caution: contents under pressure identifying drug‐induced ......obesity physical inactivity...

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Caution: Contents Under Pressure

Identifying Drug‐Induced Hypertension

Melanie Claborn, Pharm.D., BCACP

Assistant Professor of Pharmacy Practice

Southwestern Oklahoma State University College of Pharmacy

Clinical Pharmacy Specialist‐Oklahoma City Indian Clinic

Oklahoma City, OK

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Disclosure

• Under guidelines established by the Accreditation Council for Pharmacy Education, disclosure must be made regarding financial relationships with commercial interests within the last 12 months.

• I have no relevant financial relationships or affiliations with commercial interests to disclose.

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Learning Objectives

At the completion of this activity, pharmacists will be able to:

• Describe the complications of untreated hypertension

• List drugs/supplements associated with secondary hypertension

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Pre‐Assessment Question:What is the leading cause of death in the United

States?

a. Heart disease

b. Cancer

c. Accidents

d. Influenza

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Pre‐Assessment Question:A patient has blood pressure readings in the

clinic that are consistently 136/82. How would you classify his blood pressure?

a. Normal

b. Elevated

c. Stage 1 HTN

d. Stage 2 HTN

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Pre‐Assessment Question:Which of these medications can be associated with increasing blood

pressure?

a. Cyclosporine

b. Erythropoietin

c. Indomethacin

d. All of the above

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Why talk about the same old thing…

7Image: https://hochomecare.wordpress.com/

Nearly half of all adults in the

US have cardiovascular

disease

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Prevalence of cardiovascular disease in adults ≥20 years of age (NHANES, 2013–2016)

Benjamin EJ. Heart Disease and Stroke Statistics—2019 Update Circulation. 2019;139:e56–e528

Dishonorable Awards

Heart disease is the leading cause of

death in the US

Ischemic heart

disease and stroke lead worldwide

10https://www.cdc.gov/nchs/fastats/leading‐causes‐of‐death.htmImage: http://clipart‐library.com/medal‐cliparts.html

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CVD and other major causes of death for American Indians or Alaska Natives United States, 2016


Heart Failure, 9.3%

Stroke, 16.9%

High Blood Pressure, 9.8%

Diseases of the Arteries, 3.0%

Other, 17.7%

Coronary Heart Disease,

43.2%

Percentage of Deaths Attributable to Cardiovascular Disease (United States: 2016)

Adapted from Benjamin EJ. Heart Disease and Stroke Statistics—2019 Update Circulation. 2019;139:e56–e52812

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CVD Risk

FactorsHypertension

Cigarette smoking

Overweight/ Obesity

Physical inactivity

Dyslipidemia

Diabetes Mellitus

Microalbuminuria (or GFR < 60 mL/min)

Age

Family History of Premature CVD

13Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (2003). (NIH Publication No. 03–5233). Bethesda, MD: U.S. Department of Health and Human Services.http://www.highbloodpressureinfo.org

Snapshot of Hypertension in the US

14Images: https://healthmetrics.heart.org/heart‐disease‐and‐stroke‐statistics‐2019‐infographic/ Accessed May 2, 2019.

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Prevalence of hypertension in adults ≥20 years of age by sex and age (NHANES, 2013–2016


NHANES 1976‐1980

NHANES 1988‐1991

NHANES 1991‐1994

NHANES1999‐2000

NHANES2007‐2012

Aware 51% 73% 68% 70% 83%

Treated 31% 55% 54% 59% 77%

Controlled 10% 29% 27% 34% 54%

BP Control in the US

†SBP <140 mm Hg and DBP <90 mm Hg.•Age 18 to 74 years with SBP 140 mm Hg or DBP 90 mm Hg or taking antihypertensive medication.

JNC VI. Arch Intern Med. 1997;157:2413‐46.JNC VII. JAMA 2003; 289:2560‐2572

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Extent of awareness, treatment, and control of high blood pressure by age NHANES, 2013–2016


Why Blood Pressure Control Matters

18https://healthmetrics.heart.org/heart‐disease‐and‐stroke‐statistics‐2019‐infographic/

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Target Organ Damage

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Hypertension

Reducing average population systolic blood pressure by only 12‐13 mmHg could reduce:

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37%

Stroke Death from all causes

Death from cardiovascular

cause

Coronary heart disease

21%

25%

13%

CDC. http://www.cdc.gov/bloodpressure/infographic.htm Ogden LG, et al. Hypertension 2000; 35: 539‐543.Chobanian, A. V. et al. Hypertension 2003;42:1206‐1252; Hebert. Archives Int Med 1993: Moser. Am Coll Cardiol 1996

