Medication & You >> Drug Interaction

Drug Interaction

Introduction

Whenever two or more drugs are taken concurrently, there is a chance that there will be an interaction among the drugs. Drug interaction is a situation in which a substance affects the activity of a drug. Drug interactions may make the drug less effective, cause unexpected side effects, or increase the action of a particular drug. Some drug interactions can even be harmful or fatal. It is reported that 20-30% of all adverse reactions to drugs are caused by interactions between drugs. This incidence increases among the elderly and patients who take two or more medications.

There are various substances and/or factors that can alter the pharmacodynamics and/or pharmacokinetics of medications. The likelihood of drug interactions increases as the number of drugs being taken by a patient increases. These drug interactions are broadly categorized into:

• drug-drug interaction – occurs when two or more drugs react with each other. For example, combining warfarin with aspirin will cause potential increased risk of bleeding and increase INR.
• drug-food/beverage interaction – occurs when the drugs react with the intake of food/beverages. For example, tetracyclines will interact with the calcium found in dairy products (or supplement) to form chelation and the absorption of tetracyclines will be hindered. The antibacterial effect is thus reduced due to decreased body’s ability to absorb tetracyclines.
• Drug-conditions interaction – occurs when an existing health condition make certain drugs potentially harmful. For example, beta-blockers such as metoprolol and atenolol, which are used to treat hypertension can worsen the symptoms of asthma and deteriorate the severity of COPD.

Mechanism of Drug Interaction

There are a number of mechanisms by which drugs interact with each other, and most of them can be divided into two general categories: pharmacodynamic and pharmacokinetic interactions. Pharmacodynamic interactions can occur when two or more drugs have mechanisms of action that result in the same physiological outcome. Pharmacodynamic interactions can be:

• additive (effect of two drugs is the sum of the effects of each);
• synergistic (effect of two drugs is greater than the sum of their effects when used alone);
• antagonistic (drugs with opposing effects can reduce the response to one or both drugs).

Pharmacokinetic interactions involve one drug or substance altering the absorption, distribution, metabolism or elimination of another drug or substance. An interaction can result when there is a change in: (1) the absorption of a drug into the body; (2) distribution of the drug in the body; (3) metabolism of the drug; and (4) elimination of the drug from the body.

(1) Changes in absorption

Most drugs are absorbed into the blood and then travel to their sites of action. There are various potential mechanisms through which the absorption of drugs can be reduced. These mechanisms include an alteration in blood flow to the intestine, metabolism (alteration of the drug) by the intestine, increased or decreased intestinal motility (movement) within the intestine, alterations in acidity in the stomach, and a change in the bacteria of the intestine. For example, calcium (as found in diary product or supplement) will interact with tetracyclines to reduce its absorption. This may lead to failure of therapy or warrant an increase in the dose of the affected drug.

(2) Changes in distribution of drug

Changes in distribution of drugs can occur when 2 or more drugs compete for the protein- or tissue-binding sites. Drug interactions due to protein binding effects are relatively uncommon and usually not clinically significant. The affected drug can have enhanced pharmacologic action and can lead to overdose/toxicity. Examples include warfarin and cotrimoxazole, and digoxin and quinidine. Drugs that are highly protein bound, have a narrow therapeutic index, occupy most of the available binding sites, and have a small volume of distribution and a long half-life are most prone to this type of interaction.

(3) Changes in metabolism

Most drugs are eliminated through the kidney in either an unchanged form or as a by-product that results from the metabolism (alteration) of the drug by the liver. Some drugs are able to reduce or increase the metabolism of other drugs by the liver or their elimination by the kidney. Most drug metabolism takes place in the liver, but other organs also may play a role (e.g., the kidneys). The cytochrome P450 (CYP 450) enzymes are a group of enzymes in the liver that are responsible for the metabolism of most drugs. They are, therefore, often involved in drug interactions.

• Enzyme induction - drug A induces the body to produce more of an enzyme which metabolises drug B. This reduces the effective concentration of drug B, which may lead to loss of effectiveness of drug B. Drug A effectiveness is not altered. Example of CYP 450 enzyme inducers include carbamazepine, phenytoin, nevirapine dan St. John’s Wart.
  
• Enzyme inhibition – drug A inhibits the CYP-mediated metabolism of drug B, causing drug B to accumulate within the body to toxic levels, possibly causing an overdose. Example of CYP 450 inhibitors include cimetidine, erythromycin and grape fruit juice.

Additionally, drug interactions might occur in other way: drug A influences drug B, and drug B influences drug A in another way

(4) Changes in elimination

Interactions caused by alterations in elimination occur from reduced renal excretion of one drug by another. For example, when mixing probenecid and penicillins together, probenicid will block the active secretion of penicillins in the renal tubule, increasing penicillin's concentration and prolonging its activity. This probenecid-penicillins interaction is useful in certain infections requiring particularly high concentration of penicillins.  Alterations in urinary pH can also affect elimination. Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate to produce urine with a pH ≥7.5. For example, urinary alkalinization increases salicylate elimination during the treatment of salicylate toxicity.

Conclusion

Drug interactions are complex and chiefly unpredictable. A known interaction may not occur in every individual. The likelihood of the occurrence of drug interaction also depends on the differences among individuals in physiology, age, lifestyle (diet, exercise), underlying diseases, drug doses, the duration of combined therapy, and the relative time of administration of the two substances. Thus, to minimize the risk of such potential interactions and to improve the success of the therapy, patients should provide healthcare providers a complete list of all the drugs the patients are using or have used within the last few weeks.

Last Reviewed: 03 August 2009