hypokalemia and st elevation induced by angiotensin ii … · · 2013-07-29ic.6the...

Vol. 4, No. 3, 2004 • The Journal of Applied Research476

bination for 1 month, was evaluatedwith lethargy, restlessness, atypical chestpain, and presyncope at our emergencyroom. She had ST elevation in D2, D3,aVF, and severe hypokalemia.

INTRODUCTIONNumerous studies have evaluated theantihypertensive efficacy of angiotensinII receptor antagonists in patients withmild to moderate or severe hyperten-sion.1-5 The antihypertensive effective-ness of angiotensin II receptorantagonists is potentiated by the addi-tion of a small dose of a thiazide diuret-ic.6 The valsartan/hydrochlorothiazide(VAL-HCT) combination was generallymore effective than either drug givenalone.7

The incidence of adverse events invalsartan plus hydrochlorothiaziderecipients was not significantly differentthan that in placebo recipients.

Hypokalemia and ST ElevationInduced by Angiotensin II Type 1Receptor Blocker and ThiazideDiuretic Combination *Huseyin Gunduz, MD*Huseyin Arinc, MD†Ramazan Akdemir, MD ‡Ali Tamer, MD*†Hakan Ozhan, MD*Cihangir Uyan, MD

*Abant Izzet Baysal University, Izzet Baysal Medical Faculty, Department of Cardiology, Bolu,Turkey.†Abant Izzet Baysal University, Duzce Medical Faculty, Department of Cardiology, Duzce,Turkey.‡Abant Izzet Baysal University, Izzet Baysal Medical Faculty, Department of Internal Medicine,Bolu, Turkey.

KEY WO R D S : Va l s a r t a n /h y d r o c h l o r o t h i a z i d e, h y p o k a l e m i a ,ST elevation

ABSTRACTThe combination of an angiotensin IItype 1 receptor blocker (valsartan) anda thiazide diuretic (hydrochlorothiazide)has been evaluated in the treatment ofpatients with hypertension in severalclinical trials. The valsartan/hydrochloro-thiazide (VAL-HCT) combination wasfound to be generally more effectivethan either drug given alone.

The incidence of adverse events inVAL-HCT recipients was not signifi-cantly different than in placebo recipi-ents. Valsartan attenuated thehydrochlorothiazide-associated decreasein serum potassium concentrations.

In this report, a 73-year old femalepatient, who after using VAL-HCT com-

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Headache, dizziness, and fatigue werethe most common adverse events occur-ring in clinical trials. Valsartan attenuat-ed the hydrochlorothiazide-associateddecrease in serum potassium concentra-tions; hypokalemia occurred in 4.5% ofvalsartan plus hydrochlorothiaziderecipients.7

CASEA seventy three year old female patientwas evaluated at our emergency room inDuzce Medical faculty with symptoms oflethargy, restlessness, atypical chest pain,and presyncope. The patient had hyper-tension for 10 years and she was takingVAL-HCT 160/12.5 mg for 1 monthafter the discontinuation of ACEinhibitor due to dry cough. Other car-diovascular risk factors were not pres-ent.

Physical examination revealed sys-tolic blood pressure of 90/60 mmHg, reg-ular heart rate of 96 bpm, 37˚C fever,and 3/5 muscular strength. Other find-ings were normal, as was chest x-ray. TheECG showed sinusal rhythm, 1 to 2 mmST elevation on D2, D3, aVF, and a neg-ative T wave on AVL (Figure 1). Bloodcount, CK-MB, CPK, D-dimer, were all

normal, Troponin T was negative andother laboratory values were as follows:sodium, 128 mEq/L; potassium, 1.7 Eq/L;pH, 7.50; bicarbonate, 32 mEq/L.

The patient was triaged to the coro-nary care unit with a prediagnosis ofacute inferior myocardial infarction.Thrombolytic therapy, 1.5 million unitsof streptokinase in 1 hour IV, was given.In addition, potassium (K+) replacementat 40 meq/hour was started because ofhypopotasemia.

One hour later, ST elevationsresolved and chest pain subsided (Figure2). Serum potassium rose to 2.7 meq/ L.During the 1-week follow up at the car-diology clinic, cardiac enzymes did notrise. At the transthorasic echocardiogra-phy, a left ventricular wall motionabnormality was not seen and ejectionfraction was 63%. Coronary arteries,visualized at the coronary arteriography,were normal. Ergonovine provocationwas performed to exclude Prinzmetal’sangina, but the result was normal. Inaddition, the myocardial perfusion imag-ing did not show any perfusion defects.

