ACADEMIA Letters

Drug Interactions and Drug Interaction Checkers

Domina Petric

INTRODUCTION
Because individuals are living longer and accruing chronic diseases, practitioners have a new
responsibility to prescribe appropriately the many medications available to manage concur-
rent disease states. The plethora of pharmaceutical options must be balanced with the po-
tential risk of multiple medication use. These risks include, but are not limited to, adverse
effects, drug/drug interactions, drug/disease interactions and inappropriate dosing regimens.
Primary care health professionals such as physicians, physician assistants, and nurses have an
enormous opportunity to survey patients for this risk given their accessibility and roles in the
coordination of care (1).
While the most commonly used definition of polypharmacy is being on five or more
medicines, definitions are variable, which can cause confusion for researchers as well as
clinicians in practice. Numerical definitions of polypharmacy do not account for specific
comorbidities present and make it difficult to assess safety and appropriateness of therapy in
the clinical setting. There is a need for an internationally agreed definition of polypharmacy.
The results indicate the need for a shift towards the term ‘appropriate polypharmacy’ using a
holistic approach of assessing medication use in context of comorbidities present, according
to best available evidence in order to optimize health outcomes (2). I prefer the definition of
polypharmacy (polytherapy) as the necessary and justified use of multiple medication (5 or
more drugs), whilst polypragmasia (polypragmasy) would be the term for the inappropri-
ate use of multiple drugs that includes one of the errors: too many medications, duplication
of medications, dangerous drug-drug interactions or drug-disease interactions, and excessive
duration of pharmacotherapy.

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Domina Petric, [email protected]

Citation: Petric, D. (2021). Drug Interactions and Drug Interaction Checkers. Academia Letters, Article 3530.
https://doi.org/10.20935/AL3530.

1
 Patients, especially elderly and chronically ill, visit more than one physician. Sometimes
physicians do not pay attention on the drugs prescribed by other physician, and that is one of
the reasons why dangerous drug/drug interactions or drug/disease interactions can occur. The
role of general practitioners and family doctors is very important in coordinating polyphar-
macy and checking all the interactions between prescribed drugs, as well as over-the-counter
(OTC) drugs. Another cause of drug/drug interactions is self-medication. Patients rarely men-
tion to their primary care and other physicians, if they are using OTC drugs, and physicians
often forget to ask about it. Third reason for polypragmasia is lack of time. Physicians, both
primary care physicians and hospital specialists, are often overloaded with work and have too
many patients, so they do not have enough time for detailed pharmacological anamnesis.

DRUG INTERACTIONS
Drug interactions are changes in a drug’s effects due to recent or concurrent use of another
drug or drugs (drug-drug interactions), ingestion of food (drug-nutrient interactions), or in-
gestion of dietary supplements (dietary supplement-drug interactions).
A drug-drug interaction may increase or decrease the effects of one or both drugs. Clin-
ically significant interactions are often predictable and usually undesired. Adverse effects or
therapeutic failure may result. Rarely, clinicians can use predictable drug-drug interactions
to produce a desired therapeutic effect. For example, co-administration of lopinavir and ri-
tonavir to patients with HIV infection results in altered metabolism of lopinavir and increases
serum lopinavir concentrations and effectiveness. In therapeutic duplication, two drugs with
similar properties are taken at the same time and have additive effects. For example, taking
a benzodiazepine for anxiety and another benzodiazepine at bedtime for insomnia may have
a cumulative effect, leading to toxicity. In pharmacodynamic interactions, one drug alters
the sensitivity or responsiveness of tissues to another drug by having the same (agonistic)
or a blocking (antagonistic) effect. These effects usually occur at the receptor level but may
occur intracellularly. In pharmacokinetic interactions, a drug usually alters absorption, dis-
tribution, protein binding, metabolism, or excretion of another drug. Thus, the amount and
persistence of available drug at receptor sites change. Pharmacokinetic interactions alter mag-
nitude and duration, not type, of effect. They are often predicted based on knowledge of the
individual drugs or detected by monitoring drug concentrations or clinical signs (3).

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Domina Petric, [email protected]

Citation: Petric, D. (2021). Drug Interactions and Drug Interaction Checkers. Academia Letters, Article 3530.
https://doi.org/10.20935/AL3530.

