Grapefruit juice inhibits intestinal CYP 3A4 potentially
increasing the bioavailability of CYP 3A4 substrates such
Dabigatran, a substrate for P-gp, peak concentrations may
be increased by P-gp inhibitors (e.g., ketoconazole,
clarithromycin, amiodarone) leading to a significantly
Erythromycin, a potent prokinetic agent, is a motilin
receptor agonist that increases gastric motility; absorption
of coadministered drugs may be affected
Killing enteric bacteria Antibiotics can kill bacteria that produce deconjugating
enzymes; drugs that undergo enterohepatic circulation
such as birth control pills may have decreased blood
concentrations and half-life because of increased
Chelation Cations such as aluminum or magnesium antacids
decrease the GI absorption of tetracycline antibiotics by
Mixing a furosemide solution with an acidic solution (i.e.,
with midazolam) decreases the pH sufficiently to cause
furosemide precipitation and reduced availability when
Sulfamethoxazole displaces warfarin from protein-binding
sites increasing the free fraction. Sulfamethoxazole also
inhibits the metabolism of warfarin. As a result, the body
cannot compensate to increase the elimination of the high
free (active) fraction of warfarin. The end result is likely
an increase in the INR and potential risk for bleeding. See
chapter 11 for detailed warfarin–sulfamethoxazole drug
Cyclosporine may inhibit the transporter OATP1B1
decreasing the hepatic uptake of most statins; efficacy of
the statin may be lost because the site of action is located
Example 1: Fluoroquinolones inhibit metabolism of
theophylline via CYP 1A2 enzyme; the extent of the
interaction varies between the different fluoroquinolones
Example 2: Rifampin has a half-life of 4 hours; however,
time to steady state induction with propranolol does not
Methotrexate clearance may be reduced in the presence
of salicylates. Salicylates decrease renal perfusion via
, having the potential to cause renal impairment and
competitively inhibit the tubular secretion of methotrexate
Increased or decreased Example 1: Quinidine reabsorption may be increased in
renal tubular absorption alkalinized urine.
Example 2: Thiazide diuretics initially cause sodium
excretion followed by compensatory sodium reabsorption.
Administered with lithium, a cation can cause increased
lithium reabsorption and possible toxic concentrations
Common Mechanisms of Pharmacodynamic Drug Interactions
Pharmacodynamics Additive—two or more
Administration of thiopental and midazolam during induction.
Midazolam reduces the amount of thiopental required for
Example 1: Antagonism at the same receptor site: reversal of
benzodiazepines with flumazenil.
Example 2: Opposing pharmacodynamics actions:
glucocorticoids cause hyperglycemia opposing the effects of
There are several risk factors for drug interactions in critically ill patients.
Critically ill patients are susceptible to drug interactions as a result of a debilitated
condition and/or disease state (e.g., changes in physiologic pH and body temperature,
electrolyte imbalances, organ failure, etc.), as well as the multitude of medications
prescribed as treatment. ICU patients also have altered pharmacokinetics, placing
them at an increased risk for an interaction. These changes include the following:
Decreased GI absorption of enterally administered medications due to the
following: hypoperfusion from shock; increased stomach pH from PPI and
histamine blocker therapy; decreased GI motility; drug effect on carrier proteins,
Decreased subcutaneous absorption due to the following: edema; vasopressor
therapy; and disease-induced peripheral vasoconstriction;
Increased volume of distribution (Vd
) for hydrophilic medications due to increased
total body water from fluid resuscitation and third spacing;
Altered free drug fraction due to increased α-acid glycoprotein from systemic
inflammation and decreased albumin plasma concentrations; and
Half-life (t½) and Clearance (CL) may be affected from decreased hepatic blood
flow, renal or hepatic insufficiency, and induction or inhibition of hepatic
enzymes by drugs. Patients without renal insufficiency may exhibit augmented
Metabolism of HMG-CoA Reductase Inhibitors (Statins)
Lovastatin CYP3A4 substrate Caution drugs that significantly inhibit its metabolism (potent
Simvastatin CYP3A4 substrate Caution drugs that significantly inhibit its metabolism (potent
Atorvastatin CYP3A4 substrate Metabolized by CYP 3A4 but less than lovastatin and
Fluvastatin CYP2C9 substrate Metabolized primarily by CYP2C9 and to a lesser extent by
Pravastatin Excreted primarily
Not significantly metabolized by cytochrome P450 system
Rosuvastatin 2C9/2C19 Not extensively metabolized by cytochrome P450 system
aSubstrates for Pgp → drugs that inhibit Pgp may ↑ statin levels (e.g., cyclosporine, diltiazem).
Statins,” June 2010, Volume 26, Number 260611.
The mode of mechanical ventilation that is used most commonly today is positive
pressure ventilation, whereby air is forced into the lungs to improve gas exchange.
The use of mechanical ventilation may also affect drug pharmacokinetics by
decreasing cardiac output secondary to reduced preload, which in turn may
compromise perfusion to the liver and kidneys as well as GFR and urine output.
