Chapter 10: Pharmacogenetics

INTRODUCTION

Pharmacogenetics is the study of inherited and acquired genetic variations in metabolic pathways responsible therapeutic responses and adverse reactions to pharmacotherapy. Pharmacogenomics encompasses pharmacogenetics and investigates the genetic basis for variations in drug metabolism, efficacy, and targeting using techniques such as DNA sequencing and mapping. Ideally, prospective genotype determinations permit individualized therapies that are effective without harmful side effects.

Perioperative pharmacogenetic considerations include genetic susceptibility to risk factors and also potential adverse reactions to physiologic disturbances. The field of perioperative genomics seeks to understand the connection between genetic variations and differences in anesthetic responses and outcomes.

GENETIC FACTORS IN DRUG DOSE–RESPONSE RELATIONSHIPS

A wide variety of genetic polymorphisms, or changes that result in phenotype variation, occur with genetic promoter, coding, insertion, or deletion alterations. Most genetic polymorphisms only modestly impact drug action relative to the more significant nongenetic effects. Furthermore, most phenotypic traits are multigenetic, decreasing their utility in describing genetic variation.

Individual responses to drugs may be based on genetic variability in both pharmacokinetics and pharmacodynamics. Pharmacokinetic variability reflects the differences in absorption, distribution, metabolism, and excretion. This variability is due to genetic variations in transport molecules that mediate a drug’s uptake and excretion and in drug metabolizing enzymes such as cytochrome P450 liver enzymes. Pharmacodynamic variability refers to phenotypic drug variability despite equivalent delivery to sites of action, reflecting molecular differences in target functions or receptors. A clinical example of genetic variation in pharmacodynamics is the OPRM1 receptor for morphine. A certain percentage of the population exhibit a single nucleotide polymorphism (SNP) on the gene for the OPRM1 receptor that encodes a resistance to the drug morphine.

MALIGNANT HYPERTHERMIA (MH)

MH is a very rare (1/10,000), life-threatening, autosomal dominant, genetic disorder characterized by a metabolic state in which a patient exposed to a triggering agent may develop multisystem organ damage and death.

Pathophysiology

MH results from abnormal excitation–contraction (EC) coupling in skeletal muscle, leading to the uncontrolled release of calcium (Ca²⁺) from the sarcoplasmic reticulum (SR). This massively increases intracellular calcium and causes sustained muscle contractions. The ensuing hypermetabolic state produces tachypnea, tachycardia, hyperthermia, and metabolic acidosis. During typical EC coupling, the skeletal muscle membrane depolarizes to induce a conformational change in the DHPR (voltage-gated Ca²⁺ channel dihydropyridine receptor). This activates the ryanodine receptor type 1 (RYR1) protein to release Ca²⁺ from the SR. Ca²⁺ travels from a high concentration in the lumen of the SR to the skeletal muscle cytosol where it binds troponin C. Ca²⁺-bound troponin C causes tropomyosin to move away from thin-filament myosin-binding sites, resulting in muscle contractions. Contractions are terminated as Ca²⁺ is pumped back into the SR by the sarco/endoplasmic reticulum Ca²⁺–ATPase (SERCA), an ATP-dependent Ca²⁺ pump.

Mutations in ...