1. The concomitant ingestion of more than three medications. Widely recognized as an independent risk factor for falls in the elderly as well as Adverse Drug Reactions.
When a patient is prescribed more than three medications there are very important principles and statistics that come into play. In many polypharmacy cases multiple medications are ingested that require biotransformation through the same (or a related) enzymatic pathway, which can cause problems. When this happens it can be like a car accident on a four lane highway, if one lane is blocked, traffic will begin to back up. If two or more lanes become blocked, traffic will continue to back up further and further. The highway in this example is like an enzyme and each blocked lane of traffic, a different medication. This represents potential Drug-Drug Interactions that can impact medication efficacy and toxicity. It is also important to remember that we do not all possess identical enzymes, the same way that not all highways are built to be four lane highways. If one patient has a "two lane highway enzyme" and another patient has a "four lane highway enzyme" and both are prescribed multiple medications that require access to that enzyme, these patients will respond very differently to their medications because they do not have equal metabolic capacity. This represents the potential for both Drug-Gene Interactions and Drug-Drug Interactions to impact medication efficacy and toxicity at the individual level in cases of polypharmacy.
Polypharmacy Pilot Study - Drug-Gene & Drug-Drug Interactions
Polypharmacy Pilot Study - Drug Drug Interactions
Copyright PGXL Laboratories 2016
Hocum BT, White Jr. JR, Heck JW, Thirumaran RK, Moyer N, Newman R, Ashcraft K. Cytochrome P-450 gene and drug interaction analysis in patients referred for pharmacogenetic testing. American Journal of Health-System Pharmacy 2016 01/15;73(2):61-7.
The figures above display the results from two different pilot studies that were conducted to analyze real world polypharmacy patient medication plans and reveal potential drug-drug and drug-gene interactions. The PGXL study analyzed 703 patients taking a total number of 8090 medications. This study concluded that there were over 3,000 (non-minor) drug-drug interactions potentially taking place among the 703 patients and approximately 25% of each patient's medications were drugs with known genetic links. The Hocum et al study analyzed a mixed race population of over 22,000 male and female patients. The top 10 medications implicated in potential drug-drug interactions from this study's sample population are displayed in the figure above.
"Normal Metabolizers": How Normal Is Normal?
Copyright PGXL Laboratories 2016
Polypharmacy Relevant Genes In The PRIMER Panel
Gene - Gene Product Description
CYP2D6 – Metabolizes more than 25% of all drugs, including tamoxifen, many antidepressants, antipsychotics, beta-blockers, and opioids. Detecting variants of the CYP2D6 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2D6 substrates. Medications which require activation or inactivation by CYP2D6 should be used with caution in patients with CYP2D6 variants.
CYP2C19 – Metabolizes approximately 10-15% of all drugs, including clopidogrel, citalopram, diazepam, and many of the proton pump inhibitors. Detecting variants of the CYP2C19 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2C19 substrates.
CYP2C9 – Metabolizes approximately 10% of all drugs, including warfarin, phenytoin, non-steroidal anti-inflammatory drugs (NSAIDs), and antihyperglycemic sulphonylureas. Detecting variants of the CYP2C9 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP2C9 substrates.
CYP3A4 - A liver enzyme that, in concert with CYP3A5, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A4 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A4 substrates. Roughly 4-10% of the general population possesses inherited differences in 3A4 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A4.
CYP3A5 – A liver enzyme that, in concert with CYP3A4, metabolizes approximately 50% of medications, including many of the statins, benzodiazepines, antibiotics, and antipsychotics. Detecting variants of the CYP3A5 gene that cause altered enzymatic activity can identify patients who may be at increased risk of having adverse drug reactions while taking standard dosages of 3A5 substrates. More than half of the general population (60-80%) possesses inherited differences in 3A5 that cause decreased metabolism. These Decreased Metabolizers may be at increased risk for dose-dependent side effects to drugs normally inactivated by 3A5.
CYP1A2 – Metabolizes many medications, including theophylline, diazepam, caffeine, and amitriptyline. CYP1A2 can be induced by several medications, substrates, and constituents of tobacco smoke. CYP1A2 can also be inhibited by several medications. Basal metabolic capacity remains relatively consistent among the different genotypes in the absence of an inducer. Detecting variants of the CYP1A2 gene that cause altered enzymatic induction in the presence of an inducer can identify patients who may be at increased risk of having adverse drug reactions or therapeutic failure to standard dosages of CYP1A2 substrates.
VKORC1 – Warfarin is the most commonly prescribed anticoagulant for the treatment and prevention of thromboembolic events. The anticoagulant effect of warfarin is due to the inhibition of Vitamin K epoxide reductase enzyme, leading to a reduction of the Vitamin K pool and an inability to activate the Vitamin K dependant clotting factors. The active component of warfarin is metabolized by Cytochrome P450 2C9 (CYP2C9). Polymorphisms in the CYP2C9 gene are associated with decreased warfarin clearance and an increased risk of bleeding. An additional polymorphism in the Vitamin K reductase complex subunit 1 (VKORC1) gene is also associated with warfarin sensitivity and decreased maintenance dose requirements of the medication. By testing for the inherited differences in VKORC1 and CYP2C9, and taking into considerations patient physical characteristics our lab partners can estimate individual warfarin daily maintenance doses and subsequently identify those patients who will require low doses. Thus, the potential for bleeding events and other Adverse Drug Reactions can be reduced.
