Check Programme

Case one

Basil Carmody is a 79 years old patient who has been attending the practice for over 10 years. He has an active problem list of benign prostatic hypertrophy, osteoarthritis, hypertension and mild asthma. His medications included ramipril (Tritace) which he had been taking regularly for the last 3 years, occasional use of salbutamol and diclofenac (Voltaren) which was introduced three days ago for osteoarthritis of his back and hands. He attends on Monday morning, with a history of noticing mild upper lip swelling on Saturday evening as he went to bed. When he woke on Sunday morning, he had significant swelling of both upper and lower lips, as well as mild facial and tongue swelling. He had not noticed any throat swelling, or increased asthma symptoms. He took his ramipril as usual, but stopped his diclofenac as his arthritis was better. He attended the Emergency Department at the local hospital, where he was given antihistamines and oral steroids. The lip and face swelling gradually subsided over the day.

Careful review of his history did not reveal any other food or medication ingestion associated with his lip and facial swelling. Prior to the onset of swelling, he had taken his daily dose of ramipril as usual on Saturday morning, and had taken a total of a dose of diclofenac on Friday morning and evening, and Saturday morning. On physical examination there was some residual swelling noticeable in his lower lip. His blood pressure was 140/95.

HK Pract 2001;23:566-567

Question 1
What is the likelihood that the angioedema was due to the diclofenac, given that it was just introduced?

Answer 1
In trying to assess the cause of suspected adverse drug reactions, a detailed history needs to be taken to address the following questions:

• What was the temporal relationship between drug ingestion and the onset of reaction?
• Was the nature of the reaction consistent with known or reported reactions to the drug?
• Were there other drugs or underlying condition(s) which may have been responsible?
• Did the condition improve/resolve with cessation of the drug?

Feedback
In this context, the most recently commenced drug was diclofenac and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to cause urticaria and angioedema. However, the time delay of nearly 12 hours before the onset of the reaction (last dose on Saturday morning, and reaction on Saturday evening), makes this unlikely. The mechanism of NSAID-induced angioedema or urticaria is probably due to inhibition of the cyclooxygenase enzyme in susceptible individuals with generation of lipid mediators such as leukotrienes. From experience, and cases reported in the literature, this occurs within 2-3 hours of drug ingestion. However as there are no diagnostic skin or blood tests available, rechallenge is the only confirmatory test, if indicated.

Question 2
What is the likelihood that ramipril was the cause, given he has taken it for 3 years without problems, and that he had taken a dose on the Sunday morning after the swelling developed?

Answer 2
Angioedema occurring in the setting of taking an angiotensin converting enzyme (ACE) inhibitor is due to the ACE inhibitor until proven otherwise. It occurs in 0.1% to 0.5% of patients taking these drugs, and affects about 1 in 2500 patients during the first week of exposure. However, angioedema can first appear from a few hours to 8 years after an ACE inhibitor is first taken. The probable mechanism is an increase in bradykinin levels, as due to inhibition of enzymes which also break down bradykinin (ACE and neutral endopeptidase). As with NSAIDs there are no confirmatory diagnostic skin or blood tests available. However, episodes of angioedema should cease as soon as the drug is stopped and not recur. Basil should not be prescribed ACE inhibitors again.

Question 3
What other antihypertensive agents are appropriate for Basil?

Answer 3
Given his history of asthma, calcium antagonists and/or diuretics may be suitable to treat his mild hypertension.

Question 4
What about using angiotensin II receptor antagonists in Basil's case?

Answer 4
Rare instances of angioedema have also been reported with angiotensin receptor antagonists, and they may not be mediated by bradykinin. Given they are due to different mechanisms, it may be reasonable to prescribe it for Basil, but to be used with caution.

Question 5
What about taking aspirin or NSAIDs in the future?

Answer 5
Given the indication for taking NSAIDs for his arthritis in the future, as well as aspirin for possible ischaemic heart disease, Basil was referred to an Allergy Clinic.

Feedback
He was challenged with oral aspirin and did not have any reaction. It would be safe for him to use NSAIDs and aspirin in the future from this point of view.

Royal Australian College of General Practitioners