Of the commonly used drugs for benign prostatic hypertrophy (BPH), which ones may be the least likely to cause hypotension in my hospitalized patient with borderline systolic blood pressures?

5-alpha-reductase inhibitors (RIs) (eg, finasteride and dutasteride) are less likely to cause hypotension than alpha-1-adrenergic antagonists (AAs) (eg, tamsulosin, doxazocin, terazocin, and alfuzocin), the other major class of drugs commonly used for treatment of signs and symptoms of benign prostatic hypertrophy (BPH).

A Cochrane systematic review found that finasteride, an RI, has a lower risk of postural hypotension compared to doxazosin, an AA. 1 In fact, there’s no solid evidence that RIs exacerbate hypotension on their own. 2,3 Unfortunately, RIs take longer to achieve benefit because they work by reducing prostate size over time, while AAs work much faster by reducing prostate smooth muscle tone.4 So, while it’s reasonable to choose an RI over an AA in our patient with soft pressures, it’s also reasonable to expect it won’t work quite as well during his hospital stay and you may still be forced to choose an AA.  

Among AAs, tamsulosin is the least likely to be associated with hypotension when compared to others in the same class (eg, doxazocin and terazocin) which are also sometimes used for treatment of hypertension. Thus, tamsulosin may be the best choice for patients at risk of  hypotension.5 However, even tamsulosin is not totally safe in this regard, especially in the first 4 weeks after starting or re-starting treatment when its risk of hospital admission for hypotension is about double that of RIs.6

Bonus pearl: Did you know that prazocin was the first promising selective AA investigated for BPH but likely because of its availability in generic form and the general notion at the time that medical therapy of BPH would not be widely accepted by urologists, larger randomized-controlled trials were never pursued!7

References

  1. Tacklind J, Fink HA, MacDonald R, et al. Finasteride for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews, 2010 Oct 6. https://www.ncbi.nlm.nih.gov/pubmed/20927745
  2. Finasteride prescribing information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020180s037lbl.pdf
  3. Dutasteride prescribing information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021319s014lbl.pdf
  4. Rigatti P, Brausi M, Scarpa RM, et al. A comparison of the efficacy and tolerability of tamsulosin and finasteride in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Prostate Cancer and Prostatic Diseases 2003; 6:315–323. https://www.ncbi.nlm.nih.gov/pubmed/14663474
  5. Tewari A and Narayan P. Alpha-adrenergic blocking drugs in the management of benign prostatic hyperplasia: interactions with antihypertensive therapy. Urology 1999 Mar;53:14-20. https://www.ncbi.nlm.nih.gov/pubmed/10094096
  6. Bird ST, Delaney JAC, Brophy JM, et al. Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology. BMJ 2013; 347 :f6320. https://www.ncbi.nlm.nih.gov/pubmed/24192967
  7. Lepor H. Alpha blockers for the treatment of benign prostatic hyperplasia. Rev Urol 2007;9:181-90.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213889/

Contributed by Nick Bodnar, Harvard medical student, Boston, MA.

 

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Of the commonly used drugs for benign prostatic hypertrophy (BPH), which ones may be the least likely to cause hypotension in my hospitalized patient with borderline systolic blood pressures?

How does excess licorice consumption cause hypertension and hypokalemia?

The active ingredient of licorice, glycyrrhizic acid or glycyrrhizin, is first converted to glycyrrhetinic acid (GRA) in the bowel which is then absorbed. Once in the circulation, GRA inhibits activation of 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD2), an enzyme in renal tissue that converts active cortisol to inactive cortisone. Without the full action of this enzyme, proper sodium and potassium homeostasis would be difficult because cortisol is just as effective in stimulating mineralocorticoid receptors as aldosterone but with 100-1000 times higher concentration than that of aldosterone! 1-3

Other ways that GRA may cause hypertension and hypokalemia include inhibition of 5 β-reductase in the liver, an enzyme that metabolizes aldosterone and direct stimulation of mineralocorticoid receptors, though overall these mechanisms may not be as important as the effect of GRA on cortisol metabolism in renal tissue.1,2

Besides causing fluid retention, licorice ingestion has also been found to increase systemic vascular resistance possibly by increasing vascular tone and remodeling of the vascular wall, potentiating the vasoconstrictor actions of angiotensin II and catecholamines in smooth muscle, and suppressing vasodilatory systems, including endothelial nitric oxide synthase and prostacyclin synthesis.

