain.

6. What is capacity-limited elimination? Do most drugs get eliminated this way? Name some drugs that are eliminated this way?

7. What is enterohepatic cycling? What essential nutrients undergo this cycling? What types of drugs can undergo this cycling (ANSWER: steroids (such as estrogen), digoxin,vitamin A, bile acids, come chemotherapeutic agents).

8. What is first-order elimination kinetics?

9. What is the ‘half-life’ of a drug? What are the equations that can be used to calculate the ‘half-life’? What are factors that can affect the half-life of a drug?

10. How many half-lives are needed to achieve the steady-state? WHAT IS THE STEADY STATE?

11. What is a loading dose? What equation do you use to calculate the loading dose? Work out the example in the slide packet to help you learn the concept.

12. What is Bioavailability? (VY IMPORTANT CONCEPT)

13. What are the other routes of administration? Why are other routes of drug administration necessary? (ie. why can’t we just give all drugs as an oral tablet??) Know the advantages and disadvantages of the routes of administration as well as examples of drugs that can be administered via those different routes.

14. What is the “first-pass” effect? How is Bioavailability determined?

15. What are some of the major plasma proteins important for drug binding?

16. What is a “maintenance dose” ? Understand the formula and how to use the formula to calculate a maintenance dose for a drug.

17. Please make sure to do the assigned reading for today’s lecture.

Lecture 4: Introduction to Pharmacodynamics, continued

2011-03-25T06:00:00.000-04:00

Required Readings:
Katzung, 11th edition- Chapter 2

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

1. What is ‘receptor desensitization?’ Describe a possible mechanism for desensitization of the beta-adrenergic receptor.

2. What happens to receptors after they are internalized? Compare and contrast the fate of internalized EGF receptors to internalized beta-adrenergic receptors. Are all receptors internalized or just certain types like receptor tyrosine kinases and beta receptors? What is the difference between ‘desensitized’ beta receptors and ‘downregulated’ beta receptors?

3. List the major second messengers used in the pharmacological resposes of cells to drugs.

4. List several receptors that activate adenylyl cyclase via Gs? What is the effect of increased cAMP levels within the cell on cAMP-dependent protein kinase? How does that kinase work?

5. Describe three mechanisms by which cAMP-signaling is terminated in cells. Which of these mechanisms is inhibited by methylxanthines like theophylline or caffeine? In the presence of drugs like theophylline, therefore, is cAMP-dependent protein kinase activity inhibited? Why or why not?

6. List several receptors that inhibit adenylyl cyclase via Gi? What is the effect of decreased cAMP levels within the cell on cAMP-dependent protein kinase? When this kind of receptor is activated, is there even less cAMP-dependent kinase activity than before the drug bound to and activated it? What effect does Gi activation have on cardiac K+ channels?

7. List several receptors that activate phospholipase C (PLC) via Gq. What is the effect of increased IP3 levels on cytoplasmic Ca++? From what organelle does that Ca++ come from? What is calmodulin? What is Ca++/Calmodulin-dependent protein kinase? What is the effect of increased DAG levels on Protein Kinase C (PKC)? Describe three mechanisms by which signaling via Gq-protein coupled receptors be terminated?

8. What are the physiological consequences of increased cellular levels of cGMP? Do all cells use cGMP? What is cGMP-dependent protein kinase? How are the actions of cGMP terminated in these cells?

9. Why should we be concerned with ‘substrate phosphorylation?’ Does substrate phosphorylation result in cell-signaling events? What happens when things get phosphorylated? Can cAMP cause ‘activating’ phosphorylations and ‘inactivating’ phosphorylations? To answer this question, tell your study partner about the phosphorylation of glycogen synthase and phosphorylase kinase by cAMP-dependent protein kinase in liver.

10. One drug can have multiple different receptors. Explain. List some examples.

11. What is the difference between graded dose-response curves and quantal dose-response curves. Why are ‘doses’ used in animals and humans (in vivo) and ‘concentrations’ used in cells and tissues (in vitro)? What is the subtle difference between the EC50 and the ED50?

12. What is drug potency? What is maximal efficacy?

13. People respond to the therapeutic effects of drugs in a Gaussian normal distribution. People respond to the toxic effects of drugs in a Gaussian normal distribution? What is the TD50? What happens when the dose-response curve for therapeutic effects significantly overlaps with the dose-response curve for toxic effects? What is the therapeutic index of a drug?

14. Individuals may vary considerably in their responsiveness to a drug. What are some of the different responses observed in patients in response to drug therapy.

15. What are the four general mechanisms that can contribute to drug responsiveness among patients? (HINT: SEE TEXTBOOK p. 32-33).