DISCUSSIONThe results of the antihypertensive treat-

The Journal of Applied Research • Vol. 4, No. 3, 2004 477

Figure 1. ST elevation on D 2,3, AVF at 9 AM.


ment studies show that the angiotensinII antagonists are as effective as ACEinhibitors, calcium antagonists, Beta-blockers, and diuretics.2-4 The antihyper-tensive effectiveness of angiotensin IIreceptor antagonists are potentiated bythe addition of a small dose of a thiazidediuretic.6

Valsartan blocks the vasoconstrictorand aldosterone-secreting effects ofangiotensin II by selectively blockingthe binding of angiotensin II to the AT1receptor in many tissues, such as vascu-lar smooth muscle and the adrenalgland. Its action is therefore independ-ent of the pathways for angiotensin IIsynthesis.6 ACE inhibitors andangiotensin receptor antogonists cancause hyperkalemia because of adecrease in aldosterone. This effect isusually not significant in patients withnormal renal function.8

Hydrochlorothiazide is a thiazidediuretic. Thiazides affect the renal tubu-lar mechanisms of electrolyte reabsorp-tion, directly increasing excretion ofsodium and chloride in approximatelyequivalent amounts. Indirectly, thediuretic action of hydrochlorothiazidereduces plasma volume, with consequentincreases in urinary potassium loss, plas-ma renin activity, and aldosterone secre-tion, and decreases in serumpotassium.9,10

Hypokalemia, defined as a plasmaK+ concentration less than 3.5 mmol/L,may result from one (or more) of thefollowing: decreased net intake, shiftinto cells or increased net loss.11,12 Theclinical manifestations of K+ depletionvary greatly between individual patients,and the severity depends on the degreeof hypokalemia. In patients withoutunderlying heart disease, abnormalitiesin cardiac conduction are extremelyunusual, even when the serum potassiumconcentration is below 3.0 mmol/L. Inpatients with cardiac ischemia, heart fail-ure or left ventricular hypertrophy, how-ever, even mild-to-moderatehypokalemia increases the likelihood ofcardiac arrhythmias.13-15

The electrocardiographic changes ofhypokalemia are due to delayed ventric-ular repolarization and do not correlatewell with the plasma K+ concentration.Early changes include flattening orinversion of the T wave, a prominent Uwave, ST-segment depression. Severe K+depletion may result in a prolonged PRinterval, decreased voltage, and widen-ing of the QRS complex, and anincreased risk of ventricular arrhyth-mias, especially in patients with myocar-dial ischemia or left ventricularhypertrophy. None of these changes arespecific for hypokalemia.16

As noted above, ECG changes of


Figure 2. At 10 AM, 1 hour later, ST elevations resolved.


hypopotasemia are T wave flattening orinversion and ST segment depression.An increase in T wave amplitude is alsoreported, however, ST segment eleva-tion is very unusual.17 In our case, anatherosclerotic lesion that might causean ST elevation was not observed in thecoronary angiography. In addition, theergonovine test was negative. But, whenthe patient presented at our emergencyroom, she had severe hypokalemia andsystemic alkalosis and the coronary arte-riography was performed after theywere corrected. Therefore, the ST eleva-tion was thought to have been caused bya coronary artery spasm due to systemicalkalosis.

Diuretic therapy is the most com-mon cause of hypokalemia.Hypokalemia during diuretic therapy isthe result of excessive loss of potassiumin the urine (kaliuresis). All diuretics(thiazides, loop diuretics, and carbonicanhydrase inhibitors) produce kaliuresisand hypokalemia of variable severity.18

Thiazide diuretics have frequently beenrecommended as combination therapyin patients with mild to moderate hyper-tension. However, their undesirablemetabolic consequences have been sus-pected of contributing to increases incardiovascular morbidity and mortality.Even at low doses, there is a definitedecrease in potassium levels. The degreeof decrease in potassium levels has beenshown to be directly related to thehydrochlorothiazide dosage.19

In controlled trials comparing vari-ous doses of the combination of valsar-tan and hydrochlorothiazide, theincidence of hypertensive patients whodeveloped hypokalemia (serum potassi-um < 3.5 mEq/L) was 4.5%, and theincidence of hyperkalemia (serum potas-sium > 5.7 mEq/L) was 0.3%.9 HCT-induced hypokalaemia is less commonduring combination therapy.Hypokalaemia, associated with the useof thiazide diuretics, was more common-

ly reported in the higher dose HCT 25mg groups. 20 In controlled clinical trialsof valsartan/hydrochlorothiazide, theaverage change in serum potassium wasnear zero in subjects who received val-sartan/hydrochlorothiazide 160/12.5 mg,however, the average subject whoreceived valsartan/hydrochlorothiazide80/12.5 mg, 80/25 mg or 160/25 mg expe-rienced a mild reduction in serum potas-sium.20 Our patient, however, was on the160/12.5 mg form of VAL-HCT combi-nation for one month and other factorswhich could be responsible for severehypopotasemia were not present.