It’s no wonder that the FDA issued a statement in 2017: “If you’re 40 or older, eating 2 ounces of black licorice a day for a day for at least two weeks could land you in the hospital with an irregular heart rhythm or arrhythmia.” 5

Bonus Pearl: Did you know that as early as 1951, extract of licorice was reported for treatment of Addison’s disease, a combination of licorice and soy sauce has been reported to be “life-saving” in a patient with Addison’s disease (2007), and GRA food supplementation may lower serum potassium in chronic hemodialysis patients (2009)? 6,7

 

References

  1. Sontia B, Mooney J, Gaudet L, et al. Pseudohyperaldosteronism, liquorice and hypertension. J Clin Hypertens (Greenwich) 2008; 10:153-57. https://www.ncbi.nlm.nih.gov/pubmed/18256580
  2. Omar HR, Komarova I, El-Ghonemi M, et al. Licorice abuse: time to send a warning message. The Adv Endocrinol Metab 2012;3:125-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498851/
  3. Penninkilampi R, Eslick EM, Eslick GD. The association between consistent licorice ingestion, hypertension and hypokalaemia: as systematic review and meta-analysis. Journal of Human Hypertension 2017;31:699-707. https://www.ncbi.nlm.nih.gov/pubmed/28660884
  4. Black licorice: trik or treat? https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm 277152.htm
  5. Hautaniemi EJ, Tahvanainen AM, Koskela JK, et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep 2017;7:10947. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591274/
  6. Groen J, Pelser H, Willebrands AF, et al. Extract of licorice for the treatment of Addison’s disease. N Engl J Med 1951;244:471-75. https://www.ncbi.nlm.nih.gov/pubmed/14806786
  7. Cooper H, Bhattacharya B, Verma V, et al. Liquorice and soy sauce, a life-saving concoction in a patient with Addison’s disease. Ann Clin Biochem 2007;44:397-99. https://www.ncbi.nlm.nih.gov/pubmed/17594790
  8. Farese S, Kruse Anja, Pasch A, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney International 2009;76:877-84. https://www.ncbi.nlm.nih.gov/pubmed/19641483
How does excess licorice consumption cause hypertension and hypokalemia?

My hypertensive patient needs hemodialysis. How dialyzable are common antihypertensives?

Among antihypertensives, most commonly used angiotensin converting enzyme inhibitors (ACE-Is) such as captopril, enalapril, lisinopril, and benazepril are at least partially removed by hemodialysis; ramipril and fosinopril are not appreciably removed.1,2

In contrast, none of the commonly used angiotensin receptor blockers such as losartan, valsartan, and irbesartan are removed by hemodialysis.

Among β-blockers and combined α- and β-blockers, atenolol and metoprolol are removed by hemodialysis while carvedilol, bisoprolol, propranolol and labetalol are not.

Many other antihypertensives such as calcium channel blockers, α-blockers, clonidine, and hydralazine are not appreciably removed by hemodialysis, while isosorbide dinitrate appears to be.

Of interest, a 2015 retrospective cohort study found that initiation of high- dialyzability β-blockers (atenolol, acebutolol, or metoprolol) was associated with a higher risk of death in the following 180 days compared to that of low-dialyzability  β-blockers (bisoprolol or propranolol), suggesting that perhaps we should be more selective in our choice of β-blockers in this patient population.2 In contrast, no significant difference in all-cause mortality was noted among older patients receiving ACE-Is with high vs low dialyzability potential.3

 

References

  1. Inrig JK, Antihypertensive agents in hemodialysis patients: A current perspective. Semin dial 2010;23:290-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061334/pdf/nihms206964.pdf
  2. β-Blocker dialyzability and mortality in older patients receiving hemodialysis. J Am Soc Nephrol 2015;26:987-96. https://www.ncbi.nlm.nih.gov/pubmed/25359874
  3. Weir MA, Fleet JL, Dixon SN, et al. Angiotensin converting enzyme inhibitor dialyzability and outcomes in older patients receiving hemodialysis. Blood Purif 2015;40:232-42.  https://www.ncbi.nlm.nih.gov/pubmed/26382240   

Contributed in part by Andrew Lundquist, MD, PhD, Mass General Hospital, Boston, MA.

