Absorption

Drugs that increase the speed of gastric emptying (e.g., laxatives, metoclopramide [Reglan]) may cause an increase in gastric and intestinal motility and a decrease in drug absorption. Most drugs are absorbed primarily in the small intestine; exceptions include barbiturates, salicylates, and theophylline (Theo-24), which undergo gastric absorption. Opioids and anticholinergic drugs (e.g., atropine) decrease gastric emptying time and gastrointestinal (GI) motility, causing an increase in absorption rate. For drugs that undergo gastric absorption, the amount or extent of absorption increases the longer the drug remains in the stomach.

When the gastric pH is decreased, a weakly acidic drug like aspirin is less ionized and more rapidly absorbed. Drugs that increase the gastric pH decrease absorption of weak-acid drugs. Antacids such as magnesium hydroxide (Maalox) and aluminum hydroxide (Amphojel) raise the gastric pH and block or slow absorption. Some drugs may react chemically. For example, tetracycline and the heavy-metal ions (calcium, magnesium, aluminum, and iron) found in antacids or iron supplements may lead to the formation of a drug complex and thus prevent the absorption of tetracycline. This phenomenon may also be observed when products that contain divalent cations are ingested with fluoroquinolone antibiotics such as ciprofloxacin (Cipro). Consequently, dairy products, multivitamins, and antacids should be avoided 1 hour before and 2 hours after tetracycline or ciprofloxacin consumption.

Certain cholesterol-lowering drugs, such as cholestyramine and colestipol, also form complexes with drugs like carbamazepine (Tegretol) and furosemide (Lasix). The drugs are then less soluble, resulting in reduced drug absorption. Drug complexation may be desired; for example, activated charcoal may be administered after toxic ingestion of a medication to decrease its absorption and, consequently, diminish or eliminate any untoward effects associated with the overdose.

Alteration of bacteria normally found in the GI tract may affect the pharmacokinetics of a medication. For example, intestinal microflora have the ability to metabolize digoxin (Lanoxin). Digoxin is a digitalis preparation that is used to treat heart failure and arrhythmias. Metabolism of this drug by gut bacteria decreases its bioavailability. Erythromycin, a macrolide antibiotic, and tetracycline are broad-spectrum antibiotics (effective against both gram-positive and gram-negative organisms) that destroy or inhibit the growth of these GI microflora. Consequently, the administration of one of these drugs to a patient on digoxin therapy may lead to an increase in the absorption of digoxin and, ultimately, to toxicity. Another example of this phenomenon occurs with oral contraceptives. Gut bacteria are necessary to hydrolyze estrogen conjugates into free estrogens so they may be optimally absorbed to exert their contraceptive effect. Concurrent antibiotic administration may alter these intestinal bacteria, impairing this process and preventing the optimal absorption and effectiveness of the oral contraceptive. A patient who takes oral birth control to prevent pregnancy should use a barrier form of protection during sex when she takes a course of antibiotics.

Distribution

A drug’s distribution to tissues can be affected by its binding to plasma/serum protein. Only drugs unbound to protein are free active agents and can enter body tissues. Two drugs that are highly protein bound and administered simultaneously can result in drug displacements. Factors that influence displacement of drugs are (1) drug concentration in the blood, (2) protein-binding power of the drugs, and (3) volume of distribution (Vd).

Two drugs that are highly bound to protein or albumin will compete for binding sites in the plasma. The result is a decrease in protein binding of one or both drugs; therefore, more free drug circulates in the plasma and is available for drug action. This effect can lead to drug toxicity. When two highly protein-bound drugs must be taken concurrently, the drug dosage of one or both drugs may need to be decreased to avoid drug toxicity.

Drugs that are highly protein bound include the anti­coagulant warfarin, anticonvulsants such as phenytoin and valproic acid, gemfibrozil (antihyperlipidemic), most non­steroidal antiinflammatory drugs (NSAIDs), sulfisoxazole (sulfonamide), glyburide (antidiabetic), and quinidine (antidysrhythmic). Warfarin (Coumadin) is 99% protein-bound, allowing only 1% to be free drug. If 2% to 3% of warfarin is displaced from albumin binding sites, the amount of free warfarin would be 3% to 4% instead of 1%. This action has the potential to increase the anticoagulant effect of warfarin; excess bleeding may result.

A significant decrease in serum albumin level because of liver disease or poor nutritional status can increase the free amount of highly protein-bound drugs such as phenytoin and warfarin, making more drug available to exert its pharmacologic effect.

Metabolism or Biotransformation

Many drug interactions of metabolism occur with the induction or inhibition of the hepatic microsomal system. A drug can increase the metabolism of another drug by stimulating liver enzymes. These enzymes produce a cascade effect in drug function. Drugs that promote induction of enzymes are called enzyme inducers. Barbiturates like phenobarbital are enzyme inducers. Phenobarbital increases the metabolism of most antipsychotics and methylxanthine (theophylline). Increased metabolism promotes drug elimination and decreases plasma concentration of the drug. The result is a decrease in drug action. Sometimes liver enzymes convert drugs to active or passive metabolites. The drug metabolites may be excreted or may produce an active pharmacologic response.

The anticonvulsant drugs phenytoin and carbamazepine and the antimicrobial medication rifampin are hepatic enzyme inducers that can increase drug metabolism—for example, for the anticoagulant drug warfarin. A larger dose of warfarin is usually needed while the patient takes a hepatic inducer, because metabolism aids in decreasing the amount of drug. If the drug inducer is withdrawn, warfarin dosages must be decreased, because less drug is eliminated by hepatic metabolism. Usually interaction occurs after 1 week of drug therapy and can continue for 1 week after the drug inducer is discontinued. Drugs with narrow therapeutic ranges should be closely monitored.