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Categories of Blood Pressure in Adults

BP Category SBP DBP

Normal <120 mm Hg AND <80 mm Hg

Elevated 120‐129 mm Hg AND <80 mm Hg

Hypertension

Stage 1 130–139 mm Hg OR 80–89 mm Hg

Stage 2 ≥140 mm Hg OR ≥90 mm Hg

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*Individuals with SBP and DBP in 2 categories should be designated to the higher BP category

Whelton PK, Hypertension. 2018;71(19):e127–248

22HBP Guideline Tool: Updated Classification and Management of High Blood Pressure in Adults https://www.acc.org/education‐and‐meetings/image‐and‐slide‐gallery/media‐detail?id=B5A2641BE66A48C89E18066B137DE3E0

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Blood Pressure Goals

JNC 7 (2003)

JNC 8 (2014)

ASH/ESH (2013)

ACC/AHA 2017

UncomplicatedHTN

<140/90 <140/90 <140/90 <130/80

Diabetes <130/80 <140/90 <140/90 <130/80

CVD <140/90 ‐‐ <140/90 <130/80

CKD <130/80 <140/90 <140/90 <130/80

ElderlyNot

specified <140/90

<150/90 (≥60 years)

<150/90 (≥80 years)

<130(SBP)

23JNC 8: JAMA. 2014;311(5):507‐520,; Whelton PK, Hypertension. 2018;71(19):e127–248.

24http://www.cdc.gov/bloodpressure/infographic.htm

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Nonpharmacological Interventions for Prevention and Treatment of Hypertension

Recommendation Approximate

Impact on SBP

Hypertension

Weight loss Best goal is ideal body weight. Expect about 1 mm Hg

for every 1‐kg reduction in body weight.

‐5 mm Hg

Healthy diet Consume a diet rich in fruits, vegetables, whole grains,

and low‐fat dairy products, with reduced content of

saturated and total fat.

‐11 mm Hg

Reduced intake of

dietary sodium

Optimal goal is <1500 mg/d, but aim for at least a 1000‐

mg/d reduction in most adults.

‐5/6 mm Hg

Enhanced intake of

dietary potassium

Aim for 3500–5000 mg/d, preferably by consumption of

a diet rich in potassium.

‐4/5 mm Hg

Physical activity

(aerobic)

(dynamic resistance)

● 90–150 min/wk

● 65%–75% heart rate reserve

‐5/8 mm Hg

● 90–150 min/wk

● 50%–80% 1 rep maximum

● 6 exercises, 3 sets/exercise, 10 repetitions/set

‐4 mm Hg

Moderation of

alcohol intake

In individuals who drink alcohol, reduce alcohol to:

● Men: ≤2 drinks daily; Women: ≤1 drink daily

‐4 mm Hg


Screening for Secondary

Hypertension

26Whelton PK, Hypertension. 2018;71(19):e127–248.

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• Accuracy

• Apnea

• AldosteronismA

• Bruits (renovascular disease)

• Bad kidneysB• Catecholamines

• Coarctation

• Cushing’s syndromeC

• DRUGS

• Diet D

• Erythropoietin

• Endocrine disordersE27

Identifiable Causes of Hypertension

Onusko E. Am Fam Physician. 2003 Jan 1;67(1):67‐74.

Secondary Causes

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• 1‐2%Renal parenchymal disease

• 5‐34%Renovascular disease

• 8‐20%Primary aldosteronism

• 25‐50%Obstructive sleep apnea

• Less than 1%Pheochromocytoma, Cushings, Thyroid, Aortic coarctation, Hyperparathyroism,

Adrenal hyperplasia, Acromegaly

Whelton PK, Hypertension. 2018;71(19):e127–248.

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Accuracy of Blood Pressure Measurement

• Equipment inspected

• Trained operator

• Patient properly positioned

• Caffeine, exercise, and smoking should be avoided for at least 30 minutes before

• Appropriately sized cuff

• Two measurements

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Definition of Drug‐Induced Hypertension

High blood pressure caused by a response to using, or stopping

the use of, a chemical substance, drug, or medication.

