Spinal Cord (2011) 49, 955–960 & 2011 International Spinal Cord Society All rights reserved 1362-4393/11 $32.00 www.nature.com/sc REVIEW Spinal cord injury sequelae alter drug pharmacokinetics: an overview H Mestre, T Alkon, S Salazar and A Ibarra Facultad de Ciencias de la Salud, Universidad Ana´huac Me´xico Norte, Huixquilucan Edo. de Me´xico, Me´xico Study design: Literature review. Objectives: Critical review of the literature published on the physiological alterations caused by spinal cord injury (SCI) and their effect on the pharmacokinetic parameters of commonly employed drugs. The review introduces the most recent treatment protocols of a variety of drugs, enabling the modern clinician to apply efficacious and cost-effective solutions to the pharmacological treatment of SCI patients. Methods: Studies published in international indexed journals up to January 2011 were selected from the PubMed database. Results: The review evaluated the sequelae of SCI and their effect on pharmacological processes. The results demonstrated that these alterations affected the pharmacokinetics of drugs commonly administered to SCI patients, such as antibiotics, muscle relaxants, immunosuppressants and analgesics. Conclusion: There are multiple etiologies to SCI and patients present with varying degrees of impairment. Factors such as level of injury and completeness of the injury create a very heterogeneous population within the SCI community. The heterogeneity of this population creates a problem when trying to standardize pharmacokinetic (PK) parameters. It is because of this that specific physiological alterations must be linked to changes in PK and be identified within the clinical setting. This relationship between physiology and PK enables the clinician to be alert for possible pharmacological complications in individual patients based on their clinical manifestations. Future research should aim to develop rigorous therapeutic guidelines tailored to the diverse manifestations of SCI so as to provide effective, affordable and safe pharmacotherapy. Spinal Cord (2011) 49, 955–960; doi:10.1038/sc.2011.58; published online 31 May 2011 Keywords: autonomic dysreflexia; pharmacokinetics; paraplegia; pathophysiology; pharmacotherapy Introduction After spinal cord injury (SCI), a series of degenerative Currently, the incidence of SCI is between 12.1–57.8 new phenomena alter metabolic and physiological functions. cases per million inhabitants every year worldwide.3 In the These alterations persist throughout the acute, subacute and, past, acute-stage mortality reduced the prevalence of SCI; in most cases, chronic phases of disease. A SCI isolates the however, because of recent scientific advancements, patients uninjured spinal cord below the injury site, from the brain now have a 47–51-year life expectancy.4 In spite of the and the rest of the central nervous system.1 This mechanism improved life expectancy, SCI patients suffer from other of decentralization impairs communication between the challenges, such as severe financial, social and psychological central nervous system and the peripheral nervous system, burdens. resulting in an autonomic nervous system failure. SC-injured One of the major sources of financial burden is drug individuals may develop spinal shock and autonomic therapy. Injured patients develop secondary complications dysreflexia as a result of these permanent disturbances in that require large quantities of medication generating an global homeostasis.2 These life-long alterations convert SCI annual cost of $2489 USD.5 Research has proven that patients into a heterogeneous population with a physiology physiological and metabolic functions are altered in people different from that of healthy individuals. with SCI; therefore, the fundamental assumptions of phar- macokinetics (PK) and pharmacodynamics derived from Correspondence: Professor A Ibarra, Facultad de Ciencias de la Salud, able-bodied individuals do not apply. In many cases, the Universidad Ana´huac Me´xico Norte, Av. Universidad Ana´huac No. 46, Col. standard schedule of the therapy does not achieve the Lomas Ana´huac, C.P. 52786, Huixquilucan Edo. de Me´xico, Me´xico. desired therapeutic effects or entails drug concentrations at E-mail: [email protected] or [email protected] 6 Received 26 September 2010; revised 19 April 2011; accepted 21 April 2011; potentially toxic levels for the patient. Therefore, there is published online 31 May 2011 significant need for accurate and precise pharmacological Pharmacokinetic alterations in spinal cord injury H Mestre et al 956 schedules specifically developed for this population. It is subacute phase of SCI, spinal shock resolves and paralysis of imperative to modify the current treatment protocols for a the