Clinical Pharmacokinetics in Patients with Spinal Cord Injuries

Abstract

Although spinal cord injury is a catastrophic affliction with numerous victims and a variety of physiological manifestations, the associated disarray in physiology has yet to be systematically or comprehensively studied as a probable cause for altered pharmacokinetics. A significant increase in the volume of distribution of drugs such as the aminoglycosides (gentamicin, amikacin, tobramycin), which are highly distributed into the extracellular fluid space and minimally biotransformed, may be anticipated in patients with chronic spinal cord injury. Changes in total body clearance have also been observed for some of these medications. The influence of the pathophysiology of spinal cord injury on gastrointestinal motility appears to be reflected in an impairment in the bioavailability of drugs [theophylline, paracetamol (acetaminophen), doxycycline] which are passively absorbed and which require an intact postprandial gastric emptying to ensure efficient absorption. For theophylline, the impairment in gastrointestinal absorption appears to be directly proportional to both the magnitude of the impairment in gastric emptying and to the neurological level of the injury. Metoclopramide, a gastrointestinal prokinetic drug, has been shown to be extremely effective in normalising the impaired postprandial gastric emptying that characterises spinal cord injury. The systemic absorption of 2 antibiotics (gentamicin and cefotiam) injected into paralysed muscle is also impaired in patients with spinal cord injury, suggesting that a decrease in therapeutic efficacy attributable to this mode of administration may be anticipated. Despite the multiplicity of drugs commonly prescribed for patients with this injury, little is known about the influence of this illness on either bioavailability or postabsorptive pharmacokinetics. For drugs which are biotransformed and which have a relatively small volume of distribution (theophylline, lorazepam, ranitidine), single-dose intravenous pharmacokinetic profiles in patients with spinal cord injury are indistinguishable from the drug disposition profiles characteristic of healthy control populations. It may be inferred, then that the influence of the pathophysiology of spinal cord injury on drug disposition is greatest on those drugs which are the least biotransformed and most likely to be distributed into the increased extracellular fluid volume which is characteristic of patients with this disability.(ABSTRACT TRUNCATED AT 400 WORDS)

Spinal cord injury sequelae alter drug pharmacokinetics: an overview

“…Studies on intramuscular administration of cefotiam and gentamicin have confirmed that both present delayed absorption and lower peak serum concentrations. 40 Absorption of diclofenac through intramuscular administration, however, was unaltered in SCI patients. 41 Further studies are needed to understand the distinct behavior of drugs and the physiological anomalies that cause PK alteration after intramuscular administration.…”

“…Studies have shown that increases in the volume of distribution post-SCI can range from 20% for amikacin to 70% in cases such as cefotiam. 40 Other drugs with altered distribution due to an increase in volume of distribution include ketamine and lorazepam. 46,47 Moreover, altered serum lipid profile affects the quantity of drug that can bind and be distributed.…”

“…40 Compared with other PK parameters, metabolic alterations are minimal in SCI patients; nonetheless, changes in dosage quantity and intervals must be placed under scrutiny to optimize these therapies.…”

“…The effect of this altered physiology decreases clearance and elevates the elimination half-life of the drug; examples of this phenomenon have been seen in amikacin, cefotiam, doxycycline, ketamine, diclofenac, vancomycin and lorazepam. 41,46,51,40,47,52 In view of the above observations, patients may require longer dosing intervals to prevent drug toxicity. Reports have also suggested that if ibuprofen drug therapy is initiated, and the patient develops signs of drug toxicity, this may be a sign of ibuprofen-induced renal insufficiency, which further lowers drug clearance.…”

Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction

“…6 Likewise, SCI-induced changes in oral drug absorption have been reported for paracetamol, 4,7 dantrolene 8 and theophylline, 9 and it has been suggested that these changes could have an impact on the efficacy and safety of a variety of drugs in this population. 10 Characterization of the pathophysiological alterations underlying pharmacokinetic changes that occur in patients with SCI has been complicated because of the important variability induced by differences in injury characteristics, as well as in the individual conditions of each patient. 10 Moreover, not all drugs exhibit altered disposition after SCI.…”