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My hypertensive patient needs hemodialysis. How dialyzable are common antihypertensives?

My patient is asking about the benefits of smoking cessation. How soon should she realize the health benefits of quitting her habit?

She should realize the health benefits of smoking cessation (SC) almost immediately! As the effect of nicotine wears off, just 15-20 minutes after her last cigarette, her heart rate and blood pressure should begin to fall.1,2Other health benefits, some within a year others longer, soon follow. 3,4 Between 2-12 weeks after SC, your patient may notice an improvement in her breathing and pulmonary function tests.

Between 1-9 months, the cilia in the lungs should begin to regenerate and regain normal function, allowing her to adequately clear mucus and bacteria with a decrease in cough and shortness of breath.

At 1 year, the risk of cardiovascular disease (eg, myocardial infarction, stroke) falls by one-half.

At 5 years, the risk of mouth, throat, esophagus, and bladder cancer also drops by one-half.

It takes 10 years for the risk of lung cancer to drop by one-half, and 15 years for it to approach that of non-smokers asymptotically. 4Fun fact: Did you know that in hypertensive patients who smoke, the blood pressure lowering effect of beta-blockers may be partly abolished by tobacco smoking,  whereas alpha-blockers may maintain their antihypertensive effects? 5References

  1. Omvik P. How smoking affects blood pressure. Blood Press. 1996;5:71–77. https://www.ncbi.nlm.nih.gov/pubmed/9162447
  2. Mahmud A, Feely J. Effect of smoking on arterial stiffness and pulse pressure amplification. Hypertension. 2003;41(1):183-187. https://www.ncbi.nlm.nih.gov/pubmed/12511550
  3. US Surgeon General’s Report, 1990, pp. 193, 194, 196, 285, 323
  4. US Surgeon General’s Report, 2010 and World Health Organization. Tobacco Control: Reversal of Risk After Quitting Smoking. IARC Handbooks of Cancer Prevention, Vol. 11. 2007, p. 341.
  5. Trap-Jensen. Effects of smoking on the heart and peripheral circulation. Am Heart J 1988;115:263-7.   https://www.ncbi.nlm.nih.gov/pubmed/3276115

Contributed by Felicia Hsu, Medical Student, Harvard Medical School

My patient is asking about the benefits of smoking cessation. How soon should she realize the health benefits of quitting her habit?

My patient with ulcerative colitis has had colectomy. Can she still get C. difficile infection?

Yes! Although a common cause of colitis, an increasing number of reports in the literature suggest C. difficile can cause enteritis as well.Antibiotic use is a major risk factor in most reports, with nearly one-half of the cases reported in patients with inflammatory bowel disease, many post-colectomy. 1-3

Mortality of C. difficile enteritis based on the first 83 cases in the literature appears to be 23%,1 but as high as 60%-83% depending on the report!2 Its diagnosis post-colectomy requires a high index of suspicion, as patients may not complain of “diarrhea” with chronically loose stools in the ileostomy bag.  Be particularly on the lookout for C. difficile enteritis in these patients when there is increased stool output, fever, hypotension, and/or leukocytosis2, and when in doubt, send a stool specimen from the ileostomy bag for C. difficile testing.

