Irbesartan

Nicole P. Albanese PharmD, CDE, BCACP

Clinical Assistant Professor, Department of Pharmacy Practice, University at Buffalo, School of Pharmacy and Pharmaceutical Sciences
Clinical Pharmacist in Ambulatory Care, Buffalo Medical Group, Buffalo, New York

http://pharmacy.buffalo.edu/content/pharmacy/faculty-staff/faculty-profile.html?ubit=npaolini

According to their structure blood glucose 10 order irbesartan 150mg otc, prodevelopment of coronary heart disease was 48 gestogens differ largely in their antiestrogenic reported in women with high risk factors diabetes insipidus after pituitary surgery buy irbesartan 300 mg fast delivery. This the androgenic activity of a progestin which may is believed to be the physiological basis for the counteract the direct effects of estrogens on the increase in breast cancer risk during long-term arterial wall gestational diabetes test questions order generic irbesartan canada. Recent epidemiological studies regulate the thrombin receptor on vascular 236 found an increase in the relative risk by 20–30% smooth muscle cells blood sugar testing irbesartan 300mg online. In this regard, progestins with androgenic 332 this mechanism may also be involved in the activity. ProgesSource of funding the publication of this paper tins may also modify the estrogen-induced has been supported by Novo Nordisk Pharma. Treatment of hot ﬂashes with transdermal Demonstration of estrogen receptor subtypes a estradiol administration. J Clin Endocrinol and b in human adipose tissue: inﬂuence of Metab 1985;61:627–32 adipose cell differentiation and fat depot 2. Estrogen Climacteric 2001;4:194–202 receptor, a common interaction partner for a 6. Am J Effects of pulsed or continuous estradiol Obstet Gynecol 2001;185:1325–31 administration on proliferation of normal and 50 Climacteric Pharmacology of estrogens and progestogens Kuhl tumoral human breast cells (Abstract). Menosteroids to both testosterone-binding globulin pause 1999;6:362 and corticosteroid-binding globulin in human 12. Estrogen replacement therapy after tion of tritium labelled estrogens in human the menopause. Biologic effects of equilin sulfate in postmenothe gut wall metabolism of ethinyloestradiol pausal women. Br J Clin rate of equilin sulfate and its conversion to Pharmacol 1982;13:325–30 plasma equilin, conjugated and unconjugated 28. Estrogens and menopause: phar1986;62:761–6 macology of conjugated equine estrogens and 30. Phartheir potential role in the prevention of macokinetics and biotransformation of orally neurodegenerative diseases such as Alzheimer’s. Menopause Rev 2000;5/3–4:23–44 Bioavailability of norethisterone acetate alone 19. Functional role of and in combination with estradiol administered estrogen metabolism in target cells. Carcinoin single or multiple oral doses to postgenesis 1998;19:1–27 menopausal women. New concepts of Int J Clin Pharmacol Ther 2001;39:41–6 estrogenic activity: the role of metabolites in 33. Drug Res transdermal estrogen therapy and the effect 1993;43:966–73 on androgens and sex hormone blinding 23. Plasma women undergoing three common estrogen estradiol concentrations and pharmacokinetics replacement therapies: association with sex following transdermal application of Menorest hormone-binding globulin, estradiol, and es50 or Systen /Evorel) 50. Drug Res steroid hormones: binding of 21 endogenous 1997;47:761–7 Climacteric 51 Pharmacology of estrogens and progestogens Kuhl 37. Randomized bioavailability of estradiol from two matrix trial of estrogen plus progestin for secondary transdermal delivery systems, Alora and Cliprevention of coronary heart disease in postmara. Effect of estrogen plus progestin on progresweek matrix versus a twice-a-week reservoir sion of carotid atherosclerosis in transdermal estradiol delivery systems in postpostmenopausal women with heart diesease, menopausal women. Effects of estrogen replacement on the during application of three strengths of an progression of coronary-artery atherosclerosis. Maturitas Estrogen plus progestin and the risk of cor1999;32:103–13 onary heart disease. Am J Obstet Gynecol normal and atherosclerotic coronary arteries of 1985;152:1092–9 premenopausal