The History About Drug Interactions

Published Date: 02 Nov 2017

Polypharmacy is essential in the treatment of tuberculosis, especially in DR-TB. Several drugs are used in order to prevent resistance to certain susceptible drugs. However with the use of multiple drugs, the risk for potential drug-drug interactions increases. In addition to DR-TB, it is common to treat several other concurrent health conditions such as HIV/AIDS or non-communicable diseases such as diabetes or hypertension increasing the potential for drug interactions. Drug interactions are defined as a modification of the effect of a drug when co-administered with another drug. This effect may enhance or reduce the action of either drug which can result in possible over- or under-dosing and lead to a lack of drug efficacy or toxicity 63. Drug interactions can be divided in three groups: pharmacodynamic, pharmacokinetic or combined interactions 64,65,66.

Pharmacodynamic interactions occur when the effect of a drug is changed by another drug at the site of actions, without changing the plasma concentrations of either drug. It arises from an antagonistic (drug effect is decreased), additive or synergistic effect (drug effect is increased), and may alter the pharmacological response, such as toxicity and efficacy.

Antagonism of antimicrobial agents occurs when the combined killing effect or inhibitory effects of two or more antimicrobial drugs are significantly less than the activity of individual drugs. For example, rifampin can antagonise vancomycin action against staphylococci 67.

Additive/synergistic effect occurs when the activity or toxicity of a drug is enhanced due to the presence of another drug with a similar pharmacological action. An example is the great delay in development of resistance to streptomycin when co-administered with PAS 68 .

Pharmacokinetic interactions

Pharmacokinetic interactions are the most common interactions 66. Interactions of this kind may either alter the drug plasma concentration and/or its tissue distribution, consequently affecting the concentration or availability of the drug to the target site.

These particular interactions occur when absorption, distribution, metabolism and/or excretion of a drug is altered 63,64,69.

Drug interactions associated with absorption

Absorption is the movement of compounds into the circulatory system from site of administration (e.g. gastrointestinal, skin, subcutaneous site, nasal/pulmonary sites, and muscles). The absorption of drugs can be altered by several physiological factors such as intestinal motility, gastric emptying time, gastric pH, transport, intestinal metabolism, and the presence of gastrointestinal disease 69. In addition, concomitant substances such as drugs, can also affect the drug absorption by having a large surface area upon which the drug can be absorbed; alternating the gastric pH; binding or chelating; altering gastrointestinal motility or affecting the transport proteins 61,63,65.

The most common interaction affecting drug absorption is chelating, which is the binding of metal ions or other substances to the drugs in the gastrointestinal tract 61. For example, PAS absorption is decrease due to the binding of divalent cations (iron, magnesium and calcium) to PAS molecules 70.

Drug interactions associated with distribution

The important mechanisms by which drug interactions can alter drug distribution are the competition for protein binding; displacement from tissue binding sites and alterations of the local tissue barriers 65. The competition of the drugs for protein binding affects the degree of the free drug (pharmacologically active form). Theoretically the plasma concentration of the free drug will increase, but in this case the concentration is maintained due to an increase in free drug elimination 63. Therefore, protein binding displacements are usually considered to be of less clinical significance 69,71.

Drug interactions associated with drug metabolism

Co-administered drugs may directly or indirectly alter the concentration and activity of another drug by inhibiting or inducing the enzyme activity responsible for the metabolism of the drug.

Several clinically important drug interactions have been reported. Some drug interactions can be beneficial, by increasing the activity or bio variability of an effective drug. However, this can also result in high drug levels, which can be toxic and life-threatening 45,61. For example, co-administration of PAS and INH can be beneficial, but can also result in severe neurotoxicity and/or hepatotoxicity. PAS inhibits the acetylation of INH, consequently increasing the INH levels 72.

Both phase I and II enzyme activities can be altered by their substrate or other compounds. Even the transporters such as P-pg are susceptible to drug induction or inhibition 61.

The CYP enzyme group consisted out of 12 isoforms and are the major enzyme group involved in the drug metabolism 73. Several anti-TB and ARV drugs are metabolised by the CYP group and therefore are susceptible to drug interactions. Some of these drugs are also inducers and inhibitors of the CYP group, which complicates the design of regimens for DR-TB subjects that are also co-infected by HIV/AIDS 61. Alterations in the plasma levels of an antimicrobial or antiretroviral agent can cause sub-therapeutic drug concentrations, which can result in developing of pathogen drug resistance. In risk patients the plasma levels should be monitored to ensure that toxicity is reduced and the MIC is exceeded 45. The Clinical Pharmacology Division of Indiana University summarised the clinically relevant drug interactions of the CYPs. This can be found at:

http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx.

Combined toxicity

The use of combinations of drugs for a prolonged period, as in TB treatment, often results in drug toxicity 38. Several drugs have similar toxicities which can lead to increased toxicity when co-administered (shared toxicity). In combining these drugs in a regimen, the potential of organ damage is increased. For example, ethionamide and PAS have toxic effects on the thyroid. These drugs are often prescribed in a regimen and long term use can lead to hypothyroidism. In some cases, a drug(s) can enhance the organ toxicity of another drug, even if the enhancing drug has no intrinsic toxicity effect on the organ 65.

DR-TB patients often develop hepatotoxicity and renal dysfunction since multiple drugs including more toxic second-line drugs, are prescribed to these patients. These drugs are often metabolised in the liver and excreted by the kidneys. Therefore, monitoring of liver and kidney functions are important in these patients 10.