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Applied Pharmacokinetics in the Adult Critically Ill
Gil Fraser, PharmD, FCCM
Critical Care
Thomas D. Nolin, PharmD, PhD
Nephrology and Transplantation
Maine Medical Center
Portland, ME
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Slide 3
Why Study Pharmacokinetics?
• Enhance efficacy, minimize toxicity
• Avoid adverse drug events
– At least 40% of adverse drug reactions are preventable
– Almost 30% of these events involve dosing errors
• Individualize patient dosing needs
• Understand the mechanisms of drug interactions and prevent or anticipate their sequelae
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Slide 4
Pharmacokinetics
• Describes the movement of drugs in the body
• Blend of math, physiology, pharmacology
• Four components
– absorption, distribution, metabolism, excretion (ADME)
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Slide 5
Drug Absorption Occurs Via Many Routes of Administration
• Intravenous
• Subcutaneous
• Intramuscular
• Epidural
• Ocular
• Otic
• Rectal
• Dermal
• Oral/Enteral*
• Sublingual
• Buccal
• Intrasynovial
• Intranasal
• Vaginal
* This discussion pertains to enteral drug absorption
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Slide 6
Enteral Drug Absorption
• Drugs may be absorbed passively (e.g., paracellular diffusion), or via active carrier-mediated processes
• Significant types of pre-systemic clearance
– Intestinal and hepatic metabolismi.e., via cytochrome P450 (CYP) enzymes
– Active transport via P-glycoprotein
– Resulting “first-pass effect”
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Slide 7
GI drug absorption and pre-systemic metabolism
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Slide 8
Oral/Enteral Drug Administration
• Advantages
– Avoids hazards of IV lines; infections, phlebitis
– Facilitates earlier ICU discharge (example: enteral methadone instead of fentanyl infusion)
– Lowers drug acquisition costs by an average of 8-fold
• Caution! Drug bioavailability in critical illness may be deranged
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Slide 9
Oral/Enteral Drug Administration
• Should Be Avoided in Those With…
– Ileus, no active bowel sounds
– Ischemic bowel
– Gastric residuals
– Nausea and vomiting
– Malabsorption syndrome
– Questionable gut perfusion and poor hemodynamics
– Interacting substances in gut
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Slide 10
Interacting GI Substances May Interfere with Absorption
• Examples: Phenytoin, quinolones, tetracyclines
– Enteral nutrition with enteral phenytoin often lowers serum levels by as much as 80%
• Many patients require intravenous phenytoin to maintain adequate serum levels
– Bi- and trivalent cations bind to quinolone and tetracycline antibiotics, potentially leading to treatment failures
• Avoid concurrent administration of substances such as iron, aluminum (sucralfate), magnesium, etc.
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Slide 11
Distribution
• Describes rate and extent of plasma transfer
• Volume of distribution is a virtual space that relates the amount of drug administered to the measured plasma concentration
• Primary determinants are relative hydrophilicity, lipophilicity, and degree of protein binding
• Relevance?
– Explains differences in onset of activitye.g., fentanyl vs. morphine
– Explains the prolonged duration of midazolam after long-term use
– Helps predict medication removal by renal replacement therapy
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Slide 12
Central Nervous System Effects
• Medications and the Blood-Brain Barrier CNS Effects:
– Drug entry and egress is a function of lipophilicity and the ability to cross the blood-brain barrier
– The onset and offset differences between morphine and fentanyl can be explained by the fact that fentanyl is 100 x more lipid soluble than morphine.
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Slide 13
Changes in Midazolam
0
10
20
30
40
50
60
<24 h 1-7days >7d
Extubation
CNS RecoveryHo
urs
Duration of midazolam therapy
Chest 1993;103:55
Why Does Midazolam Change From a Short- to a Long-Acting Benzodiazepine When Given for a Prolonged Period of Time?
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Slide 14
Accumulation in a deep compartment is a function of fat solubility and may explain the long duration of action of midazolam after long-term use
Context Specific Half-Life
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Slide 15
Distribution
• How can the volume of distribution help predict removal by hemodialysis?
– If a drug has a large volume of distribution, very little resides in the circulation and is available for removal via hemodialysis. Examples: digoxin and tricyclic antidepressants
• How about the extent of protein binding?
– Highly protein-bound drugs are typically not removed by hemodialysis.