women. Methylation of the estrogen receptor gene 2001;56:38–44 is associated with aging and atherosclerosis in 45. Cardiovasc Res Percutaneous 17b-estradiol gel for the treat1999;43:985–91 ment of vasomotor symptoms in postmeno57. Risks and beneﬁts of Epidemiol 1995;142:1011–9 estrogen plus progestin in healthy post-meno59. Effects of conjugated equine estrogen in prospective, observational study of postmenopostmenopausal women with hysterectomy. The new conundrum: do estroDifferent effects of oral and transdermal gens have any cardiovascular beneﬁts? A population-based nested plasma von Willebrand factor in postmenocase-control study. Effect of oral and transdermal lower occurrence of carotid atherosclerotic estrogen replacement therapy on hemostatic plaques but not with intima-media thickness variables associated with venous thrombosis. Am J vices Task Force Ann Intern Med Obstet Gynecol 2003;189:1221–7 2002;136:680–90 78. Thromb Haemost tial association of oral and transdrmal 1997;78:765–9 oestrogen-replacement therapy with venous 79. Lancet 2003;362:428– Differential effects of oral and transdermal 32 estrogen/progesterone regimens on sensitivity 68. Risk to activated protein C among postmenopausal of venous thromboembolism in users of horwomen. Hormone replacement therapy and progestin replacement therapy: effects on serum risk of venous thromboembolism: population lipids and lipoproteins. Oral, more than transdermal, estrogen treating postmenopausal women with non-oral therapy improves lipids and lipoprotein(a) in hormone replacement therapy. Br J Obstet postmenopausal women: a randomized, placeGynaecol 1997;104(Suppl 16):4–13 bo-controlled study. Effects of postmenopausal horversus oral estrogens on biliary markers of mone rplacement therapy on lipid, lipoprotein, gallstone formation in postmenopausal women. Effects of replacement therapy on markers of coagulapostmenopausal hormone replacement with tion, ﬁbrinolysis, inﬂammation and serum oral and transdermal estrogen on high density Climacteric 53 Pharmacology of estrogens and progestogens Kuhl lipoprotein metabolism. Route of Biological effects of estradiol-17b in postmeestrogen replacement confers divergent effects nopausal women: oral versus percutaneous on energy metabolism and body composition in administration. Hormone effects of transdermal estradiol administration replacement therapy reduces mean 24-hour on plasma levels of nitric oxide in postmenoblood pressure and its variability in postmenopausal women. Fertil Steril study of transdermal estrogen replacement 1998;69:58–61 therapy on hypertensive postmenopausal wo99. Am J Obstet Gynecol 1999;180:334–9 with cyclical oral norethindrone acetate on 100. Admininsulin sensitivity, secretion, and elimination in istration of transdermal estrogen without postmenopausal women. Metabolism progestin increases the capacity of plasma and 2000;49:742–7 serum to stimulate prostacyclin production in 89. Fertil Steril and twice a week transdermal estradiol delivery 2000;73:72–4 systems: clinical efﬁcacy and plasma estrogen 101. Body composition, effects of hormone therapy on serum markers visceral fat distribution and fat oxidation in of inﬂammation in postmenopausal women postmenopausal women using oral or transderwith coronary artery disease on appropriate mal oestrogen. Am J Obstet Different effects of oral and transdermal estroGynecol 2000;183:593–600 gen replacement therapy on matrix 94. Effect of metalloproteinase and their inhibitor in postmenopause and different combined estradiolmenopausal women. Arterioscl Thromb Vasc progestin regimens on basal and growth horBiol 2003;23:1948–9 mone-releasing hormone-stimulated serum 105. Efﬁcacy and Cardiol 2003;41:1358–63 acceptability of intranasal 17b-oestradiol for 106. Doseblind, randomized study of estradiol replaceranging studies of a novel intranasal estrogen ment therapy on markers of inﬂammation, replacement therapy. Prevention of postmenopausal bone loss Differing effects of oral and transdermal by pulsed estrogen therapy: comparison hormone replacement therapy on cardiovascuwith transdermal route. Cirmized comparison of intranasal and culation 2002;106:1224–8 transdermal estradiol.