SLC6A4 – The 5-HTTLPR (5-hydroxytryptamine transporter linked polymorphic region) polymorphism is a 44-bp insertion/deletion in the promoter region of the serotonin transporter gene, 5-HTT or SLC6A4. The two most frequent alleles are defined by their length: the (L)ong allele, and the (S)hort allele characterized by a 43-bp deletion. The S allele results in 50% less expression of the active transporter protein as compared to the Long form. Presence of the short form may increase the time to therapeutic response with selective serotonin antidepressant therapy and may also affect efficacy. The short form has also been associated increased risk of side effects, and the nature and extent of depressive symptoms experienced. The Long allele of 5-HTTLPR contains an A>G polymorphism which generates a restriction site that may be detected by restriction fragment length polymorphism analysis. Presence of the G allele is thought to result in a phenotype similar to that of the Short 5-HTTLPR allele. Therefore, the presence of the LG allele is associated with the same risks as that of the Short allele.
OPRM1 – Opioid agonists, such as morphine, hydromorphone, and oxymorphone, exert their analgesic properties via stimulation of the mu-1 opioid receptor. Analgesic efficacy of mu-acting drugs has been linked to the 118A>G single nucleotide polymorphism (SNP) of OPRM1, the gene encoding the mu-1 receptor. The frequency of the variant G allele varies from 10% to 48% depending on the population studied. Studies show that patients carrying the GG (homozygous variant) genotype require much higher opioid doses to achieve pain relief. Additionally, patients with the AA genotype display higher relapse rates with respect to naltrexone treatment for alcohol dependence.
SLCO1B1 – This gene encodes the liver enzyme OATP1B1, which assists in transport of statins medications into the liver. Roughly 15% of the population possess the *5 variant, an inherited form of SLOC1B1 which increases risk of statin-induced myopathy 3 to 5 fold. Risk of myopathy with the *5 variant is most closely associated with simvastatin and to a lesser extent, atorvastatin. Patients with the *5 variant may need the lowest doses of simvastatin or an alternative statin to reduce risk of myopathy.
MTHFR – The MTHFR (Methylenetetrahydrofolate Reductase) enzyme catalyzes the formation of 5-methyltetrahydrofolate, the major circulating form of active folate. Absence of active folate leads to accumulation of plasma homocysteine. The 677 C>T polymorphism of MTHFR leads to decreased MTHFR enzymatic activity and elevated homocysteine. The 1298 A>C polymorphism is associated with significant increases plasma homocysteine levels only when in combination with the 677 C>T polymorphism. Elevated plasma homocysteine has been shown to be a risk factor for atherosclerotic heart disease, myocardial infarction, cerebrovascular disease, and venous thrombosis. Additionally, associations between the 677 C>T polymorphism and increased risk for methotrexate toxicity, increased chemosensitivity of colon and breast cancers to 5-fluorouracil, and increased risk of fetal neural tube defects in pregnant women have also been reported, although these associations remain controversial.
COMT – This enzyme degrades dopamine and norepinephrine, primarily in the prefrontal cortex of the brain. A common single nucleotide polymorphism (SNP) 472G>A, also referred to by the amino acid change 158 Val>Met, is associated with altered COMT enzymatic activity. The 158 Met allele has lower enzymatic activity resulting in less dopamine degradation and higher dopamine concentrations as compared to those carrying the Val allele. Conversely, the 158 Val allele has higher activity and results in lower dopamine levels in the prefrontal cortex. Low dopamine concentrations are associated with cognitive impairments including working memory deficits. Val/Val homozygotes with depression are less likely to achieve remission when treated with SSRI antidepressants, and Val/Val homozygotes with schizophrenia are less likely to demonstrate improved cognitive effects when treated with antipsychotics. In contrast, the Met/Met homozygotes are more likely to achieve remission and demonstrate cognitive improvement when treated with SSRIs and antipsychotics, respectively. The frequency of the 158 Met variant varies from 25-43% depending on the population studied.
Factor 2 – The Factor II (prothrombin) polymorphism is the result of a single point mutation (20210 G>A) in the 3’ untranslated region of the gene. The 20210 G>A gives rise to increased circulating prothrombin levels, thus creating the potential of a hypercoagulable state. This polymorphism is found in approximately 2% of individuals in the U.S. and it raises the risk of thrombosis significantly for both males and females in all age groups. People with this polymorphism are at 2-3 fold increased risk of deep venous thrombosis (DVT), without other confounding non-genetic factors such as smoking, hormone therapy, and immobility.
Factor 5 - The Factor V Leiden polymorphism is the result of a single point mutation (1691 G>A) that results in substitution of a glutamine for arginine at amino acid 506. The amino acid change prohibits the inactivation of Factor V by activated protein C, thereby creating a state of activated protein C resistance (APCR) and increasing the risk of thrombosis. Individuals with this polymorphism have a 10-20 fold increased thrombotic risk.