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Slide 16
Deranged Protein Binding
• The Clinical Relevance of Deranged Protein Binding of Drugs Has Been Overstated (Except for Phenytoin) ~ Clin Pharmacol Ther 2002; 71:115
– Pharmacologically active drug is in the “free” state, not protein bound
– Normally, 90% phenytoin is protein bound and inactive (only 10% is “free”)
– The free fraction of phenytoin increases with hypoalbuminemia and uremia
• Under these conditions, it is preferred to measure active drug, i.e., “free” phenytoin levels, rather than “total” phenytoin levels
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Slide 17
P-glycoprotein (P-gp)and Drug Distribution
• Promiscuous ATP-dependent active transporter
– evolved as a protective mechanism against a wide variety of toxic substances
• Located in intestine, renal tubule, biliary system, CNS, WBC, testes, tumor cell
• Relevance: acts as an efflux pump to limit absorption and distribution; expedites elimination of toxins (digoxin, etoposide, mitoxantrone, paclitaxel, tacrolimus)
– Can P-gp inhibitors be used therapeutically for multidrug-resistant tumors?
– May explain why quinidine and amiodarone double digoxin levels
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Slide 18
P-gp Inhibitors:VerapamilGrapefruit juiceAmiodaroneQuinidineClarithromycinTariquidar
P-gp Inducers:RifampinSt. John’s wort
The transmembrane protein P-glycoprotein is an energy-dependent efflux pump or drug
transporter
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Slide 19
Drug Metabolism
• a.k.a. “biotransformation”
• Refers to the “enzyme-catalyzed changes in drug structure” or “the process by which drugs are converted in vivo into one or more structural derivatives (metabolites)”
• Sites: liver, gut, lungs, kidney, brain, plasma, skin
• Originally viewed as detoxification reaction
hydrophilicity, which promotes excretion
• May change the pharmacological activity or toxicity of the molecule
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Slide 20
Substrate(drug)
EnzymeMetabolite
Active Inactive
Inactive Active
Toxic
Nontoxic
Nontoxic
Toxic
Detoxification
Prodrug
Reactive metabolite
Activation
Consequences of Drug Metabolism
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Slide 21
Phases of Drug MetabolismPhase I
• “Functionalization” reactions
• Involve introduction or unmasking of a polar functional group (e.g., -OH, -NH2, -SH, -COOH) on substrate to ↑ hydrophilicity and prepare for phase II metabolism
• Reaction classes:
– oxidation, reduction, hydrolysis
• Oxidative metabolism mediated by cytochrome P450 (CYP) most important phase I pathway!
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Slide 22
Phases of Drug MetabolismPhase I
• “Conjugation” reactions
• Involve addition of an endogenous compound (e.g., glucuronic acid, amino acid, acetyl group, sulfate) to functional group contained on drug molecule or product of phase I metabolism
• ↑ hydrophilicity, detoxification, excretion
• Reaction classes:
– glucuronidation, sulfation, glutathione conjugation, acetylation, methylation
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Slide 23
OH SO3H
Phase I Phase II
benzene phenol phenylsulfate
Increasing polarity of drug/metabolite
Phases of Drug Metabolism
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Slide 24
Drug Metabolism
• Changes in drug metabolism are more commonly the result of acquired alteration of hepatocyte function via drug interactions than from intrinsic hepatic derangements
• May be genetically determined
– Racial differences in functionality of many phase I reactions (CYP 2D6, 2C9, 2C19, etc) NEJM 2003; 348:529
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Slide 25
Cytochrome P450
• Most significant contributors to drug metabolism
• Catalyze biotransformation of endogenous substrates, dietary compounds, environmental chemicals, and up to 60% to 80% of drugs currently marketed!
