Drug interaction

Synergy and antagonism

When the interaction causes an increase in the effects of one or both of the drugs the interaction is called a synergistic effect. An "additive synergy" occurs when the final effect is equal to the sum of the effects of the two drugs (Although some authors argue that this is not true synergy). When the final effect is much greater than the sum of the two effects this is called enhanced synergy. This concept is recognized by the majority of authors, although other authors only refer to synergy when there is an enhanced effect. These authors use the term "additive effect" for additive synergy and they reserve use of the term "synergistic effect" for enhanced synergy. The opposite effect to synergy is termed antagonism. Two drugs are antagonistic when their interaction causes a decrease in the effects of one or both of the drugs.

Both synergy and antagonism can both occur during different phases of the interaction of a drug with an organism, with each effect having a different name. For example, when the synergy occurs at a cellular receptor level this is termed agonism, and the substances involved are termed agonists. On the other hand, in the case of antagonism the substances involved are known as inverse agonists. The different responses of a receptor to the action of a drug has resulted in a number of classifications, which use terms such as "partial agonist", "competitive agonist" etc. These concepts have fundamental applications in the pharmacodynamics of these interactions. The proliferation of existing classifications at this level, along with the fact that the exact reaction mechanisms for many drugs are not well understood means that it is almost impossible to offer a clear classification for these concepts. It is even likely that many authors would misapply any given classification.

Underlying factors

It is possible to take advantage of positive drug interactions. However, the negative interactions are usually of more interest because of their pathological significance and also because they are often unexpected and may even go undiagnosed. By studying the conditions that favour the appearance of interactions it should be possible to prevent them or at least diagnose them in time. The factors or conditions that predispose or favour the appearance of interactions include:

Analytical interference

The detection of laboratory parameters is based on physicochemical reactions between the substance being measured and reagents designed for this purpose. These reactions can be altered by the presence of drugs giving rise to an over estimation or an underestimation of the real results. Levels of cholesterol and other blood lipids can be overestimated as a consequence of the presence in the blood of some psychotropic drugs. These overestimates should not be confused with the action of other drugs that actually increase blood cholesterol levels due to an interaction with its metabolism. Most experts consider that these are not true interactions, so they will not be dealt with further in this discussion.

These chemical reactions are also known as pharmacological incompatibilities. The reactions occur when two or more drugs are mixed outside the body of the organism for the purpose of joint administration. Usually the interaction is antagonistic and it almost always affects both drugs. Examples of these types of interactions include the mixing of penicillins and aminoglycosides in the same serum bottle, which causes the formation of an insoluble precipitate, or the mixing of ciprofloxacin with furosemide. The interaction of some drugs with the transport medium can also be included here. This means that certain drugs cannot be administered in plastic bottles because they bind with the bottle's walls, reducing the drug's concentration in solution.

Many authors do not consider them to be interactions in the strictest sense of the word. An example is the database of the General Council of Official Pharmacists Colleges of Spain (Consejo General de Colegios Oficiales de Farmacéuticos de España), that does not include them among the 90,000 registered interactions.

Pharmacodynamic interactions

The change in an organism's response on administration of a drug is an important factor in pharmacodynamic interactions. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist and the fact that many drugs can cause their effect through a number of different mechanisms. This wide diversity also means that, in all but the most obvious cases, it is important to investigate and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions than known ones.

Pharmacodynamic interactions can occur on:

