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 clinicalcorrelations@gmail.com. What follows is our first review-the thiazide diuretics.
Thiazide 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.
References:
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. http://online.statref.com. 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
One comment on “Clinical Pharmacy Corner-The Thiazides”
Cardiovascular disease, I surmise, is very concerning to both patients and their care givers, if this disease is expected, or in fact does exist. Furthermore, this disease is likely a cause of distress as well as confusion for many who seek the best treatment options for such diseases. As a result, there are increasingly many pharmacological options available to delay if not prevent such diseases, and these drugs work in different ways for the same cardiovascular diseases that are acquired often. Many health care providers are understandably unclear as to which treatment option would be most beneficial for their cardiac patient.
One increasingly progressing cardiovascular disorder is hypertension, or high blood pressure, as it affects possibly over 70 million Americans- many of which are not either treated or have their hypertension controlled as it needs to be to prevent future cardiovascular events caused by prolonged hypertension in such individuals. Such events include an increased risk for strokes, heart attacks, and kidney failure, among other damage that can be caused in the unmanaged hypertensive patient. While hypertension is evaluated according to different stages of severity, most hypertensive patients have what is called primary, or essential hypertension, and often require medicinal treatment to control their high blood pressure.
Additional reassurance for health care providers was made available regarding which pharmacological therapy for hypertension should be chosen by them due to the results of the ALLHAT trial. This trial lasted 4 years and was published in the Journal of the American Medical Association in 2002. Also, the trial was conceptualized and implemented by the National Institute of Health during the 1990s. This trial was the largest study to date addressing, among other variables, those patients in the study with hypertension, and the study examined which class of medications were most effective for these types of patients placed on these different classes of medications for their hypertension treatment that were involved to be studiedin the ALLHAT trial. In addition, the ALLHAT trial included over 40,000 subjects over the age of 55 who were evaluated in over 600 clinics during the course of this trial. Nearly half of the patients in this trial had metabolic syndrome, which is a syndrome where one is obese, has dyslipidemia, and glycemic issues as well. While Pfizer financially contributed a small portion to support this trial, ALLHAT was overall funded by the National Institutes of Health at a cost of around 130 million dollars, which again was for the purpose to determine the best medicinal treatment for the patients that were studied in this trial according to the trial’s study plan to compare the effectiveness of the different classes of medications in this trial, which had not been done to this degree in the past.
Because the NIH developed and funded this study, the ALLHAT trial, as a result, was largely if not completely void of bias and commercial interference compared with those trials that are sponsored by the manufacturers of drugs studied in other trials often. Because of the ideal design and methodology in which this trial was performed, most concur the results of this trial are quite accurate and valid that demonstrated the effectiveness of each class of medications in the ALLHAT trial.
ALLHAT provided data that allowed a true comparative analysis of these various classes of drugs for hypertension, which included calcium channel blockers, ACE inhibitors, Alpha Blockers, Beta Blockers, and diuretics. The researchers examined the action of these classes of medications on the subjects who possessed various cardiovascular disease states- with a focus on the ability of each one of these different classes of drugs on the disease of hypertension the patients in the study had during the trial.
As the trial was completed with data collected and analyzed after a 4 year period, the ALLHAT trial concluded that one particular class of medications involved in this study proved to be the most advantageous for the subjects as it relates to safety, efficacy and cost for those who require treatment for their cardiovascular disease state, as well as the prevention or the delay of progression of additional cardiovascular disease states studied and examined. Amazingly, this one drug class in this study is in fact nearly as old as the subjects involved in the trial.
ALLHAT results specifically and clearly concluded that thiazide diuretics are, overall, the preferred choice of initial medicinal therapy for hypertensive patients, as this class of drugs overall proved to be equivalent if not superior in many ways compared with the other classes of drugs in the study. Diuretics offered great protection against cardiovascular disease and controlled hypertensive patients as they needed to be, and proved that diuretics should be the first line drug of choice in such patients. The diuretics also decreased the risk of heart failure and stroke, as well, and this class of drugs have been studied in such areas associated with cardiovascular disease for over 40 years.
This class of medications, diuretics, have been available in the United States for well over 50 years, and presently costs about 25 dollars a year, instead of a few dollars a day for many if not most branded medications for CV conditions that were examined in the ALLHAT trial. So this finding, of course, concludes that diuretics not only provide equivalent if not superior benefits for cardiovascular disease patients, but also provides cost savings as well as illustrated in this trial. The ALLHAT trial was rare and unique in that it compared diuretics to these other classes of medications directly, which is not done frequently with clinical trials involving branded pharmaceuticals, as they usually do comparative studies with simply placebos most of the time, so their efficacy comes into question as a result.
