Through the eons of evolution, our ancestors developed a digestive tract which breaks down foods into amino acids, carbohydrates and lipids. With the addition of water, electrolytes, microelements and vitamins, the body thrives. However, among the edible berries, tubers, beasts and other vittels lurked compounds that were not only useless for the body, but even dangerous.
These "foreign" substances [ xenobiotics (xenoV = foreigner or stranger)] had to be neutralized and eliminated when the compounds found access to the interior of the body. Gradually a system developed in the small intestine and especially in the liver where foreign substances would be trapped, metabolized and neutralized before excretion by bile or urine. That system is now known as the "Cytochrome P-450 Isozymes1" (CYP450) in the liver and gut wall. This ingenious trapping mechanism is set up in anticipation of detoxifying chemicals that the body has never seen before. Thus, the need for a chemically omnivorous neutralizing machine!
Our body will manipulate many drugs as xenobiotics.1 Consequently, the intended action of a drug (pharmacodynamics) is greatly influenced by the fate of the drug once it is inside the body (pharmacokinetics). In addition, the pharmacokinetic processes of absorption, distribution, excretion and especially metabolism are susceptible themselves to interactions by drugs which are taken concurrently. The drugs affected by the interaction are called the "substance" drugs. The drugs producing the interaction are termed the "precipitant" drugs. The precipitant drug can slow down the metabolic breakdown (inhibitors) or speed up the metabolic breakdown (inducers).2 Even with normal doses, the concentration of an affected drug may be excessively increased through inhibition of its metabolism and become dangerous; conversely, the concentration of a drug may be overly reduced through rapid breakdown and become subtherapeutic.
To penetrate through the different membranes most drugs have to be relatively lipid-soluble, and yet they must be dissolved before they can be absorbed through the gastrointestinal (GI) tract. Most drugs will solubilize easily with or without food with the help of digestive enzymes. For some drugs, the dissolution process is greatly dependent upon the acidity of the stomach. Ketoconazole and powdered itraconazole need an acid milieu, while didanosine and indinavir need a neutral environment for dissolution.
A few drugs bind readily to bivalent or trivalent cations, such as aluminum, iron, zinc, magnesium or calcium, even calcium in dairy products. As complexed drugs, the tetracyclines and ciprofloxacin are not soluble and cannot be easily absorbed; therefore, their concentrations will be subtherapeutic.
After absorption into the circulation, most drugs are bound to plasma proteins, primarily albumin. Bound to a protein, a drug is inactive, but the protein-drug complex easily dissociates. Free drugs diffuse readily into the body's compartments and tissues, except for the brain, eyes and prostate, where penetration may be difficult. Recommended drug dosages are adjusted for protein-binding. If two protein-bound drugs are used simultaneously, the more weakly bound drug will be displaced. The increased free drug concentration of the displaced drug can exert the effect of an overdosage. For instance, sulfonamides will displace warfarin, such that the warfarin dose must be reduced when a need for concomitant sulfonamide therapy arises.
The body considers most drugs as xenobiotics which have to be metabolized and/or eliminated through bile or urine. A rare drug will be eliminated unchanged by the kidney or biliary tract. Most drugs, unchanged, cannot be adequately filtered through the glomeruli or secreted in the bile, and whatever amount is filtered or secreted will be reabsorbed by the tubules and the intestinal tract. Therefore, the body will have to make hydrophilic conjugates out of these strange compounds.
There are four possible pathways with regard to the metabolism of drugs before elimination:
Most metabolites are inactive, but some have their own intrinsic activity, e.g. desacetyl-cefotaxime. Some metabolites are the primary drugs whose pharmacodynamic properties are sought with the administered drug only being a prodrug. For example, amoxicillin becomes ampicillin, famciclovir becomes penciclovir, and codeine becomes morphine. The metabolite often has different physical chemical properties from the parent compound, e.g. pK or dissociation constant.