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First-time seizure in child in child <12 months of age that has no known cause and is not associated with fever if the infant has an open fontanelle diabetes mellitus dogs generic irbesartan 300mg with amex. Increase in severity or frequency of seizures despite documented therapeutic antiepileptic drug levels c diabetes type 2 differential diagnosis discount irbesartan 150mg on-line. Neuroimaging should not be performed in the routine evaluation of children with simple febrile seizures 3 metabolic disorder vlcad cheap irbesartan 150 mg online, 13-32 V diabetes type 1 getting pregnant cheap 150 mg irbesartan mastercard. Due to the length of time for image acquisition and the need for the patient to lie still, anesthesia is required for almost all infants and young children (age <7 years), as well as older children with delays in development or maturity. Suspected obstruction of nasolacrimal duct due to excessive tearing References: 1. Positron emission testing for six cancers (brain, cervical, small cell lung, ovarian, pancreatic and testicular), prepared for the Agency for Health Care Research and Quality. Ing C, DiMaggio C, Whitehouse A et al, Long-term differences in Language and Cognitive Function After Childhood Exposure to Anesthesia, Pediatrics 2012 Sep;130 (3) :e476-e485. Monteleone M, Khandji A, Cappell J et al, Anesthesia in children: Perspectives From Nonsurgical Pediatric Specialists, J Neurosurg Anesthesiol 2014;26 (4) :396-398. New York State Department of Health, Guidelines for Determining Brain Death, December 2011, Available at:. Society of Nuclear Medicine procedure guideline for brain death scintigraphy, Version 1. Diagnosing idiopathic normal-pressure hydrocephalus, Neurosurgery 2005;57 (3 Suppl): S2-4-S2-16. Infrequently performed studies in nuclear medicine: Part 2, J Nucl Med Technol 2009 Mar; 37: 1-13. Suspected normal pressure hydrocephalus with gait disturbance and one of the following 1. Patient with a shunt (ventriculo-peritoneal, ventricular-pleural or 3 ventricular venous) that may be blocked [Certify 78645] References: 1. American College of Radiology Appropriateness Criteria – Dementia and Movement Disorders. Diagnosing idiopathic normal-pressure hydrocephalus, Neurosurgery, 2005; 57:S2-4-S2-16. Infrequently performed studies in nuclear medicine: Part 2, J of Nuclear Medicine Technology, 2008; 36:132-143. Mostly pediatric patients with prior pyelonephritis causing scarring, or known ureteral reflux that could lead to pyelonephritis and scarring. Acute pyelonephritis with bacteriuria for children age 2 months to 3 years may be performed 4-6 months after the infection to 1-4 detect scarring V. American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children, Pediatrics, 1999, 103:843-852. Acute pyelonephritis as a second line test to detect renal 2-5 cortical scarring V. Assessment of global and differential renal function to estimate prognosis for recovery References: 1. Society of Nuclear Medicine, Procedure Guideline for Renal Cortical Scintigraphy in Children, version 3. Expert Panel on Pediatric Imaging, American College of Radiology Appropriateness Criteria – Urinary Tract Infection – Child. Acute pyelonephritis history of urinary tract infection in child 2 1 months to 3 years 4-6 months ago References: 1. Society of Nuclear Medicine Procedure Guideline for Renal Cortical Scintigraphy in Children, version 3. Suspected obstructive uropathy (78708 or 78709 renal scan with pharmacologic intervention) V. Society of Nuclear Medicine Procedure guideline for diagnosis of renovascular hypertension, version 3. European Association of Urology, European Society for Paediatric Urology, Guidelines on Paediatric Urology, 2009. Refractoriness to aggressive medical therapy (usually failure to respond to 3 drug therapy) B. American College of Radiology Appropriateness Criteria – Renovascular Hypertension. Expert Panel on Urologic Imaging, American College of Radiology Appropriateness Criteria – Renal Failure. Urinary tract infection in a child with poor response to 48 hours of antibiotics with urinary retention, elevated creatinine or 1 recurrent febrile urinary tract infections References: 1. Expert panel on pediatric imaging, American College of Radiology Appropriateness Criteria – Urinary Infection – Child. It does not involve imaging, but may be ordered in error by someone actually seeking a renal scan with function. Suspicion of urinary retention with ultrasound not diagnostic [One of the following] A. Society of