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PHARMACOLOGY REVIEW
From the Cleveland Clinic’s Comprehensive Anesthesiology Review,
presented April 30 to May 5, 2005
Basic Pharmacology for the Anesthesiologist— John E. Tetzlaff, MD, Professor of
Anesthesiology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve
University, and Program Director, Center for Anesthesiology Education, Division of
Anesthesiology and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland
Pharmacokinetics: simple model considers body as single box or compartment; amount
of drug injected defined as dose; concentration of drug in compartment determined by
volume of distribution (physiologic distribution); drug-specific volume of distribution
equals amount of drug in body divided by concentration in blood
Metabolism: half-life—time required for plasma concentration to decrease by
half; first-order elimination—constant fraction of change in clearance per unit time; zeroorder elimination—constant amount of change in clearance per unit time
Central compartment: contains high-volume or high blood flow (BF) organs (eg,
heart, great vessels, lungs); instant peak blood levels attained; with drugs metabolized or
rapidly redistributed, relatively rapid fall in concentration without continuous infusion;
highly related to initial drug action for most anesthetic drugs
Peripheral compartment: includes several compartments; size depends on
peripheral BF and whether tissue in question ionic or lipid-soluble; change much slower,
especially in highly lipid-soluble peripheral compartments; peak levels achieved slowly
and decrease slowly; in general, intial effect of drugs in central compartment and
sustained effects in peripheral compartment
Clearance
Hepatic: major source of drug clearance; main metabolic actions oxidation,
reduction, hydrolysis, and conjugation; cytochrome system capable of oxidation and
reduction; conjugation of large or lipid-soluble molecules occurs by unique enzymes;
elimination of anesthetic drugs directly proportional to hepatic BF; drugs administered
orally pass through liver before redistribution to central compartment
Renal clearance: as primary source of elimination, favors small molecules, and
water-soluble over lipid-soluble molecules; decreases slightly with age; proportional to
renal BF
Tissue clearance: minor component to elimination of majority of anesthetic
agents; may be enzyme-mediated ester hydrolysis; classic examples are succinylcholine
and ester local anesthetics; also some spontaneous ester hydrolysis; amount of clearance
limited and rapidly shifts from first-order to zero-order elimination; subject to BF, but to
lesser extent
Protein binding: contributes to drug clearance to extent that agents protein
affiliated; determined by protein-binding capacity; principal proteins in plasma and serum
involved in protein binding include albumin and α1 -acid glycoprotein; influenced by
nutrition and aging
Factors that alter clearance
Continuous infusion: avoids competition between sudden effect in central
compartment and sustained effect in peripheral compartment; achieve steady state by
determining balance between rate of administration and clearance; steady state achieved
by continuous infusion or infusion as adjunct to loading dose
Route of administration: uptake slower when drug administered into poorly
vascularized area or area with low regional BF; target effect achieved quickly when drug
injected into area with high BF; accelerated redistribution in areas of high BF and slow
redistribution in areas of low BF; ionic substances can have absorbance limited by pH;
ion trapping may cause artificially elevated concentrations
Patient variability: coadministration of other medications may induce enzymes
that accelerate or reduce clearance; renal BF decreases with increasing age; variety of
metabolic enzyme systems dependent on maturity; maternal and fetal α1 -acid
glycoproteins can be reduced; illness or severe comorbidity in mother may cause reduced
albumin concentration
Disease: renal clearance proportional to creatinine clearance; liver disease affects
molecules metabolized in liver; also reduces protein binding; causes reduction in
metabolic capacity as hepatic parenchyma damaged; intrahepatic shunting causes
