Pharmacogenetics and pharmacogenomics
Definitions and history
Since the human genome was mapped in 2003, there have been continuous efforts to use this information to enhance the field of medicine1. Predicting a patient’s response to medications and preventing adverse drug reactions (ADRs) are two goals specific to the field of anesthesia, where providers regularly see high variability in how their patients respond. A number of factors, such as age, sex, and underlying chronic conditions can affect a patient’s peri-operative response to anesthesia. Additionally, genetics have been shown to play a role, with up to 50% of severe ADRs demonstrating a genetic predisposition2. ADRs (including post-operative nausea and vomiting (PONV), malignant hyperthermia (MH), and hemodynamic instability) are estimated to extend post-operative hospital stays by 1-4 days at an increased cost of $2300-$56003.
The earliest description of pharmacogenetics came in the late 1950s, shortly after the discovery that prolonged paralysis after succinylcholine administration could be linked to genetic causes4, 5. Pharmacogenetics was defined as a variable response to a medication based on a single genetic variation6, 7. Later, as the understanding of genetics progressed, the term pharmacogenomics was used to include all of the various genes within the human genome that may be affecting a drug response. Genetic variation can affect pharmacokinetics and pharmacodynamics by altering the drug target, metabolism, uptake/transport, and other various biochemical processes that can lead to ADRs.
Therapeutic class concerns
Commonly used for pre-operative anxiolysis, most benzodiazepines are metabolized by the hepatic CYP enzyme system. Although polymorphisms within the genes encoding CYP3A4 and CYP3A5 have been shown to either increase or decrease midazolam metabolism (depending on the specific variation), this has not been demonstrated to have any clinical significance 3, 8. Alternatively, polymorphisms within CYP2C19 genes can decrease diazepam clearance, increasing its half-life up to four times the typical duration.
Pain is an extremely complex process, and genetic variability can contribute to differences in opioid requirements, potential of ADRs, and drug metabolism. Perception of pain, and thus opioid demand in the peri- and post-operative periods, has been linked to mutation in the gene for the mu-opioid receptor OPRM19. There are six currently identified polymorphisms at the mu receptor that cause clinically relevant alterations in opioid efficacy, the most studied of which (A118G) has been shown to increase post-operative opioid requirements in the first 24-hours following surgery. The A118G mutation has also demonstrated reduced severity of PONV and sedation3, indicating that these patients are able to tolerate the higher doses of opioid required for pain relief.
The enzyme catechol O-methyl transferase (COMT) has also been demonstrated to play a role in the perception of pain, through its modulation of adrenergic and dopaminergic pathways. The Val158Met polymorphism of COMT has up to a fourfold reduction in enzymatic activity, and was associated with reduced binding of opioid and reduced mu-receptor binding of carfentanil in a study by Zubieta et al10. Although more study on the significance of this are needed, it may indicate that those with COMT mutations have higher pain control requirements.
Transport of opioids into the central nervous system (CNS) have been shown to be affected by polymorphisms in the p-glycoprotein ABCB1 gene9. Patients with the rs9282564 polymorphism were shown to have increased respiratory depression following post-operative fentanyl administration, with subsequent increases in the length of hospital admission. However, opioid demands for analgesia among those with the mutation remained similar to those without it.
Metabolism of opioids has also been linked to genetic mutation. Codeine, which must be converted to its metabolite morphine to exert an analgesic effect, is rendered ineffective in patients with specific mutations of the CYP2D6 gene that decrease its function6. Other patients have mutations that enhance the activity of CYP2D69, or even have more than two copies of the CYP2D6 gene11, creating a spectrum of those ranging from poor-metabolizers to ultra-rapid metabolizers. Therapeutic doses of codeine in patients with ultra-rapid metabolism may therefore lead to doses of morphine well above those needed to achieve analgesia, producing ADRs such as respiratory depression. Other enzymes are also related to the metabolism of opioids such as oxycodone, fentanyl, and alfentanil. In addition to CYP2D6, the CYP3A4 enzyme plays a major role in the pharmacokinetics of these medications. Much like CYP2D6, the other CYP enzymes have known polymorphisms that create a spectrum of slow and fast metabolizers. Biologic sex plays a further role, with CYP3A4 metabolism being approximately 40% more rapid in females, potentially explaining why females are three times more likely to have inter-operative awareness or awaken quickly from total intravenous anesthesia (TIVA)3. Mutations in the uridine diphosphate gylcosyl transferase enzyme genes (C161T and C802T, always inherited together) cause increased glucuronidation of morphine. In a patient with functioning kidneys, the downstream metabolic products of this (~50% morphine-3-glucuronide (M3G) and ~10% morphine-6-glucuronide (M6G)) will be renally eliminated and the patient will experience decreased analgesic effect. However, in a patient with renal disease, these products will accumulate and produce neurotoxic and other negative side effects12.