Nuclear Medicine, Procedure Guideline for Radionuclide Cystography in Children, version 3. Paediatric Committee of the European Association of Nuclear Medicine, Guidelines for direct radionuclide cystography in children. American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection, Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children, Pediatrics, 1999, 103:843-852. Paediatric Committee of the European Association of Nuclear Medicine, Guidelines for direct radionuclide cystography in children. American College of Radiology Appropriateness Criteria – Acute Onset of Scrotal Pain–without Trauma, without Antecedent Mass. Octreoscan [One of the following for initial evaluation] (not recommended for routine surveillance) A. Neuroendocrine tumors of thymus, bronchopulmonary, stomach (may have elevated or normal gastrin levels), small bowel, appendix, or pancreas for initial staging and evaluation of unresectable or metastatic disease B. Patients with a history of prostate carcinoma treated with a radical prostatectomy 1. Patients with a history of prostate carcinoma treated with radiation or seed implantation, etc. The role of imaging with 111In-ibritumomab tiuxetan in the ibritumomab tiuxetan (Zevalin) regimen: results from a Zevalin Imaging Registry, J Nucl Med, 2005; 46:1812-1818. Chronic bone alterations from trauma or surgery General statement: Combining bone scintigraphy with a labeled leukocyte scan enhances sensitivity. In the presence of orthopedic hardware or prosthesis, normal bone marrow is disrupted and displaced, making interpretations difficult in these regions. Comparison of 111Inleukocyte localization with 99mTc-sulfur colloid uptake using combined or sequential 111In-leukocyte/99mTc colloid images is often necessary. A white-cell scan should be accompanied by a bone marrow scan using 99mTc sulfur colloid performed either together or sequentially. Infection is likely when there is abnormal 111In-leukocyte localization without corresponding 99mTc-sulfur colloid bone marrow activity (discordant activity). Society of Nuclear Medicine Procedure Guideline for 111In-Leukocyte Scintigraphy for suspected infection /inflammation, Version 3. Infection, inflammation, trauma, post-operative healing, granulomatous disease, rheumatological conditions 2. Surveillance of an asymptomatic individual not on treatment and having no new signs or symptoms concerning for recurrence 10. Restaging during chemotherapy in a member with known metastases, if conventional imaging is equivocal or inconclusive C. Restaging during treatment of breast cancer with bone-only metastases when there is no prior bone scan done for comparison D. Surveillance of an asymptomatic individual not on treatment and having no new signs or symptoms concerning for recurrence 8. Initial staging of anaplastic or medullary thyroid cancer if conventional imaging is inconclusive D. To guide laryngoscopic examination under anesthesia and biopsy, when primary site is not clinically accessible E. Surveillance of an asymptomatic individual not on treatment and having no new signs or symptoms concerning for recurrence 11 V.

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Basic Pharmacology Methotrexate is a folate antimetabolite that inhibits diPhenylbutazone-Type Drugs hydrofolate reductase and other folate-dependent enthe phenylbutazone-type drugs include phenylbutazymes in cells diabetes type 2 weight gain purchase 150mg irbesartan amex. The absorption managing diabetes in children cheap irbesartan 150 mg overnight delivery, metabolism diabetes in dogs insulin costs discount 300 mg irbesartan visa, and excrezone diabete 097 generic irbesartan 300 mg with visa, oxyphenbutazone, antipyrine, dipyrone, and tion of methotrexate are fully described in Chapter 56. The use of these drugs has decreased beWhen given in high doses, methotrexate exerts potent cause of their propensity to cause blood dyscrasias. At the low doses used in the therapy (Otocalm), is available in the United States today; of rheumatoid arthritis, methotrexate appears to be actphenylbutazone is used in Canada, and dipyrone is used ing more as an antiinﬂammatory agent than as an imin some European countries. Methotrexate inhibits folate-dependent enzymes involved in adenosine degradation, Acetaminophen increasing concentrations of extracellular adenosine. Changes in liver rheumatoid arthritis, they do nothing to halt the loss of aminotransferases and mild to moderate immunosupbone associated with this disease. Severe toxicity is possible varying capacities to slow