The Effect of Respiratory Disorders on Clinical Pharmacokinetic Variables

Abstract

Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or antimicrobial agents in pulmonary disease. In patients under mechanical ventilation, the half-life of midazolam, a new benzodiazepine used as a sedative, has been found to be lengthened but the underlying mechanism is not well understood. Pulmonary absorption of pentamidine was found to be increased in patients under mechanical ventilation. Pharmacokinetic impairment does occur in patients with severe pulmonary disease but more work is needed to understand the exact mechanisms and to propose proper dosage regimens.

Optimal PEGylation can Improve the Exposure of Interferon in the Lungs Following Pulmonary Administration

“…It is worth noting, however, that the PK of pulmonary administered proteins may be altered in the disease state. Factors such as altered alveolar permeability and vasculature remodeling, infiltration of immune cells, and changes to respiratory mucus lining may influence the absorption and clearance of proteins from the lungs . This will need to be investigated prior to translation into humans.…”

Hypoxia—implications for pharmaceutical developments

“…In addition, with a shift from aerobic to anaerobic metabolism, there may occur a fall in pH [7]. Local pH conditions in the cell can also contribute to an alteration in clinical effect or metabolism [24, 25]. …”

The Effect of Hypoxic Hypoxia on the Systemic and Myocardial Pharmacokinetics and Dynamics of Lidocaine in Sheep

“…However, once the hypoxia progresses to the point in which oxygen delivery to the myocardium cannot be maintained, there may be a precipitous and critical decrease in cardiac output and myocardial blood flow with attendant bradycardia and hypotension 6. The mechanisms by which these processes could influence the disposition of drugs therefore include: (1) circulatory changes altering blood flow to organs of distribution or metabolism, (2) changes in pH influencing protein binding and distribution volumes, and (3) reduced rates of drug metabolism by cytochrome P450 enzymes, for which oxygen is a substrate 4…”

“…A systematic analysis requires a knowledge of the physiological factors influencing the disposition of drugs, and how these are affected by the individual disease processes that may comprise critical illness in an individual patient. Hypoxia is one of these processes, and previous workers have studied its effects on drug disposition 4. However, it is difficult to make general conclusions because of the variety of physiological states produced by hypoxia.…”