The patient is a 79 year old woman of Chinese ethnic origin admitted to hospital with a vertebral fracture sustained by falling over in her home. The patient felt light headed and lethargic when she fell over. She also suffers from cellulitis, the inflammation of the skin, in her right leg and the accompanying symptoms of high fever, drowsiness and lethargy.
She has no known allergies. She is currently suffering from hypertension, insulin-dependent diabetes, depression, chronic cardiac failure, atrial fibrillation and low vitamin D levels.
She is taking metoprolol, digoxin, insulin glargine, sertraline, frusemide, aspirin, and flucloxacillin, whose mechanisms of action are discussed in detail below, along with the interaction between these drugs.
Metoprolol is a cardio-selective beta-blocker used to treat hypertension, myocardial infarction and chronic heart failure. Consistent with the patient’s report of light headedness, one of metoprolol’s adverse side effects is dizziness.
Metoprolol targets beta receptors and competitively blocks beta adrenergic receptors to inhibit sympathetic drive to the heart. Metoprolol preferentially blocks beta-1 receptors with little or no effect on beta-2 receptors. Orally administered, as in the case of the patient, metoprolol exhibits immediate release with rapid and complete absorption. Metoprolol is metabolised in the liver by the CYP2D6 pathway with an elimination half-life of 3-4 hours. The patient’s dose of 25mg twice daily is the maintenance dosage for hypertension and myocardial infraction.
Metoprolol interacts seriously with digoxin. Its toxicity is increased markedly when taken with digoxin, by unspecific interaction mechanisms. Metoprolol also increases the pharmacodynamics synergism of digoxin, thereby increasing its effects. Both metoprolol and digoxin increase serum potassium, and should be used with caution. It is recommended that an alternative combination of drugs is used if it is proposed that digoxin is to be administered.
Digoxin is a cardiac glycoside used to treat congestive heart failure and to slow the heart rate of patients with atrial fibrillation. Administered at the elderly-adult maintenance dosage of 125mcg each morning, digoxin increases the force of myocardial contraction by inhibiting sodium/potassium ATPase pump in myocardial cells, which subsequently promotes the release and availability of stored intracellular calcium. Dizziness is an adverse side effect, as is depression which is less common.
As discussed in the section for metoprolol, digoxin increases the toxicity of metoprolol and metoprolol increases the effects of digoxin. It is recommended that digoxin be avoided if metoprolol is to be used. The effect of digoxin is increased by pharmacodynamic synergism if taken in conjunction with furosemide, and should be used with caution or monitored. In addition, the interaction of digoxin with glucloxacillin, if both taken in oral form, is such as to increase the level or effect of digoxin by altering the intestinal flora. Review should be given to the medication, dose and form.
Insulin Glargine, also known as Lantus, is a synthetic form of a hormone that is produced in the body. It is administered to improve glycemic control in adults with types 1 or 2 diabetes and lower the level of glucose in the blood. With an onset action of 3-4 hours upon administration, insulin glargine is a long-acting insulin that exhibits relatively constant glucose-lowering profile within 24 hours of its administration. Its mechanism of action is by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production to lower blood glucose levels.
The patient’s insulin glargine dose of 100U per night is quite high and, if administered intravenously, appears to exceed the maximum dose of 80 units per injection. This dose may need to be reviewed, as the adverse effects of insulin, particularly if overdosed, include erythema, the inflammation of the skin in reddening patches, a cardinal sign of cellulitis which the patient reportedly suffers from. The patient reports to be insulin-dependent. The dosage of insulin glargine should be monitored closely, in conjunction with her symptoms of erythema, and adjusted accordingly.
The effect of insulin glargine is increased when taken with aspirin through pharmacodynamic synergism. The increase is minor and its significance is not known, but caution should nevertheless be exercised.
Sertraline is administered to treat the patient’s major depressive disorder. It works by inhibiting the pre-synaptic re-uptake of serotonin. It is metabolised by hepatic cytochrome P450 enzymes with a half-life of 26 hours. Dizziness and rashes are common adverse side effects. The patient’s dosage of 50mg each morning is the maintenance dose.
Sertraline will increase the effect or level of metoprolol by affecting hepatic enzyme CYP2D6 metabolism. It should be used with caution and the dose reviewed. Sertraline and aspirin both increase the toxicity of each other and care should be taken in administering both together. Sertraline has minor interactions with furosemide through pharmacodynamics synergism, but the effect is minor.
Frusemide, also known as furosemide, is a loop diuretic (water pill) that prevents the body from absorbing too much salt and building up fluid due to heart failure, liver scarring or kidney disease. Loop diuretics work by inhibiting the re-absorption of sodium and chloride ions at proximal and distal renal tubules and by interfering with chloride-binding co-transport systems. In the case of the patient, frusemide is most likely administered to reduce hypertension cause by fluid retention. Dizziness is a side effect, as is fainting and less frequently, skin rash.
Its administration at 80mg twice daily is within the recommended dosage, although a maximum maintenance dosage of 1g daily is possible.