the progression of joint erobut rare and may be a function of drug accumulation. Folic acid supplementation is ofthe later stages of the disease in which signiﬁcant joint ten used to alleviate certain side effects of methotrexate erosion had already occurred. Methotrexate is teratogenic and is contraindicated during pregnancy and breast-feeding. It is indicated for the treatment ministration include kidney, liver, and lung disease; of rheumatoid arthritis and psoriasis; it is also used for moderate to high alcohol use; immunodeﬁciency; blood psoriatic arthritis, systemic lupus erythematosus, and dyscrasias; and hypersensitivity. Elderly persons may be 36 Antiinﬂammatory and Antirheumatic Drugs 433 at increased risk for toxicity because of decreased renal cylic acid is antiinﬂammatory; however, these effects do and hepatic function. Adverse Effects Mild to moderate side effects, including nausea, vomitSulfasalazine ing, abdominal pain, diarrhea, anorexia, and headache, occur in up to 33% of patients taking this drug. Skin Sulfasalazine (Azulﬁdine) is approved for the treatment rash and discoloration, fever, reversible male infertility, of rheumatoid arthritis and ulcerative colitis. It has a greater degree of toxicity than hydroxychloroquine Contraindications and Drug Interactions but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued Sulfasalazine is contraindicated in individuals with hysulfasalazine therapy, primarily because of a lack of efﬁpersensitivity to salicylates, sulfonamides, sulfonycacy as opposed to intolerable side effects. Because it can cause kernicterus, sulfasalazine is contraindicated in infants Basic Pharmacology and children under 2 years of age. Sulfasalazine passes Sulfasalazine is a prodrug of which 70% is converted into breast milk and is therefore contraindicated for by colon bacteria to two active metabolites, sulfapyrinursing mothers. Psoriasis and porphyria are freshould not be used by individuals with bowel or urinary quently exacerbated by the administration of the obstruction. Sulfasalazine can inhibit the absorption of cardiac Aminoquinolines can increase plasma concentraglycosides and folic acid. It may displace certain drugs, tions of penicillamine, hence the potential for serious including warfarin, phenytoin, methotrexate, tolbuhematological or renal toxicity. Similarly, aminoquinotamide, chlorpropamide, and oral sulfonylureas, from lines can increase digoxin levels. Sulfasalazine can diminish quinoline probably should not be administered concurthe effectiveness of penicillins and estrogen-containing rently because of the propensity of each to produce oral contraceptives. Limited data suggest that it is comparable in efﬁthe treatment of rheumatoid arthritis and systemic lucacy to sulfasalazine and produces fewer adverse efpus erythematosus; their use as antimalarials is detailed fects. Because of this, these agents Basic Pharmacology show promise as ingredients of combination therapies Leﬂunomide is a prodrug that is converted to an active for rheumatoid arthritis. M1 inhibits T-cell proliferation by blocking de novo pyrimidine synBasic Pharmacology thesis and inhibiting the tyrosine kinases that are associHydroxychloroquine and chloroquine are similar in acated with certain cytokine and growth factor receptors. Adverse Effects these drugs are weak bases that enter and interfere Diarrhea occurs in approximately one-third of patients with the functioning of lysosomes and other subcellular taking this drug; indigestion, nausea, and vomiting occur compartments of Tand B-lymphocytes, monocytes, and in about 10%. This in turn inhibits the ability of these weight changes, headache, skin rashes, pruritus, and recells to produce and release inﬂammatory cytokines versible alopecia and hepatic enzyme elevation. Leﬂunomide is teratogenic in animal models; it is abthe incidence of the most serious toxic reaction, irresolutely contraindicated in pregnancy, in women who versible retinopathy with resultant blindness, is dose remay become pregnant, and in breast-feeding women. Eye examinations should be therefore, a drug elimination procedure using cholesperformed regularly during treatment with these drugs. This drug is not recommended for use in chilcytopenia, aplastic anemia) is rare. Caution should be used when administering this fects observed during high-dose, long-term therapy with drug to individuals with renal or hepatic disease, heavy the aminoquinolines include lichenoid skin lesions, alcohol use, or immunosuppression. Similarly, any ocular patholthe P450 enzyme