Who is the “real murderer” in the drug case mystery?

Author: Shi Yanling

On this day, a worried lady came to the pharmacy clinic and asked anxiously: "Pharmacist, I have stomachache after taking these two drugs. Can you help me see if these two drugs are the cause?" I checked the drugs the lady brought and found that they were alendronate sodium tablets and calcium carbonate D3 tablets. The usage and dosage on the drug labels were all normal. To determine whether the drug caused the patient's stomach discomfort, it is necessary to collect the patient's physical condition, disease status and medication information, and then combine the evaluation method of the causal relationship of adverse drug reactions to find the "real culprit".

1. Collect relevant information

I asked: "Do you usually have a history of stomach pain or stomach diseases such as gastric ulcers, gastritis, etc.?"

The lady said: "I never had stomach pain or stomach problems before."

I continued to ask: "Apart from these two drugs, do you take any other drugs? When did you start taking these two drugs? How many times did you take them? How did you take them? How long did you take the drugs before you had stomach pain? How long did the stomach pain last?"

The lady slowly recalled and answered, "I have only taken these two medicines during this period, and I started taking them yesterday. I took the two medicines with water after breakfast yesterday morning. I only took them once. I stopped taking the medicine today because I started to have stomach pain. I have had stomach pain for several hours."

Knowledge link:

1. Adverse drug reactions

Adverse drug reactions refer to harmful reactions that are unrelated to the purpose of medication and occur when a qualified drug is used in normal dosage and usage. [1]

2. Evaluation methods for causal relationships of adverse drug reactions

The evaluation method for causal relationships of adverse drug reactions used in my country is the method recommended by the WHO Uppsala Monitoring Center.

(1) Five evaluation criteria:

① Time connection: Is there a reasonable sequence between the time of starting medication and the time of occurrence of adverse reactions?

②Past history: whether the suspected adverse reaction is consistent with the known adverse reaction type of the drug, and whether there have been reports and comments on the reaction to the drug in the past;

③ Confounding factors: whether the suspected drug can be explained by the effects of co-medication, the patient's clinical symptoms or the effects of other therapies;

④ The results after drug withdrawal: whether the reaction disappears or is alleviated after stopping the drug or reducing the dosage;

⑤ The result of re-administration of the drug: whether the same reaction occurs when the adverse reaction symptoms are eliminated.

(2) Five grading standards: The law divides the degree of causality into five levels: certain, probable, possible, doubtful and impossible.

① Affirmation: The time sequence since medication is reasonable; the reaction is consistent with known adverse drug reactions; it cannot be reasonably explained by combined medication or the patient's disease; the reaction stops after discontinuation of medication; the reaction reappears after re-administration of medication;

② Very likely: the time sequence is reasonable; the reaction is consistent with the known adverse drug reactions; it cannot be reasonably explained by combined medication or the patient's disease; the reaction stops after stopping the drug; there is no repeated medication;

③ Possible: reasonable time sequence; consistent with known adverse drug reactions; the patient's disease or other treatments may also cause the same result;

④ Suspicious: The time sequence is reasonable; it cannot be reasonably explained by combined medication and patient disease;

⑤ Impossible: can only be explained by concurrent medication and the patient’s illness; does not meet the other criteria listed above. [2]

2. Analysis

The patient took the medicine yesterday and had stomach pain today. The time sequence is reasonable. The instructions for alendronate sodium tablets list reported esophageal adverse reactions such as esophagitis, esophageal ulcers and esophageal erosions. The instructions for calcium carbonate D3 tablets list adverse reactions such as abdominal pain, diarrhea, gastrointestinal bloating and other gastrointestinal discomfort. The stomach pain symptoms that the patient experienced after taking the medicine are consistent with the known adverse reactions of the two drugs. The patient did not take other drugs and had no stomach pain or stomach diseases in the past, so it cannot be reasonably explained by combined medication and the patient's disease. Although the patient only took the medicine once, the stomach pain did not ease temporarily, so it cannot be determined that the reaction stopped after stopping the drug; as of the time of consultation, the patient did not use repeated medication. The degree of causal relationship between the two drug adverse reactions is temporarily determined to be "possible", that is, the patient's stomach pain may be caused by the two drugs.

I continued to analyze that the patient took the two medicines with water after breakfast yesterday morning. This is a wrong way to take alendronate sodium tablets. Compared with the calcium supplement calcium carbonate D3 tablets, alendronate sodium tablets are more likely to be the "real culprit" causing the patient's stomach pain.

Knowledge link:

Alendronate sodium tablets are a bisphosphonate that can be used as a specific inhibitor of osteoclast-mediated bone resorption. They are suitable for the treatment of osteoporosis in postmenopausal women and osteoporosis in men to increase bone mass. Alendronate sodium tablets can cause local irritation to the upper gastrointestinal mucosa, so they need to be taken according to the following method:

1. Alendronate sodium tablets can only be used in the morning on a fixed day of the week;

2. It must be taken with a full glass of water (175-250 ml) at least half an hour before the first meal, drink or other medication of the day, because other drinks (including mineral water), food and some drugs may reduce the absorption of alendronate sodium tablets and thus weaken its effect.

3. Patients should avoid lying down for at least 30 minutes after taking the medicine and before the first meal of the day.

4. Alendronate sodium tablets should not be taken at bedtime or before getting up early in the morning, otherwise it will increase the risk of esophageal adverse events.

5. Taking calcium supplements at the same time may interfere with the absorption of alendronate sodium tablets. You must wait at least half an hour after taking alendronate sodium tablets before taking calcium supplements. [3]

I told the lady the results of my analysis and suggested that she temporarily stop taking alendronate sodium tablets and go to a gastroenterology specialist for examination and treatment. After the stomach pain is relieved, she can try taking alendronate sodium tablets strictly according to the above-mentioned medication precautions to observe whether the adverse reaction of stomach pain occurs again. If no adverse reaction occurs, she can continue to take the medicine. If stomach pain occurs, stop taking the medicine immediately and seek medical attention.

3. Identify the “Real Murderer”

The patient followed my advice and received treatment. Follow-up revealed that his stomach pain was relieved and he took alendronate sodium tablets correctly without any adverse reactions. Through careful investigation, we were able to determine that the real culprit for the patient's stomach pain was that he did not take alendronate sodium tablets correctly.

Improper use of medicines may not only fail to exert their therapeutic effects, but may also cause adverse drug reactions. Therefore, you need to read the instructions carefully before using the medicines and use the medicines strictly in accordance with the doctor's instructions and precautions.

[1] Wu Yi and Zheng Xiaoyu. Measures for the Reporting and Monitoring of Adverse Drug Reaction[J]. Judicial Business Selection, 2011(22):12.DOI:CNKI:SUN:YWWX.0.2011-22-004.

[2] Kan Quancheng. Advanced Course of Hospital Pharmacy[M]. Chinese Medical Electronic Audiovisual Publishing House, 2018.

[3] Alendronate sodium tablets instructions. Savio Industrial SrL2019-12-10.