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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2593_Библиотеки_им_академика_М_И_Перельмана
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Patient Risk Factors
Older age: 79 years old—altered pharmacokinetics and pharmacodynamics
Female gender: decreased ability to metabolize compared to males
Renal dysfunction: decreased clearance of renally eliminated
medications, which may result in increased serum concentrations
of drug and accumulation
With regard to drug-specific factors, F.D. has been taking
phenytoin, a drug with an NTI, for the past several years. She will be
receiving warfarin, another agent with NTI. Both medications are
metabolized via the CYP system. In addition, F.D. is at increased risk
of additional drug interactions owing to polypharmacy because she
has chronic disease comorbidities (ie, seizure disorder,
hypercholesterolemia, and osteoporosis).
Drug Risk Factors
Warfarin—NTI, highly protein bound to albumin, small volume of
distribution, metabolized by the CYP system
Phenytoin—NTI, highly protein bound to albumin, metabolized by
CYP2C9 and CYP2C19 isoforms, and susceptible to drugs that
inhibit hepatic microsomal enzymes
Fluvastatin and other agents in this class (eg, atorvastatin,
rosuvastatin, and simvastatin)—suspected or known to alter the
INR in patients who receive warfarin, whereas pravastatin does not
appear to interact with warfarin
35–37
Unknown OTC product
Other Risk Factors
Polypharmacy—before admission, she is already taking three
prescription drugs and also takes OTC products. She is a poor
historian.
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Number of pharmacies used—pharmacist may not have knowledge
of all drugs prescribed to patient.
MECHANISMS OF DRUG INTERACTIONS
Pharmacokinetics
ADMINISTRATION/ABSORPTION
Following oral administration, most drug absorption occurs in the
proximal small intestine.38 However, drug interactions that alter
absorption may occur throughout the gastrointestinal (GI) tract by a
variety of mechanisms, including complexation (adsorption or
chelation), changes in pH, changes in GI motility, altered drug
transport, and enzymatic metabolism. The net effect of one or more
of these mechanisms is a change in the rate of absorption, the
extent of absorption, or a combination of both. Although interactions
that result in a reduced rate of absorption are generally not clinically
significant for drugs given over the long term in multiple doses, for
acutely administered drugs, such as analgesics or hypnotics, this
can lead to an unaccepted delay or therapeutic failure.
1,39
With regard to changes in gastric pH, the majority of drugs that are
orally administered must be dissolved and absorbed in a gastric pH
between 2.5 and 3. Drugs, such as antacids, proton-pump inhibitors
(PPIs), or H2-antagonists, can alter the kinetics of coadministered
drugs.3 Antifungal agents, such as ketoconazole or itraconazole,
require an acidic environment to be properly dissolved.
Coadministration with drugs that increase gastric pH may cause a
reduction in the dissolution and absorption of antifungal drugs. It is
recommended that these antifungal agents be administered at least
2 hours after the administration of antacids.
Coadministration of medications around the same time can result
in drug interactions that may be clinically significant. Some
antibiotics, such as tetracyclines, will combine with metal ions (eg,
calcium, magnesium, aluminum, iron) to form complexes that are
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poorly absorbed. Antacids also reduce the absorption of
fluoroquinolones (eg, ciprofloxacin) because the metal ions form
complexes with the drug. Therefore, the antacids and
fluoroquinolones should be administered at least 2 hours apart.
These types of interactions can decrease clinical effectiveness of the
antibiotic and can lead to the emergence of resistant organisms.
34
Drugs that are able to increase the gastric transit, such as
metoclopramide owing to its prokinetic properties, may accelerate
gastric emptying, resulting in decreased absorption of drugs, such as
digoxin or theophylline.
