Factors Affecting Drug Response.

Everyone responds to drugs differently: what works for one person can cause terrible side effects for another. ADME (for absorption, distribution, metabolism and excretion) is the acronym used in pharmacology to refer to the four processes that take place once a drug has been administered.

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Figure 1:  ADME represent the key principles of pharmacokinetics.[1]

The first stage is absorption. After all, if the drug is not absorbed, it will have no therapeutic effect. Absorption is the process by with a drug passes through barriers (such as cell membranes) before entering the bloodstream.[2] Drugs given orally will generally be absorbed by the gastrointestinal tract. Already at this stage, there are several individual factors that can affect drug response, such as the patient’s age, gastric pH, a high-fat diet, cardiovascular or digestive diseases, rate of gastric emptying and gastric motility.[3] The steps in the absorption process can vary, depending on how the drug is administered. If it is administered intravenously, the drug will go straight to the second stage (distribution), since it passes immediately into the bloodstream 

Next comes the distribution stage. As the name implies, this is the stage when the drug is distributed to the body's tissues. Possible factors affecting this stage include the rate of blood flow (perfusion) to the tissue, the tissue mass itself, and vascular and tissue membrane permeability.[4] In addition, the degree of plasma protein binding of certain drugs also influences an individual's response to the drug, since only the unbound (i.e., free) fraction of the drug is active.[5]

The next stage is metabolism. This crucial stage converts active drugs to inactive substances metabolites so they can be more easily excreted. In some cases the reverse occurs: inactive drugs (or prodrugs) are converted to active metabolites. In both cases, the drug is converted into a chemically different form. While drug metabolism can occur in other organs, the primary site of drug metabolism is the liver, as the enzymes that facilitate the reactions are concentrated there.[6] Cytochrome P450 refers to a family of liver enzymes that play an important role in drug metabolism. The activity of these enzymes varies depending on people’s age and genetic predisposition. Also, a number of cytochrome P450 mutations have been observed, which can affect the rate of drug metabolism and thus affect the patient's response to treatment.[7] (Lien vers article sur la pharmacogénétique) Thereafter, conjugation transforms the drugs to make it soluble so they can be readily excreted by the kidneys. While age usually has no effect on this process, the rate of conjugation in newborns is slower than in other population groups. Environmental factors such as stress, pregnancy and smoking also affect drug response (see Figure 2).[8]

 The last stage is elimination. Once the drug has been converted to an inactive substance through metabolism, the body must excrete it. The kidneys are the main organs of the body’s excretory system. However, small amounts of the drug can also be excreted in the bile and through minor excretion routes, such as sweat, saliva, exhalation, etc.[9]  There is a strong correlation between age and renal clearance: for example, the renal excretion rate of an 80-year-old is about 50% of that of a 30-year-old.[10] This is why patient age is an important factor to consider when prescribing drugs.

In conclusion, every person is unique, as is his or her response to a drug. Drug response can be affected by a wide range of factors, including genetics, age and certain environmental considerations. Therefore, in order to get the best possible treatment, it is important that your healthcare professional factors in all these elements before prescribing a drug.

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Figure 2: Factors potentially affecting drug response.[11]

Sources:

[1] Académie européenne des patients, Pharmacocinétique, 2015, Site officiel, [site web] consulté le 21 mars 2017, https://www.eupati.eu/non-clinical-studies/key-principles-pharmacology/

[2] Cloutier, B. et Ménard, N., Pharma-Fiches, 4e édition, Montréal, Gaëtan Morin, 2005, p. 26-27.

[3] Faculté de médecine Pierre et Marie Curie, 4.2 Absorption d’un médicament, 2006, Site officiel, [site web], consulté le 20 mars 2017, http://www.chups.jussieu.fr/polys/pharmaco/poly/cinetique.html

[4] Le, J., Drug Distribution to Tissues, Merck Manual, 2016, Site officiel, [site web], consulté le 20 mars 2017, http://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-distribution-to-tissues

[5] Collège National de Pharmacologie Médicale, Devenir normal du médicament dans l’organisme : Distribution, 2016, Site officiel, [site web], consulté le 20 mars 2017, https://pharmacomedicale.org/pharmacologie/devenir-normal-du-medicament-dans-l-organisme/36-etapes-du-devenir/73-distribution

[6] Le, J., Drug Metabolism, Merck Manual, 2016, Site officiel, [site web], consulté le 20 mars 2017, http://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism

[7] Genetics Home Reference, Cytochrome p450, 2017, Site official, [site web], consulté le 21 mars 2017, https://ghr.nlm.nih.gov/primer/genefamily/cytochromep450

[8] Hussar, D.A., Pharmacogénétique, Le Manuel Merck, 2016, Site officiel, [site web], consulté le 20 mars 2017, http://www.merckmanuals.com/fr-ca/professional/pharmacologie-clinique/facteurs-affectant-la-réponse-aux-médicaments/pharmacogénétique#v1108724_fr

[9] Faculté de médecine Pierre et Marie Curie, 4.4 Métabolisme et élimination des médicaments, 2006, Site officiel, [site web], consulté le 20 mars 2017, http://www.chups.jussieu.fr/polys/pharmaco/poly/POLY.Chp.4.4.html

[10] Le, J., Drug Excretion, Merck Manual, 2016, Site officiel, [site web], consulté le 20 mars 2017, http://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-excretion

[11] Hussar, D.A., Présentation de la réponse aux médicaments, Le Manuel Merck, 2016, Site officiel, [site web], consulté le 22 mars 2017, http://www.merckmanuals.com/en-ca/home/drugs/factors-affecting-response-to-drugs/overview-of-response-to-drugs