The interaction of frusemide when administered alongside of metaprolol is unclear. Metoprolol and furosemide have opposite effects on serum potassium and it is possible that the efficacy of frusemide is reduced when administered with metoprolol. Metoprolol increases serum potassium, while furosemide decreases serum potassium and their combined usage should be monitored closely. Aspirin can decrease the effect of metoprolol by pharmacodynamic antagonism and they both can increase serum potassium.
Aspirin has anti-inflammatory, anti-platelet and analgesic actions. It prevents synthesis of prostaglandins by non-competitively inhibiting both forms of cyclo-oxygenase. It can inhibit platelet aggregation in the blood, thereby thinning blood in elderly patient. For the patient, aspirin is likely to be administered to treat atrial fibrillation and to reduce her symptoms of fever associated with cellulitis as well as a pain reliever.
An adverse side effect of taking aspirin for the patient is that it may exacerbate heart failure and hypertension. Aspirin induces reduction in glomerular filtration rate and renal blood flow, thereby causing sodium and fluid retention.
The patient’s dosage of 100 mg each morning is below the recommended dosage of 300-900 mg every 4-6 hours as necessary. It is unknown whether her administration of aspirin, being below the recommended dose, actually assists with her fever symptoms and pain. This should be reviewed.
Aspirin decreases the effects of metoprolol by pharmacodynamics antagonism for extended use (longer than 1 week). Aspirin, digoxin, and metoprolol all increase serum potassium, and the effect of that should be monitored. Aspirin increases serum potassium, while furosemide decreases serum potassium. Aspirin might decrease slightly the effect of furosemide by pharmaco-dynamic antagonism. Aspirin and flucloxacillin, when taken together, increase the level of the other by plasma protein binding competition or decreasing renal clearance and should be administered with care.
Flucloxacillin is a type of penicillin that works to fight infections. It has bactericidal effects in interfering with bacterial cell wall peptidoglycan synthesis by binding to penicillin-binding proteins. It treats staphylococcal skin infections, in the case of the patient, caused by cellulitis. Flucloxacillin should be administered with precaution in patients with sodium restriction or the risk of heart failure, as each injection of flucloxacillin contains approximately 50.6 mg of sodium per gram.
Like penicillin, flucloxacillin is most effective during the stage of active multiplication of bacterial. Inadequate concentrations may produce only bacteriostatic effects.
The patient’s dose of flucloxacillin, if administered orally, exceeds the recommended adult oral dosage of 250-500 mg every 6 hours, up to a maximum of 4g per day. If administered intravenously, then she is taking the higher dosage of 2g per 6 hours, up to a maximum of 12 g daily.
To summarise the drug interactions discussed above, metoprolol and digoxin exhibit the strongest adverse interactions and consideration should be given to avoiding taking both together or prescribing an alternative mediation.
Aspirin exhibits interaction with the greatest number of other drugs, and attention should be paid in particular to its interaction with sertraline, both of which increase the toxicity of the other. Although not interacting in an adverse or toxic way, aspirin’s interactions with metoprolol, by decreasing its effect, and its slight decrease of the effect of furosemide should be considered when prescribing the patient’s dosage of those medicines.
Review of Medication
Given aspirin’s interaction with several of the patient’s other medications, consideration should be given to an alternative anti-coagulant medication to treat atrial fibrillation, and medication targeting the fever and pain associated with her fracture.
Recent studies show that aspirin has been overused as a primary prevention for cardiovascular disease in patients with diabetes. In another unrelated study with relevant findings, also published in 2016, the researchers’ analysis of 295,000 participants with atrial fibrillation at risk of stroke showed that 40.2% were treated with aspirin alone. The researchers found that having hypertension and a past myocardial infraction were factors that were associated with aspirin prescription instead of anti-coagulant treatment. Having a higher body mass index (or being male) was associated with being treated with an oral anti-coagulant. The researchers concluded that in at least one-third of the cases, patients qualifying for anti-coagulants were prescribed aspirin and they stress that aspirin is not an anticoagulant and is ineffective in the prevention of thromboembolism related to non-valvular atrial fibrillation.
For elderly patients, in particular, research has found in favour of the use of anticoagulation therapy. In a study published in 2007, 973 patients aged 75 and over with atrial fibrillation were given warfarin (the common anticoagulant) or aspirin. After 2.7 years, a follow up showed 24 strokes in patients given warfarin and 48 in patients given aspirin. The result was statistically significant, and the researchers concluded that anticoagulation therapy should be preferred to aspirin in patients over the age of 75 years who have atrial fibrillation, unless there are contraindications or if the patients decides that the benefits are not worth the inconvenience.
Another more recent study of 41,810 Swedish participants with non-valvular atrial fibrillation published in 2014, researchers confirmed findings of earlier experiments that patients were undertreated with anti-coagulant and that half of the high-risk patients who were treated with aspirin were obvious candidates for anticoagulant treatment. As our patient has no evident contraindications to the use of anticoagulants, consideration can be given to their use as an alternative to aspirin, which exhibits interaction with several of her other current medications.
It’s noted that the patient currently takes no medication for her Vitamin D deficiency. Her light-headedness is most likely the combined side-effect of several drugs she currently takes all of which report dizziness as a common adverse effect. This, along with the symptoms of the patient’s cellulitis, most likely contributed to her fall at home causing her vertebral fracture.