– U.S. National Library of Medicine/National Institutes of Health

30http://www.nlm.nih.gov/medlineplus/ency/article/000155.htm

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Image: http://millionhearts.hhs.gov /Docs/BP_Toolkit/TipSheet_HCP_MedAdherence.pdf31

Risk Factors for Drug‐induced Hypertension

• History of elevated blood pressure

• Decreased GFR

• Metabolic syndrome

• Advanced age

• Persistent use

32Image: http://www.clipartpanda.com/clipart_images/american‐indian‐elder‐70241502

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Drugs Associated with Increases in BP

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Amphetamines Bevacizumab Buspirone Caffeine

Cocaine Corticosteroids CyclosporineErythropoietin Stimulating Agents

Estrogen‐containing oral contraceptives

Herbals LicoriceMonoamine Oxidase Inhibitors

NSAIDSPhenylephrine/ Pseudoephedrine

Protease Inhibitors

Sibutramine (off market)

Sorafenib/ Sunitinib

Tacrolimus Venlafaxine

Mechanism for Increasing BP

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• Glucocorticoids/mineralocorticoids

• Hormones

• NSAIDSVolume retention

• Decongestants

• Stimulants

Activation of the sympathetic nervous

system

• Cyclosporine

• TacrolimusDirect vasoconstriction

• Erythropoietin

• Alcohol

• VEGFCombined

Unknown

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Steroids/Glucocorticoids

• Occurs in at least 20% of patients– More in elderly and with family history

• Dose dependent

• Oral cortisol doses of 80‐200 mg/day can increase systolic BP up to 15 mmHg in 24 hours– At low doses cortisol has less effect

• Cessation usually results in normalization of BP

• Management– Use short term or non‐systemic options

– Consider diuretic if long term therapy needed

35Grossman E, Am J Med. 2012 Jan;125(1):14‐22. Gyamlani G. South Med J. 2007 Jul;100(7):692‐9. Whelton PK, Hypertension. 2018;71(19):e127–248.


Licorice

• Main ingredient‐glycyrrhizic acid

• Excess mineralocorticoid

• Dose dependent

• Can have a sustained increase in BP

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Grossman E, Am J Med. 2012 Jan;125(1):14‐22. Image: http://www.candyfavorites.com/candy‐flavors/black‐licorice

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Estrogens (Oral Contraceptives)

• Oral contraceptives induce HTN in ~5% of users– 50 mcg of estrogen and 1‐4 mg of progestin

• Usually minimal but can be severe, even malignant HTN

• Risk decreases with cessation of oral contraceptive

• Postmenopausal HRT has minimal effect on BP in normotensive women‐may even reduce

• If BP not controlled‐may consider progestin only or IUD

37Grossman E, Am J Med. 2012 Jan;125(1):14‐22.Gyamlani G. South Med J. 2007 Jul;100(7):692‐9

Nonsteroidal Anti‐Inflammatory DrugsCox‐2 Inhibitors

• Ibuprofen, naproxen, piroxicam• Celecoxib • Implicated in increasing BP and CVD risk• Can antagonize effects of some BP agents • NSAIDS inhibit PG vasoconstriction and

volume retention

• Recommended – Lifestyle changes and nonpharmacologic

therapies for pain – Use lowest effective NSAID dose– Modifying antihypertensive therapy and

diuretic management

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Prostaglandins

Vasodilation

Excretion of sodium and

water

Gyamlani G. South Med J. 2007 Jul;100(7):692‐9

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Change of BP in Hypertensives and Normotensives

39Armstrong EP. Clin Ther. 2003 Jan;25(1):1‐18.

Atypical Antipsychotics

• Linked to metabolic syndrome and weight gain

• More likely with clozapine and olanzapine

• Management

– Lower dose

– Consider alternative agent and behavioral therapy

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Whelton PK, Hypertension. 2018;71(19):e127–248.

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Stimulants

• Nicotine, amphetamines• Unpredictable• Methylphenidate, amphetamines usually only cause modest increases– BP: 2‐5/1‐3 mmHg– HR: 3‐6 bpm

• Some can experience significant increases in BP or HR

• Management– Consider behavioral therapy

41Grossman E, Am J Med. 2012 Jan;125(1):14‐22.Whelton PK, Hypertension. 2018;71(19):e127–248.

Cocaine, Anesthetics, Narcotics

• Cocaine– Abuse causes adrenergic overactivity

– Acute increases in BP, but not usually chronic increases

– Problematic when used while taking beta blockers

• Ketamine

• Naloxone– Hypertensive responses seen in reversal of narcotics

– Can acutely reverse antihypertensive effects of clonidine

42Whelton PK, Hypertension. 2018;71(19):e127–248.