Although the pathophysiology of C. difficile enteritis is not fully understood, few observations are particularly intriguing: 

  • Small bowel mucosa may be colonized by C. difficile in about 3% of the population, potentially serving as a reservoir.2
  • Patients with ileostomy may develop a metaplasia of the terminal end mimicking colonic environment.4  
  • Exposure of rabbit ileum to C. difficile toxin A also causes significant epithelial necrosis with destruction of villi and neutrophil infiltration.5

 

References

  1. Dineen SP, Bailey SH, Pham TH, et al. Clostridium difficile enteritis: a report of two cases and systematic literature review. World J Gastrointest Surg 2013;5:37-42. https://www.wjgnet.com/1948-9366/full/v5/i3/37.htm
  2. Boland E, Thompson JS. Fulminant Clostridium difficile enteritis after proctocolectomy and ileal pouch-anal anastomosis. Gastroenterology Research and Practice 2008; 2008: Article ID 985658. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633454/pdf/GRP2008-985658.pdf
  3. Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clin Infect Dis 2001;33:1429-31. https://pdfs.semanticscholar.org/333b/d84978cfc4ac8fd21a15bc8fd26ff3160387.pdf
  4. Apel R, Cohen Z, Andrews CW, et al. Prospective evaluation of early morphological changes in pelvic ileal pouches. Gastroenterology 1994;107:435-43. http://www.gastrojournal.org/article/0016-5085(94)90169-4/pdf
  5. Triadafilopoulos G, Pothoulakis C, Obrien MJ, et al. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 1987;93:273-279. https://www.ncbi.nlm.nih.gov/pubmed/3596162
My patient with ulcerative colitis has had colectomy. Can she still get C. difficile infection?

How should I manage hypertension in my patient with neurogenic orthostatic hypotension?

The frequent concurrence of supine hypertension (SH) and neurogenic orthostatic hypotension (nOH)1 makes treatment of SH in these patients particularly challenging.

To begin with, your threshold for treatment of SH in patients with neurogenic orthostatic hypotension (nOH) may need to be higher than that commonly recommended by national guidelines for treatment of essential hypertension to avoid exacerbation of nOH.  Although SH in nOH patients is often arbitrarily defined as a systolic BP ≥150 mmHg or diastolic BP≥90 mmHg, a supine systolic BP of up to 160 mmHg may not warrant treatment, particularly if the symptoms of nOH have improved.2

A 2017 consensus panel recommends treatment of SH in the setting of nOH if systolic BP exceeds the range of 160-180 mmHg or diastolic BP exceeds 90-100 mmHg.  “Permissive” approach to SH in this setting may be reasonable, particularly in those with the largest drops in BP upon standing ( >80 mmHg drop). 2

Regardless, all patients with nOH and SH should be advised to avoid supine posture during the day and elevate the head of the bed as tolerated during the night.

If necessary, significant SH may be treated with short acting agents, including2:

  • Captopril 25 mg qhs
  • Clonidine 0.2 mg with evening meal
  • Hydralazine 10-25 mg qhs
  • Losartan 50 mg qhs
  • Nitroglyerine patch 0.1 mg/h patch qhs (remove patch in am)

Long acting antihypertensive agents and diuretics should be avoided given their inherent risk of significant exacerbation of nOH.

 

References

  1. Goldstein DS, Pechnick S, Holmes C, et al. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension 2003; 42:136-142. https://www.ncbi.nlm.nih.gov/pubmed/12835329
  2. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a concensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-82. https://www.ncbi.nlm.nih.gov/pubmed/28050656
How should I manage hypertension in my patient with neurogenic orthostatic hypotension?

What pharmacological options should I consider when treating neurogenic orthostatic hypotension in my elderly patient with supine hypertension?

Treating symptomatic neurogenic orthostatic hypotension (nOH) in patients with supine hypertension can be challenging.

Before adding new agents, consider discontinuation or dose reduction of medications that can potentially aggravate orthostatic symptoms (eg, diuretics, vasodilators, negative chronotropic agents, including beta blockers).

Midodrine (an α1-adrenoreceptor agonist) and droxidopa (a norepinephrine pro-drug) are the only 2 FDA-approved drugs for the treatment of OH.

