Clinical Question: Pharmacology

December 28, 2007

lantus.jpgIs there evidence to support the use of Lantus® (human insulin analog glargine) administered Q12h in Type 1 Diabetes?

Commentary by Kathy Lee, Pharmacy Resident 

The goal of diabetes management is to reduce the risk of long-term complications by maintaining near-normal glycemic control, in addition to reducing other risk factors. Patients with type 1 diabetes have an absolute deficiency in insulin and require exogenous insulin replacement. Lantus®, human insulin analog glargine, is the only long-acting insulin that exhibits a “peakless” action profile with duration of action of up to 24 hours(1). Because the clinical trials demonstrating its safety and efficacy involved a once a day bedtime administration, Lantus® received a FDA indication for once-daily dosing for diabetic patients who require basal insulin.

Theoretically, since insulin glargine has a 24-hour action profile with no pronounced peak, the time of administration should not be significant. A 24-week randomized clinical trial(2) investigated this idea by comparing administration of glargine at breakfast, dinner, or bedtime in patients with type 1 diabetes. The study concluded that the efficacy and safety of insulin glargine was not affected by the timing of administration. Despite limited studies there have been some evidence implying the appropriateness of twice-daily insulin glargine in select type 1 diabetic patients.

In August 2002, a patient case regarding the use of twice-daily insulin glargine was published(3). In this case, a 53 year old male with a history of type 1 diabetes did not receive sufficient insulin coverage with a once daily injection. Before hospitalization, the patient had a history of widely variable blood glucose levels. He was on a 4-injection regimen of premeal insulin lispro and ultralente at dinner. The patient also had a history of heavy alcohol abuse and on admission, the patient developed left arm weakness and progressive loss of consciousness. He was diagnosed with compensated diabetic ketoacidosis, and after treatment, was maintained on IV insulin infusion between 1-2 units/h. On the fifth day of his hospital course, the patient was started on enteral feeding with total nutrition intake of 1680 kcal/day. He was then later given 30-unit dose of insulin glargine at 9:00 p.m. and was weaned off of the insulin infusion over the next 4 hours. From day 6 to day 12 (period 1), the patient received insulin glargine as a single dose. In addition, he received subcutaneous insulin lispro when glucose exceeded 200 mg/dl. Marked hyperglycemia was noted at 10:00 p.m. after the single-dose regimen, requiring that the patient receive a supplemental lispro injection 4 out of the 6 days. From days 13-18 (period 2), glargine was divided into two doses, administered at 9:00 a.m. and 9:00 p.m. The mean glucose level was significantly higher at 10:00 p.m. in treatment period 1 versus period 2. This data suggested that the slow onset of action for the subsequent nighttime dose resulted in higher blood glucose levels at night. Giving insulin glargine as a split dose every 12 hours eliminated the window of insulinopenia and provided effective 24 hour insulin coverage.

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FDA Warns of Possible Link Between Chantix Therapy and Mood Disturbances

December 14, 2007

chantix.jpgCommentary by Robert Leonard PharmD, Pharmacy Resident New York Harbor Healthcare System

On November 20, 2007 the FDA announced mounting evidence linking varenicline (Chantix®) therapy for smoking cessation with suicidal ideation and erratic and aggressive behavior. The announcement comes in response to post-marketing case reports submitted to the FDA by the makers of Chantix®, Pfizer Inc. Early review of the cases reveal new onset of depressed mood, suicidal thoughts, and changes in emotions or behaviors within days to weeks of starting Chantix® therapy. A direct causal relationship remains limited at this time due to the nature of smoking cessation and the emergence of withdrawal symptoms with or without treatment. Nicotine withdrawal alone has been associated with acute exacerbation of underlying psychiatric disorders. Further confounding the interpretation of these reports is the presence of co-morbid conditions often associated with tobacco use disorder that predispose patients to mood disorders such as alcohol dependence. However, despite these limitations, reported cases include mood disturbances in patients who have no prior history of psychiatric illness and in patients who continue to smoke.

Pfizer Inc. has also submitted case reports to the FDA describing drowsiness associated with Chantix ®that influences the ability to safely drive or operate machinery.

