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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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CASE 3-2, QUESTION 2: The medical team is concerned that J.A.’s condition
may have worsened; he may have had a neurologic event (eg, stroke)
overnight. J.A. is clinically unstable to bring to computed tomography (CT). The
team needs J.A. to be alert for purposes of conducting a neurologic
examination. To undergo the examination, J.A. must have his neuromuscular
blockade discontinued and sedation lightened. One and one-half hours after
discontinuation of cisatracurium, J.A. is still not moving (TOF 0/4). The medical
team feels cisatracurium’s paralytic effect should have worn off by now and is
concerned about his prognosis. Why has J.A.’s neuromuscular blockade not
worn off?
After reviewing the case, the clinician identifies potential drug–
condition/disease and drug–drug pharmacodynamic interactions that
may contribute to the prolonged neuromuscular blockade. These
interactions are discussed as follows.
Background: The incidence of ICU-acquired weakness
(polyneuropathy and myopathy) in patients with ARDS is 34% to
60%. This condition can last for months to years and can severely
affect a patient’s quality of life.83 There are several risk factors for
ICU-acquired weakness that includes prolonged mechanical
ventilation, number of days with dysfunction in two or more organs
before wakening, corticosteroids, female sex,84 toxins (eg, botulism),
neuromuscular disease states (eg, Guillain–Barré syndrome), severe
electrolyte imbalances, prolonged recovery from neuromuscular
blockers, deconditioning, length of vasopressor support, and
hyperglycemia, just to name a few.
83,85,86
Neuromuscular blockade
alone has been associated with ICU-acquired weakness. However,
in a multicenter, double-blind trial, investigators found no statistical
difference in ICU-acquired paresis between cisatracurium and
placebo groups at day 28 or ICU discharge.
85,87
Prolonged recovery
from neuromuscular blockade may occur in patients with organ
failure and/or conditions that affect the overall clearance of the
neuromuscular blocking agent (eg, decreased metabolism of a
parent drug, decreased elimination of the parent drug, and/or the
active metabolite). In addition to these, certain disease states,
conditions, or drugs that may potentiate a blockade may also lead to
an increased recovery time.
85,86
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Drug–Condition/Disease Interactions
PHARMACOKINETICS—DRUG METABOLISM/ELIMINATION
The nondepolarizing agent, cisatracurium, is a benzylisoquinolinium
compound. It is one of the 10 isomers of the intermediate-acting
neuromuscular blocker, atracurium. It is primarily eliminated by
Hofmann degradation; optimal breakdown occurs at physiologic
temperature (37 °C or 98.60 °F) and pH (7.40).79 This process
results in therapeutically inactive metabolites, monoquaternary
alcohol, monoquaternary acrylate, and laudanosine.
88
Cisatracurium’s organ-independent elimination is a benefit for J.A.
because he has renal and hepatic insufficiency. However, because
cisatracurium is degraded by the Hofmann process, alterations in pH
and temperature will affect the elimination of the drug. For example,
the neuromuscular blockade effect is prolonged with acidosis,
whereas elimination is enhanced with an increase in pH. In addition,
hypothermia decreases the elimination of cisatracurium, whereas
hyperthermia accelerates it. In patients with ICU, the recovery rate
from neuromuscular blockade is reported to range from 45 to 75
minutes after discontinuation of a prolonged cisatracurium
infusion.
89–91
Because J.A. has both a fever (101 °F [38.33 °C]) and
metabolic acidosis (pH 7.30 and HCO
3
−
19), it is difficult to predict
the clearance of the neuromuscular blocker.
PHARMACODYNAMIC INTERACTION
A second condition that may add to J.A.’s prolonged blockade is his
low phosphate (phosphate 0.9 mg/dL). Phosphate is a building block
of ATP. ATP produces energy via an enzymatic reaction by releasing
a phosphate group. This reaction is necessary for physiologic and
metabolic functions, including muscle contraction. Therefore, a
patient with hypophosphatemia is at risk for a myopathy.
92
Drug–Drug Interaction
PHARMACODYNAMIC—ADDITIVE EFFECTS OF MEDICATIONS
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J.A.’s medications may also have additive effects with cisatracurium.
A rare adverse effect of amikacin is neuromuscular blockade. The
mechanism of blockade involves inhibiting acetylcholine release by
competing with Ca2+ at the preganglionic nerve terminal and, to a
smaller degree, noncompetitive blocking of the receptor.
93
Corticosteroids (eg, hydrocortisone) may also enhance blockade and
increase recovery time. Proposed mechanisms for steroidal ICUacquired weakness include increased muscle sensitivity to
corticosteroids because of the lack of movement and skeletal muscle
atrophy from the steroid’s catabolic actions. In addition,
corticosteroids may cause myopathy by denervation; corticosteroids
have been shown to inhibit the nicotinic receptor; when combined
with the neuromuscular blocking agent, vecuronium, this inhibition is
potentiated.