IV anesthetic agents
Genes encoding enzymatic metabolism are responsible for variability in response to multiple intravenous anesthetic agents, including propofol, ketamine, etomidate, thiopental, and methohexital. Of these agents, most studies have concerned propofol and ketamine9. The enzyme primarily responsible for inter-patient variability in both of these agents is CYP2B6, with CYP3A4 and CYP2C9 playing minor (and less studied) roles. In patients with the CYP2B6*6 variant, decreased metabolism was encountered, leading to longer wake-up times and more drowsiness2, 8. After observations that females frequently required higher induction doses and awoke faster from propofol infusion than males, it was discovered that those carrying the T allele of CYP2B6 c.516C>T had increased dose requirements to achieve the same effect. The UGT1A9 gene, although responsible for a majority of propofol metabolism via glucuronidation, is responsible for less variation than CYP2B6. However, patients with the 188T/G variant required higher induction doses of propofol, and those with the 188T/C mutation had higher propofol clearance.
The target of many anesthetics, the GABAA receptor, has been shown to have in-vitro resistance to benzodiazepines, barbiturates, etomidate, and propofol when it includes an epsilon subunit. The GABRE gene encoding this mutation has not been proven to cause clinically significant differences in human studies, but more research may be needed1.
Sevoflurane, isoflurane, and desflurane are largely excreted unchanged by the lungs, with less than 2% undergoing hepatic metabolism by the CYP2E1 enzyme8. No clinically significant mutations in the genes encoding for this enzyme have been discovered to date1. However, halothane undergoes 20% hepatic metabolism and has been linked to the development of fulminant hepatitis. No studies have been done on CYP2E1 in this group, and further investigation is warranted.
The melanocortin-1 receptor gene (MC1R) is associated with mutations leading to higher anesthetic requirements5. Three specific mutations (R151C, R160W, and D294H) have been linked to higher intra-operative desflurane and analgesic requirements. Of note, these mutations also result in the phenotype of red hair and pale skin.
Malignant hyperthermia (MH), an uncontrolled release of calcium ions from the sarcoplasmic reticulum of skeletal muscle leading to many deleterious effects, can be induced by both volatile anesthetics and succinylcholine. It has been linked to genetic variation in the RYR1 gene in about 70% of cases11. The alpha1 subunit of L-type calcium channels within skeletal muscle T-tubules has also been indicated in 1% of North American cases3. The prevalence of RYR1 mutations in the US is estimated at 1: 2,0001, but the incidence of MH is only about 1: 50,000. It is thought this discrepancy is due to the fact that there are many yet unknown factors that also contribute to the development of MH.
One of the most well-known pharmacogenetic conditions is that of butyrylcholinesterase (pseudocholinesterase) deficiency. A single mutation in the BChE gene (Asp70Gly) on chromosome 3q26 causes prolongation of the effects of succinylcholine and mivacurium1. In those patients who are heterozygous for Asp70Gly, the effects of neuromuscular blockade may be prolonged three to eight times that of normal3. In those who are homozygous for the polymorphism, this may extend the prolongation to sixty times that of normal, causing these patients to require prolonged mechanical ventilation. Some gene variants may also modify the efficacy of rocuronium, but the clinical significance of this is uncertain8.
Lidocaine may have reduced efficacy for analgesia in patients carrying mutations in the SCN9A or MCR1 genes11.
Autonomic nervous system modulators
Dexmedetomidine, an alpha-2 agonist, has demonstrated interpatient variability due to subtypes of the alpha-2 receptor. In one study of patients undergoing CABG, the ADRA2A G allele polymorphism caused patients to be less sedated5. Other mutations in the alpha-2 receptor have also been found to cause statistically significant differences in blood pressure among patients when dexmedetomidine was administered.