responsible for converting leﬂunomide 36 Antiinﬂammatory and Antirheumatic Drugs 435 to its M1 metabolite. Cholestyramine enhances the clearInﬂiximab produces an acute infusion-related reacance of leﬂunomide and its M1 metabolite. Etanercept (Enbrel) is indicated for the inﬂiximab seems to be more immunogenic than etanertreatment of moderate to severe rheumatoid arthritis in cept. It is also indicomitant therapy with methotrexate or immunosupcated for therapy of Crohn’s disease. It is possiterm, the efﬁcacy of these drugs in the treatment of ble that inﬂiximab may increase the incidence of rheumatoid arthritis appears to be superior to that of autoimmune diseases and malignancies; however, longmethotrexate alone; however, their ability to prevent term data are needed to determine whether this is the bone erosion for longer than 24 months must be further case. Etanercept is a recombinant fusion protein produced in Chinese hamster ovary cells. Two p75 molecules are attached to each Fc son taking etanercept, he or she should be closely monmolecule. If a serious infection or sepsis occurs, the drug and forms inactive complexes, effectively lowering should be discontinued. It is administered with caution in individuals who have conditions predissubcutaneously, generally twice weekly. Live virus vaccines are conheavy chain and partial -light chain fused to a murine traindicated because of the potential for secondary hypervariable region. Inﬂiximab is administered intravenously, usually at 4to Inﬂiximab should not be given to individuals with 8-week intervals. As with etanercept, precautions for the prevention of serious inAdverse Effects fections must be taken, and live virus vaccines are conthe most common adverse reaction to etanercept is traindicated. Rare cases of pancytopenia may be asAnakinra may be used alone or in combination with sociated with this drug. Clinical no increased risk of infection with etanercept treattrials have shown anakinra to be more effective ment, postmarketing reports of serious infections, septhan placebo, either alone or in conjunction with sis, and associated fatalities exist. It is produced in a recomthese complexes are termed gold preparations or gold binant Escherichia coli expression system and has an compounds in this chapter. In the mechanism by which gold compounds produce rheumatoid arthritis patients, the amount of naturally their antiarthritic effects is not known. Adverse Effects Generally, 2 months of multiple dosing of gold the most common adverse reactions to anakinra are compounds is required to reach steady-state levels. Neutropenia may occur, and the risk of serious gold concentrations than does treatment with parinfection is somewhat elevated, particularly in asthenteral gold compounds, but it also produces a lower inmatic patients. Toxic manifestations of gold therapy are most common Contraindications and Drug Interactions after a minimal total amount (200–300 mg) of gold has been administered. Serious reactions necessitating disNo drug interaction studies have been conducted in hucontinuance of therapy or antidotal therapy are enmans. Animal studies indicate no change in the clearcountered in perhaps 5% of the patients. The response to which may be preceded by a metallic taste in the mouth vaccines may be diminished in patients taking anakinra. Blue or gray skin discoloration can arise from gold deposition in that tissue, and photosensitivity Gold Compounds may also occur. Unlike parenteral gold compounds, auranoﬁn does not accumulate appreciably in the skin. Pamost frequently causes diarrhea (about 50%), abdomirentally administered gold is generally believed to be nal pain, nausea, and anorexia. Gold comways require discontinuance of therapy; however, sepounds take several months to produce a measurable vere proteinuria may indicate a toxic nephritis. Among patients who can tolerate this therapy, teinuria is usually reversible when gold administration some beneﬁt will be obtained in about 80%, and complete is stopped. Remissions are Fatalities from gold therapy have been reported, usually maintained for varying periods after discontinuing thera consequence of a blood dyscrasia. Serious less severe in such patients, and a second course of gold blood dyscrasias, such as thrombocytopenia, agranulotherapy usually produces beneﬁcial effects. To complement steroidal and other measures used Basic Pharmacology in treating gold toxicity, it may be necessary to hasten the gold preparations available in the United States inthe elimination of gold from the body.