2
Nutrient-Drug Interactions
Foods can enhance, delay, or decrease drug absorption. Foods impair absorption of many
antibiotics. They can alter metabolism of drugs. For example, high-protein diets can ac-
celerate metabolism of certain drugs by stimulating cytochrome P-450. Eating grapefruit
can inhibit cytochrome P-450 34A, slowing metabolism of some drugs (amiodarone, carba-
mazepine, cyclosporine, certain calcium channel blockers). Diets that alter the bacterial flora
may markedly affect the overall metabolism of certain drugs. Some foods affect the body’s re-
sponse to drugs. For example, tyramine, a component of cheese and a potent vasoconstrictor,
can cause hypertensive crisis in some patients who take monoamine oxidase inhibitors and eat
cheese. Nutritional deficiencies can affect drug absorption and metabolism. Severe energy
and protein deficiencies reduce enzyme tissue concentrations and may impair the response to
drugs by reducing absorption or protein binding and causing liver dysfunction. Changes in the
gastrointestinal tract can impair absorption and affect the response to a drug. Deficiency of
calcium, magnesium, or zinc may impair drug metabolism. Vitamin C deficiency decreases
activity of drug-metabolizing enzymes, especially in older people (4).

Transporter-Mediated Drug-Drug Interactions

Drug transporters are considered to be determinants of drug disposition and effects/toxicities
by affecting the absorption, distribution, and excretion of drugs. Drug transporters are gener-
ally divided into solute carrier (SLC) family and ATP binding cassette (ABC) family. Widely
studied ABC family transporters include P-glycoprotein (P-GP), breast cancer resistance pro-
tein (BCRP), and multidrug resistance proteins (MRPs). SLC family transporters related to
drug transport mainly include organic anion-transporting polypeptides (OATPs), organic an-
ion transporters (OATs), organic cation transporters (OCTs), organic cation/carnitine trans-
porters (OCTNs), peptide transporters (PEPTs), and multidrug/toxin extrusions (MATEs).
These transporters are often expressed in tissues related to drug disposition, such as the small
intestine, liver, and kidney, implicating intestinal absorption of drugs, uptake of drugs into
hepatocytes, and renal/bile excretion of drugs. Most of therapeutic drugs are their substrates
or inhibitors. When they are co-medicated, serious drug-drug interactions may occur due to
alterations in intestinal absorption, hepatic uptake, or renal/bile secretion of drugs, leading to
enhancement of their activities or toxicities or therapeutic failure (5).

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Domina Petric, [email protected]

Citation: Petric, D. (2021). Drug Interactions and Drug Interaction Checkers. Academia Letters, Article 3530.
https://doi.org/10.20935/AL3530.

3
DRUG INTERACTION CHECKERS
There are several available free Drug Interaction Checkers (DICs) on the internet, as well as
applications for mobile phone, such as Drug Interaction Checker on Drugs.com, Multi-Drug
Interaction Checker Medscape, Drug Interaction Checker WebMD, as well as more detailed
DICs such as Lexicomp (UpToDate) and Micromedex.