  • Midodrine is typically dosed between 2.5 mg-15 mg 1-3x/d during waking hours (prior to getting out of bed, before lunch, mid-afternoon).
  • Droxidopa is dosed from 100-600 mg 3x/day during waking hours (eg, 8 AM, noon, 4PM).
  • To reduce the risk of supine hypertension, these agents are not recommended to be taken within 5 h of bedtime, and should be used with caution in patients with congestive heart failure and chronic renal failure.

Fludrocortisone and pyridostigmine are used off-label for treatment of nOH.

  • Fludrocortisone (typical dose 0.1-0.2 mg/day) expands intravascular blood volume by increasing renal sodium and water reabsorption, with an attendant risk of exacerbating supine hypertension, hypokalemia, and edema.
  • Pyridostigmine (typical dose 30-60 mg 1-3x/day) is an acetylcholinesterase inhibitor that potentiates neurotransmission in the sympathetic ganglia and has the advantage of not worsening supine hypertension. Side effects include abdominal cramps, diarrhea, excessive sweating and urinary incontinence.

In practice,  1 or more of these agents are often used along with non-pharmacological measures.

Go to a related pearl at https://pearls4peers.com/2017/09/18/which-non-pharmacological-approaches-may-help-symptoms-of-orthostatic-hypotension-in-my-patient-with-autonomic-insufficiency/.

 

Reference

Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a concensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-82.https://www.ncbi.nlm.nih.gov/pubmed/28050656

 

What pharmacological options should I consider when treating neurogenic orthostatic hypotension in my elderly patient with supine hypertension?

Does hypertension cause epistaxis?

Although traditionally we think of epistaxis as a potential sign of hypertension, particularly when severe, whether hypertension causes epistaxis is unclear and even the association of these 2 conditions has been challenged in recent years.

A 2014 systematic review found that although the majority of studies reported an association between these 2 conditions, many did not include a control group, were of poor methodological quality and did not adjust for confounding variables such as age, sex, and anticoagulation1.  Indeed, a larger study that controlled for many potential confounding factors failed to confirm such an association2.  A small prospective study also found no correlation between the severity of hypertension and epistaxis3.

Even when an association between hypertension and epistaxis has been found, it is unclear how much of the stress of bleeding itself and white coat syndrome may affect the readings1. However, an interesting 2017 study found masked hypertension (normal blood pressure in office, abnormal on ambulatory measurements) in 33.3% of patients with epistaxis with night time blood pressures that were significantly higher among patients with epistaxis4.

So the data is all over the place! It makes sense that long standing hypertension through its effects on blood vessels such as atherosclerosis and endothelium dysfunction may set the stage for epistaxis1,5, particularly in our ever-aging population on anticoagulants.  But whether hypertension by itself is enough to cause epistaxis is likely to be debated for years to come.  

 

References

  1. Kikidis D, Tsioufis K, Papanikolaou V, et al. Is epistaxis associated with arterial hypertension? A systematic review of the literature 2014;271:237-243. https://www.ncbi.nlm.nih.gov/pubmed/23539411
  2. Fuchs FD, Moreira LB, Pires CP, et al. Absence of association between hypertension and epistaxis: a population-based study. Blood Press 12:145-48. http://www.tandfonline.com/doi/abs/10.1080/08037050310001750
  3. Knopfholz J, Lima-Junior E, Précoma-Neto D, et al. Association between epistaxis and hypertension: A one year follow-up after an index episode of nose bleeding in hypertensive patients. Internat J Cardiol 2009;134:e107-e109. https://www.ncbi.nlm.nih.gov/pubmed/18499285
  4. Acar B, Yavuz B, Yildiz E, et al. A possible cause of epistaxis: increased masked hypertension prevalence in patients with epistaxis. Braz J Otorhinolaryngol 2017;83:45-49. http://www.scielo.br/pdf/bjorl/v83n1/1808-8694-bjorl-83-01-0045.pdf
  5. Celik T, Iyisoy A, Yuksel UC, et al. A new evidence of end-organ damage in the patients with arterial hypertension: epistaxis? Internat J Cardiol 2008;141:105-107. https://www.ncbi.nlm.nih.gov/pubmed/19138805
Does hypertension cause epistaxis?