16. Describe how the anti-breast cancer drug tamoxifen can achieve beneficial and toxic effects by binding to the same receptor in different tissues.

17. Describe how the antihypertensive drug prazosin can achieve beneficial and toxic effects by binding to the same receptor in the same tissue.

18. What is orthostatic intolerance? How does that differ from orthostatic hypotension? What is postural hypotension?

19. Please make sure to do the assigned reading for today’s lecture.

Lecture 3: Introduction to Pharmacodynamics, continued

2011-03-23T11:00:00.000-04:00

Required Readings:
Katzung, 11th edition- Chapter 2

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

1. Why do some drugs produce effects that last for minutes, hours, or even days after the drug is no longer present?

2. How do cellular mechanisms for amplifying external chemical signals explain the phenomenon of spare receptors?

3. How is most transmembrane signaling by drugs accomplished? Are there infinite possibilities or just a few different molecular mechanisms? What two general types of receptors found in cells [HINT: cell surface receptors (also known as ‘transmembrane’) and intracellular receptors]. Ask yourself, ‘what kind of receptor is this?’ Lastly, describe five basic mechanisms of transmembrane signaling.

4. Many hormones and drugs are able to diffuse into cells and cross the cell membrane to activate intracellular receptors. What specific kinds of agonists were discussed in class that work in this manner?. Describe the signaling mechanisms induced by two of these agonists (These examples are also in your text).

5. With respect to the glucocorticoid hormone receptor-mediated signaling pathway, what is heat shock protein 90? How does the activated glucocorticoid receptor alter the transcription of specific genes? Are the pharmacological effects of glucocorticoids immediate? Delayed? Why?

6. What are receptor tyrosine kinases? How do the sit in the plasma membrane? What are the important domains involved with these receptors? List at least three or four of the well-known receptor tyrosine kinases. How do these receptors respond to occupancy by drug agonists? Do they undergo conformational changes and dimerization? What else happens? Talk about the tyrosine kinase portion of the receptors. What is receptor downregulation? (Use the EGF receptor as an example to illustrate this concept) Talk about the role of vesicles in receptor downregulation. NOTE: receptor downregulation is NOT receptor desensitization!!

7. What is special about the intracellular enzymatic domain of the receptor for atrial natriuretic factor? Is it a receptor tyrosine kinase? Why or why not?

8. What are receptor serine-threonine kinases? How do they sit in the plasma membrane? Describe what happens when the TGF-beta receptor is activated. What are smad proteins? What happens to smad proteins when the receptor is activated? Are the pharmacological effects of TGF-beta immediate? Delayed? Why?

9. What are cytokines? What are cytokine receptors? Do they have extracellular and intracellular domains? Do they form dimers in response to drug binding? Describe the JAK-STAT signaling pathway to your study partner.

10. The nicotinic acteylcholine receptor is an example of a ligand-gated transmembrane ion channel that can be induced to open by ligand binding. What other types of ligand-gated ion channels are found in nature? Describe the nicotinic acetylcholine receptor in detail. How many polypeptide subunits does it have and what are they called? How are those subunits arranged in the membrane? Are the pharmacological effects of ligand-gated ion channels immediate? Delayed? Why? What coupling molecules are involved in the signaling induced by ligand-gated ion channels?

11. What are G-proteins? Are they receptors? Are they coupling molecules? To what kind of receptors are they coupled? Are they activated by agonist binding? When G-proteins are activated (by drug binding to the receptors), are they bound to GTP? What happens to effector molecules in the presence of activated G-proteins? What are the major types of G-proteins? The major effectors of each G-proteins? How are G-proteins inactivated?

12. Please make sure to do the assigned reading for today’s lecture.

Lecture 2: Introduction to Pharmacodynamics

2011-03-18T06:00:00.000-04:00

Required Readings:
Katzung, 11th edition- Chapter 2
POWERPOINT SLIDES FOR LECTURE 2

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

1. Many drug receptors happen to be proteins. Why do proteins make good receptors?

2. What are the major categories of protein receptors? Provide examples of each of the different categories of protein receptors as well as the drugs discussed in lecture which work by binding to those receptors.

3. What is the difference between in vitro pharmacology and in vivo pharmacology?

4. In idealized or in vitro systems, the relationship between drug concentration (C) and effect (E) is best described by a hyperbolic curve according to what equation?

5. What is a concentration-effect curve? What important aspects of the curve tell you something about a particular drug?

6. In idealized or in vitro systems, the relationship between drug bound to receptors (B) and the concentration of unbound drug (C) is best described according to what equation? Draw a graph depicting the percentage of drug bound to receptors versus drug concentration. What important aspects of the curve tell you something about a particular drug?