Altered drug transport
Transport proteins, which are present in the intestinal mucosa, are
important considerations in clinically relevant DDIs.38 Some proteins
are involved in the transport of compounds from the lumen of the
intestine into the portal bloodstream, whereas others are involved in
the efflux of compounds from the intestinal mucosa back into the gut
lumen. The efflux transporters, particularly a specific glycoprotein,
which resides in the cell membrane, P-glycoprotein (P-gp), are the
most well known. P-gp is an adenosine triphosphate (ATP)dependent transporter that is genetically encoded and located on the
apical surface of mucosal cells in the intestine, generally in
increasing concentration from the stomach to the colon. In addition,
P-gp is also present on a number of lymphocyte subsets and within
the brain capillary endothelial cells. The primary role of P-gp is to
limit systematic drug exposure, pumping compounds from the inside
of the cell back into the gut lumen, into renal tubules in the kidney,
and into bile in the liver. Given its presence in various anatomic
locations, drug-induced modulation of P-gp activity may affect the
absorption and/or distribution of a coadministered substrate
medication. There are several drugs that are known to block the
action of P-gp and are known as P-gp inhibitors, and there are drugs
that have been shown to cause induction of P-gp. Coadministration
of a P-gp substrate with an inhibitor increases the amount of
substrate available for absorption and may result in an elevated
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serum drug concentration. For drugs such as rifampin that increase
expression of P-gp (ie, P-gp inducer), the coadministration of a
substrate results in an enhanced efflux of the substrate into the gut
lumen and lowers serum concentration of the substrate.
DISTRIBUTION
CASE 3-1, QUESTION 2: What is the interaction of warfarin and phenytoin
based on protein binding?
Following administration and absorption, drugs are distributed
throughout the body.
38,39
Drugs such as warfarin and phenytoin are
highly bound to protein (primarily to albumin) with the same affinity
binding sites (Fig. 3-1). Drugs that are highly protein bound (>90%),
those with an NTI, and those with a small volume of distribution are
more likely to result in significant drug interactions.
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Figure 3-1 Examples of drugs that bind to and compete for one of
two sites, designation I and II, on albumin. (Adapted with permission
from Drug interactions. In: Derendorf H, Schmidt S, eds. Rowland
and Tozer’s Clinical Pharmacokinetics and Pharmacodynamics:
Concepts and Applications. 5th ed. Wolters Kluwer; 2020.)
Warfarin can be displaced from protein-binding sites by drugs such
as phenytoin. Although this displacement occurs quickly with rapid
changes in serum warfarin levels, typically, this interaction is not
clinically significant. Warfarin that is displaced from protein-binding
sites is readily available for elimination by hepatic metabolism,
resulting in increased clearance without a significant change in the
free drug concentration. Because warfarin’s anticoagulant action
takes several days because of the long half-lives of some of the
vitamin K–dependent clotting factors, warfarin equilibrium is
reestablished before a new steady state can be reached for these
clotting factors.
33
METABOLISM
Pharmacokinetic interactions that involve changes in metabolism are
a common cause of clinically significant drug interactions. Drug
metabolism is divided into two general categories: phase I and
phase II reactions.
38,39
Phase I reactions involve intramolecular
changes including oxidation, reduction, and hydrolysis, which
increases the polar nature of the drug, generally making it less toxic.
Phase II reactions generally involve combining a phase I product
with an endogenous substance, resulting in glucuronidation,
sulfation, acetylation, and methylation, and primarily results in
termination of biologic activity of the drug.
40,41
The main enzymes
that are responsible for drug-metabolizing systems in phase I
reactions are the CYP enzymes, which play a key role in many
therapeutically important drug interactions.
1,2
Drugs that are
metabolized by the same CYP enzyme family, when administered
concurrently, may interact with each other as a result of induction or
inhibition.
40,41
Of the human CYP enzyme family, the six isoenzymes
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5
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contribute to the metabolism of a vast majority of drugs compared
with other enzymes (Fig. 3-2).