Yet, even though this trial was potentially beneficial for so many who are involved with prescribing medications such as diruetics reasonably and necessary for their hypertensive patients, the acknowledgement of diuretics as being superior and preferred as initial medicinal therapy never really materialized or was fully recognized following the release of the results of the ALLHAT trial by the medical community, and this diuretic still is not utilized as often as it should be, according to others.
There was hope that there would be an increase in the prescribing of diuretics based on the results of this trial for those patients who are determined to have the disease states in the ALLHAT trial. Even after the researchers of the ALLHAT trial implemented what was called an ALLHAT dissemination plan from the years 2003 to 2006 at a cost of close to 4 million dollars to educate health care providers about the ALLHAT results, and the significance of the findings, the acknowledgement of the benefits of diuretics continue to be unrecognized by health care providers who select other classes of drugs to treat their hypertensive patients, as they still do today. The other classes aside from diuretics do in fact have benefits with cardiovascular patients, with compelling indications in particular. Yet the etiology for the prescribing habits regarding diuretics and why this class of medications is not chosen as often as they should be is largely unknown.
Others have speculated why this issue with diuretics in the ALLHAT trial never caught the attention to change the prescribing habits of health care providers, overall.
For example, and of no great surprise, these results of the ALLHAT study appeared to be of notable concern to those pharmaceutical companies who promote the other classes of medications in the ALLHAT trial that are more expensive than a thiazide diuretic. Reportedly, these companies who market these other classes of drugs increased their promotional spending in order to blunt the potential effects this trial may have on the usage of their cardiovascular medications that again belong to the classes that were involved in the ALLHAT trial soon after the results from this trial were published. Sampling of their branded medications to health care providers increased noticeably as well from those pharmaceutical companies that had branded medications for cardiovascular disease states. Thiazide diuretics, while clearly the apex for the prevention and management of hypertension and other cardiovascular disease states, do not engage in this promotional behavior that appears to be more of a powerful force than evidence-based medicine, as with the case of this diuretic and the benefits of this class of drugs that has been discussed.
Furthermore, drugs combining two medications from different classes of medications for hypertension and other cardiovascular disease states are increasingly preferred by many health care providers for understandable reasons presently- depending on the severity of the cardiovascular disease states that may exist, along with the risk of developing these cardiovascular conditions. It has been said that nearly 70 percent of hypertensive patients alone require more than one medication to adequately have their hypertension controlled. It is not unusual, for example, for a branded pharmaceutical company to combine their medication for hypertension with a diuretic for those patients that may have a stage of hypertension that requires simply more than just one drug for reduction of their high blood pressure.
On the other hand, some cardiovascular combination medications are absent of a diuretic. Yet diuretics remain the first line choice of treatment based on the results of the ALLHAT trial, regardless, and should be included in any combination drug chosen for the treatment of most cardiovascular disease patients with hypertension that requires more than one drug for control of their high blood pressure, according to others.
More convincing is that the JNC-7, a report that concludes which medication is best for the prevention and treatment of high blood pressure as well as other cardiovascular conditions, concurs with the results of the ALLHAT trial, and as a result, the JNC states in their report that diuretics are preferred for first-step hypertension therapy, and acknowledge that this class of medications is presently under-utilized. The Report is rather thorough, and is developed by the American Heart Association. The report is also recognized and respected by health care providers who treat cardiovascular disease.
I’m comfortable as a layperson in suggesting that the cardiovascular experts should and in fact be obligated to continue to make others aware of the results of the ALLHAT trial, and convince other health care providers that diuretics should be the preferred choice of medicinal therapy for the medical conditions illustrated and treated in the ALLHAT trial. . In particular, thiazide diuretics are most beneficial for those hypertensive patients that are African American, the elderly, obese patients, those with heart failure, or those with chronic kidney disease, others have concluded. And it should be noted that this type of diuretic depletes potassium from the patient taking this drug, so caution should be utilized regarding this issue, as well as the patient who is prescribed a diuretic should be informed of additional possible side effects associated with a thiazide diuretic, although they are infrequent.
Along with the cost savings that could amount to billions of dollars saved annually, diuretic medicinal therapy would ensure both health care provider and patients that they are receiving the proven and ideal treatment which will control their hypertension, and delay the progression and prevent additional cardiovascular events with this particular drug.
Unfortunately, it appears what may be one of the most authentic trials conducted has been and continues to be largely disregarded or not recalled by those who treat hypertension- possibly due to the forces of others whose objectives are of a different nature besides the restoration of the health of others as it relates to the diseases addressed in the ALLHAT trial. So again, it appears in this situation that promotion has been a more powerful force than what science has provided.
Dan Abshear
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