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Tto enlisting experts in pharmacology to provide Reﬁned Focus: In this edition diabetes 95 generic irbesartan 150mg on line, we chose to focus a textbook that is up-to-date and comprehensive diabetes insipidus neonate cheap 150mg irbesartan amex. Demore on drug classes rather than on individual drugs diabetes type 1 causes purchase irbesartan 300 mg with amex, signed to be used during a single semester med surg diabetes test questions buy irbesartan online pills, the book foeliminate unnecessary detail such as chemical struccuses on the clinical application of drugs within a contures, and maintain emphasis on structure–activity relatext of the major principles of pharmacology. With these revisions, we hope we have provided a this edition includes a number of new or updated feabook that is readable, up-to-date, comprehensive but tures that further enhance the appeal of the text. States Medical Licensing Examination guidelines) with detailed answers to help students test their knowledge Charles R. Stitzel Case Studies: Appearing at the end of each chapter, case studies present students with real-life examples of Table of Contents I. Contemporary Bioethical Issues in Pharmacology and Pharmacology 281 Pharmaceutical Research 73 Charles R. Synthetic Organic Antimicrobials: Sulfonamides, Adrenal Cortex 686 Trimethoprim, Nitrofurans, Quinolones, Ronald P. Parathyroid Hormone, Calcitonin, Vitamin D, and Other Vijaya Somaraju Compounds Related to Mineral Metabolism 754 50. Those who became the ancient Chinese wrote extensively on medical most proﬁcient in the use of drugs to treat disease were subjects. The Pen Tsao, for instance, was written about the mediators between this world and the spirit 2700 B. The Chinese doctrine the community was derived from the cures that they of signatures (like used to treat like) enables us to uncould effect with drugs. It was believed that the sick derstand why medicines of animal origin were of such were possessed by demons and that health could be regreat importance in the Chinese pharmacopoeia. The largest and perhaps the most imporOriginally, religion dominated its partnership with tant of these, the Ebers papyrus (1550 B. However, the use of drugs to effect today in that they have one or more active substances as cures led to a profound change in both religious thought well as vehicles (animal fat for ointments; and water, and structure. As more became known about the effects milk, wine, beer, or honey for liquids) for suspending or of drugs, the importance of divine intervention began to dissolving the active drug. These prescriptions also comrecede, and the treatment of patients effectively became monly offer a brief statement of how the preparation is a province of the priest rather than the gods whom the to be prepared (mixed, pounded, boiled, strained, left priest served. This process lead to a growing underovernight in the dew) and how it is to be used (swalstanding of the curative powers of natural products and lowed, inhaled, gargled, applied externally, given as an a decreasing reliance on supernatural intervention and enema). Cathartics and purgatives were particularly in forever altered the relationship between humanity and vogue, since both patient and physician could tell alits gods. Furthermore, when the priests began to apply most immediately whether a result had been achieved. The level of drug usage achieved by the Egyptians this was the cornerstone for the formation of a scienceundoubtedly had a great inﬂuence on Greek medicine based practice of medicine. Battle wounds frequently were covcian and protopharmacologist alike that there was ered with powdered plant leaves or bark; their astrinmuch variation to be found from one biological extract gent and pain-reducing actions were derived from the to another, even when these were prepared by the same tannins they contained. It was reasoned that to fashion a rational and root (containing atropinelike substances that induce a reproducible system of therapeutics and to study phartwilight sleep) that protected Ulysses from Circe. The macological activity one had to obtain standardized and oriental hellebore, which contains the cardiotoxic uniform medicinal agents. Veratrum alkaloids, was smeared on arrow tips to inAt the turn of the nineteenth century, methods becrease their killing power. The fascination of the Greeks came available for the isolation of active principles from with the toxic effects of various plant extracts led to an crude drugs. The development of chemistry made it posincreasing body of knowledge concerned primarily with sible to isolate and synthesize chemically pure comthe poisonous aspects of drugs (the science of toxicolpounds that would give reproducible biological results. Plato’s description of the death of Socrates is an In 1806, Serturner (1783–1841) isolated the ﬁrst pure acaccurate description of the toxicological properties of tive principle when he puriﬁed morphine from the the juice of the hemlock fruit. Many other chemically pure active comparalysis of sensory and motor nerves, followed eventupounds were soon obtained from crude drug preparaally by central nervous system depression and respirations, including emetine by Pelletier (1788–1844) from tory paralysis, precisely matches the known actions of ipecacuanha root; quinine by Carentou (1795–1877) the potent hemlock alkaloid, coniine. The use of drugs played an intian analysis of what was to become one of the basic conmate part in the rites, religions, history, and knowledge of cerns of pharmacology, that is, the quantitative study of the South American Indians. It was soon realized that drug action is prowas closely tied to religious thought, and Indian cultures duced along a continuum of effects, with low doses protreated their patients with a blend of religious rituals and ducing a less but essentially similar effect on organs and herbal remedies. It also was noted that the appearvarious deities were as important as the appropriate apance of toxic effects of drugs was frequently a function