Affiliation：Monash University,Victoria 3168,Australia

Drug interactions;Drug incompatibility;Comorbidity

1　History

Li Heng is a 60 year old nurse with a 12 year history of osteoarthritis of the hands and knees treated with paracetamol initially and subsequently with the non-steroidal anti-inflammatory agent(NSAID)-diclofenac.She has a strong family history of cardiovascular disease including stroke,coronary artery disease and cardiac failure.About 3 years ago she developed mild hypertension(145/90 mm Hg) for which she was managed with conservative lifestyle measures.The hypertension persisted.Voltaren was ceased and the selective COX-2 inhibitor-meloxicam(Mobic) instituted to continue treating the pain of her persistent osteoarthritis.It provided satisfactory relief.

However in the past two years she had progressed to significant moderate hypertension(170/100 mm Hg) and was commenced on beta blockers.She had a relatively poor response to beta-blockers and in addition developed bronchial asthma which she last experienced as a child and teenager.

2　Questions

2.1What are the significant adverse effects and interactions of these NSAIDs?

2.2What is the current status of beta-blockers as a first line treatment for hypertension?

2.3What would be your next step in the management of her hypertension?

3　Answers

3.1NSAIDs including aspirin have many important adverse effects including gastrointestinal e.g.ulceration and bleeding,hypersensitivity including rash,liver and kidney dysfunction,fluid retention and elevation of blood pressure.

3.2Beta blockers which should be used with caution in anyone with a history of asthma are not regarded as first line agents for hypertension but useful where angina is present.

3.3An appropriate first line agent is an angiotensin converting enzyme inhibitor(ACEI).

4　Further history

The beta blocker was discontinued and Li was commenced on the ACE inhibitor agent -perindopril.The dose was increased to 10 mg per day but she developed a distressing cough and the angiotensin II receptor antagonist(ARB)-irbesartan was substituted.She tolerated this agent well to the maximum dose of 300mg a day but the BP remained unsatisfactory at 160/95 mm Hg.A decision was made to add hydrochlorothiazide to the irbesartan so the combined tablet 300 mg/12.5 mg was introduced.Jackpot! The BP settled to 130/80 mm Hg so she continued taking the combined ARB-diuretic agent and meloxicam.

5　Subsequent history

About 3 months after satisfactory hypertensive control Li presented with what she describes as malaise and deteriorating health.She felt tired and weak,anorexic and nauseated,depressed with lack of concentration and difficulty sleeping,discomfort in the flanks and shortness of breath on minimal exertion.She described reduced output of urine.

Examination revealed a sluggish sick looking woman.There was evidence of reduced cognition(intellectual clouding).Vital signs were pulse 90/min,BP 140/90 mm Hg,respiration rate 16/minute,temp 37.5 ℃.There were fine crackles at the lung bases and mild pitting oedema of the ankles.Urinalysis was positive for albumen.

6　Further questions

6.1What is your provisional diagnosis?

6.2What are first line investigations?

6.3What is the cause of the problem?

7　Answers of further questions

7.1The patient has evidence of kidney failure and cardiac failure.The typical clinical features of acute kidney failure(AKF) namely malaise,anorexia and nausea,altered sensorium,oliguria and pale skin were present.

7.2Investigations should include serum electrolytes,urea and creatinine,eGFR,full blood examine,urine microscopy and culture.A rise in urea and creatinine,albuminuria,and elevated serum potassium and phosphate support the diagnosis.A reduced eGFR supports the diagnosis but is not as reliable in AKF as it is in chronic KF.

7.3The key issue here is the triple drug exhibition of an ARB,thiazide diuretic and a NSAID.This combination can be nephrotoxic and precipitate pre-renal kidney failure and is known as the ′triple whammy effect′.Aspirin also causes the triple whammy syndrome so careful surveillance of drugs is mandatory.

Note:a potentially lethal drug combination is that of allopurinol with azathioprine or 6-mercaptopurine.