7. If the Kd of an agonist is low, binding affinity of drug for receptor is high. Explain.

8. What are ‘spare receptors?’ Are all receptors ‘spare?’ How can you experimentally determine whether or not a particular tissue contains spare receptors? Name at least one tissue that has a high percentage of spare receptors.

9. What is signal transduction? What is receptor-effector coupling? What are coupling molecules? What is a receptor? What is an effector? Do all receptors use coupling molecules? Is it possible that some receptors can also be the effectors of drug action?

10. What are antagonists? What types of antagonists exist? How do antagonists work? Do they bind to and activate receptors? What is the major difference between the two types of antagonists?

11. True or False? In competitive antagonism, the presence of antagonist increases the agonist concentration required for a given degree of response, and the agonist concentration-effect curve shifts to the right. Draw a concentration-effect plot for a full agonist. On the same graph, plot the concentration-effect plot for a full agonist in the presence of a fixed concentration of competitive antagonist.

12. What is the Schild equation? What is KI?

13. What is the difference between an irreversible antagonist and a insurmountable antagonist? (Hint: The answer is “none.”) Draw a concentration-effect plot for a full agonist. On the same graph, plot the concentration-effect plot for a full agonist in the presence of a fixed concentration of irreversible antagonist.

14. The duration of action of an irreversible antagonist is relatively independent of its own rate of elimination and more dependent upon the rate of turnover of receptor molecules. Explain.

15. Why is phenoxybenzamine used to treat pheochromocytoma?

16. What is the difference between a full agonist and a partial agonist?

17. As compared with full agonists, partial agonists produce concentration-effect curves that resemble those with full agonists in the presence of an antagonist that irreversibly blocks receptor sites. Explain.

18. Draw a graph depicting the percentage of receptor occupancy resulting from full agonist (present at a single concentration capable of binding all receptors) binding to receptors in the presence of increasing concentrations of a partial agonist.

19. Draw a concentration-effect curve depicting simultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist. Make sure to indicate the Emax value on the graph.

20. What is chemical antagonism? Provide at least one example.

21. What is physiological antagonism? Provide at least one example. What is bradycardia?

Please make sure to do the assigned reading for today’s lecture.

Lecture 1: Introduction to the Subject of Pharmacology

2011-03-16T02:05:00.000-04:00

Required Readings:
Katzung, 11th edition- Chapter 1

Recommended Readings:
STANLEY SCHEINDLIN
A brief history of pharmacology
http://pubs.acs.org/subscribe/journals/mdd/v04/i05/html/05timeline.html

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

1. How can ‘pharmacology’ be defined?

2. Outline the history of pharmacology. Who is considered the ‘father’ of modern pharmacology? What University did he work for?

3. Define what a ‘drug’ is. What is a ‘receptor’ molecule? Other than receptors, what else can a small number of drugs interact with to elicit therapeutic effects?

4. What features concerning the physical nature of drugs will impact pharmacological activity? (For example, does the size of the drug matter? Why or why not?)

5. How do drugs interact with receptors? What are the three major types of these chemical forces or bonds? Give some examples of the strongest type of drug-receptor interactions. What is the strongest type? Hmm… is that the most common type of interaction observed with drugs and receptors? Does the covalent-bound drug readily dissociate from the receptor?

6. How does the phenomenon of ‘chirality’ affect the pharmacological actions of drugs? First of all, what is chirality? Can you provide several examples of chiral drugs in which one enantiomer is more potent than the other?

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8. What is the difference between pharmacodynamics and pharmacokinetics?

9. What is an agonist drug? Explain what we mean when we say, ‘Whereas some receptors incorporate effector machinery in the same molecule, other receptors are linked through one or more intervening coupling molecules to a separate effector molecule” What is an antagonist drug? Does an antagonist bind to and activate a receptor?

10. How is the termination of drug action at the receptor level achieved?

11. What is the difference between a receptor and an inert binding site like plasma albumin?

12. A drug should be able to reach its intended site of action after administration by some convenient route. How can drugs permeate, or move across, the various barriers that separate body compartments? Describe each of the four mechanisms by which drugs permeate throughout the body.

13. What is “Fick’s Law of Diffusion?”

14. What is the difference between a weak acid and a weak base? Do many drugs fit into one of these two categories? Do all drugs fall into one of these categories?

15. Can you derive the Henderson-Hasselbalch equation? Assume that the weak acid propylthiouracil (a drug used to treat overactive thyroid disorders) has a pKa of 8.3and that the pH of the duodenum is 6.0. Will the drug be mostly protonated or unprotonated in the upper gut? What does that mean with respect to absorption?

16. What are the pH ranges of some of the different body compartments?

17. Please make sure to do the assigned reading for today’s lecture.

THE PHARMACOLOGIST

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