6,42–44
Examples of drug that induce
enzymes are rifampin, phenytoin, carbamazepine, St. John’s wort,
and nevirapine. Enzyme inducers cause an increase in the synthesis
of the enzyme(s) responsible for metabolism of the substrate drug.
The mechanisms of induction are complex involving presystemic
metabolism via induction of hepatic and/or intestinal drug–
metabolizing enzymes, subsequently reducing serum concentrations
with a loss of pharmacologic activity of the drug. In some cases,
induction will increase the formation of metabolites that are
pharmacologically or toxicologically active.
1,44,45
There are many
drugs that are inhibitors of CYP including some drugs within these
classes: statins, macrolide antibiotics, antifungal azoles,
fluoroquinolones, and HIV protease inhibitors. Inhibition of drug
metabolism slows down the rate of drug metabolism, resulting in an
increase in the amount of drug in the body and potential toxicity.
Grapefruit juice is an inhibitor of CYP3A4 and has been known to
increase the bioavailability and reduce the clearance of many drugs,
including HMG-CoA reductase inhibitors (statins), calcium
antagonists, HIV protease inhibitors, and immunosuppressant
agents.
46–49
Inhibition can be described as reversible or irreversible,
with the reversible ones being a more common process. There are
three mechanisms of reversible inhibition: competitive inhibition
(competition between the inhibitor and the substrate for the
enzyme’s active site), noncompetitive inhibition (binding of the
inhibitor to a separate site on the enzyme, rendering the enzyme
complex nonfunctional), and uncompetitive inhibition (binding of the
inhibitor only to the substrate–enzyme complex, rendering it
ineffective).
1,49,50
Irreversible inhibition occurs when the perpetrator
drug forms a reactive intermediate with the enzyme that leads to a
permanent inhibition of the enzyme. Irreversible drug interactions
tend to be more profound than those caused by reversible
mechanisms. Examples of drugs that are known to cause irreversible
inhibition include macrolide antibiotics, erythromycin, clarithromycin,
paroxetine, and diltiazem.
16,51,52
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CASE 3-1, QUESTION 3: The medical team starts warfarin therapy for F.D. for
postoperative thromboembolism prophylaxis. What are the mechanisms of drug
interactions to consider with the use of warfarin and phenytoin because F.D. has
been taking phenytoin for several years and her seizure disorder has been
controlled on it?
Figure 3-2 Graphic representation of the different forms of
cytochrome P450 (circles) in humans with different but some
overlapping substrate specificities. The arrows indicate single
metabolic pathways. Representative substrates are listed for each
enzyme. Also listed are relatively selective inhibitors and inducers of
the enzymes. (Reprinted with permission from Drug interactions. In:
Derendorf H, Schmidt S, eds. Rowland and Tozer’s Clinical
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Pharmacokinetics and Pharmacodynamics: Concepts and
Applications. 5th ed. Wolters Kluwer; 2020. )
There are two potential mechanisms for a warfarin (drug)–
phenytoin (drug) interaction. In early therapy, there could be a
displacement of warfarin from protein-binding sites by phenytoin (as
described in the previous case question) and a possible
enhancement of the anticoagulant effect and risk for bleeding. This is
primarily a concern in patients with hepatic impairment. With
prolonged therapy, there could be a phenytoin-induced CYP enzyme
induction, thereby enhancing warfarin metabolism, resulting in a
decreased warfarin effect. INR monitoring on postoperative days 1
through 5 will provide information on the impact of the DDI, and
incorporation of a warfarin initiation guideline or algorithm will help
adjust dosing until a stable regimen is established. After the initial
period, weekly INR monitoring will provide information on enzyme
induction and further adjustment of warfarin doses.
Warfarin is rapidly and completely absorbed after oral
administration, with the proximal duodenum appearing to be the
most likely location of absorption. Case reports of warfarin
malabsorption, whether acquired, related to surgery, or inflammatory
conditions, are rare.