83,94
It is thought that this interaction is more likely to
occur with neuromuscular blockers that have a steroid structural ring,
such as the aminosteroids (eg, pancuronium, pipecuronium,
vecuronium, and rocuronium). However, there have been case
reports of prolonged paralysis with the benzylisoquinoliniums (eg,
atracurium, cisatracurium, doxacurium, mivacurium, and dtubocurarine).
85,86,95
J.A. may need a longer period than 1½ hours to recover from his
paralysis because of the following factors: decreased elimination of
cisatracurium as a result of acidosis, hypophosphatemia, and
medications (amikacin and hydrocortisone). J.A. should also have
his phosphate slowly repleted.
CASE 3-2, QUESTION 3: How do you explain the drug interactions affecting the
antibiotic efficacy of J.A.’s regimen to the medical team?
After reviewing the case, the clinician identifies potential drug–
drug physiochemical interaction, as well as drug–condition and
drug–drug pharmacodynamic interactions. The mechanism of action
of these interactions is discussed in the subsequent section.
Drug–Drug Interaction
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PHYSIOCHEMICAL INACTIVATION
It has been well documented that the coadministration of β-lactam
antibiotics with aminoglycoside antibiotics can lead to inactivation of
the aminoglycoside. The mechanism involves the amino group of the
aminoglycoside antibiotic forming an inactive amide with the βlactam ring of penicillin antibiotics.
96,97
Because penicillins have wide
therapeutic index, this interaction primarily affects the efficacy of the
aminoglycoside antibiotic.
This interaction has been shown to occur with the extendedspectrum penicillins (eg, azlocillin, carbenicillin, mezlocillin, ticarcillin,
and piperacillin). J.A. is currently on amikacin and imipenem–
cilastatin antibiotics for the treatment of a multiresistant organism.
According to the literature, amikacin is the aminoglycoside that is
least susceptible to this interaction.97 In addition, no inactivation of
amikacin was observed when incubated in cilastatin 120 μg/mL
human serum for 48 hours at 98.6 °F (37 °C).
98
This inactivation increases with contact time and is directly
proportional to the concentration of penicillin.99 The rate of
elimination of aminoglycoside and imipenem–cilastatin may be
decreased because of J.A.’s renal dysfunction. This would increase
the contact time of the medications.
Recommendations for J.A.’s antibiotic therapy include
administration of medications separately; serum concentrations of
aminoglycosides should be assayed immediately after drawn, or if
analysis is delayed, either add penicillinase to the blood sample or
freeze at −158 °F (−70 °C); and because of his renal dysfunction,
close monitoring of aminoglycoside serum concentrations is
indicated.
99,100
Drug–Condition/Disease Interaction
PHARMACODYNAMIC INTERACTION
The pharmacodynamic actions of amikacin may be decreased
because J.A. is acidotic.
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Amikacin enters the bacterial cell and reaches its site of action in
three stages: ionic binding, energy-dependent phase I (EDP-I), and
energy-dependent phase II (EDP-II) transport or uptake.
Ionic Binding to the Outer Membrane: At physiologic pH, amikacin
(pKa 8.1) is a highly ionized basic cation. It binds to anionic
lipopolysaccharides (LPSs), polar heads of phospholipids, and
proteins on the outer cell membrane of gram-negative bacteria and
phospholipids and teichoic acids of Gram-positive bacteria.
101
This
leads to displacement of cell wall Mg2+ and Ca2+ bridges that link
LPS, resulting in the formation of pores in the cell wall where
amikacin can enter into the periplasmic space.
102
EDP-I: Amikacin is transported across the cytoplasmic membrane.
EDP-I is dependent on pH and oxygen. Amikacin activity will decline
in low pH and anaerobic conditions (eg, abscesses).
102
EDP-II: Amikacin is transported to the site of action, binding to the
ribosomes.
102
Drug–Drug Interaction
PHARMACODYNAMIC—ADDITIVE/SYNERGISTIC EFFECT OF
MEDICATIONS
Penicillins form a covalent bond with the enzymes, the penicillinbinding proteins (PBPs) (specifically transpeptidase, endopeptidase,
and carboxypeptidase), inhibiting their action. These enzymes are
needed for the final step of bacterial cell wall synthesis, the crosslinking between peptide side chains on the polysaccharide
backbones of the peptidoglycan.
103
Cell wall inhibitors such as
penicillins and vancomycin may expedite aminoglycoside entry into
the bacterial cell, resulting in synergistic effects when treating some
organisms.