In light of these preliminary findings, the FDA has made three recommendations concerning the use of Chantix® for smoking cessation. The official recommendations reported in the press release by the FDA are as follows:

“Healthcare professionals should monitor patients taking Chantix for behavior and mood changes. Patients taking Chantix should contact their doctors if they experience behavior or mood changes. Patients should use caution when driving or operating machinery until they know how quitting smoking with Chantix may affect them.” (1)

The FDA, in conjunction with Pfizer Inc., will continue to review data concerning the safety of Chantix®, the potential association with mood disturbances and the impact on driving or operating machinery. Patients and healthcare providers are encouraged to report adverse affects with Chantix® to the FDA via the MedWatch Adverse Event Reporting program available online at

1. Food and Drug Administration. Early communication about an ongoing safety review varenicline (marketed as Chantix). Available at Accessed November 21, 2007.

FDA Approves Raltegravir- A First in New Class of HIV Medications

November 14, 2007

220px-raltegravir.pngCommentary by Helen Kourlas PharmD, Pharmacology Section Editor

On October 16th the FDA announced the approval of raltegravir (Isentress®) for the treatment of Human Immunodeficiency Virus (HIV)-1 infection in combination with other antiretroviral agents. The use of raltegravir is recommended for patients who have HIV-1 strains resistant to multiple antiretroviral medications. Raltegravir belongs to a new pharmacologic class of antiretrovirals called HIV integrase strand transfer inhibitors. Integrase is one of the three enzymes necessary for the HIV-1 virus to replicate, and integrase inhibitors can stop the HIV-1 virus from inserting its genes into uninfected DNA. The other two enzymes necessary for viral replication are reverse transcriptase and protease which already are targeted by a variety of antiretrovirals.

According to the FDA’s press release, raltegravir was approved based on data from two double-blind, placebo-controlled studies in 699 HIV-1 infected adult patients with histories of extensive antiretroviral use. HIV viral loads dropped below a measurable threshold of 50 copies per milliliter in 65% of the patients taking the drug, nearly five times as many as the placebo group. Common adverse events reported with raltegravir use were diarrhea, nausea, and headache and abnormal elevated levels of muscle enzymes. Caution is advised when using raltegravir in patients at increased risk for certain types of muscle problems. Currently, raltegravir has not been shown to affect disease progression and patients may still be at risk for developing opportunitistic infections.

Reference: FDA Approves New HIV Drug. Raltegravir Tablets Used in Combination with Other Antiretroviral Agents. FDA News. Accessed 10/18/07

Image of Raltegravir, courtesy of Wikipedia

FDA Approves Label Revision for Erectile Dysfunction Drugs

October 24, 2007

viagra7.jpgCommentary by Kathy Lee, Pharm.D. Pharmacy Practice Resident

On October 18 2007, the FDA announced the approval of labeling changes to erectile dysfunction (ED) drugs in the class known as phosphodiesterase type 5 (PDE-5) inhibitors. This includes drugs Cialis®, Levitra®, Viagra®, as well as Revatio®, a PDE-5 inhibitor indicated for pulmonary arterial hypertension (PAH). The label revisions draw attention to the potential risk of sudden hearing loss, sometimes associated with vestibular symptoms such as tinnitus, vertigo, and dizziness. Based on 29 postmarketing reports of this incidence, most patients experienced one-sided hearing loss, partial or complete. Thirty three percent of cases reported temporary hearing loss, while the remainder had either ongoing hearing loss or no final outcome described at the time of report.

If hearing loss does occur, patients taking PDE-5 inhibitors for the treatment of erectile dysfunction should discontinue therapy and immediately contact their healthcare provider. On the other hand, due to the potentially life-threatening condition of PAH, patients taking Revatio® are advised to seek medical attention without abruptly discontinuing therapy.

With the new product labeling, the FDA urges all healthcare providers to warn patients about the risk of sudden hearing loss and provide proper instructions in the event this adverse reaction occurs.


FDA announces revisions to labels for Cialis, Levitra, and Viagra. FDA News. Accessed 10/23/07.

Erectile dysfunction drugs linked to risk for hearing loss. Medscape Medical News. Accessed 10/22/07

Clinical Pharmacy Corner: How Do Sulfonylureas Work?