1. Pharmacological receptors: Receptor interactions are the most easily defined, but they are also the most common. From a pharmacodynamic perspective, two drugs can be considered to be:
   1. Homodynamic, if they act on the same receptor. They, in turn can be:
      1. Pure agonists, if they bind to the main locus of the receptor, causing a similar effect to that of the main drug.
      2. Partial agonists if, on binding to one of the receptor's secondary loci, they have the same effect as the main drug, but with a lower intensity.
      3. Antagonists, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These include:
         1. Competitive antagonists, if they compete with the main drug to bind with the receptor. The amount of antagonist or main drug that binds with the receptor will depend on the concentrations of each one in the plasma.
         2. Uncompetitive antagonists, when the antagonist binds to the receptor irreversibly and is not released until the receptor is saturated. In principle the quantity of antagonist and agonist that binds to the receptor will depend on their concentrations. However, the presence of the antagonist will cause the main drug to be released from the receptor regardless of the main drug's concentration, therefore all the receptors will eventually become occupied by the antagonist.
   2. Heterodynamic competitors, if they act on distinct receptors.
2. Signal transduction mechanisms: these are molecular processes that commence after the interaction of the drug with the receptor. For example, it is known that hypoglycaemia (low blood glucose) in an organism produces a release of catecholamines, which trigger compensation mechanisms thereby increasing blood glucose levels. The release of catecholamines also triggers a series of symptoms, which allows the organism to recognise what is happening and which act as a stimulant for preventative action (eating sugars). Should a patient be taking a drug such as insulin, which reduces glycaemia, and also be taking another drug such as certain beta-blockers for heart disease, then the beta-blockers will act to block the adrenaline receptors. This will block the reaction triggered by the catecholamines should a hypoglycaemic episode occur. Therefore, the body will not adopt corrective mechanisms and there will be an increased risk of a serious reaction resulting from the ingestion of both drugs at the same time.
3. Antagonic physiological systems: Imagine a drug A that acts on a certain organ. This effect will increase with increasing concentrations of physiological substance S in the organism. Now imagine a drug B that acts on another organ, which increases the amount of substance S. If both drugs are taken simultaneously it is possible that drug A could cause an adverse reaction in the organism as its effect will be indirectly increased by the action of drug B. An actual example of this interaction is found in the concomitant use of digoxin and furosemide. The former acts on cardiac fibres and its effect is increased if there are low levels of potassium (K) in blood plasma. Furosemide is a diuretic that lowers arterial tension but favours the loss of K⁺. This could lead to hypokalemia (low levels of potassium in the blood), which could increase the toxicity of digoxin.

Pharmacokinetic interactions

Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolization or excretion of one or both of the drugs compared with the expected behaviour of each drug when taken individually. These changes are basically modifications in the concentration of the drugs. In this respect two drugs can be homergic if they have the same effect in the organism and heterergic if their effects are different.

Changes in motility

Some drugs, such as the prokinetic agents increase the speed with which a substance passes through the intestines. If a drug is present in the digestive tract's absorption zone for less time its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal motility.

Certain drugs require an acid stomach pH for absorption. Others require the basic pH of the intestines. Any modification in the pH could change this absorption. In the case of the antacids, an increase in pH can inhibit the absorption of other drugs such as zalcitabine (absorption can be decreased by 25%), tipranavir (25%) and amprenavir (up to 35%). However, this occurs less often than an increase in pH causes an increase in absorption. Such as occurs when cimetidine is taken with didanosine. In this case a gap of two to four hours between taking the two drugs is usually sufficient to avoid the interaction.

Transport and distribution interactions

The main interaction mechanism is competition for plasma protein transport. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, which modifies its concentration. The organism has mechanisms to counteract these situations (by, for example, increasing plasma clearance), which means that they are not usually clinically relevant. However, these situations should be taken into account if there other associated problems are present such as when the method of excretion is affected.

Metabolism interactions

Many drug interactions are due to alterations in drug metabolism. Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors. One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases.

CYP450

Cytochrome P450 is a very large family of haemoproteins (hemoproteins) that are characterized by their enzymatic activity and their role in the metabolism of a large number of drugs. Of the various families that are present in human beings the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The majority of the enzymes are also involved in the metabolism of endogenous substances, such as steroids or sex hormones, which is also important should there be interference with these substances. As a result of these interactions the function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition).

Enzymatic inhibition

If drug A is metabolized by a cytochrome P450 enzyme and drug B inhibits or decreases the enzyme's activity, then drug A will remain with high levels in the plasma for longer as its inactivation is slower. As a result, enzymatic inhibition will cause an increase in the drug's effect. This can cause a wide range of adverse reactions.

It is possible that this can occasionally lead to a paradoxical situation, where the enzymatic inhibition causes a decrease in the drug's effect: if the metabolism of drug A gives rise to product A₂, which actually produces the effect of the drug. If the metabolism of drug A is inhibited by drug B the concentration of A₂ that is present in the blood will decrease, as will the final effect of the drug.

Enzymatic induction

If drug A is metabolized by a cytochrome P450 enzyme and drug B induces or increases the enzyme's activity, then blood plasma concentrations of drug A will quickly fall as its inactivation will take place more rapidly. As a result, enzymatic induction will cause a decrease in the drug's effect.