102
J.A. is critically ill with renal failure, ARDS, pneumonia caused by
a multiresistant organism, septic shock, and a metabolic acidosis. It
is important to closely monitor his aminoglycoside therapy for
efficacy (peaks) and toxicity (troughs).
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This case illustrates the difficulties surrounding drug interaction
identification, assessment, and follow-up intervention. Clinicians
must recognize that literature to support the presence of a drug
interaction is often scant and not always definitive and that the
optimal intervention may rely on clinical judgment. Refer to Chapter
56, Care of the Critically Ill Adult.
CASE 3-3
QUESTION 1: D.T. is a 67-year-old male who began taking imatinib about 10
years ago to treat a rare sarcoma: partially resected gastrointestinal stromal
tumor (GIST). D.T. currently takes 600-mg imatinib daily, as well as rabeprazole
and furosemide. He states that he is currently not taking any nonprescription
medications. He continues to go to the cancer treatment center for continued
monitoring. He contacts the cancer clinic to let them know that in 4 weeks he
will be traveling to Africa to go on a safari. He mentioned that the friends whom
he will be traveling with told him that he will need malaria prophylaxis.
Are there are any potential drug interactions, and which antimalarial agent
would be an appropriate selection?
Imatinib mesylate belongs to a class of drugs known as selective
tyrosine kinase inhibitors (TKIs).
104
It inhibits the BCR-ABL tyrosine
kinase, the constitutive abnormal tyrosine kinase created by the
Philadelphia chromosome abnormality in chronic myeloid proteins.
97
It also inhibits the tyrosine kinase for platelet-derived growth factor
(PDGF) and c-kit. TKIs, such as imatinib, are extensively
metabolized via CYP enzymes (with a large degree of interindividual
variability).
105
Imatinib is metabolized primarily by CYP3A4, whereas
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A5 are reported
to have a minor role in its metabolism.
106
In addition, imatinib is a
substrate of human organic cation transporter type 1 (hOCT1), P-gp,
and BCRP, though it is unclear whether imatinib is a substrate or an
inhibitor of Breast Cancer Resistance Protein (BCRP).
107–110
Imatinib
also competitively inhibits the metabolism of drugs that are CYP2C9,
CYP2C19, CYP2D6, and CYP3A4 substrates.
111
It is also highly
protein bound, with ~95% bound to human plasma proteins.
106,112–114
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Drug–Drug Interaction
PHARMACOKINETICS—DRUG METABOLISM/ELIMINATION
There are several considerations of potential drug interactions with
imatinib. Drug interactions should be considered when imatinib is
administrated with other agents in the CYP3A family.
104
In particular,
interactions are likely with inhibitors of CYP3A4, such as
voriconazole or amiodarone, resulting in increases in the plasma
concentration of imatinib. Concomitant use of rifampicin or other
strong CYP3A4 inducers with imatinib should be avoided. In
addition, concomitant administration of imatinib with agents that are
both inhibitors of CYP3A4 and P-gp increases plasma and
intracellular imatinib concentrations. Examples of dual CYP3A4 and
P-gp inhibitors include verapamil, erythromycin, clarithromycin,
ketoconazole, fluconazole, and itraconazole.
107,115,116
TKIs, such as
imatinib, also can inhibit drug transporters and enzymes, resulting in
changes in the exposure of coadministered drugs. St. John’s wort
significantly altered the pharmacokinetic profile of imatinib, with
reductions of 30% in the medium area under the concentration–time
curve (AUC). Patients should be cautioned regarding the
concomitant use of products, such as St. John’s wort, as well as
other inducers, that may necessitate an increase in imatinib dosing
to maintain therapeutic efficacy.
117,118
Drug interactions involving
protein binding of imatinib and other highly protein-bound drugs are
not well understood.
104
A study published in 2016 examined DDIs observed in patients
treated with imatinib.
119
The investigators performed two
observational studies to identify the medications that were most
frequently dispensed simultaneously with imatinib through the
French health insurance reimbursement database SNIIRAM
(Systeme National d’Information Inter-Regimes Assurance Maladie)
as well as the ADRs related to DDIs involving imatinib using the
French Pharmacovigilance Database. A sample of 544 patients from
SNIIRAM with at least one reimbursement for imatinib were identified
between January 2012 and August 2015. Of this cohort of 544
patients, 89.3% (486) of patients had at least one prescription
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medication that could potentially interact with imatinib based on
mechanism of action (eg, metabolism pathways). The results of the
study also found that the most frequent DDI was with paracetamol
(acetaminophen; 77.4%), which resulted in an increased risk of
paracetamol toxicity. Other study findings with >10% of patients with
potential DDIs were with PPIs (33.3% for omeprazole) or
dexamethasone (23.7%) that could reduce imatinib’s effectiveness
and with levothyroxine (18.5%) that could decrease levothyroxine’s
effectiveness. The suspected mechanisms of this drug interaction
with levothyroxine are an induction by imatinib of nondeiodination
clearance or induction by imatinib of uridine diphosphate glucuronyl
transferases.