October 17, 2007

Commentary by Helen Kourlas, PharmD and John Papadopoulas, PharmD, Pharmacology Section Editors

The sulfonylureas are members of a class of substituted arylsulfonylureas that have been used clinically since the 1950s. These agents are usually divided into two categories or generations. First generation agents include acetohexamide, chlorpropamide, tolazamide, and tolbutamide (the first widely utilized agent). The more potent second-generation agents include glimepiride, glipizide, and glyburide.

Sulfonylureas acutely lower plasma glucose by stimulating the release of insulin. The primary mechanism is through binding to sulfonylurea receptors (SUR-1) on functioning pancreatic beta-cells. Binding closes the linked ATP-sensitive potassium channels, which leads to decreased potassium influx and subsequent depolarization of the beta-cell membrane.1 Voltage-dependent calcium channels open and result in an influx of calcium, causing translocation and exocytosis of secretory granules of insulin to the cell surface (see figure 1).1

These agents may also alter the hepatic clearance of insulin and prolong insulin’s plasma half-life. Interestingly, in the presence of euglycemia or adequate glycemic control, plasma insulin levels decline to pre-treatment levels after several months of sulfonylurea pharmacotherapy. This may be a function of pancreatic beta-cell down regulation or somatostatin-mediated suppression of glucose secretion with subsequent reduction in insulin release; sulfonylureas may stimulate the release of somatostatin.1 Extra-pancreatic effects of sulfonylureas may contribute to glucose control in patients with diabetes mellitus. These effects include increasing insulin receptor density on adipocytes (increasing insulin sensitivity) and increasing the synthesis of glucose transporters.


  1. Davis SN and Granner DK. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th Edition. 2001.
  2.…/diabetographia/ud/4/3.gif. Accessed October 1, 2007

Figure 12


Table 1. Second Generation Sulfonylureas

Generic Brand Dosage Strengths (mg) Starting Dose (mg) Doses per day Max Dose (mg) Duration of effect Active metabolite
Glipizide Glucotrol 5, 10 5 1-2 40 10-24 hours No
Glipizide Glucotrol XL 2.5, 5, 10 5 1 20 24 hours No
Glyburide Diabeta, Micronase 1.25, 2.5, 5 2.5-5 1-2 20 16-24 hours Yes
Glyburide micronized Glynase 1.5, 3, 4.5, 6 1.5-3 1-2 12 12-24 hours Yes
Glimepiride Amaryl 1,2,4 1-2 1 8 24 hours Yes

Adapted from Drug Facts and Comparisons. Wolters Kluwer Health. St. Louis, Missouri. 2007.

Breaking News: FDA Issues New Warnings for Haldol

September 21, 2007

haldol.jpgCommentary by Helen Kourlas, PharmD

On September 17th 2007, the FDA issued an advisory warning healthcare professionals to avoid the use of higher than recommended doses of haloperidol, marketed as Haldol, Haldol Decanoate and Haldol Lactate. In addition to this warning, the FDA also emphasized that the injectable form of haloperidol is only approved to be administered as an intramuscular injection. Common off – label intravenous administration of haloperidol has led to numerous case reports of QT prolongation, Torsades de Piontes (TdP) and sudden death. Seventy three reports of TdP resulted because of haloperidol use, and 8 of the 11 fatal cases were linked to the intravenous administration of haloperidol at various doses. These cases occurred in the absence of predisposing factors, such as electrolyte imbalances, underlying cardiac abnormalities, or the use of medications that are known to prolong the QT interval. Additional cases have also demonstrated a dose-response relationship between the intravenous haloperidol dose and the development of TdP. These events have led the FDA to update the product labeling of haloperidol to include a warning statement alerting healthcare professionals to observe and monitor patients receiving higher than recommended doses of haloperidol as well as patients receiving haloperidol through intravenous administration. Currently, although intravenous administration of haloperidol is a relatively common off label use, this advisory serves as a reminder that injectable haldol is not FDA approved for intravenous administration.

Information for Healthcare Professionals. Haloperidol.