Some drugs are enzyme inhibitors. The antiulcer drug cimetidine (Tagamet) is an enzyme inhibitor that decreases metabolism of certain drugs such as theophylline, causing an increase in the plasma concentration of theophylline. The theophylline dose must be decreased to avoid toxicity. If cimetidine or any enzyme drug inhibitor is discontinued, the theophylline dosage should be adjusted. Other well-known hepatic enzyme inhibitors are erythromycin (an antibacterial) and itraconazole (an antifungal).

The use of tobacco and alcohol may have variable effects on drug biotransformation. Polycyclic aromatic hydrocarbons found in cigarette smoke induce production of the specific family of enzymes responsible for theophylline metabolism. Chronic cigarette smoking leads to an increase in hepatic enzyme activity and can increase theophylline clearance. Asthmatics who smoke and take theophylline to manage their disease may require an increase in theophylline dosage. The ingestion of alcohol may have variable effects on biotransformation. With chronic alcohol use, hepatic enzyme activities are increased; with acute alcohol use, metabolism is inhibited.

Natural or herbal products may also have an impact on metabolism. St. John’s wort, an OTC herbal product used to manage symptoms of depression, induces the metabolism of certain drugs such as warfarin, digoxin, and theophylline. This action potentially decreases the effectiveness of these medications, possibly necessitating a dose increase to sustain efficacy. Flavonoids, a group of naturally occurring compounds found in the juice and pulp of citrus fruits, are potent inhibitors of the metabolism of certain drugs. Patients who are stabilized on therapeutic doses of carbamazepine, diazepam, statins, calcium channel blockers, or erectile dysfunction drugs may subject themselves to adverse effects from greater-than-expected drug levels if they eat or drink grapefruit products concurrently with the drug.

Excretion

Most drugs are filtered through the glomeruli and excreted in the urine. With some drugs, excretion occurs in the bile, which passes into the intestinal tract. Drugs can increase or decrease renal excretion and have an effect on the excretion of other drugs. Drugs that decrease cardiac output, decrease blood flow to the kidneys, and decrease glomerular filtration rate can also decrease or delay drug excretion. The antiarrhythmic drug quinidine decreases the excretion of digoxin; therefore, the plasma concentration of digoxin is increased, and digitalis toxicity can occur.

Additive Drug Effect

When two drugs with similar action are administered, the drug interaction is called an additive effect and is the sum of the effects of the two drugs. Additive effects can be desirable or undesirable. For example, a desirable additive drug effect occurs when a diuretic and a beta blocker are administered for the treatment of hypertension. In combination, these two drugs use different mechanisms to have a more pronounced blood pressure–lowering effect. As another example, aspirin and codeine are two analgesics that work by different mechanisms but can be given together for increased pain relief.

An example of an undesirable additive effect is that from two vasodilators: hydralazine (Apresoline) prescribed for hypertension and nitroglycerin prescribed for angina. The result could be a severe hypotensive response. Another example is the interaction of aspirin and alcohol. Aspirin is directly irritating to the stomach, causes platelet dysfunction, and inhibits prostaglandin-mediated mucus production of the gastric mucosa, which protects the underlying tissues of the stomach. Alcohol disrupts the gastric mucosal barrier and suppresses platelet production. Both aspirin and alcohol can prolong bleeding time and, when taken together, may result in gastric bleeding.

Synergistic Drug Effect or Potentiation

When two or more drugs are given together, one drug can potentiate or have a synergistic effect on another. In other words, the clinical effect is substantially greater than the combined effect of the two. An example of this is the combination of meperidine (Demerol, synthetic opioid analgesic) and promethazine (Phenergan, antihistamine). One of the major side effects of promethazine is sedation. When used with meperidine in postsurgery patients, promethazine enhances or potentiates the drowsiness effect of meperidine. Less meperidine is required when it is combined with promethazine, which can be desirable. An example of an undesirable effect occurs when alcohol and a sedative-hypnotic drug, such as chlordiazepoxide (Librium) or diazepam (Valium), are combined. The resultant effect of this example is increased central nervous system (CNS) depression.

Some antibacterials (antibiotics) have an enzyme inhibitor added to the drug to potentiate the therapeutic effect. Examples are ampicillin with sulbactam (Unasyn) and amoxicillin with clavulanate (Augmentin), in which sulbactam and clavulanate potassium are bacterial enzyme inhibitors. Ampicillin and amoxicillin can be given without these inhibitors; however, the desired therapeutic effect may not occur because of the bacterial beta-lactamase, which inactivates the drugs and causes bacterial resistance. The combination of the antibiotic with either sulbactam or clavulanate inhibits bacterial enzyme activity and enhances the effect or broadens the spectrum of activity of the antibacterial agent. Not all bacteria secrete beta-lactamase enzyme; only those that do will inhibit these antibiotics and result in bacterial resistance. (Refer to Unit IX for information on antibacterial agents.)

Antagonistic Drug Effect

When two drugs that have opposite effects, or antagonistic effects, are administered together, each drug cancels the effect of the other. In other words, the actions of both drugs are nullified. An example of an antagonistic effect occurs when the adrenergic beta stimulant isoproterenol (Isuprel) and the adrenergic beta blocker propranolol (Inderal) are given together. Isoproterenol is a drug that is used in emergency situations to treat bradycardia, which is defined as a heart rate of less than 60 beats per minute. If given to a patient receiving a drug that decreases blood pressure and heart rate, the action of each drug is canceled. Neither drug delivers the expected therapeutic effect.

There are some situations in which the antagonistic effect is desirable. In morphine overdose, naloxone is given as an antagonist (antidote) to block the narcotic response. This is a beneficial drug interaction of an antagonist.