• Present in species from bacteria to mammals; localized intracellularly in smooth endoplasmic reticulum
• >270 gene families described; >18 families in man
• CYP1, CYP2, and CYP3 families most clinically relevant
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Slide 26
Contribution of CYP toDrug Metabolism
1A23%
2C18%
2A61%
2D625%
2E1%
3A52%
Adapted from Clin Pharmacokinet. 1997;32:210
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Slide 27
3A4/530%
1A213%
2E17%
2D64%
2C8<1%
2B6<1%
2A64%
2C192%
2C918%
NicotineBupropion
MephenytoinOmeprazoleDiazepam
Coumarin
LosartanNSAIDsWarfarin
TolbutamidePhenytoin
MidazolamCyA/Tacrolimus
CCBsStatins
CisaprideTerfenadine
CaffeineTheophyllineImipramine
ChlorzoxazoneAcetaminophen
NitrosaminesAnesthetics
AzolesMacrolidesCimetidineGrapefruit
BarbsRifampin
DexamethasoneCarbamazepineSt. John’s wort
AzolesMacrolidesCimetidineGrapefruit
CYP450Substrates
SSRIsDesipramineNortriptylineß-blockers
DebrisoquineD-methorphan
RetinoidsPaclitaxel
Inhibitors DisulfiramQuinidine
Methadone
Cimetidine
Azoles Azoles
Inducers BarbsRifampin
BarbsRifampin
OmeprazoleBarbs
RifampinPAHs
EthanolIsoniazidBenzene
Rifampin
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Slide 28
Drug Metabolism Often Results in Active Metabolites That Can Accumulate (Especially
in Renal Disease)
• Normeperidine from meperidine
– Epileptogenic
• Morphine 3- and 6-glucuronide salts
– Prolonged narcosis
• Desacetylvecuronium from vecuronium
– Prolonged paralysis
• Cyanide from nitroprusside
– Death
• Hydroxymidazolam from midazolam
– 66% the activity of the parent drug
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Slide 29
Drug Excretion
• Largely the domain of the kidney
– Minor pathways: bile, lung, and feces
• Common issue for drug dosing in the ICU
– 7%-25% ICU population develop significant acute kidney injury and many more have pre-existing chronic kidney disease
– Age-related changes in organ function including the kidneys• Approximately 1% functional loss per year after 30 years
of age
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Slide 30
Estimating Renal Function UsingSerum Creatinine
• Creatinine is freely filtered and serves as conventional surrogate for glomerular filtration
• The assumption is that there is a normal production of creatinine
– May not be true in catabolic, malnourished critically ill patients!
• MDRD equation derived from multiple regression analyses incorporates race, serum albumin, and urea nitrogen and may be more accurate Ann Intern Med 1999;130:461
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Slide 31
Problem Drugs in Renal Disease
• Most cephalosporins and quinolones, imipenem, vancomycin, aminoglycosides, acyclovir, fluconazole
• Procainamide, digoxin, atenolol
• Meperidine, morphine, and midazolam
• Famotidine
• Milrinone
• Low molecular weight heparins
• Phenytoin (increased free fraction)
• Many drugs removed via renal replacement therapy (RRT)
– Specifics vary with type of RRT and individual drugs
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Slide 32
Pharmacokinetic Principles
• Steady-state: the amount of drug eliminated equals the amount of drug administered
• Results in a plateau or constant serum drug level
• Is a function of drug half-life
– Steady-state occurs after 4-5 half-lives
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Slide 33
Half-Life
• Time it takes for half of an administered drug to be eliminated
• Defines the time needed for steady-state to occur and the time needed for complete elimination of drug from the body (4-5 half-lives)
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Slide 34
Loading Doses
• Used to reach therapeutic levels quickly, especially if drug has long half-life
• Not affected by organ dysfunction
– Except digoxin: use 75% typical loading dose
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Slide 35
Simulated Serum Concentrations
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Slide 36
Linear Kinetics
• Constant fraction of total drug stores eliminated in a given time
• Almost all drugs follow linear kinetics (except in overdose situations)
• Dose increases result in proportional increases in serum levels
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Slide 37
Nonlinear Kinetics
• Constant amount (vs %) eliminated per unit time
• Examples: phenytoin, aspirin, ethanol
• At point of metabolic limit, lose proportionality of dose with serum level
– Example: 50% increase in phenytoin dose may result in 300% increase in level
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Slide 38
Ste
ady-
stat
e p
lasm
a co
nce
ntr
atio
n
Effect of increasing daily dose on steady-state drug concentrations for drugs undergoing nonlinear ( ) and linear ( ) kinetics
Daily Dose
Enzyme saturation for nonlinear drug
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Slide 39
Contribution of Pharmacogenetics to Interindividual Variability in Drug
Response
• Genetic polymorphisms in drug metabolizing enzymes, drug transporters, or receptors can cause clinically relevant effects on the efficacy and toxicity of drugs
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Slide 40
Clinical Relevance
• Most drugs are dosed on a “one size fits all” basis
• Likely a major contributor to the high incidence of adverse drug reactions
• People can vary substantially in how they respond to a given drug!