Clinical Pharmacology Corner: Beta-Adrenergic Receptors Antagonists

August 14, 2007

betablocker.jpgCommentary by Helen Kourlas, PharmD

Beta-adrenergic receptor antagonists, commonly known as beta-blockers (B-blockers) have been used for decades to treat hypertension, ischemic heart disease and some arrhythmias – and more recently to treat congestive heart failure. (1,2) Typically, B receptors are located in the heart (B1) and in peripheral vessels (B2) and the binding of catecholamines (epinephrine, norepinephrine and dopamine) to B1 receptors produce positive chronotropic and inotropic effects, while the binding of the B2 receptors produce a vasodilatory response in the peripheral circulation. The most profound therapeutic actions seen with the use of B-blockers are on the cardiovascular system; additionally B-blockers have effects on cardiac rhythm and automaticity.(2 )Slowed atrioventricular (AV) conduction with an increased PR interval is a related result of adrenoceptor blockade in the AV node. In the vascular system, B-receptor blockade opposes B2-mediated vasodilation. This may acutely lead to a rise in peripheral vascular resistance from unopposed α-receptor-mediated effects as the sympathetic nervous system responds to a lowered blood pressure due to the fall in cardiac output. (3)Although the acute administration of these agents can cause a rise in peripheral vascular resistance, chronic use leads to a decrease in peripheral vascular resistance in patients with hypertension. How this phenomenon eventually occurs is still unknown. Nonselective and B1-blocking agents have also been shown to antagonize the release of renin caused by the sympathetic nervous system with chronic administration of these agents. (3)

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Clinical Pharmacy Corner: Sulfonamide Allergy and Cross-Reactivity

July 26, 2007

Commentary By Susan Morey PharmD, Pharmacy Practice Resident

Approximately 3% of patients who use sulfonamide antibiotics develop an allergic reaction, with the most common being the development of a maculopapular rash. (1, 2, 3) Sulfonamides are chemical compounds which contain a SO2NH2 moiety and can be divided into 3 groups based on their structure. (1, 2)  The first group, the sulfonylarylamines includes the sulfonamide antibiotics. The second group, the nonsulfonylarylamines, includes carbonic anhydrase inhibitors (CAI), cyclooxygenase 2 (COX-2) inhibitors, loop diuretics, thiazides, and sulfonylureas and the protease inhibitors amprenavir and fosamprenavir. (1, 2) The third group is labeled sulfonamide-moiety containing drugs and includes 5-HT antagonists and other agents including zonisamide (1, 2). 


Two types of allergic reactions have been described in relation to these compounds.  One being an IgE mediated maculopapular or urticarial rash developing 1-3 days after medication initiation and the other being a hypersensitivity reaction.  The hypersensitivity reaction, consisting of fever and non-urticarial rash, usually develops 7-14 days after medication initiation. (3) 

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Can You Give A Cephalosporin to a Patient Who is Allergic to Penicillin?

June 21, 2007

Commentary by Susan Morey, PharmD. Pharmacy Practice Resident

A true allergy to penicillin is known to occur in less than 10% of patients exposed to penicillin. 1, 2 The cross-reactivity to cephalosporins has been reported to be approximately 8% to 18% in patients with a documented penicillin allergy. True allergic, type I reactions are IgE mediated, with a spectrum of presentation ranging from urticaria to severe anaphylactic shock.1, 2

The beta-lactam ring has been implicated as the structure responsible for cross-reactivity between the penicillins and cephalosporins.3 However, they differ in that the 5-membered thiazolidine ring of penicillin is replaced with a 6-membered dihydrothiazine ring in cephalosporins. The early reports of cross-reactivity may have been overestimated because, before 1989, the first-generation cephalosporins produced by the Cephalosporium acremonium mold contained small amounts of penicillin. The side-chains have been reported to play a role in allergic reactions to the beta-lactams, and the incidence of cross-reactivity between penicillins and cephalosporins with the same side-chain is 12% to 38%.3 For example, cephalosporins bearing a side-chain similar to benzylpenicillin may be more likely to cross-react with penicillins. Cefadroxil, cephalexin, cefaclor, cefprozil, and cefadroxil have 7-position side-chains similar to that of ampicillin and amoxicillin (Table 1).3 In a small study of patients with an allergy to amoxicillin but tolerance to benzylpenicillin and phenoxymethyl penicillin, the patients were challenged with cefadroxil and cefamandole. Cefadroxil possesses the same side chain as amoxicillin whereas cefamandole does not. Eight of the 21 patients enrolled had an allergic response to cefadroxil while none reacted to cefmandole.4

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Clinical Commentary: The Travesty of Grinding Axes with Science: Rosiglitazone and Cardiac Risk

June 12, 2007

Welcome to our first blog commentary. One of the purposes of the blog is to generate discussion about issues in health care. This “Clinical Commentary” section is an invitation to our housestaff and faculty to submit their own thoughts and viewpoints on current issues. The views expressed in this section are soley those of the authors and do not necessarily represent the views of Clinical Correlations.