As a result, although it is knownthat ACEI and angiotensin II receptorblockers are capable of causing hyper-potasemia, it must also be kept in mindthat diuretic combinations of thesedrugs can cause hypopotasemia, espe-cially in older patients. Therefore,patients on thiazide should be carefullyfollowed for electrolyte imbalance suchas hypopotasemia, hypochloremic alka-losis, and hyponatremia periodically andwhen symptoms (ie, dry mouth, thirst,lethargy, restlessness, confusion, musclepain, cramps, muscle weakness, oliguria,tachycardia, nausea, vomiting) occur,serum electrolytes should be urgentlymeasured and necessary treatment insti-tuted.

REFERENCES1. Weber MA, Byyny RL, Pratt JH, et al. Blood

pressure effects of the angiotensin II receptorblocker, losartan. Arch Intern Med.1995;155:405-411.

2. Weir MR, Elkins M, Liss C, Vrecenak AJ,Barr E, Edelman JM. Efficacy, tolerabilityand quality of life of losartan, alone or withhydrochlorothiazide, versus nifedipine GITSin patients with essential hypertension. ClinTher. 1996,18:411-428.

3. Tikkanen I, Omvik P, Jensen HA.Comparison of the angiotensin II antagonistlosartan with the angiotensin convertingenzyme inhibitor enalapril in patients withessential hypertension. J Hypertens.1995;13:1343-1351.

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4. Goldberg AI, Dunlay MC, Sweet CS. Safetyand tolerability of losartan potassium, anangiotensin II receptor antagonist, comparedwith hydrochlorothiazide, atenolol, felodipineER, and angiotensin converting enzymeinhibitors for the treatment of systemichypertension. Am J Cardiol. 1995;75:793-795.

5. MacKay JH, Arcuri KE, Goldberg AI,Snapinn SM, Sweet CS. Losartan and low-dose hydrochlorothiazide in patients withessential hypertension. A double-blind, place-bo-controlled trial of concomitant administra-tion compared with individual components.Arch Intern Med. 1996;156:278-85.

6. Burnier M. Cardiovascular drugs: angiotensinII type 1 receptor blockers. Circulation.2001;103:904.

7. Wellington K, Faulds DM.Valsartan/hydrochlorothiazide: a review of itspharmacology, therapeutic efficacy and placein the management of hypertension. Drugs.2002;62:1983-2005.

8. Givertz MM. Manipulation of the renin-angiotensin system. Circulation.2001;104:E14-8.

9. Opie LH, Kaplan NM. Diuretics. In: OpieLH, ed. Drugs for the heart. Philadelphia, Pa:WB Saunders; 1991:74-99.

10. Field MJ, Stanton BA, Giebisch GH.Differential acute effects of aldosterone, dex-amethasone, and hyperkalemia on distaltubular potassium secretion in the rat kidney.J Clin Invest. 1984;74:1792-1802.

11. Gennari FJ. Hypokalemia. N Engl J Med.1998;339:451-458.

12. Schrock H, Kuschinsky W. Consequences ofchronic K+ depletion for the ionic composi-tion of brain, heart, skeletal muscle and cere-brospinal fluid. Miner Electrolyte Metab.1989;15:171-177.

13. Schulman M, Narins RG. Hypokalemia andcardiovascular disease. Am J Cardiol.1990;65:4-9.

14. Hoes AW, Grobbee DE, Peet TM, Lubsen J.Do non-potassium-sparing diuretics increasethe risk of sudden cardiac death in hyperten-sive patients? Recent evidence. Drugs.1994;47:711-733.

15. Krishna GG. Effect of potassium intake onblood pressure. J Am Soc Nephrol. 1990;1:43-52.

16. Isaac G, Holland OB. Drug-inducedhypokalemia. A cause for concern.Drugs Aging. 1992,2:35-41.

17. Weber S, Cabanes l, Simon JC, et al. Systemicalkalosis as a provocative test for coronaryartery spasm in patients with infrequent rest-ing chest pain. Am Heart J. 1998;115:54-59.

18. Mandal AK. Hypokalemia and hyperkalemia:Med Clin North Am. 1997,81:611-639.

19. Hollifield JW. Potassium and magnesiumabnormalities: diuretics and arrhythmias inhypertension. Am J Med. 1984;77:28-32.

20. Langtry HD, McClellan KJ.Valsartan/hydrochlorothiazide. Drugs.1999;57:751-758.



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