53
The rate and extent of phenytoin absorption varies considerably
among oral dosage forms.54 Phenytoin suspension is poorly
absorbed when administered via feeding tube with continuous
enteral feedings.55 The time to reach maximum plasma levels
increases with increasing dose.56 This is a reflection of low phenytoin
solubility and capacity-limited metabolism. Therefore, a small change
in the dosage form or bioavailability, coupled with limited
metabolism, can produce a large change in plasma drug
concentration.57 GI surgery and GI inflammatory conditions (Crohn
disease, ulcerative colitis, scleroderma, etc.) can change the
anatomy of the GI tract. Alterations to surface area, gastric emptying
time, gastric pH, and inflammation of the intestinal lining may lead to
abnormal plasma concentrations.
58
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F.D.’s GI function is still preserved after orthopedic surgery.
Warfarin administration and absorption is unlikely to be impacted.
She should continue on the same phenytoin dose and formulation
that she has been taking at home with appropriate monitoring.
Pharmacokinetic interactions influencing the metabolism of
warfarin and clinically significant interactions are likely with warfarin
use when its metabolism is induced or inhibited.49 Warfarin is a
racemic mixture of R- and S-enantiomers. Interactions involving
agents known to influence the hepatic microsomal enzyme systems
responsible for the metabolism of the more potent S-enantiomer
(CYP2C9) are more significant than those that influence the
enzymes that metabolize R-enantiomer (CYP1A2, CYP3A4).
Phenytoin is also predominately metabolized via the CYP2C9
enzyme and has been reported to interact with warfarin in a biphasic
manner.
50–52
Genetic polymorphism also is a significant factor affecting warfarin
dosing and response. Nucleotide polymorphisms have been
identified that influence warfarin metabolism and sensitivity, including
variants of CYP2C9 and variants in vitamin K epoxide reductase
complex (VKORC1).
59
EXCRETION/ELIMINATION
Drugs are excreted and eliminated mainly via the kidneys
(glomerular filtration, tubular reabsorption, and active tubular
secretion); other important, though less common, routes are via
biliary secretion, plasma esterases, and other minor pathways. Drug
interactions may occur during the elimination of drugs and their
metabolites by the kidney as a result of competition at the level of
active tubular secretion, interference with tubular transport, or during
tubular reabsorption.
Urinary alkalinization and acidification by some drugs can affect
the excretion of other drugs changing their elimination rate. For
example, the use of probenecid, a potent inhibitor of the anionic
pathway of renal tubular secretion, increases the serum
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concentration of penicillins, which can be used for therapeutic
purposes.
Pharmacodynamics
Pharmacodynamic interactions occur when the response of one drug
is modified by the presence of another one without alterations in
pharmacokinetics. These types of interactions may be predicted if
the pharmacologic effects of a drug are known, and the patient
response may be additive or antagonistic.
2,8
For example, there may
be an interaction in which one drug, an angiotensin-converting
enzyme (ACE) inhibitor, and another drug, a thiazide diuretic, each
act by a different mechanism of action to lower blood pressure (BP),
producing an exaggerated hypotensive effect.
CASE 3-1, QUESTION 4: What pharmacodynamic interactions are clinically
relevant to warfarin?
Pharmacodynamic interactions with warfarin are those that alter
the physiology of hemostasis, particularly interactions that influence
the synthesis or degradation of clotting factors or that increase the
risk of bleeding through inhibition of platelet aggregation. In patients
receiving warfarin, the addition of any drugs that increase or
decrease clotting factor synthesis, enhance or reduce clotting factor
catabolism, or that impair vitamin K production by normal flora will
increase the risk of drug interactions.
Tables 3-3 and 3-4 provide examples of common mechanisms of
pharmacokinetic and pharmacodynamic drug interactions,
respectively.
Table 3-3
Common Mechanisms of Pharmacokinetic Drug
Interactions
1,3,6,17,32–34,38,60–65
Mechanism Example
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