Over forty different enzymes belong to the CYP450 isozyme system. A special nomenclature has been developed to identify these enzymes. CYP, the designate of the system, is followed by an arabic number to designate the family, followed by a capital letter for the subfamily, and finally an arabic number again for the gene1. Only 10 or 11 cytochrome enzymes are involved in the biotransformation of drugs (Table 1), with the major enzymes being CYP1A2, CYP 2C, CYP 3A4 and CYP3A6. Drug interactions involve the metabolic breakdown by the cytochrome P-450 isozymes whose action can be diminished (inhibited) by certain drugs or augmented (induced) by other drugs. When a substrate drug is exposed to these modified CYP450 enzymes, that drug can accumulate to toxic levels in the face of a paralyzed CYP450 system. Alternatively, a drug can be metabolized so rapidly by the primed CYP450 enzymes that it becomes ineffective or less active due to its rapid elimination.3
Metabolic inhibition can be either competitive or noncompetitive. Competitive inhibition is the more common with reversible inhibition at the enzyme's site. Once the enzyme is inhibited, the return to action of the enzyme is dependent upon the half-life of the inhibiting drug. For example, delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, inhibits indinavir's metabolism via CYP3A4 for 24 hours after a single dose, whereas amio-darone's interaction through CYP2C9 may last up to 30 days because of its long half-life.4 The free amiodarone molecules have to be cleared from the blood before the competitively bound molecules can be released and become active. The second type of metabolic inhibition is noncompetitive; the inhibiting drug permanently inactivates the CYP enzyme through a nonreversible chemical reaction. Chloramphenicol is such an inhibitor of CYP2C9.2 This pattern of inhibition is much less common.
The priming or induction of a CYP enzyme also relies on the half-life of the inducing drug. In addition, drugs used in the treatment of HIV-1, mostly the protease inhibitors (PIs) and NNRTIs, may either inhibit or induce the CYP enzymes. For instance, the combination of saquinavir, a PI, and delavirdine, an NNRTI, both inhibit CYP3A: the saquinavir concentration increases five-fold, while delavirdine levels are reduced 20%.5
Renal elimination can be altered by changes in the glomerular fitration or in tubular secretion. Trimethoprim/sulfamethoxazole and probenecid inhibit tubular secretion of certain drugs (many penicillins and cephalosporins, acyclovir, lamivudine). Biliary excretion is only compromised in patients with severe liver failure. Drugs with a dual excretion can find a "safety valve" through biliary excretion in the case of renal insufficiency, and vice versa.
At this moment more than 50 drugs are being used in HIV-1-infected patients for treatment of HIV-1 disease, or for the prophylaxis or therapy of opportunistic infections. More than 140 new drugs are undergoing testing, some of which are already at the Food and Drug Administration (FDA) to be released soon. Drug-drug interactions cannot be avoided. Even with the help of a computer program dedicated to drug interactions, no one can predict what is going to happen to a patient who takes a multitude of drugs, not to mention foods and products from the health food store. Most interactions are not dangerous and are inconsequential; some are even desirable.6 In the world before the AIDS epidemic, investigators discovered the incidence of dangerous drug-drug interactions became exponentially higher when more than five drugs were used at a given time in a given patient.7 This is still true today.
Therefore, physicians treating HIV-1-infected patients end up inventing for themselves a set of rules based on the principles outlined above, a modus operandi that has delivered a certain degree of predictability and safety.8,9 Still, monitoring their patients by history, physical examination and laboratory tests is a necessity since every person can and will react differently. If a new combination of drugs is indicated with which one is unfamiliar, one should learn from the literature or colleagues who have used the combination.
Most drugs are best absorbed with food and can easily be taken at the end of a meal. Didanosine and indinavir are only absorbed when the stomach is empty, so that the administration of these two drugs must be at least two hours after a meal or one hour before the next meal.
Ketoconazole and the encapsulated itraconazole need an acid milieu for absorption. This acidity can be attained with citrus juices, cranberry juice, or soft drinks with a high acidity, like Coca-ColaŽ. Perhaps preferable is the use of fluconazole whose absorption is independent of acidity. A liquid preparation of itraconazole is now available which does not have this absorptive disadvantage.
