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
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| 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
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 | Metabolism: half-life—time required for plasma concentration to decrease by half; first-order elimination—constant fraction
of change in clearance per unit time; zero-order elimination—constant amount of change in clearance per unit time
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| 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
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| 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
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| 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
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| 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
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| 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
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| 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
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| Factors that alter clearance
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| 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
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| 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
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| 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
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| 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
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| 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
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| 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 sulfur-containing molecules, sulfate
formation, amide synthesis, and methylation
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| Pharmacogenetics: ≈6 sites where cytochrome P450 system active; lesions known to cause specific conditions
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| 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)
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| 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
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| Opioids —Peter K. Schoenwald, MD, Staff Anesthesiologist, Department of General Anesthesiology, and Emeritus
Head, Section of Vascular Anesthesia, Cleveland Clinic Foundation, Cleveland
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| History: in 1806, Serturner isolated morphine from poppy plant; in 1900, intraoperative usage occurred, but technique
abandoned due to high mortality; in 1933, meperidine (first synthetic opioid) formulated; in 1947, balanced anesthesia introduced;
in 1969, Lowenstein used high-dose morphine and O2 for open-heart surgery; in 1974, endogenous opioids discovered;
1963 to present, synthetic opioids (not derived directly from morphine) came into practice
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| Definitions: opiate—any product derived from opium; includes morphine, codeine, and papaverine; opioid—any natural
or synthetic compound with morphine-like properties (including analgesia); narcotic—present-day connotation usually
implies illicit opioid and nonopioid drugs; derived from Greek, meaning any drug that produces sleep or narcosis
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| Structure: morphine configured in form of “T”; levo isomer and dextro isomer (only levo isomer analgesic); consists of
phenanthrene ring (isomer of 3 benzene rings) combined with piperidine ring and quaternary carbon
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| Opioid classification: initially classified as naturally occurring, semisynthetic, or totally synthetic; more practically classified
as agonist, antagonist, or combination agonist/antagonist
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| Endogenous opioids: 2 pentapeptides originally discovered in ≈1973 (incorporated into larger parent compound enkephalins);
effects occur through receptors that bind to endogenous compounds; in 1995, new compound discovered called nociceptin
(orphanin FQ), may actually lower pain threshold; in 1997, reported that endomorphin-1 and endomorphin-2
also endogenous opioids, but role to be determined; localization of receptors and compounds not uniformly distributed;
lock-and-key receptor mechanism; acute opioid effects include analgesia, respiratory depression, sedation, euphoria, vasodilation,
bradycardia, cough suppression, and miosis; long-term effects include tolerance and physical dependence
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| Cardiovascular effects: minimal myocardial depression (except meperidine); bradycardia; tachycardia (using high-dose
techniques); hypotension (due to histamine release, particularly with morphine and meperidine); venodilation; relaxation
of arterial smooth muscle
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| Respiratory effects: respiratory depression (decrease in CO2 and O2 responsiveness, depending on dose); decreased rate, especially
in low doses; tidal volume maintained; change in rhythmicity; apnea may occur in awake patient; cough suppression;
histamine release may cause bronchoconstriction; as dose increased, CO2 response curve shifted to right and downward
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| Central nervous system (CNS) effects: pain relief by receptor activation; sedation; cerebral BF, cerebrospinal fluid production,
and intracellular pressure remain constant if patient ventilated and maintained at normal arterial Paco2 ; seizure activity
with high doses (true for meperidine); however, tonic-clonic movements not associated with
electroencephalography (EEG) changes indicative of seizure activity; pupillary constriction due to stimulation of Edinger-
Westphal nucleus; nausea and vomiting due to stimulation of chemoreceptor trigger zone, vomiting center, and vestibular
center
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| Musculoskeletal effects: rigidity may occur in truncal area and neck; dependent on total dose and type of drug; time of
occurrence usually when patient loses consciousness; dependent on rate of administration; deepen anesthetic level;
small doses of muscle relaxants used for treatment; slow administration preventive
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| GI effects: decreased lower esophageal sphincter tone; increased intestinal smooth muscle and rectal sphincter tone; decreased
gut motility; leads to constipation and increased chance for reflux and residual volume; patient from emergency