Commentary by Gregory Mints MD and Nirav Shah MD, MPH

The meta-analysis of Rosiglitazone’s effect on cardiovascular events by Nissen(1) had the effect of an exploding bomb in both the lay and medical media. Unfortunately, much of the ensuing discussion had relatively little to do with the quality of the paper itself (2), with disproportionate attention to the failure of drug safety oversight in general and to the attempts at assigning blame for it on the manufacturer of Rosiglitazone and/or the FDA(3, 4). It thus appears that the paper has become a political leverage tool in the fight over the future direction of drug oversight in this country. We contend that the concerns about the medication approval process in the U.S. and the impact of drug manufacturers on that process, however important and acute, should not interfere with objective analysis of the presented studies. We do not believe that the ends justify the means (i.e. wrong arguments are o.k. for the right reasons), but also think that politicizing the data interpretation is harmful to the cause of reforming the relationships among the FDA, the pharmaceutical companies and the consumers. Most of our thoughts on this issue came about in the discussions we had with the two other members of our faculty: Drs. Natalie Levy and Tanping Wong. It is our opinion that the meta-analysis in question is of extremely poor methodological quality, which precludes any meaningful interpretation of the data. We therefore believe that no change in current existing practice is warranted, a conclusion supported by a recent editorial in the Lancet (5).

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Not So Rosi…

May 24, 2007

Commentary by Seagram Villagomez MD, Chief Resident

Since its approval in 1999, nearly 1 million Americans have used the thiazolidinedione (TZD) rosiglitazone (Avandia – GlaxoSmithKline) for the treatment of Type 2 Diabetes.  However, in a drug class which seems plagued by concerns, the safety profile associated with rosiglitazone has been brought to question. Previously, troglitazone (Rezulin) was pulled off the market secondary to hepatoxicity, while muraglitazar was not approved by the FDA given adverse cardiovascular events during early clinical trials.  In a study just released by the New England Journal of Medicine and making headlines across the world, Steven Nissen and colleagues at the Cleveland Clinic demonstrate that rosiglitazone has been associated with an increased risk of myocardial infarction and death from cardiovascular causes.

Nissen et al. conducted a meta-analysis which included searches of published data, as well as publicly available data from the FDA website and GlaxoSmithKline’s clinical trial registry.  Their inclusion criteria consisted of trials whose duration was >24 weeks,  included a randomized control group and had available data on MI and cardiovascular death.  In the end, 42 trials were included in this meta-analysis (including the recently published DREAM and ADOPT Trials).

Approximately 28,000 patients who were predominately white males in their late-50’s with poorly controlled diabetes (A1c = 8.2%) were randomized by these trials between a treatment regimen including rosiglitazone and a control group (any regimen not including rosiglitazone).  Nissen et al. found that the odds ratio for MI was 1.43 ( 95% CI 1.03 to 1.98, p = 0.03) and the odds ratio for death from cardiovascular causes was 1.64 (95% CI 0.98 to 2.74, p = 0.06). However, the total event rates in these combined trials were small. There were 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. 39 deaths from cardiovascular causes occurred in the rosiglitazone group compared to 22 in the control group.

The exact mechanism for the purported increased risk is unknown. The authors speculate it may be secondary to its effects on LDL levels (increasing it by as much as 18%), volume overload, or its effects on reducing hemoglobin levels and thus increased cardiovascular stress.  In comparison, pioglitazone (Actos – Takeda) was shown to have favorable cardiovascular outcomes including MI in previous randomized trials, which is thought to be secondary to reduced effect on the above.

The results presented by Nissen et al. are of concern given a population already at a higher risk for cardiovascular mortality and morbidity. However, this study is not without its flaws.  This study was limited by the use of publicly available trial data and not the raw patient level data obtained by the manufacturer.  The included trials were multiple small ones of short duration and therefore the event rates remained small and a time to event analysis could not be performed.  Trial regimens were not standardized (i.e. dosages and medications) and an exact control group was never determined. Furthermore, these trials in which MIs and cardiovascular deaths were secondary endpoints were not powered to determine significant changes.