molecules to pass through shunts without exposure to enzyme system, resulting in lower
metabolism; cardiac failure influences elimination (hepatically and renally); causes
diminished hepatic BF, alters regional BF, decreases renal BF, and alters tissue clearance
Postoperative period: absorption from gastrointestinal (GI) tract reduced; metabolic rates
also reduced; in patient with multiple surgical procedures or critical care needs, reduced
drug binding because of catabolism eliminating serum proteins; intra-abdominal or
intrathoracic procedure associated with diminished liver BF
Metabolism: many anesthetic drugs have first-order elimination, but some have high
molecular weight, high lipid solubility, or both; depends on metabolic alteration to be
further metabolized or excreted intact through renal system; involves adding polar
molecules and oxidation, reduction, and hydrolysis steps to allow renal elimination of
smaller molecules; oxidation occurs in smooth endoplasmic reticulum almost exclusively
in liver; oxidation can involve aliphatic substitution, desulfuration, or dehalogenation;
reduction occurs at anaerobic conditions almost completely in liver via cytochrome P450
system; hydrolysis can occur via variety of enzyme systems in liver, lung, and other
tissues; pseudocholinesterase system highly active; phase II reactions modify molecules
to facilitate clearance; most common reactions glucuronic acid conjugation on amine side
or acetylation on hydrophobic side; others include mercapturic acid synthesis for sulfurcontaining molecules, sulfate formation, amide synthesis, and methylation
Pharmacogenetics: ≈6 sites where cytochrome P450 system active; lesions known to
cause specific conditions
Pharmacodynamics: relationship between plasma concentration and designed drug
effects; majority of receptors have balance between agonist and antagonist activity;
receptor activity dependent on concentration and altered by drugs, physiologic
conditions, and disease; receptor structure and function related; complex chemical event
involving G-proteins, ion channels, ion restoration pumps, and second messengers
(including hormones)
Compounding local anesthetics to reduce toxicity: depends on selection of local
anesthetics; ideally, choose short-acting anesthetic from one category and longer-acting
anesthetic from another category to reduce toxicity.
Suggested Reading
Bernards CM et al: Epidural, cerebrospinal fluid, and plasma pharmacokinetics of
epidural opioids (part 1): differences among opioids. Anesthesiology 99:455, 2003;
Egan TD et al: Remifentanil versus alfentanil: comparative pharmacokinetics and
pharmacodynamics in healthy adult male volunteers. Anesthesiology 84:821, 1996;
Elfstrom J: Drug pharmacokinetics in the postoperative period. Clin Pharmacokinet 4:16,
1979;
Greenwood-Van Meerveld B et al: Preclinical studies of opioids and opioid antagonists
on gastrointestinal function. Neurogastroenterol Motil 2:46, 2004;
Hogue CW Jr et al: A multicenter evaluation of total intravenous anesthesia with
remifentanil and propofol for elective inpatient surgery. Anesth Analg 83:279, 1996;
Hug CC Jr: Pharmacokinetics of drugs administered intravenously. Anesth Analg 57:704,
1978; Krejcie TC et al: A recirculatory model of the pulmonary uptake and
pharmacokinetics of lidocaine based on analysis of arterial and mixed venous data from
dogs. J Pharmacokinet Biopharm 25:169, 1997;
Leslie JB: Alvimopan for the management of postoperative ileus. Ann Pharmacother
39:1502, 2005;
Lowenstein E et al: Cardiovascular response to large doses of intravenous morphine in
man. N Engl J Med 281:1389, 1969;
Lowenstein E et al: Narcotic "anesthesia" in the eighties. Anesthesiology 55:195, 1981;
Shand DG et al: Effects of route of administration and blood flow on hepatic drug
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Wilkinson GR et al: Commentary: a physiological approach to hepatic drug clearance.
Clin Pharmacol Ther 18:377, 1975;
Wolff BG et al: Alvimopan, a novel, peripherally acting mu opioid antagonist: results of
a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major
abdominal surgery and postoperative ileus. Ann Surg 240:728, 2004;
Yuan CS: Clinical status of methylnaltrexone, a new agent to prevent and manage opioidinduced side effects. J Support Oncol 2:111, 2004.