Although numerous studies have investigated genetic variation in the beta1 (ADRB1) and beta2 (ADRB2) adrenergic receptors, the clinical relevance to the peri-operative period is weak. However, the Gly16 or Glu27 polymorphisms of the ADRB2 gene were associated with lower ephedrine and phenylephrine requirements to raise systolic blood pressure in obstetric patients undergoing Caesarean section11.
Two variants of the p-glycoprotein ABCB1 gene (C3435T and G2677T) have been demonstrated to cause increased chemo-therapy induced nausea and vomiting, despite treatment with ondansetron2. The effect was theorized to be from increased activity at the p-glycoprotein efflux pump, preventing therapeutic levels of ondansetron from accumulating in the CNS. CYP2D6 ultra-rapid metabolizers can also have an increased rate of failure with ondansetron or tropisetron therapy1.
A number of genetic considerations affecting anesthesiology have been found to be specific to children. Nitrous oxide use is associated with an irreversible inhibition of vitamin B12, and all of the downstream biochemical processes related to this5. At issue for the pediatric patient are the formation of the myelin sheath, various neurotransmitters, and DNA synthesis. When a mutation occurs in the MTHFR gene, repeated exposure to nitrous oxide can lead to deterioration of neurologic processes, and possible death. The prevalence of the most common mutations (677C>T and 1298A>C) is up to 10% in Western Europe, 25% in Southern Europe and East Asia, and 36% in Mexico1.
Malignant hyperthermia, described earlier, occurs in children at a rate much higher than adults (1:15,000 versus 1:50,000)3. The reason for this is yet unknown, but it is thought that this also demonstrates how MH behaves as a complex genetic disease.
In young children, mutations at the gamma2 subunit of the GABA-A receptor were associated with greater incidence of emergence agitation following sevoflurane administration5.
Codeine administration in children who are CYP2D6 ultra-metabolizers can be extremely dangerous. With standard doses, children can experience dangerously high exposure to morphine, leading to respiratory depression and death. After multiple cases of documented harm in the US, the FDA added a black-box warning to codeine for post-operative pain in children, urging providers to choose a different medication that did not undergo conversion to an active metabolite.
Clinical implications and cost
It is clear that genetic variations across the human genome are associated with a number of pharmacotherapy concerns directly applicable to the field of anesthesiology. With narrow therapeutic indexes and high inter-patient variability, anesthetic medications are prime targets for pharmacogenomic guided therapy. Future pre-operative testing may include panels to categorize CYP enzyme function, MH risk, and the optimal opioid to prescribe for post-operative pain control. This information could then be stored in its own section of the electronic medical record, and cross-checked against all future medication prescribing, much like the alerts physicians currently receive when a patient has an allergy to a medication they are trying to order.
Despite the continuously declining costs of these tests, the question of cost versus benefit remains. An excellent example is that of MH, which has an incidence of 1: 50,000 adults. If about 70% of these are related to an RYR1 mutation, the MH associated mutations would be expected in about 1: 71,000 adults. At a cost of $100 per test (with most tests available today at a cost actually much higher than this3), this would equate to a cost of about $7 million to prevent MH in just one adult surgical patient. However, if testing were restricted to only first-degree relatives of those known to have experienced MH the incidence falls to 1: 4, meaning a cost of only $400 to prevent an episode.
Ethical issues regarding genetic testing should be mentioned, as well. If testing of any type were to be paid by a patient’s insurance, they would then have access to that specific genetic information. Currently, patients are protected from being denied coverage based on pre-existing genetic conditions by laws such as GINA and the Affordable Care Act, but this was not true in the past and could change again in the future. If a patient demonstrated certain genetic variations that were relevant to anesthesia, could an insurance company possibly deny coverage of intra-operative medications based on the fact that these are not shown to be effective with their polymorphisms? What if the genetic variation tested, although benign for anesthetic purposes, was then used to deny coverage for a different disease state? Patients should be carefully counseled before all genetic tests to ensure they understand the implications.
Many other medications related to surgical procedures have pharmacogenomic considerations as well, including warfarin, clopidogrel, and omeprazole, among others4, 6, 7. As further research is done, perhaps our knowledge of the human genome will not only guide prescribing of the best medication for each individual patient, but also help to develop specific therapies that are more effective and avoid the most worrisome adverse effects to keep our patients safe.
For a thorough review of terminology relevant to pharmacogenetics and pharmacodynamics, please refer to source articles #6 and #7.
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