Even though the data may be of borderline significance, this report raises many interesting questions concerning the safety and approval of rosiglitazone.  Currently, several larger trials are underway to investigate its effect on cardiovascular events. These trials may provide the information to make clear decisions,  however the tremendous publicity this article has generated may have already altered our practice for better or worse.

Are you telling your patients to stop Avandia based on this new data?

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Clinical Pharmacy Corner-The Thiazides

May 17, 2007

 We’d like to introduce you to Clinical Correlations’ newest feature-Clinical Pharmacy Corner. This will be a bimonthly pharmacy themed post which will tackle both basic and complicated pharmacy issues. We will review the mechanisms of actions of various classes of medications, a worthwhile refresher for those of us who may have forgotten what we learned in pharmacology 101 in medical school. We will also answer our reader’s pharmacy questions based on actual cases. As always please send your clinical questions and feedback to What follows is our first review-the thiazide diuretics.

NephronThiazide and “thiazide-like” diuretics exert their pharmacological effect by being secreted into the proximal convulated tubule into the lumen of the nephron and traveling through the loop of Henle to the distal end of the nephron. In the early portion of the distal convoluted tubule, thiazides inhibit the action of the Na+/Cl- symport and inhibit water and electrolyte reabsorption. (1,3) The distal convulated tubule expresses thiazide binding sites and is the primary site of action, while the proximal convulated tubule represents a secondary site of action. The resultant electrolyte excretion includes the depletion of sodium, potassium, chloride, bicarbonate and magnesium. Calcium is not eliminated but paradoxically retained by the action of thiazide diuretics. (3) Thiazide diuretics have additional actions that potentially explain their ability to lower blood pressure beyond what is observed with loop diuretics. Thiazides may mobilize sodium and water from arterial walls, resulting in decreased luminal diameter and tone. Furthermore, thiazides may possess direct vascular smooth muscle dilatory properties. This is extrapolated from our knowledge on the mechanism of action of diazoxide; a potent arterial vasodilator structurally related to thiazide diuretics.

Hydrochlorothiazide (HydroDiuril®, HCTZ) and Chlorothiazide (Diuril®) are traditional thiazide diuretics used in clinical practice to manage hypertension and lessen edema by increasing diuresis. Other agents that are classified as “thiazide-like” and have the same mechanisn of action include, Chlorthalidone (Hygroton®), Indapamide (Lozol®), and Metolazone (Zaroxolyn®).1 The mechanism in which these agents exert their clinical effect involves their ability to reach the distal convulated tubule in the nephron. Therefore, patients with severe renal disease (CrCl < 30mL/min) severe congestive heart failure, and cirrhosis of the liver do not respond as effectively to the action of thiazide diuretics. (1, 2) Adverse reactions associated with thiazide use include the expected extracellular volume and electrolyte depletion, especially sodium and potassium. Additional adverse reactions include dysglycemias, dyslipidemias, hypercalcemia, hyperuricemia, and pancreatitis. Metabolic side effects may be limited when utilized in low doses (e.g., hydrochlorothiazide 12.5-25 mg per day). Encourage patients to monitor for signs and symptoms of electrolyte disturbances and to use sun block to avoid photosensitivity reactions. Thiazides are contraindicated in patients with a documented hypersensitivity to sulfonamides.

1.Brutnon LL, Lazo JS, Parker KL. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th Edition. McGraw Hill Medical Publishing Division. 2006
2.DrugDex® Evaluations System. Greenwood Village, Colo: 1974-2006 Thomson MICROMEDEX. Accessed April 17th 2007.
3.Thiazide Diuretics. 40:28.20. AHFS Drug Information 2007. Statref! Metropolitan New York Library Council. Accessed April 17, 2007.

For further info on thiazide diuretics, check out Sarah Huen, PGY3 and David Goldfarb’s article on adverse metabolic side effects of the thiazide diuretics from the April 2007 issue of the American Journal of Urology

Adverse Metabolic Effects of Thiazides 

Image Courtesy Gray’s Anatomy, originally published 1918