Other routes of administration are less commonly used but exist as feasible options nonetheless. Intraosseous ketamine, for instance, has slightly slower anesthetic onset compared to IV administration (71.3 s and 56.3 s, respectively; Aliman et al., 2011) but may be used in emergency settings. Ketamine can also be administered intranasally, though it has a lower bioavailability of approximately 45% (Yanagihara et al., 2003) and can vary depending on the amount absorbed through the nasal mucosa and the amount swallowed. Due to ketamine’s extensive first-pass metabolism, rectal and oral formulations have limited bioavailability with relatively high concentrations of the active (but less-potent) metabolite ketamine (Malinovsky et al., 1996; Chong et al., 2009; Rolan et al., 2014). Historically, these routes are used infrequently in humans, though increasing efforts are being made to develop suitable oral and sublingual formulations given the recent move towards using low-dose Ketamine for sale for pain and depression in the outpatient setting (Chong et al., 2009; Rolan et al., 2014).
Distribution, Metabolism, and Excretion
Due to ketamine’s high lipid solubility and relatively limited protein binding, it is rapidly taken up by the brain and redistributed, with a distribution half-life of only 10–15 min (Wieber et al., 1975; Domino et al., 1984). Ketamine has a large volume of distribution of nearly 3 L/kg (Clements and Nimmo, 1981). Once in the body, ketamine undergoes liver metabolism to several metabolites (Clements and Nimmo, 1981). Of note, metabolism through cytochrome systems forms the active metabolite ketamine, which retains anesthetic activity but at one-third the potency of ketamine (Cohen and Trevor, 1974; Domino et al., 1984). Inactive ketamine conjugates and metabolites are really excreted (Wieber et al., 1975), and elimination half-life is 2–3 h (Domino et al., 1984).
Ketamine’s wide therapeutic range makes it one of the safest anesthetics available. General anesthesia can be induced with both IV and IM routes (Table (Table1)1) and maintained with repeated doses of 0.5–1 mg/kg (Domino et al., 1984). Good analgesia and sedation can also be achieved at subanesthetic doses (e.g., 0.2–0.8 mg/kg IV, 2–4 mg/kg IM), and infusions at subanesthetic doses (e.g., 0.5 mg/kg/h) may also provide continuous sedation and analgesia (Allen and Macias, 2005; Miller et al., 2011).
At both subanesthetic and anesthetic doses, ketamine is predominantly a sympathomimetic, producing increased arterial pressures and heart rate (Corssen and Domino, 1966) through direct stimulation of central nervous system structures (Traber et al., 1970). At higher doses (e.g., 20 mg/kg), however, ketamine also acts as a direct myocardial depressant (Traber et al., 1968), and in the setting of compromised autonomic control (e.g., spinal cord transection, catecholamine depletion), these depressive effects may be unmasked. Ketamine also causes direct relaxation of vascular smooth muscle, though due to its sympathetically-mediated vasoconstriction, it has a relatively stable net effect on systemic vascular resistance (Diaz et al., 1976; Akata et al., 2001; Jung and Jung, 2012).