Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes

Abstract

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life‐threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and http://www.pharmgkb.org).

<p>Genetic Testing for <em>BCHE</em> Variants Identifies Patients at Risk of Prolonged Neuromuscular Blockade in Response to Succinylcholine</p>

“…34,35 For example, variants in RYR1 and CACNA1S are associated with increased risk of malignant hyperthermia with succinylcholine and potent volatile anesthetic agents. 4 Response to opioids, which are frequently used during general anesthesia and for postoperative pain management, may be impacted by variation in cytochrome P450 metabolism genes such as CYP2D6 and CYP3A4 and pharmacodynamic genes such as OPRM1 and COMT. 36 Testing for BCHE and other pharmacogenes could be performed with a single oral sample prior to surgery.…”

“…Prolonged post-succinylcholine apnea is estimated to occur in approximately 1 in 1800 anesthesias, 3 and as such is more common than malignant hyperthermia. 4 Moreover, affected patients may become aware of paralysis during emergence from anesthesia, leading to distress consistent with post-traumatic stress disorder. 5,6 Prolonged neuromuscular blockade can also lead to increased postoperative recovery time and costs.…”

<p>Potential role of pharmacogenomics testing in the setting of enhanced recovery pathways after surgery</p>

“…Benzodiazepines are the most commonly used anxiolytic premedication drugs. The hepatic CYP enzyme family is responsible for metabolizing most benzodiazepines 18. Variations and genetic polymorphisms of CYP enzymes have been shown to alter the metabolization and pharmacologic effects of benzodiazepines 19,20.…”

“…Patients carrying homozygous alleles for CYP3A5*3 have been noticed to have more than 50% induction of these enzymes, and thus a higher rate of metabolizing and eliminating midazolam 19. However, studies comparing different polymorphisms (CYP3A5*1/*3 and CYP3A5*3/*3) have shown inconsistent variations in midazolam clearance 18. Despite the extensive midazolam use as anxiolytic premedication before surgical procedures, inconclusive evidence of clinical variations in polymorphisms of CYP3A5 may require further research to show the efficacy of the pharmacogenomics administration of midazolam 18…”

“…However, studies comparing different polymorphisms (CYP3A5*1/*3 and CYP3A5*3/*3) have shown inconsistent variations in midazolam clearance 18. Despite the extensive midazolam use as anxiolytic premedication before surgical procedures, inconclusive evidence of clinical variations in polymorphisms of CYP3A5 may require further research to show the efficacy of the pharmacogenomics administration of midazolam 18Table 1 shows examples of commonly used drugs in anesthesia, metabolizing enzyme, known variants, and their impact on metabolism.…”