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Slide 41
The study of heredity as it relates to the absorption, distribution,
elimination, and action of medicines
A tool to limit variability and individualize therapy
Pharmacogenetics
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Slide 42
Pharmacogenetics
N Engl J Med. 2003;348:529
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Slide 43
Clinical Consequences of Genetic Polymorphisms
• Toxicity
– Can be profound for drugs with a narrow therapeutic index that are inactivated
• mercaptopurine, fluorouracil
• Reduced efficacy or therapeutic failure
– Drugs that are activated• codeine
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Slide 44
Drug: Gene Interaction
Evaluated by Dalen et al in 21 healthy Caucasian volunteers
• Nortriptyline is a tricyclic antidepressant metabolized by CYP2D6 to 10-hydroxynortriptyline
Do allelic variants of drug metabolizing enzymes impact pharmacokinetics and response?
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Slide 45
Relationship between CYP2D6 geneticstatus and nortriptyline pharmacokinetics
Clin Pharmacol Ther. 1998:63:444TIPS 1999;20:342
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Slide 46
Utility of Pharmacogenetics
Ann Rev Genomics Hum Genet 2001;2:9
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Slide 47
Summary Management of Drug Therapy Using PK Principles
• For each medication prescribed you need to know
– Which organs are involved in drug clearance
– If genetic/race issues influence drug clearance
– Whether active metabolites are formed
– The half-lives of parent drug and metabolites to estimate time to steady-state (and therefore time for drug evaluation)
– Potential drug or food interactions
– If there is an oral or dermal formulation that patients can transition to if appropriate
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Slide 48
Self Assessment
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Slide 50
Case Studies
The following are case studies that can be used for review of this presentation.
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Slide 51
Case Study #1
• 23-year-old 100-kg man with multiple fractures and traumatic brain injury resulting from a motor vehicle crash
• 1800 mg (18 mg/kg) IV phenytoin load for seizure prophylaxis with maintenance dose of 300 mg IV every 12 hours (6 mg/kg/d); serum level = 10 μg/mL day 3 of therapy
• Phenytoin suspension (same dose) begun when enteral nutrition initiated, with repeat phenytoin level in 2 days = 2 μg/mL
• Explain these findings
• What strategy can we use to achieve therapeutic phenytoin levels?
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Slide 52
Case Study #1 – answer
• The oral absorption of phenytoin may be dramatically reduced in the setting of enteral feedings
• Consider discontinuing phenytoin if treatment duration longer than 7 days and if no seizures have occurred
• If continued prophylaxis indicated, offer phenytoin IV and avoid any GI absorption issues or advance the dose of enteral phenytoin (mindful that drug absorption will increase when a regular diet is resumed)
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Slide 53
Case Study #2
• 68-year-old man post-open heart surgery becomes acutely agitated and is treated successfully with 3 mg midazolam IV
• Requires additional CV support in the form of an IABP and experiences more consistent agitation treated with a continuous infusion of midazolam 8 mg/hr for 3 days
• CV status improves and he is ready to extubate. Midazolam is discontinued, but he remains in a drug-induced stupor for 3 days.
• Why?
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Slide 54
Case Study #2 – answer
• Midazolam’s lipophilicity and ability to enter the CNS explain its rapid onset and offset with acute use
• Lipophilicity (and accumulation in adipose tissue) can also explain midazolam’s prolonged duration of action with long-term use
• An additional confounder is the formation and potential accumulation of the active hydroxy-midazolam metabolite
• Because of this, the SCCM suggests that lorazepam is the preferred benzodiazepine for long-term use
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Slide 55
Case Study #3
• 60-year-old man recovering from acute coronary syndrome receives aggressive LDL therapy: simvastatin 80 mg daily
• His med list includes NTG, ASA, an ACE inhibitor, amiodarone
• Within 3 days, he experiences extreme muscle pain with a CK of 20,000
• What is the pharmacologic explanation for these findings?
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Slide 56
Case Study #3 – answer
• Most statins are metabolized by CYP 3A4 and are susceptible to drug interactions
• Amiodarone (and many other drugs) interfere with CYP 3A4 function and may lead to statin toxicity, perhaps even to rhabdomyolysis
• Simvastatin dosing should be limited to 20 mg daily or less in these circumstances
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Slide 57
Selected References
• Michalets EL. Update: clinically significant cytochrome P-450 interactions. Pharmacotherapy. 1998;18:84-112.
• Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348:529-537.
• Matheny CJ, Lamb MW, Brouwer KR, Pollack GM . Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy. 2001; 21:778-796.
• DeBellis K. Drug dosing in critically ill patients with renal failure: a pharmacokinetic approach. J Intensive Care Med. 2000;15;273.
• Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211-2221.