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Decongestants

• Pseudoephedrine, phenylephrine, epinephrine, oxymetazoline

• Mainly due to activation of the sympathetic nervous system

• Counteract pharmacological treatment

• Sympathomimetics with beta‐blockers may increase BP due to unopposed alpha vasoconstriction

• Management– Consider alternative therapies (nasal saline, intranasal corticosteroids, antihistamines)

43Grossman E, Am J Med. 2012 Jan;125(1):14‐22.Whelton PK, Hypertension. 2018;71(19):e127–248

Caffeine

• Potential activation of the sympathetic nervous system

• More pronounced in males and African‐Americans

• Caffeine in 2‐3 cups of coffee can raise as much as 10 mmHg (average is 3‐5 mmHg)

• Tolerance usually develops

• Caffeine content in drinks vary

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Grossman E, Am J Med. 2012 Jan;125(1):14‐22. Whelton PK, Hypertension. 2018;71(19):e127–248Image: http://www.theprospect.net/a‐users‐guide‐to‐caffeine‐11237

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Antidepressants

• Venlafaxine‐SNRI‐3‐13%

–Meta‐analysis showed increase

• Dose dependent

• Older patients

• Men

– Elevated diastolic BP (>90 mmHg) was statistically at doses > 300 mg/day

• Monoamine oxidase inhibitors‐selegiline

• Thioridazine‐in overdose


Immunosuppressive Agents

• Cyclosporine‐BLACK BOX WARNING

– Can be mild to severe and up to 80%

– 1 year after renal transplant 32.7‐81.6%

– Bone marrow transplants 57% incidence of HTn vs. 4% with methotrexate

– Cardiac transplant‐may be up to 100%

• Tacrolimus‐associated much less than cyclosporine


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Recombinant Human Erythropoietin

• Dose‐related• Reported to develop (or worsen) in 20‐30% of patients

• May appear as early as 2 weeks and as late as 4 months

• Increase risk– Pre‐existing HTN, genetic predisposition, rapid rise in hematocrit

• Can be controlled with dialysis and antihypertensives


Alcohol

• Excessive intake can raise BP and resistance to antihypertensives

• Increase in prevalence of 7‐11%

• Prospective cohort study

– ~4,000 Japanese men

– Greater in those who consume > 300 g/week

• Also can see HTN with disulfiram

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Grossman E, Am J Med. 2012 Jan;125(1):14‐22.Whelton PK, Hypertension. 2018;71(19):e127–248

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Anti‐vascular Endothelial Growth Factor (VEGF)

• Bevacizumab– Dose related– Severe HTN (>200/100) >3‐5‐fold higher– Up to 32% – More pronounced in elderly, preexisting HTN, renal cell

carcinoma

• Sorafenib– Study using 24‐hour ambulatory BP monitoring, 400 mg twice a

day increased systolic BP by 8.2 mm Hg, and diastolic BP by 6.5 mm Hg within 24 hours of treatment

• Sunitinib– Increased risk of severe HTN‐relative risk 22.7, 95% CI 4.48‐

115.29 (p= 0.001) in comparison to controls

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Grossman E, Am J Med. 2012 Jan;125(1):14‐22.Whelton PK, Hypertension. 2018;71(19):e127–248

Adverse effects of VEGF inhibitors

50Rigas G. Current Vascular Pharmacology (2018) 16: 23.

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Antiretroviral therapy‐Protease Inhibitors

• May increase more than 10 mmHg (systolic or diastolic)

• Elevations more likely in elderly, higher baseline systolic BP, higher cholesterol, low CD4 count

• Usually seen more with the therapy that causes metabolic changes

– Highest risk with lopinavir/ritonavir

• Drug interaction with calcium channel blockers

51Grossman E, Am J Med. 2012 Jan;125(1):14‐22.

Herbal Products

• Yohimbine– Increases norepinephrine and sympathetic activation

– Interacts with clonidine

• Ginseng– Information to suggest increase or decrease

• Ma huang/ephedra–Many case reports involving young adults

• St John’s Wort

52Grossman E, Am J Med. 2012 Jan;125(1):14‐22.

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53http://www.heart.org/HEARTORG/

Patient Case

• 76 year old female presents to the pharmacy with a new prescription for clonidine. When talking with the patient, she reports “my doctor put me on another new medication to help control my high blood pressure”

• Current medications: hydrochlorothiazide 25 mg daily, losartan 100 mg daily, metoprolol 50 mg twice daily, amlodipine 10 mg daily

• She reports that her blood pressures at home are in the “150s on the top”

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Patient Case (continued)

• When you question her about any medications that she takes OTC or supplements‐she reports that she takes ibuprofen 3 tabs daily for her arthritis and ginger to help with her nausea.

• You also verify how (and if) she is taking all of her medications.

