Drug interaction

Drug interactions happen when a substance like food, drink, or another drug alters how a medication works. A well-known example is grapefruit juice affecting how certain drugs are broken down. These interactions can occur when two substances target the same receptor, either directly or indirectly. For instance, taking Zolpidem with alcohol can overstimulate GABAA receptors, potentially causing loss of consciousness. When two drugs affect each other, it is called a drug–drug interaction (DDI), and the risk grows as more medications are taken. Many older adults regularly use five or more medications or supplements, which significantly raises the chance of side effects from DDIs.

There are three types of drug interactions: additive (the combined effect is simply the sum of each drug’s individual effect), synergistic (the combined effect is greater than expected), and antagonistic (the combined effect is smaller than expected). It can be hard to tell synergistic and additive interactions apart because individual drug effects vary. Direct interactions between drugs are also possible, especially when they are mixed before an intravenous injection. For example, mixing thiopentone and suxamethonium can cause thiopentone to precipitate.

Pharmacodynamic interactions occur at a biochemical level, mainly through biological processes. They happen when drugs act on the same target, like a receptor or signaling pathway. If two drugs act on the same receptor, they are called homodynamic. Homodynamic effects include pure agonists (bind to the main receptor site and produce a similar effect), partial agonists (bind to a secondary site and produce a weaker effect), and antagonists (bind to the main site but produce the opposite effect). Antagonists can be competitive (they compete with the main drug for the receptor) or uncompetitive (they bind irreversibly). Drugs that act on different receptors but share similar downstream pathways are called heterodynamic competitors. Interactions can also occur through signal transduction. For example, low blood glucose triggers the release of catecholamines, which cause symptoms that prompt eating. If a patient takes insulin (which lowers blood sugar) and also beta-blockers, the body is less able to handle an insulin overdose.

Pharmacokinetic interactions involve how drugs are absorbed, transported, distributed, metabolized, and excreted. Compounds can affect any of these processes, altering drug availability. For absorption, drugs that change intestinal motility can affect other drugs. Prokinetic agents speed up digestion, which may reduce absorption by moving drugs through too quickly. Changing pH can also affect absorption. Drugs exist in ionized or non-ionized forms depending on their pKa, and neutral forms are usually better absorbed. Antacids can raise pH and inhibit absorption of drugs like zalcitabine, tipranavir, and amprenavir. Conversely, cimetidine can stimulate absorption of didanosine. Some sources suggest a two- to four-hour gap between such drugs to avoid interaction. High-fat foods can alter drug solubility, as seen with oral anticoagulants and avocado. Non-absorbable complexes can form through chelation—for example, calcium in dairy products can bind tetracycline or fluoroquinolones, reducing absorption. Drugs like sucralfate bind to proteins, especially if those proteins have high bioavailability, so its use is contraindicated with enteral feeding. Some drugs affect absorption by acting on P-glycoprotein in enterocytes, which is one way grapefruit juice increases the bioavailability of certain drugs beyond its effect on first-pass metabolism.

For transport and distribution, drugs may compete for plasma proteins like albumin. The first drug to arrive binds to the protein, leaving the other drug free in the plasma, which changes its expected concentration. The body usually compensates by increasing clearance, so these interactions are rarely clinically relevant unless there are other problems, like issues with excretion.

Many drug interactions stem from changes in metabolism. Human drug-metabolizing enzymes are typically activated through nuclear receptors. A key system involved is the cytochrome P450 oxidase enzyme family.