EXAMPLES OF IMPORTANT DRUG INTERACTIONS

Alcohol. Chronic alcoholism results in enzyme induction. Acute alcoholic intoxication tends
to inhibit drug metabolism. Severe alcohol-induced hepatic dysfunction may inhibit ability
to metabolize drugs. In the case of acetaminophen, there is an increased formation of hepato-
toxic acetaminophen metabolites in chronic alcoholics. Patients who take oral anticoagulants
may have increased hypoprothrombinemic effect with acute alcohol intoxication. Central ner-
vous system depressants have additive or synergistic effect with alcohol on central nervous
system depression. Acute alcohol intake may increase hypoglycemic effect of insulin, espe-
cially in fasting patients. In patients that take acitretin and drink alcohol there may be an
increased conversion of acitretin to etretinate. Etretinate is teratogenic. Drugs that may pro-
duce a disulfiram-like reaction are cephalosporins, chloral hydrate, disulfiram, metronidazole
and sulfonylureas.
Oral anticoagulants. These drugs are metabolism inducible and susceptible to inhibi-
tion of CYP2C9-mediated metabolism. Oral anticoagulants highly bound to plasma pro-
teins. Drugs that may increase anticoagulant effect are acetaminophen, amiodarone, an-
abolic steroids, chloramphenicol, cimetidine, clofibrate, clopidogrel, danazol, dextrothyrox-
ine, disulfiram, erythromycin, fluconazole, fluoxetine, gemfibrozil, lovastatin, metronidazole,
miconazole, nonsteroidal anti-inflammatory drugs, propafenone, quinidine, salicylates, sulfin-
pyrazone, sulfonamides, thyroid hormones, trimethoprim-sulfamethoxazole, voriconazole, al-
cohol and allopurinol. Drugs that may decrease anticoagulant effect are aminoglutethimide,
barbiturates, bosentan, carbamazepine, cholestyramine, glutethimide, nafcillin, phenytoin,
primidone, rifabutin, rifampin, St. John´s wort and oral hypoglycemics.
Digitalis glycosides. Digoxin is susceptible to alteration of gastrointestinal absorption.
Digitalis toxicity may be increased by drug-induced electrolyte imbalance (hypokalemia).
Digitoxin is metabolism inducible. Renal and non-renal excretion of digoxin is susceptible
to inhibition. Drugs that may increase digitalis effect are amiodarone, azithromycin, clar-
ithromycin, diltiazem (additive AV conduction effect), erythromycin, potassium-depleting
drugs (increased likelihood of digitalis toxicity), propafenone, quinidine, spironolactone and

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Domina Petric, [email protected]

Citation: Petric, D. (2021). Drug Interactions and Drug Interaction Checkers. Academia Letters, Article 3530.
https://doi.org/10.20935/AL3530.

4
verapamil (additive AV conduction effect). Drugs that may decrease digitalis effect are kaolin-
pectin, rifampin and sulfasalazine.
NSAID. Prostaglandin inhibition may result in reduced renal sodium excretion, impaired
resistance to hypertensive stimuli and reduced renal lithium excretion. Most NSAIDs inhibit
platelet function and thus, may increase likelihood of bleeding due to other drugs that im-
pair hemostasis. NSAIDs decrease hypertensive response to ACE inhibitors, angiotensin II
receptor blockers, hydralazine and decrease hypertensive, diuretic and natriuretic response to
furosemide and thiazide diuretics. NSAIDs may increase methotrexate toxicity. Combined
with SSRIs they may increase risk of bleeding due to platelet inhibition (6).

CONCLUSION
Drug interactions are very important cause of morbidity and mortality. Today´s availability
of OTC drugs and increased self-medication emphasizes the need of physician´s awareness.
Detailed pharmacological anamnesis with drug interaction checkup should be a part of every
pharmacological anamnesis, both in primary care settings and in hospitals. Very important
factor in preventing polypragmasia is good education of patients, especially when it comes
to OTC drugs and self-medication. Good communication between physician and patient is
crucial in establishing high quality polypharmacy in patients with comorbidities. It may be
useful to create a mobile application for patients, a simplified patient-oriented Drug Interac-
tion Checker, so that patients can check themselves drug-drug interactions before buying a
new OTC drug. Drug Interaction Checkers for professionals are based on generic name of the
drug, thus making it difficult for the patient´s use. Patient-oriented Drug Interaction Checker
should be made using Brand Name of the drug, so that the patient can easily check for interac-
tions. Possible problems in establishing good control of polypharmacy and drug interactions
are financial, institutional, organizational and lack of time.

REFERENCES
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3. Lynch SS. Drug Interactions. Jul 2019. Retrieved from https://www.msdmanuals.com/

Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Domina Petric, [email protected]

Citation: Petric, D. (2021). Drug Interactions and Drug Interaction Checkers. Academia Letters, Article 3530.
https://doi.org/10.20935/AL3530.

5
 professional/clinical-pharmacology/factors-affecting-response-to-drugs/drug-interactions
(Accessed on September 8, 2021)

4. Youdim A. Nutrient-Drug Interactions. May 2019. Retrieved from https://www.msdmanuals.

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(Accessed on September 8, 2021)

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Academia Letters, September 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0

Corresponding Author: Domina Petric, [email protected]

Citation: Petric, D. (2021). Drug Interactions and Drug Interaction Checkers. Academia Letters, Article 3530.
https://doi.org/10.20935/AL3530.