• What medications might be worsening her blood pressure?

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Strategies to Help with Adherence

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• Simplify the regimenS

• Impart knowledgeI

•Modify patients’ beliefs and behaviorM

• Provide communications and trustP

• Leave the biasL

• Evaluate adherenceEMillionhearts.hhs.gov

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Conclusion

• Hypertension affects many Americans

• Controlling hypertension can help prevent complications

• In most cases, the cause of hypertension is unknown

• Identifying agents that can increase blood pressure can help patients to improve control

• All patients should follow lifestyle modifications

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Contact Information

• [email protected]

• [email protected]

• 405‐948‐4900

extension 494

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References• Benjamin EJ, Muntner P, Alonso A, et al. on behalf of the American Heart Association Council on

Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2019 update: a report from the American Heart Association [published online ahead of print January 31, 2019]. Circulation. doi: 10.1161/CIR.0000000000000659. Accessed May 2, 2019.

• Heart Disease and Stroke Statistics 2019 Infographic https://healthmetrics.heart.org/heart‐disease‐and‐stroke‐statistics‐2019‐infographic/ Accessed May 2, 2019.

• Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. A Report of the American college of cardiology/American heart association task force on clinical practice guidelines. Hypertension. 2018;71(19):e127–248.

• Chobanian AV, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (2003). National Heart, Lung, and Blood Institute; National High Blood pressure Education Program Coordinating Committee. Hypertension. 2003; 42: 1206‐1252

• Ogden LG, et al. Long‐term absolute benefit of lowering blood pressure in hypertensive patient according to the JNC VI risk stratification. Hypertension 2000; 35: 539‐543.

• James PA, Oparil S, Carter BL, et al. 2014 evidence‐based guideline for the management of high blood pressure in adults. JAMA 2014;311:507‐20.

• Grossman E, Messerli FH. Drug‐induced hypertension: an unappreciated cause of secondary hypertension. Am J Med. 2012 Jan;125(1):14‐22. doi: 10.1016/j.amjmed.2011.05.024.

• Rigas G. Kalaitzidis, Elisaf MS. “Uncontrolled Hypertension and Oncology: Clinical Tips”, Current Vascular Pharmacology (2018) 16: 23.

• Gyamlani G, Geraci SA. Secondary Hypertension due to Drugs and Toxins. South Med J. 2007 Jul;100(7):692‐9.

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References• Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension

in the community. J Clin Hypertens 2014;16:14‐26.

• Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013;29:528‐42.

• Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens 2013;31:1281‐357.

• American Diabetes Association (ADA). Standards of medical care in diabetes – 2019. Diabetes Care Jan 2019, 42 (Supplement 1) DOI: 10.2337/dc19‐Sint01. Accessed Jan 21, 2019.

• Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2019. American Diabetes Association. Diabetes Care Jan 2019, 42 (Supplement 1) S103 S123; DOI: 10.2337/dc19‐S010

• Smith SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update. Circulation 2011;124:2458‐73.

• Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl 2012;2:337‐414.

• Aronow WS. Drug‐induced causes of secondary hypertension. Ann Transl Med. 2017;5(17):349. doi:10.21037/atm.2017.06.16

• Onusko E. Diagnosing secondary hypertension. Am Fam Physician. 2003 Jan 1;67(1):67‐74.

• Armstrong EP, Malone DC The impact of nonsteroidal anti‐inflammatory drugs on blood pressure, with an emphasis on newer agents. Clin Ther. 2003 Jan;25(1):1‐18.

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Self‐Check

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Post‐Assessment Question:What is the leading cause of death in the United

States?

a. Heart disease

b. Cancer

c. Accidents

d. Influenza

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Post‐Assessment Question:A patient has blood pressure readings in the

clinic that are consistently 136/82. How would you classify his blood pressure?

a. Normal

b. Elevated

c. Stage 1 HTN

d. Stage 2 HTN

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Post‐Assessment Question:Which of these medications can be associated with increasing blood

pressure?

a. Cyclosporine

b. Erythropoietin

c. Indomethacin

d. All of the above

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65http://www.taxguru.net

Stress‐Does it increase BP?

Caution: Contents Under Pressure

Identifying Drug‐Induced Hypertension

Melanie Claborn, Pharm.D., BCACP

Assistant Professor of Pharmacy Practice

Southwestern Oklahoma State University College of Pharmacy

Clinical Pharmacy Specialist‐Oklahoma City Indian Clinic

Oklahoma City, OK

66

caution: contents under pressure identifying drug‐induced ......obesity physical inactivity...

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