Patients should avoid coadministration of drugs with sucralfate, or divalent and trivalent cations (calcium, magnesium, aluminum, iron, zinc). Although these cations make unabsorbable complexes mainly with the fluoroquinolones and the tetracyclines, a good rule is not to use these drugs in HIV-1-infected patients because highly negatively-charged drugs are subject to the same chemical reaction. Therefore, patients should be instructed to avoid antacids, zinc lozenges and multivitamins with iron or minerals while taking anti-HIV-1 drugs.
The plasma of malnourished patients contains less albumin, which is the main carrier of drugs. After absorption of a drug in a hypo-albuminemic patient, the increased level of unbound drug will exert a greater pharmacodynamic effect than in a patient with normal albumin. Certain drugs, especially sulfonamides, may displace whatever drug is bound to the albumin and produce toxicity.
Drugs whose metabolism is inhibited by one or more often-used medications in the management of HIV-1 should be avoided. Others, when used, should immediately cause an alert in our minds (Table 2, first column).
The strongest inhibitors of the CYP450 system should also be avoided (Table 2, underlined drugs in the second column). The inhibitors will allow high and even toxic accumulations of the substrate.
Inducers of CYP450 may metabolize the substrate drug rapidly and thereby render some agents ineffective, with potential consequences for complications (warfarin, cyclosporin, birth control pills). The strongest CYP450 inducers are rifampin and the barbiturates3. This issue raises the problem of treating tuberculosis (TB) in HIV-1-infected patients. In view of the fact that the rifamycins are our most effective drugs against TB, several options for dealing with this dilemma have been proposed10:
This last modality is beginning to be preferred by most physicians dealing with such patients.
Overlapping toxicities: Each drug used has a set of undesirable pharmacodynamic properties. We cannot avoid the toxicity of a given drug, but we can avoid combining drugs that have similar adverse side-effects (Table 3).
Desirable interactions: There are occasions when we can take advantage of drug interactions to increase the effect of a drug that is poorly bioavailable. Dual protease inhibitor therapy is one example. The combination of ritonavir (400 mg bid) and saquinavir (400 mg bid) is the best studied. Ritonavir inhibits saquinavir's metabolism via CYP3A resulting in a more than tenfold increase of the blood level of saquinavir. Cocktails of other drugs are currently being studied as well11,12.
Interactions with herbal preparations: As a group, HIV-1-infected patients take many over-the-counter drugs and herbal preparations. In a study of 114 randomly selected AIDS patients, Kassler found that 22% reported taking herbal preparations during the three months preceding the study13. One fourth of the patients could not identify the herbals they had taken, and one fifth admitted that their physicians were not aware of their use of herbal preparations. Many patients do not know the "drug" content of the herbals taken. Because herbs are classified as dietary supplements, the FDA has no regulatory power over these products. The medical claims of these products are untested14. Of more concern is that some preparations contain traces of drugs that are not listed on the label.
Table 4 lists the common drugs in use for HIV-1 treatment and their form of elimination from the body. Drugs that are fully excreted through the kidneys should be adjusted according to the remaining glomerular filtration. Drugs which have a dual excretion (kidney and bile), which are excreted solely through liver and gut, or which are eliminated through metabolic pathways do not require dose adjustment.
Drug interactions cannot be avoided. A single drug behaves differently from person to person. Adding a second drug more than doubles that variability by introducing interactions, some of which can produce serious side-effects. HIV-1-infected patients in particular are in danger of therapeutic failure and/or toxicity. Treatment of their disease requires a minimum of three drugs, five drugs during the advanced stages. The problem of excessive numbers of drugs is further compounded by opportunistic infections, especially tuberculosis, which requires four more drugs. Many patients easily take an additional half a dozen medications, mostly over-the-counter drugs, for various reasons, but often to counteract side-effects of other drugs.
The dangerous expectation among patients that every ailment requires a pill should be counteracted by their physicians. But, such attitude changes take time.
References
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