As in the previous case it is possible to find paradoxical situations where an active metabolite causes the drug's effect. In this case the increase in active metabolite A₂ (following the previous example) produces an increase in the drug's effect.

It can often occur that a patient is taking two drugs that are enzymatic inductors, one inductor and the other inhibitor or both inhibitors, which greatly complicates the control of an individual's medication and the avoidance of possible adverse reactions.

An example of this is shown in the following table for the CYP1A2 enzyme, which is the most common enzyme found in the human liver. The table shows the substrates (drugs metabolized by this enzyme) and the inductors and inhibitors of its activity:

Enzyme CYP3A4 is the enzyme that the greatest number of drugs use as a substrate. Over 100 drugs depend on its metabolism for their activity and many others act on the enzyme as inductors or inhibitors.

Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:

Any study of pharmacological interactions between particular medicines should also discuss the likely interactions of some medicinal plants. The effects caused by medicinal plants should be considered in the same way as those of medicines as their interaction with the organism gives rise to a pharmacological response. Other drugs can modify this response and also the plants can give rise to changes in the effects of other active ingredients. There is little data available regarding interactions involving medicinal plants for the following reasons:

1. False sense of security regarding medicinal plants. The interaction between a medicinal plant and a drug is usually overlooked due to a belief in the "safety of medicinal plants."
2. Variability of composition, both qualitative and quantitative. The composition of a plant-based drug is often subject to wide variations due to a number of factors such as seasonal differences in concentrations, soil type, climatic changes or the existence of different varieties or chemical races within the same plant species that have variable compositions of the active ingredient. On occasions an interaction can be due to just one active ingredient, but this can be absent in some chemical varieties or it can be present in low concentrations, which will not cause an interaction. Counter interactions can even occur. This occurs, for instance, with ginseng, the Panax ginseng variety increases the Prothrombin time, while the Panax quinquefolius variety decreases it.
3. Absence of use in at-risk groups, such as hospitalized and polypharmacy patients, who tend to have the majority of drug interactions.
4. Limited consumption of medicinal plants has given rise to a lack of interest in this area.

They are usually included in the category of foods as they are usually taken as a tea or food supplement. However, medicinal plants are increasingly being taken in a manner more often associated with conventional medicines: pills, tablets, capsules, etc.

Renal excretion

Only the free fraction of a drug that is dissolved in the blood plasma can be removed through the kidney. Therefore, drugs that are tightly bound to proteins are not available for renal excretion, as long as they are not metabolized when they may be eliminated as metabolites. Creatinine clearance is used as a measure of kidney functioning but it is only useful in cases where the drug is excreted in an unaltered form in the urine. The excretion of drugs from the kidney's nephrons has the same properties as that of any other organic solute: passive filtration, reabsorption and active secretion. In the latter phase the secretion of drugs is an active process that is subject to conditions relating to the saturability of the transported molecule and competition between substrates. Therefore, these are key sites where interactions between drugs could occur. Filtration depends on a number of factors including the pH of the urine, it having been shown that the drugs that act as weak bases are increasingly excreted as the pH of the urine becomes more acidic, and the inverse is true for weak acids. This mechanism is of great use when treating intoxications (by making the urine more acidic or more alkali) and it is also used by some drugs and herbal products to produce their interactive effect.

Bile excretion

Bile excretion is different from kidney excretion as it is always involves energy expenditure in active transport across the epithelium of the bile duct against a concentration gradient. This transport system can also be saturated if the plasma concentrations of the drug are high. Bile excretion of drugs mainly takes place where their molecular weight is greater than 300 and they contain both polar and lipophilic groups. The glucuronidation of the drug in the kidney also facilitates bile excretion. Substances with similar physicochemical properties can block the receptor, which is important in assessing interactions. A drug excreted in the bile duct can occasionally be reabsorbed by the intestines (in the entero-hepatic circuit), which can also lead to interactions with other drugs.

Epidemiology

Among US adults older than 55, 4% are taking medication and or supplements that put them at risk of a major drug interaction. Potential drug-drug interactions have increased over time and are more common in the low educated elderly even after controlling for age, sex, place of residence, and comorbidity.