PHARMACODYNAMIC—ADDITIVE EFFECTS OF MEDICATIONS
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 Ca
terminal and to a smaller degree noncompetitive blocking of the receptor.
Corticosteroids (e.g., hydrocortisone) may also enhance blockade and increase
recovery time. Proposed mechanisms for steroidal ICU-acquired weakness include
increased muscle sensitivity to corticosteroids because of lack of movement and
skeletal muscle atrophy from the steroid’s catabolic actions. Additionally,
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.
interaction is more likely to occur with neuromuscular blockers that have a steroid
structural ring, such as the aminosteroid (e.g., pancuronium, pipcuronium,
vecuronium, and rocuronium). However, there have been case reports of prolonged
paralysis with the benzylisoquinoliniums (e.g., atracurium, cisatracurium,
doxacurium, mivacurium, and d-tubocurarine).
J.A. may need a longer period than an hour and one-half 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.
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
It has been well documented that the coadministration of beta-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 beta-lactam ring of penicillin antibiotics.
penicillins have wide therapeutic index, this interaction primarily affects the efficacy
of the aminoglycoside antibiotic.
This interaction has been shown to occur with the extended-spectrum penicillins
(e.g., azlocillin, carbenicillin, mezlocillin, ticarcillin, and piperacillin). J.A. is
currently on amikacin and imipenem–cilastatin antibiotics for treatment of a
multiresistant organism. According to the literature, amikacin is the aminoglycoside
that is least susceptible to this interaction.
90 Additionally, no inactivation of amikacin
was observed when incubated in cilastatin 120 µg/mL human serum for 48 h at
This inactivation increases with contact time and is directly proportional to the
92 The rate of elimination of aminoglycoside and
imipenem–cilastatin may be increased 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 freeze at −70°C; and because of his
renal dysfunction, close monitoring of aminoglycoside serum concentrations is
Drug-Condition/Disease Interaction
The pharmacodynamic actions of amikacin may be decreased because J.A. is
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
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.
leads to displacement of cell wall Mg
2+ bridges that link LPS, and the result
is the formation of pores in the cell wall where amikacin can enter into the
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 (e.g., abscesses).
EDP-II: Amikacin is transported to the site of action, binding to the ribosomes.
PHARMACODYNAMIC—ADDITIVE/SYNERGISTIC EFFECT OF
Penicillins form a covalent bond with the enzymes, the penicillin-binding proteins
(PBPs) (specifically transpeptidase, endopeptidase, carboxypeptidase) inhibiting
their action. These enzymes are needed for the final step of bacterial cell wall
synthesis, the cross-linking between peptide side chains on the polysaccharide
backbones of the peptidoglycan.
96 Cell wall inhibitors such as penicillins and
vancomycin may expedite aminoglycoside entry into the bacterial cell resulting in
synergistic effects when treating some organisms.
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
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
the optimal intervention may rely on clinical judgment. Refer to Chapter 56 for the
Care of the Critically Ill Adult Patient.
the friends that he will be traveling with told him that he will need malaria prophylaxis.
drug interactions and which antimalarial agent would be an appropriate selection.
Imatinib mesylate belongs to a class of drugs known as selective tyrosine kinase
It inhibits the BCR-ABL tyrosine kinase, the constitutive
abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in
It also inhibits the tyrosine kinase for platelet-derived
growth factor (PDGF) and c-kit. TKIs, such as imatinib, are extensively metabolized
via cytochrome P450 enzymes (with a large degree of interindividual variability).
Imatinib is metabolized primarily by CYP 3A4, whereas CYP1A2, CYP2C9,
CYP2C19, CYP2D6, and CYP3A5 are reported to have a minor role in its
In addition, imatinib is a substrate of human organic cation transporter
type 1 (hOCT1), Pgp, and BCRP, though it is unclear whether imatinib is a substrate
Imatinib also competitively inhibits the metabolism of
drugs that are CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates.
highly protein bound with approximately 95% bound to human plasma
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
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 Pgp
inhibitors include verapamil, erythromycin, clarithromycin, ketoconazole,
fluconazole, and itraconazole.
100,108,109 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.
110,111 Drug interactions involving
protein binding of imatinib and other highly protein-bound drugs are not well
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