The application of surgical treatments is greatly enhanced by the availability of anesthetic agents, such as neuromuscular blockers. Succinylcholine chloride (2,2′-[(1,4-dioxo-1, 4-butanediyl) bis (oxy)] bis [N, N, N-trimethylethanaminium] dichloride), also known as suxamethonium chloride, is a depolarizing neuromuscular blocking agent (NMBA) on the World Health Organization's List of Essential Medicines. Because of its rapid onset of action and short half-life, it is commonly used in medical procedures that require short-term skeletal muscle paralysis, including rapid intubation in emergency medical situations. The clinical application of succinylcholine (SCH) is tempered by the occurrence of rare, but dramatic adverse reactions and some were the earliest known examples of pharmacogenetics. In many cases, patients with functionally characterized single nucleotide polymorphisms (SNPs) in specific genes in either the pharmacokinetic (PK) or pharmacodynamic (PD) pathways of SCH are at increased risk of these adverse reactions. The ubiquity of SCH in medical procedures makes understanding the pharmacogenomics of SCH critical for identifying susceptible patients such that suitable interventions and alternatives may be utilized. Figure 1 illustrates the PD and PK pathways of SCH and a fully interactive version of these pathways can be accessed at PharmGKB (https://www.pharmgkb.org/pathway/PA166122732). Figure 1 Stylized cells depicting the metabolism and mechanism of action of succinylcholine. Note: the star symbol on the DHPR indicates that it has been activated by depolarization of the t-tubules. A fully interactive version is available at PharmGKB http://www.pharmgkb.org/pathway/PA166122732 ... Pharmacodynamics Structurally, SCH consists of two acetylcholine (ACh) molecules linked end to end by their acetyl groups [1, 2]. ACh is the endogenous agonist of the nicotinic acetylcholine receptor (nAChR), a ligand-gated, non-specific cation channel that is formed by five sub-units organized around a central pore. There are two α1 subunits, and one β1, δ, and e sub-units. Each sub-unit of the nACHR is encoded by one of four genes (α1 is encoded by CHRNA1, β1 is encoded by CHRNB1, δ is encoded by CHRND, and e is encoded by CHRNE) (Figure 1). The nAChR is located on the motor end plate of neuromuscular junction (NMJ) of the skeletal muscle membrane, also known as the sarcolemma. Binding of an agonist, such as ACh or SCH, promotes the open state of the channel. When the nAChR opens, sodium ions rush into the cell and potassium ions rush out resulting in membrane depolarization and generation of an action potential. In myocytes, depolarization stimulates muscle contraction [3-5]. L-type voltage gated calcium channels, also known as dihydropyridine receptors (DHPR), are located on invaginations of the sarcolemma called the transverse tubules (T-tubules). The DHPR is a complex of four sub-units (α1, α2δ, β, γ) and a distinct gene encodes each sub-unit. CACNA1S encodes the α1 sub-unit (also called Cav1.1), the primary sub-unit of the channel that contains the voltage sensor, gating apparatus and channel pore of DHPR [6]. The DHPR is mechanically coupled to the ryanodine receptor (RYR1), a homotetrameric voltage gated calcium channel that is located on the sarcoplasmic reticulum (SR) and encoded by the RYR1 gene [7] (Figure 1). When skeletal muscles are at rest, the troponin complex allosterically inhibits the formation of a cross-bridge between myosin and actin. When calcium is released into the myoplasm, it binds the troponin complex and allows myosin to bind to actin to initiate muscle contraction and continues for as long as ATP is freely available [8]. Upon depolarization of the sarcolemma, the DHPR undergoes a conformational change and transmits a signal to RYR1, which opens to release SR calcium stores into the myoplasm to initiate muscle contraction. Muscle relaxation occurs when calcium ATPases on the sarcoplasmic reticulum (SERCA) remove calcium from the myoplasm and pump it back into the SR [9]. Because it is a depolarizing NMBA, SCH first induces muscle fasiculations followed by flaccid muscle paralysis. SCH takes effect within 60 seconds of intravenous administration and paralysis lasts between 4-6 minutes during which time patients are monitored with an electric nerve stimulator [1]. Because of its short half-life SCH is indicated for medical procedures requiring short-term muscle paralysis, such as endotracheal intubation, neuromuscular surgery, and electroconvulsive therapy. Because SCH paralyzes the respiratory muscles, patients require mechanical ventilation and close monitoring for the duration of paralysis. It has no direct effect on smooth or cardiac muscle contraction. SCH is often administered in combination with other anesthetics, analgesics and narcotics because although it blocks muscle contraction it has no effect on pain perception [1, 2, 10].