Pharmacokinetic and Pharmacodynamic Considerations When Treating Patients with Sepsis and Septic Shock

Abstract

Sepsis and septic shock are accompanied by profound changes in the organism that may alter both the pharmacokinetics and the pharmacodynamics of drugs. This review elaborates on the mechanisms by which sepsis-induced pathophysiological changes may influence pharmacological processes. Drug absorption following intramuscular, subcutaneous, transdermal and oral administration may be reduced due to a decreased perfusion of muscles, skin and splanchnic organs. Compromised tissue perfusion may also affect drug distribution, resulting in a decrease of distribution volume. On the other hand, the increase in capillary permeability and interstitial oedema during sepsis and septic shock may enhance drug distribution. Changes in plasma protein binding, body water, tissue mass and pH may also affect drug distribution. For basic drugs that are bound to the acute phase reactant alpha(1)-acid glycoprotein, the increase in plasma concentration of this protein will result in a decreased distribution volume. The opposite may be observed for drugs that are extensively bound to albumin, as the latter protein decreases during septic conditions. For many drugs, the liver is the main organ for metabolism. The determinants of hepatic clearance of drugs are liver blood flow, drug binding in plasma and the activity of the metabolic enzymes; each of these may be influenced by sepsis and septic shock. For high extraction drugs, clearance is mainly flow-dependent, and sepsis-induced liver hypoperfusion may result in a decreased clearance. For low extraction drugs, clearance is determined by the degree of plasma binding and the activity of the metabolic enzymes. Oxidative metabolism via the cytochrome P450 enzyme system is an important clearance mechanism for many drugs, and has been shown to be markedly affected in septic conditions, resulting in decreased drug clearance. The kidneys are an important excretion pathway for many drugs. Renal failure, which often accompanies sepsis and septic shock, will result in accumulation of both parent drug and its metabolites. Changes in drug effect during septic conditions may theoretically result from changes in pharmacodynamics due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor. The lack of valid pharmacological studies in patients with sepsis and septic shock makes drug administration in these patients a difficult challenge. The patient's underlying pathophysiological condition may guide individual dosage selection, which may be guided by measuring plasma concentration or drug effect.

Clinical pharmacology of exogenously administered alkaline phosphatase

“…Knowledge of clinical pharmacology of drugs in patients with sepsis is scarce despite profound sepsis-induced pathophysiological changes in these patients often affecting drug absorption, distribution, metabolism, and excretion [19]. Mammalian APs are membrane-bound enzymes; and in humans, four AP isoenzymes exist of which three are tissue-specific (placental, PLAP; germ cell, GCAP; and intestinal, IAP) and one is tissue nonspecific (TNAP) and is expressed in virtually all tissues (e.g., bone, liver, and kidney).…”

Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: The central role of proinflammatory cytokines

“…Environmental factors known to alter CYP isoforms include medications (e.g. barbiturates, anticonvulsants, rifampin), food (cruciferous vegetables), social habits (alcohol consumption, cigarette smoking), development, and disease conditions (diabetes, inflammation, and infection) (17). Mediators involved in inflammation and sepsis can alter the drug metabolizing capabilities of hepatic CYPs (18-21) Proinflammatory cytokines play an important role in the regulation of CYP expression (5,6).…”

Systematic review of the evidence for rational dosing of colistin

“…A loading dose is required in serious infections to rapidly achieve therapeutic concentrations. Critically ill patients with severe sepsis have significant capillary leak, [23][24] which increases the volume of distribution of colistin 4 -15-fold. [25][26] The loading dose in critically ill patients is therefore higher than in less-ill patients.…”