120,121
Study results also found that the most frequently
used drugs that could increase imatinib toxicity were ketoconazole
and clarithromycin (5.1% and 4.7%, respectively).
119
The overall
findings of this study suggest that at least 40% of patients who are
receiving imatinib are at risk of DDIs and may reach an even higher
rate according to the results of the study performed in SNIIRAM. The
highest rate of potential DDIs in this study with imatinib was with the
following agents: paracetamol, PPIs, dexamethasone, or
levothyroxine. Based on the study findings, the investigators
provided recommendations regarding the use of imatinib with
specific agents. It is recommended that the reader refers to the
package insert of imatinib for drug interactions and dosing
guidelines. Further study regarding DDIs with imatinib, as well as
other TKIs, is warranted.
With regard to selection of an antimalarial agent for D.T.,
chloroquine, mefloquine, and atovaquone-proguanil (Malarone®) may
have potential interactions with imatinib. The proguanil component is
metabolized via the CYP2C19 pathway. Given the options that can
be used for malaria prophylaxis in D.T., doxycycline would be an
appropriate antimalarial agent used for malaria prophylaxis that does
not interact with imatinib or D.T.’s other medications (refer to Chapter
81, Parasitic Infections, for malaria prophylaxis options). The most
commonly reported adverse effects with doxycycline are GI effects,
including nausea, vomiting, abdominal pain, and diarrhea.
Esophageal ulceration associated with doxycycline is a rare but well-
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described adverse event. D.T. should be counseled to take
doxycycline with food and plentiful fluids, in an upright position in
order to minimize GI adverse effects. Because doxycycline can
cause photosensitivity and D.T. will be on a safari, the risk of
photosensitivity can be reduced by the use of an appropriate
sunscreen and wearing protective clothing, including a hat. D.T.
should also be counseled regarding the use of paracetamol
(acetaminophen) and also to check in advance with his pharmacist
before taking any natural products that may be metabolized via CYP.
RESOURCES AND EVIDENCE FOR CLINICAL
DECISION SUPPORT
Health care providers have become increasingly challenged on
devising optimal approaches to managing drug interactions. Patient
safety initiatives have expanded in efforts to improve the health care
delivery system with medication error prevention as a high-priority
area. The consensus recommendations published by the expert
group in 2015 have provided a road map for addressing the key
concerns to improve the approach to evaluating DDI evidence for
clinical decision-making.5 As part of this process, it was important to
review existing methods for evaluating DDIs. The Drug Interaction
Probability Scale (DIPS), a 10-item scale, was developed to evaluate
individual case reports for DDIs by assessing an adverse event for
causality by a DDI.
122
This tool was developed to address limitations
of previous assessment instruments, such as the Naranjo scale. The
reader is referred to Appendix C of the consensus recommendations
for further information regarding DIPS and other available
instruments.5 The expert group also discussed the current
systematic approaches using clinical decision support (CDS)
systems, their limitations, and the need for a new assessment
instrument to objectively evaluate a body of evidence to establish the
existence of a DDI. One of the key challenges of CDS systems is to
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determine what evidence is required for a DDI to be applicable to an
entire drug class. Pharmacokinetic interactions are rarely
generalizable to all agents within a drug class, and if there is class
effect, the magnitude of the effect can often vary, which typically
necessitates that each drug is reviewed individually. In some cases,
pharmacokinetic interaction data may be extrapolated from one
agent to other agents in the small class if the purported mechanism
of interaction involves common pharmacologic effects.
To advance this important initiative, recently, another group of
experts convened to address the following: (a) to outline the process
to use for developing and maintain a standard set of DDIs, (b) to
determine the information that should be included in a knowledge
base of standard DDIs, (c) to determine whether a list of
contraindicated drug pairs can or should be established, and (d) to
determine how to more intelligently filter DDI alerts.
123
Their
recommendations for selecting DDIs for CDS were released in 2016.
The reader is referred to both the 2015 and the 2016
recommendations.
5,123
Because various avenues are examined to reduce the risk of drug
interactions within society, it is essential as health care providers that
we improve patient education regarding medication information. This
strategy includes our communications with patients both verbal
instructions and patient instruction leaflets given with the
prescription. It is important to consider translation of information into
different languages and to also promote culturally competent
communication within every health care setting. The use of auxiliary
warning labels placed on the medication package, books, and
referring patients to quality health information on the Internet.
Pharmacists are uniquely positioned to provide important information
regarding OTC medications, including herbal products when patients
receive prescription information, and when they are seeking
recommendations for OTC products.
124
CONCLUSION
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