Current Clinical Pharmacology - Volume 10, Issue 1, 2015

From uncertain beginnings over four decades ago, heart transplantation is now the definitive therapy for end-stage heart failure. This review will attempt to comprehensively cover the broad gamut of anesthetic, hemodynamic, antimicrobial, immunosuppressive and hemostatic agents used by the cardiothoracic anesthesiologist in the perioperative management of patients with endstage heart disease.

In the past two decades, lung transplantation has become an increasingly important surgical option for the patient with end stage lung disease. Compared with the other solid organ transplants (heart, liver and kidney), lung transplantation carries immense clinical and logistic challenges; long-term organ viability is particularly problematic, with an expected five-year mortality of 40-50%. The number of lung transplants performed in the U.S. has been increasing steadily since 1988, when UNOS (United Network for Organ Sharing) started recording statistical data. In that year, 33 cases of lung transplantation were performed. As of today, a total of 23,815 lung transplants have been performed, and the largest number of yearly lung transplants (n=1,822) was performed in 2009. From appropriate patient selection, to optimal organ selection, surgical procedure, and immediate and long-term postoperative care, the medical process involves multiple healthcare providers and requires a very well-organized and committed healthcare system to achieve optimal surgical results. Understanding the pharmacology involved in the care of the lung transplant patient is of utmost importance to achieve appropriate organ preservation, immunosuppression, hemodynamic stability, and adequate anesthetic depth, while avoiding drug toxicity and side effects. The purpose of this review is to summarize the pharmacokinetics and pharmacodynamics of the medications most commonly administered to this patient population, throughout the perioperative period.

The number of patients with end stage liver disease is growing worldwide. This is likely a result of advances in medical science that have allowed these patients to lead longer lives since the incidence of diseases such as alcoholic cirrhosis and viral hepatitis have remained stable or even decreased in recent years, at least in more developed nations. Many of these patients will require anesthetic care at some point. The understanding and application of basic principles of pharmacokinetics is paramount to the practice of anesthesia. An understanding of pharmacokinetic principles provides the anesthesiologist with a scientific foundation for achieving therapeutic objectives associated with the use of any drug; however, pathologic conditions often alter the expected kinetic profile of many drugs. Anesthesia providers caring for these patients must be aware of the altered pharmacokinetics that may occur in these patients. We review normal liver physiology, pathophysiology of liver disease in general, and how liver failure affects the pharmacokinetics and pharmacodynamics of anesthetic agents; providing some specific examples.

Kidney transplants are routinely performed at medical centers around the world. Concurrent with improved surgical techniques, a better understanding of the pharmacology involved in the perioperative anesthetic management has led to improved outcomes in these patients. This chapter reviews the perioperative pharmacologic considerations surrounding kidney transplant patients from the viewpoint of the transplant anesthesiologist.

Orthotopic liver transplantation (OLT) recipients have been reported to have decreased perioperative opioid and intraoperative inhalational anesthetic requirements when compared to patients without liver disease undergoing other types of major abdominal surgeries. The severity of the liver disease and the process of the transplantation itself may alter the pharmacokinetic and pharmacodynamic effects of different pain medications. Chemical injury of the liver and the high degree of surgical stress may also increase the levels of neuropeptides involved in pain modulation. Per the U.S. Department of Health and Human Services Organ Procurement and Transplantation Network, more than 5,000 OLT cases are being done per year since 2000. With better understanding of the pathophysiology of liver disease and the development of perioperative anesthesia management, the recent concept of improving patient outcome following OLT includes a fast-track approach in selected patients, which may shorten or completely bypass intensive care unit stay and reduce costs. With this development, the understanding of the analgesic pharmacology in the care of the OLT patients is even more important. Proper dosage of medications can achieve adequate intraoperative anesthetic depth and postoperative pain control, while avoiding over-sedation which increases risk of prolonged postoperative mechanical ventilation. The purpose of this review is to summarize the pharmacokinetics and pharmacodynamics of the analgesic medications commonly administered to this patient population.

Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis (MTB) and still an important public health problem worldwide. Some factors like the emergence of multidrug resistant (MDR) and extensively drug-resistant (XDR) strains make urgent the research of new active compounds. Searching for new inorganic compounds against TB, three new dioxovanadium(V) complexes were obtained upon reaction of [VO(acac)2] with hydrazone and thiosemicarbazone ligands derived from di-2-pyridyl ketone. Spectroscopic studies and X-ray crystallography revealed asymmetrically oxo bridged binuclear complexes of the type [{VO(L1,2)}2(μ-O)2], involving the hydrazone ligands, while a mononuclear square pyramidal complex of the type [VO2(L3)] was formed with the thiosemicarbazone ligand. The compounds were tested against M. tuberculosis and three of them, with MICs values between 2.00 and 3.76 μM were considered promising for TB treatment. Such MIC values are comparable or better than those found for some drugs currently used in TB treatment.

Activating Ras mutations, present in about 20% of human cancers, compromise the GTPase activity of Ras and therefore trigger accumulation of Ras in the GTP-bound state. Among the three family members, K-Ras, H-Ras and N-Ras, K-Ras is the most frequently mutated gene, with 30-50% of colon cancer patients harboring activating K-Ras mutations. Oncogenic mutations of K-Ras have been found at codons 12, 13, 61 and 146. Activation of Ras triggers constitutive activation of signaling pathways, including the MAPK and AKT pathways, which allows tumor cells to proliferate in the absence of growth factors and increases their survival. In addition, activated Ras triggers inflammation and thus promotes tumor progression in a cell non-autonomous manner. The presence of K-Ras mutations not only has prognostic value, but it also predicts the responsiveness of colon cancer patients to inhibitors of EGFR signaling.