limbs below the lesion occurs owing to the conductive population-specific approach to pharmacology that opti- impairment of the descending tracts. This phase is no longer mizes the absorption, distribution, metabolism and excre- characterized by flaccid paralysis but rather by a state of tion of drugs in SCI patients. This manuscript reviews the spastic paralysis. The spastic muscle groups will depend on main physiological and metabolic alterations in SCI patients which tracts are affected by the SCI.7 Paralysis leads to a loss and their effect on PK parameters and introduces the most in neural tone causing a marked increase in muscle wasting.8 recent population-specific treatment protocols of a variety of If there is muscular atrophy, it reduces the biomass that a drugs, enabling the modern clinician to apply efficacious drug must cross to enter systemic blood flow and may and cost-effective solutions to the pharmacological treat- therefore pose alterations in IM absorption of certain drugs. ment of SCI patients. On the other hand, if descending visceral autonomic fibers The length of the spinal cord and the distribution of the are also interrupted, bladder and intestinal functions will no functional ascending and descending tracts make location of longer be under functional control; the implications of these the lesion very important in determining the clinical will be discussed later. manifestations of SCI. These factors make the SCI commu- nity highly heterogeneous and therefore complicate the Cardiovascular. If the injury to the spinal cord is above the development of standard PK models. It is the clinician’s level of the sixth thoracic (T6) vertebrae, this will affect responsibility to understand the sequelae that their SCI sympathetic innervation of the cardiovascular system and patient possesses and determine the possible alterations in the autonomic nervous system becomes unbalanced.9 The PK that may cause complications in traditional drug therapy. decrease in sympathetic tonus promotes vasodilatation, resulting in hypotensive crisis, hypoperfusion of vital organs and hypoxemia. Eventually, partial autonomic regulation Methods returns and can trigger autonomic dysreflexia. Sensorial Review of the literature consisted of a methodological search stimuli from peripheral nerves are prevented from reaching on the PubMed database. The primary search used keywords the inhibitory supraspinal centers, causing the sympathetic such as SCI therapy, SCI PK, SCI altered PK, SCI PK ganglia to become hyperexcitable.9 Sympathetic hyperactiv- absorption, SCI PK distribution, SCI PK metabolism and ity causes increased vasoconstriction below the injured SCI PK excretion. Studies relevant to the review were taken spinal cord.2 Vasoconstriction induces an elevated BP, and into consideration. The last literature review published on thereby the central nervous system tries to lower BP by this topic (1989) was also incorporated into this review. Only activating injury-excluded parasympathetic stimulation of studies that had been published in international indexed the heart, which triggers a state of bradycardia and vasodila- journals up to January 2011 were used. The results were tion above the site of injury.10 The hemodynamic instability included if the studies achieved a significant statistical alters normal blood flow. Bradycardic hypotension results in difference (Po0.05) against controls. Studies that satisfied hypoperfusion, which can have a negative effect on drugs the criteria were analyzed and reported. Analysis consisted of administered through intravenous or intraarterial routes and identifying the PK parameter that is altered in SCI and the could decrease microvascular blood flow to certain organs. process causing it. The secondary search used the following Studies show that SCI induces a significant decrease in keywords: SCI pathophysiology, SCI sequelae, SCI altered microvascular blood flow in the liver, the spleen, muscle and physiology, SCI syndrome, spinal shock, neurogenic shock, fore footpad skin in rats.11 These animal models allow us to spasticity and autonomic dysreflexia. Owing to the progres- extrapolate a similar pathophysiology in SC-injured humans. sive understanding of SCI pathophysiology, only studies These alterations in blood flow and perfusion may affect the published in indexed journals after 2007 were taken into distribution of some drugs. consideration. Respiratory. The loss of supraspinal regulatory mechanisms over the respiratory system results in the acute loss of motor Results function of the respiratory muscles and complications such The importance of understanding the altered physiology and as respiratory failure, atelectasis, neurogenic pulmonary its implications on PK warrants a brief