Judith Jacobi, PharmD, FCCM, BCPS; Gilles L. Fraser, PharmD, FCCM; Douglas B. Coursin, MD; Richard R. Riker, MD; Dorrie Fontaine, RN, DNSc, FAAN; Eric T. Wittbrodt, PharmD; Donald B. Chalfin, MD, MS, FCCM; Michael F. Masica, MD, MPH; H. Scott Bjerke, MD; William M. Coplin, MD; David W. Crippen, MD, FCCM; Barry D. Fuchs, MD; Ruth M. Kelleher, RN; Paul E. Marik, MDBCh, FCCM; Stanley A. Nasraway, Jr, MD, FCCM; Michael J. Murray, MD, PhD, FCCM; William T. Peruzzi, MD, FCCM; Philip D. Lumb, MB, BS, FCCM. Developed through the Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), in collaboration with the American Society of Health-System Pharmacists (ASHP), and in alliance with the American College of Chest Physicians; and approved by the Board of Regents of ACCM and the Council of SCCM and the ASHP Board of Directors

/pdf/clinical-practice-guidelines-for-the-sustained-use-of-550x8gqibj.pdf

Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.

National High Blood Pressure Education Program.

Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.

http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Pharma_Toxicol/Human_Cyp3A.pdf

In vitro and in vivo drug interactions involving human cyp3a

The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

/pdf/pharmacokinetics-and-dosage-adjustment-in-patients-with-5bewfq2iab.pdf

Pharmacokinetics and dosage adjustment in patients with renal dysfunction

Drug glucuronidation in humans.

Midazolam kinetics and psychomotor function were studied after an intravenous dose of 0.075 mg/kg body weight in seven patients with alcoholic cirrhosis and eight control patients. Four of the seven cirrhotics died of complications of their liver disease within six months of the study. The metabolism of midazolam was significantly impaired in the cirrhotic patients (p less than 0.025). These patients also had evidence of greater sedation than the control group for up to six hours after the dose was administered (p less than 0.05). The clearance of midazolam did not correlate significantly with the serum albumin, or bilirubin, or with the kinetics of antipyrine, or indocyanine green. This study shows significant delay in the elimination of midazolam and decreased psychomotor function in patients with severe alcoholic liver disease. Caution is needed in using this drug for premedication in such patients before endoscopy.

https://gut.bmj.com/content/gutjnl/27/2/190.full.pdf

Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis.

Kinetic analysis was carried out after single intravenous (25 mg) and oral (200 mg) doses of the novel partial opioid agonist meptazinol (Meptid) in patients with non-cirrhotic liver disease (NCLD) and biopsy proven cirrhosis. Comparison was made with a group of patients with normal hepatic function. Elimination half-lives after the intravenous dose were slightly prolonged in the cirrhotics (n = 10; 4.2 +/- 0.6 h) compared with the control (n = 8; 2.7 +/- 0.2 h: p less than 0.05) and NCLD (n = 8; 3.2 +/- 0.5 h) groups. There was no significant difference in meptazinol plasma clearance between the groups (cirrhotics = 72 +/- 8 l/h; NCLD = 89 +/- 9 l/h; control = 83 +/- 10 l/h). After the oral dose, seven of 15 cirrhotic patients vomited but only one patient in each of the other groups was unable to tolerate the drug (p = 0.06). This may be explained by very much higher peak meptazinol concentrations in the cirrhotic (n = 8; 184 +/- 37 ng/ml, p less than 0.01) and NCLD (n = 8; 131 +/- 38 ng/ml, p less than 0.05) patients than those of the controls (n = 7; 53 +/- 12 ng/ml) reflecting a mean four-fold and two-fold increase in oral bioavailability respectively (cirrhotics: n = 8; 27.9 +/- 5.3%: p less than 0.001; NCLD: n = 7; 13.7 +/- 3.9% p less than 0.05; controls: n = 7; 6.5 +/- 1.3%). There was no evidence of accumulation after chronic dosing with 200 mg meptazinol four times daily for 13 doses in seven control, seven NCLD and six cirrhotic patients. There were no detectable differences in psychomotor function measured objectively using the Leeds Psychomotor Tester of subjectively by linear analogue scoring between the groups in all three parts of the study. The oral use of meptazinol in patients with chronic liver disease is associated more with the development of nausea and vomiting rather than excessive sedation. These data suggest that dosage reduction in cirrhotic patients is advisable particularly if the drug is taken by mouth.

https://gut.bmj.com/content/gutjnl/28/3/248.full.pdf

T Murray

Papers

Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis.

Enhanced oral bioavailability of meptazinol in cirrhosis.