plication of poultices, decoctions, and infusions. Early drug practitioners, both in Europe and South Until the nineteenth century, the rapid development America, gathered herbs, plants, animals, and minerals of pharmacology as a distinct discipline was hindered by and often blended them into a variety of foul-smelling the lack of sophisticated chemical methodology and by and ill-ﬂavored concoctions. The preparations were so distasteful led to an attempt to signiﬁcant advances made through laboratory studies of improve on the cosmetic properties of these mixtures animal physiology accomplished by early investigators to ensure that patients would actually use them. Estonia, in the late 1840s by Rudolph Bucheim (1820– There has long been a tendency of some physicians 1879) (Fig. The laboratory, built in Bucheim’s to prescribe large numbers of drugs where one or two home, was devoted to studying the actions of agents would be sufﬁcient. We can trace the history of this such as cathartics, alcohol, chloroform, anthelmintics, polypharmaceutical approach to Galen (A. Bucheim believed that the investiwho was considered the greatest European physician gation of drugs. Galen believed that drugs had cerfor a chemist or pharmacist, who until now have been tain essential properties, such as warmth, coldness, dryexpected to do this. Unfortunately, he often formulated more was required to raise this discipline to the same general rules and laws before sufﬁcient factual informaprominent position occupied by other basic sciences; this tion was available to justify their formulations. They not only created new laboratories devoted to the laboratory investigation of drugs but also ﬁrmly established the new discipline through the training of future faculty, the writing of textbooks, and the founding of scientiﬁc journals and societies. The latter task was accomplished largely by Bucheim’s Pharmacology, as a separate and vital discipline, has pupil and successor at Dorpat, Oswald Schmiedeberg interests that distinguish it from the other basic sciences (1838–1921), undoubtedly the most prominent pharmaand pharmacy. Its primary concern is not the cataloguing cologist of the nineteenth century (Fig. In addition to of the biological effects that result from the administraconducting his own outstanding research on the pharmation of chemical substances but rather the dual aims of cology of diuretics, emetics, cardiac glycosides, and so (1) providing an understanding of normal and abnormal forth, Schmiedeberg wrote an important medical texthuman physiology and biochemistry through the applibook and trained approximately 120 pupils from more cation of drugs as experimental tools and (2) applying to than 20 countries. Many of these new investigators either clinical medicine the information gained from fundastarted or developed laboratories devoted to experimenmental investigation and observation. A report in the Status of Research in Pharmacology One of Schmiedeberg’s most outstanding students has described some of the founding principles on which was John Jacob Abel, who has been called the founder of the discipline is based and that distinguish pharmacolAmerican pharmacology (Fig 1. These principles include chair of pharmacology ﬁrst at the University of Michigan the study of the following: and then at Johns Hopkins University. The relationship between drug concentration of the chemistry and isolation of the active principles and biological response from the adrenal medulla (a monobenzyl derivative of. He also examined mushroom poisons, investigated ing, metabolism, and elimination of chemicals the chemotherapeutic actions of the arsenicals and anti-. Structure-activity relationships monials, conducted studies on tetanus toxin, and de-. Biological changes that result from repeated signed a model for an artiﬁcial kidney. In addition, Abel drug use: tolerance, addiction, adverse reactions, founded the Journal of Experimental Medicine, the altered rates of drug metabolism, and so forth Journal of Biological Chemistry, and the Journal of. Antagonism of the effects of one drug by anPharmacology and Experimental Therapeutics. The process of drug interaction with cellular training of students in this new discipline, and his estabmacromolecules (receptors) to alter physiologlishment of journals and scientiﬁc societies proved critiical function. This provision allowed the prescription atic approach to the understanding and treatment of drug to come under special control by requiring that it disease. The experimental method and technological carry the legend Caution—to be used only by or on the advances are the foundations upon which modern medprescription of a physician. A major defect of the generally strong 1938 law was its inadequate control of advertising. Medicines were thought to pose cal manufacturer makes claims for its product beyond problems similar to those presented by foods. Efﬁcacy (proof of effectiveness) became a reA landmark in the control of drugs was the 1906 quirement in 1962 with the Kefauver-Harris drug Pure Food and Drug Act. This law gave the Pharmacopoeia and the tiﬁc training and experience to evaluate the effectiveNational Formulary equal recognition as authorities for ness of the drug, on the basis of which such experts drug speciﬁcations. In the ﬁrst contested criminal proscould fairly and responsibly conclude that the drug ecution under the law, action was taken against the would have the claimed effect under the conditions of maker of a headache mixture bearing the beguiling use named on the label. In 1912, Congress Drug regulation in the United States is continuing to passed an amendment to the Pure Food and Drug Act evolve rapidly, both in promulgation of speciﬁc regulathat banned false and fraudulent therapeutic claims for tions and in the way regulations are implemented (Table patent medicines. The abolition of patent medicines is an outstanding Prescription drugs also were subject to control unexample, as is control over the accuracy of claims made der the 1906 law.

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