department should be considered to have full stomach; increased biliary pressure due to spasm of sphincter of
Oddi; fentanyl causes most increase in bile duct pressure, meperidine and butorphanol lowest increase
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| Renal effects: increased smooth muscle tone; urinary retention due to increased urinary sphincter and detrusor muscle
tone; morphine can cause antidiuretic hormone (ADH) release and may decrease glomerular filtration rate
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| Pharmacokinetics: usual factors include lipid solubility, ionization, protein binding, and volume of distribution; metabolism
occurs in liver (except remifentanil); excretion pathway either biliary or renal (small amounts excreted unchanged);
90% of alfentanil not ionized at pKa of 7.4; morphine least lipid-soluble, other drugs have higher lipid solubility (especially
sufentanil); relatively high plasma protein binding (except morphine) and hepatic extraction ratio; most opioids leave
blood rapidly, but can accumulate in parenchymal organs (eg, liver, lung, kidney, spleen); only small amount enters
brain; nonionized, nonprotein-bound drug enters CNS; most opioids accumulate; dosing age-dependent
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| Use as anesthetic agents: advantages include hemodynamic stability, minimal cardiac depression, decreased minimum alveolar
concentration (MAC) for other agents, potential for stress-free anesthetic, no renal or hepatic toxicity, no trigger
for malignant hyperthermia [MH], and no teratogenicity; disadvantages include potential for recall in high doses, possible
hypotension, delayed emergence, side effects, and abuse potential; MAC reduced when combined with inhalational
agents; induction dose reduced with opioid; also blunt blood pressure (BP) response to intubation when given in
advance; if mixed with other agents, may cause myocardial depression
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| Morphine: least lipophilic (95% hematic transformation); urinary excretion of metabolites; plasma kinetics do not parallel
clinical effects; least protein bound (30%)
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| Meperidine: some local anesthetic qualities; more lipid soluble than morphine (faster onset); more protein bound (≈60%);
metabolized to active compound normeperidine (may cause seizures); use with caution in renal failure
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| Fentanyl: ≈100 times more potent than morphine; more fat-soluble; readily distributed; short duration of action; long
elimination half-life; 95% protein bound
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| Sufentanil: most fat-soluble opioid available; 95% protein bound; extensive use in cardiac surgery
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| Alfentanil: less potent than fentanyl, but more than morphine; extremely rapid onset due to pKa ; used in outpatients; most
potential for nausea
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| Naloxone: administered intravenously (IV) or intramuscularly (IM); pure antagonist; half-life usually shorter than other
opioids
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| Agonists/antagonists: unfavorable effects on myocardial contractility; cardiac work increased; respiratory depressants;
dysphoric properties; antagonist properties when mixed with usual intraoperative opioids; cannot be used as sole anesthetic;
abuse potential
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| Remifentanil: unique breakdown via nonspecific esterases; pure mu agonist with no accumulation; elimination independent
of infusion time, renal function, or hepatic function; context-sensitive half-time (time required for plasma concentration
to be reduced by 50% after discontinuation of drug administration) “very short”
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| Peripheral opioid antagonists: include methylnaltrexone and alvimopan; quaternary compounds; no central effects (do
not penetrate blood-brain barrier); alleviate suppression of gut motility without counteracting analgesic effects
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Educational Objectives
| The goal of this program is to educate the listener about basic pharmacology and the use of opioids in anesthesia. After
hearing and assimilating this program, the participant will be better able to:
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| 1. Define pharmacodynamics and pharmacokinetics.
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| 2. Discuss factors that influence drug metabolism and clearance.
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| 3. Explain the influence of patient factors and disease states on drug metabolism and clearance.
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| 4. Describe basic structural features of opioids.
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| 5. Recognize the role of opioids in anesthetic techniques.
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Discussed on This Program
Alfentanil HCl [Alfenta]
Alvimopan (investigational)
Butorphanol tartrate [Stadol, Stadol NS]
Codeine PO4
Diazepam [Diastat, Diazepam Intensol, Valium]
Fentanyl citrate [Sublimaze]
Meperidine HCl [Demerol]
Mepivacaine HCl (several trade names)
Methylnaltrexone
Morphine sulfate (several trade names)
Naloxone HCl [Narcan]
Naltrexone HCl [ReVia]
Nitroglycerin (several trade names)
Papaverine HCl [Pavabid Plateau Caps, Pavagen TD]
Propranolol HCl [Inderal, Inderal LA, InnoPran XL]
Remifentanil HCl [Ultiva]
Succinylcholine chloride [Anectine, Anectine Flo-Pack, Quelicin]
Sufentanil citrate [Sufenta]
Tetracaine HCl [Pontocaine, Pontocaine HCl, Viractin]
Theophylline (many trade names)
Thiopental sodium [Pentothal]
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 elimination. J Pharmacol Exp Ther 195:424, 1975; Thompson JP et al: Remifentanil--an opioid for the
21st century. Br J Anaesth 76:341, 1996; 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 opioid-induced side effects. J Support Oncol 2:111, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Schoenwald received research support for an esophageal Doppler from Arrow International, Inc.
Drs. Tetzlaff and Schoenwald were recorded at Comprehensive Anesthesiology Review, presented April 30-May 5, 2005,
by the Cleveland Clinic, Division of Anesthesiology and Critical Care Medicine, and held in Cleveland. The Audio-Digest
Foundation thanks the speakers and the Cleveland Clinic Foundation for their cooperation in the production of this program.
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