Clinical Therapeutics and the Recognition of Drug-Induced Disease

Case Study
NSAIDS in a Geriatric Patient

Presenting History

A 68 year old mildly obese female with known hypertension and adult onset diabetes mellitus (DM) presents to the emergency room (ER) complaining of chest pain and shortness of breath (SOB) of 3 days duration. She is currently taking digoxin, hydrochlorothiazide (HCTZ), potassium chloride (KCl), cimetidine, tolazamide for 1 year and a new analgesic nonsteroidal anti-inflammatory drug (NSAID) called "ALLPROFEN" for low back pain for the past 5 days. (Note: "ALLPROFEN" is a hypothetical new analgesic.) The patient has no known drug allergies. Her physical exam is unremarkable except for a presystolic cardiac extra sound (S4). Her blood pressure is 150/90 sitting, heart rate is 80 and regular. Lab: ECG shows LVH and nonspecific ST-T wave changes.

List at least four major possible etiologies for chest pain in this patient.

1. [Cardiac origin, e.g., coronary artery disease (CAD) or congestive heart failure. The patient has a history of hypertension and adult onset diabetes which are major risk factors for CAD. In addition, she is taking digoxin and HCTZ consistent with previous history of congestive heart failure.]

2. [Noncardiac musculoskeletal chest wall pain.]

3. [Noncardiac pain originating from the gastrointestinal tract which can present as chest pain similar to cardiac disease. This includes hiatal hernia with reflux esophagitis-gastritis, etc. related to previous disorder (the patient is on cimetidine) or a new problem related to the new NSAID.]

4. [Pulmonary embolus]

List at least three important points (positive or negative) that should be ascertained from this patient's history regarding chest pain.

1. [The PQRST symptom analysis of pain. This includes questions about Provocative-palliative factors, Quality, Region, Severity, and Temporal characteristics of pain.⁽²⁶⁾]

2. [Prior history of similar symptoms and clinical course (diagnosis and treatment).]

3. [If a specific disease entity is suspected, e.g., coronary artery disease (CAD) or gastroesophageal reflux disorder, other pertinent points might include family history of similar disorder and compliance with current drug regimen related to cimetidine.]

Hospital/Home Course

She is admitted to the CCU for further observation. The ER physician decides to maintain all of her current medications but discontinue the new NSAID. The patient does well clinically over the next 24 hours. The cardiac enzymes are normal and the ECG remains unchanged. The patient is then discharged home on her regular medications except for the new NSAID. At home, the back pain returns 3 days later. She decides to take the NSAID analgesic which had been previously prescribed and goes to bed. Within 1 hour after taking this medication, she develops dyspnea, wheezing, tightness and pain in the chest which radiates to the left shoulder and down her left arm.

She returns to the ER. The exam is essentially unchanged from her previous visit except for some bibasilar rales. Her BP is 160/95. Heart rate is 90 and regular. ECG shows ST-T wave changes consistent with ischemia.

List your top two etiologies for chest pain and dyspnea.

1. [Ischemic heart disease secondary to coronary artery disease.]

2. [An ADE associated with ALLPROFEN. This is somewhat problematic given the temporal sequence. One general mechanism for NSAID - induced ADEs relates to their pharmacologic effect (inhibition of prostaglandins) on the kidney leading to sodium and fluid retention. This could theoretically precipitate congestive heart failure and lead to nocturnal angina pectoris. It is doubtful, however, that a single dose could produce this effect. However, more plausible could be an allergic pulmonary drug reaction which could account for the SOB and wheezing. The patient may have taken NSAIDs in the past. Allergic reactions with NSAIDs are thought to involve several mechanisms including pharmacologically mediated reactions and an immune response to a chemical antigen or cross-sensitization (i.e., classical anaphylaxis).]

If your list included an adverse drug reaction, what should you do, if anything?

1. [Treat the patient symptomatically for ischemic heart disease. In addition, supportive therapy including nasal oxygen and possible diphenhydramine should be considered for the possible allergic drug reaction.]

2. [Check relevant drug information sources such as the PDR for previous reports of allergic reactions associated with ALLPROFEN.]

3. [Report this possible allergic drug reaction to your hospital drug monitoring committee even if you are not sure that is was definitely an adverse drug reaction.]

Subsequent Course:

The patient is started on several new medications including nitroglycerin and an ACE inhibitor. She is told to discontinue the NSAID and to take acetaminophen prn for back pain.

Six months later, the patient undergoes arthroscopic chondroplasty and a partial meniscectomy of the left knee under epidural anesthesia with 2% mepivacaine. The anesthetic wears off and she complains of throbbing knee pain 2 hours after the procedure. She receives ketorolac 30 mg IM with prompt relief. Thirty minutes later the patient is discharged, but collapses in the hospital lobby. The hospital administrator who happens to be in the lobby calls code "blue". The code team arrives and finds the patient unresponsive, cyanotic, hypotensive (BP-50/30) with urticaria and a palpable carotid pulse of 80.

List the two most likely causes of her problem.

1. [Anaphylactic shock secondary to ketorolac. The constellation of sudden collapse associated with hypotension, wheezing, and urticaria is classic. However, if urticaria was not present, then an acute MI would be a real possibility.]

2. [Acute MI with cardiogenic shock.]

An airway is established and she is started on O₂ with positive pressure ventilation. She regains consciousness and begins to wheeze. Epinephrine (1 mg) is administered followed by IV fluids. By the next day, the patient is stabilized with return of her usual blood pressure and normal breathing.

You now think that the above syndrome of sudden collapse associated with hypotension, urticaria and wheezing 30 minutes after taking ketorolac may be drug related but you are not sure.

What are your responsibilities to report this suspected ADE to your hospital monitoring committee?

[Clearly, this serious reaction needs to be reported even if you are not absolutely sure it was caused by the drug in question.]

What should the hospital monitoring committee do about reporting this suspected ADE?

[Clearly, this serious reaction should be reported to MEDWATCH/FDA. This is true even if this kind of anaphylactic reaction has been documented in the PDR and thus is a known ADE of ketorolac.]

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