This effect is most pronounced in patients who are hypovolemic. These hemodynamic
changes can result in a decrease of the clearance of several drugs.
J.A. has several risk factors for drug interactions. Many of his risk factors are
patient-specific, including J.A.’s age, organ dysfunction, and acute medical
conditions. Additional risk factors are the extended hospital stay in the ICU and
multiple medications. J.A.’s specific risk factors are outlined below.
Age: 69 years old—altered pharmacokinetic and pharmacodynamics
Renal dysfunction: baseline SCr 1.0 mg/dL and current SCr 1.8 mg/dL—decreased
Mild hepatic dysfunction: AST 105 U/mL and ALT 85 U/mL—decreased
Pneumonia: T 101°F, WBC 14.6 × 10
3μ/L, poly 80%, bands 12%—increased
Hypotension (result of shock): BP 95/60 on norepinephrine, vasopressin, and
lactated Ringer’s solution—decreased clearance
Hyperthermia: T 101°F—increased clearance
Hypophosphatemia: phosphate 0.9 mg/dL—increased neuromuscular blockade (see
discussion Case 3-2 Question 2)
Norepinephrine and vasopressin infusions: potential for decreased blood delivery
Mechanical ventilation: decreased cardiac output
Polypharmacy: risk of adverse drug interaction increases with multiple medications
Duration of hospital stay: 18 days—susceptible to hospital-acquired conditions and
CASE 3-2, QUESTION 2: The medical team is concerned that J.A.’s condition may have worsened; he may
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 below.
Background: The incidence of ICU-acquired weakness (polyneuropathy and
myopathy) in ARDS patients is 34% to 60%. This condition can last for months to
years and can severely affect a patient’s quality of life.
factors for ICU-acquired weakness that includes prolonged mechanical ventilation,
number of days with dysfunction in 2 or more organs before wakening,
toxins (e.g., botulism), neuromuscular disease states
(e.g., Guillain-Barre Syndrome), severe electrolyte imbalances, prolonged recovery
from neuromuscular blockers, deconditioning, length of vasopressor support, and
hyperglycemia just to name a few.
76,78,79 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.
recovery from neuromuscular blockade may occur in patients with organ failure
and/or conditions that affect the overall clearance of the neuromuscular blocking
agent (e.g., decreased metabolism of a parent drug, decreased elimination of the
parent drug, and/or the active metabolite). In addition to that, certain disease states,
conditions, or drugs that may potentiate a blockade may also lead to an increased
Drug-Condition/Disease Interactions
PHARMACOKINETICS—DRUG METABOLISM/ELIMINATION
The nondepolarizing agent, cisatracurium, is a benzylisoquinolinium compound. It is
one of the ten isomers of the intermediate-acting neuromuscular blocker, atracurium.
It is primarily eliminated by Hofmann degradation; optimal breakdown occurs at
physiologic temperature (37°C or 98.6°F) and pH (7.40).
therapeutically inactive metabolites, monoquaternary alcohol, monoquaternary
81 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 while elimination is enhanced with an increase in
pH. Additionally, hypothermia decreases the elimination of cisatracurium whereas
hyperthermia accelerates it. In ICU patients, the recovery rate from neuromuscular
blockade is reported to range from 45 to 75 minutes after discontinuation of a
prolonged cisatracurium infusion.
82-84 Because J.A. has both a fever (101°F) and
metabolic acidosis (pH 7.30 and HCO3
− 19), it is difficult to predict the clearance of
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 adenosine triphosphate
(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
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
A study published in 2016 examined DDIs observed in patients treated with
112 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 1 reimbursement for
imatinib were identified between January 2012 through August 2015. Of this cohort
of 544 patients, 89.3% (486) of patients had at least 1 prescription medication that
could potentially interact with imatinib based on mechanism of action (e.g.,
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 greater than 10% of patients with
potential DDIs were with proton pumps inhibitors (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.
113,114 Study results also found that the most
frequently used drugs that could increase imatinib toxicity were ketoconazole and
clarithromycin (respectively, 5.1% and 4.7%).
112 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 2C19 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-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 cytochrome P450.
RESOURCES AND EVIDENCE FOR CLINICAL
Healthcare providers have become increasingly challenged on devising optimal
approaches to managing drug interactions. Patient safety initiatives have expanded in
efforts to improve the healthcare 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.
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
115 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
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
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
To advance this important initiative, recently another group of experts convened to
address the following: (1) to outline the process to use for developing and maintain a
standard set of DDIs; (2) to determine the information that should be included in a
knowledge base of standard DDIs; (3) to determine whether a list of contraindicated
drug pairs can or should be established; and (4) to determine how to more
intelligently filter DDI alerts.
116 Their recommendations for selecting drug–drug
interactions for CDS were released in 2016. The reader is referred to both the 2015
Because various avenues are examined to reduce the risk of drug interactions
within society, it is essential as healthcare 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 healthcare 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
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