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Mechanism Example
Pharmacokinetics:
administration/absorption
Drugs that alter
the pH of the
stomach can
affect absorption
of other drugs
Itraconazole requires an acidic
gastric pH to become soluble;
absorption may be decreased
if a patient is taking a drug
that increases gastric pH such
as a PPI or H2-blocker.
Induction or
inhibition of CYP
enzymes in the
GI tract
Grapefruit juice inhibits intestinal
CYP3A4, potentially
increasing the bioavailability
of CYP3A4 substrates such
as nifedipine and verapamil.
Induction or
inhibition of P-gp
(an efflux pump
that expels
drugs) in GI tract
Dabigatran, a substrate for P-
gp, peak concentrations may
be increased by P-gp
inhibitors (eg, ketoconazole,
clarithromycin, amiodarone),
leading to a significantly
increased risk of bleeding.
Increase or delay
gastric
emptying/motility
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
excretion in the feces.
Chelation Cations such as aluminum or
magnesium antacids
decrease the GI absorption of
tetracycline antibiotics by
forming drug–metal
complexes.
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Mechanism Example
Physiochemical
inactivation
Mixing a furosemide solution
with an acidic solution (ie,
with midazolam) decreases
the pH sufficiently to cause
furosemide precipitation and
reduced availability when
administered intravenously.
Pharmacokinetics:
distribution
Interaction
between two
highly proteinbound drugs
(eg, a precipitant
drug has
stronger affinity
for the same
protein-binding
site)
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 interaction.
Inhibition of carrier
proteins such as
P-gp located in
blood–brain
barrier and
OATPs located
in the liver
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 in
the liver.
Pharmacokinetics:
metabolism
Induction or
inhibition of CYP
enzymes in the
liver
Example 1: Fluoroquinolones
inhibit metabolism of
theophylline via CYP1A2
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 occur
until 10–14 days.
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Mechanism Example
Pharmacokinetics:
excretion/elimination
Administration of
two drugs that
use the same
transport system
and undergo
active tubular
secretion by the
kidneys
Methotrexate clearance may be
reduced in the presence of
salicylates. Salicylates
decrease renal perfusion via
PGE2, having the potential to
cause renal impairment and
competitively inhibit the
tubular secretion of
methotrexate.
Increased or
decreased renal
tubular
absorption
Example 1: Alkalization of the
urine with sodium bicarbonate
will decrease the reabsorption
of acidic compounds such as
salicylates, a treatment in
overdose.
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.
GI, gastrointestinal; INR, international normalized ratio; OATP, organic anion
transporting peptide; P-gp, P-glycoprotein; PPI, proton-pump inhibitor.
Table 3-4
Common Mechanisms of Pharmacodynamic Drug Interactions
66
Mechanism Example
Pharmacodynamics Additive—two or more
medications with
comparable
pharmacodynamic
effects result in an
exaggerated and/or
toxic response
An adverse effect of each of the
drugs, clarithromycin and
saquinavir, is QTc prolongation.
Administration of them together
increases the risk for QTc
prolongation and an increase in
plasma concentrations.
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Mechanism Example
Antagonistic—the
effects of one drug
oppose the actions
of another drug
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 hypoglycemic
medications.
Source: Reprinted from Pleuvry BJ. Pharmacodynamic and pharmacokinetic drug
interactions. Anaesth Intensive Care Med. 2005;6(4):129–133. Copyright © 2005
Elsevier. With permission.
MANAGEMENT OF DRUG INTERACTIONS
CASE 3-1, QUESTION 5: The medical intern on the team also plans to prescribe
a combination analgesic (oxycodone/acetaminophen) in place of intravenous
(IV) morphine for the pain management.
In addition, F.D. remembers St. John’s wort is the name of the OTC product
that she takes. She said it helps with her seasonal depression.
As the pharmacist on the multidisciplinary team, your role is to assess
therapy and make recommendations as needed. What recommendations
regarding F.D.’s therapy do you make, including the use of St. John’s wort?
Although acetaminophen is a commonly used nonprescription
analgesic and antipyretic medication for mild-to-moderate pain and
fever, its presence is often unrecognized in combination products
containing opioids prescribed for moderate-to-severe pain. Several
studies have identified acetaminophen as a culprit drug in
potentiating the effects of warfarin.
67,68
Patients who take four 325mg acetaminophen tablets per day for longer than a week were more
likely to have an INR >6.0 than those who did not take
acetaminophen.
There is no evidence for a pharmacokinetic interaction between
acetaminophen and warfarin.69 However, acetaminophen is
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metabolized by CYP2E1, producing the metabolite N-acetyl-pbenzoquinone-imine (NAPQ1). NAPQ1 oxidizes vitamin Khydroquinone (KH2), the “active” form of vitamin K, and directly
inhibits vitamin K–dependent carboxylation.70 There may be other
oxidative changes, producing enzymatic disruption, that impact
vitamin K synthesis and activity. The end result is an exaggerated
response to warfarin and an increased INR.
Therefore, if F.D. is to be placed on oxycodone/acetaminophen
therapy, her INR should be monitored more frequently and her dose
adjusted accordingly. This is important particularly if she requires
higher sustained doses of warfarin.
Dietary supplements, including herbal medicinals, amino acids,
and other nonprescription products, are not tested before marketing
for interactions with other medications, including warfarin. Little is
known about their interactive properties, other than published case
reports of varying quality. In addition, dietary supplements are not
required to meet U.S. Pharmacopeia standards for tablet content
uniformity.
St. John’s wort, an herb whose yellow flowers and leaves are used
to make herbal supplements, has been used for the treatment of
depression. It has also been shown to lower patient INR values and
potentially decrease warfarin’s effectiveness.
71,72
Although this
interaction is probably because of the induction of CYP2C9, the
degree of induction is unpredictable owing to variable quality and
quantity of the herbal constituent in the preparations. Similarly, St.
John’s wort has been suspected of reducing phenytoin plasma
concentrations through induction of CYP3A4.
The addition of St. John’s wort to F.D.’s current drug regimen
would not be advisable because it would increase her risk for drug
interactions. The implications for initiating St. John’s wort in F.D.
would require measurement of phenytoin and more frequent INR
testing to ensure a new steady state for each agent has been
reached. At this point, it is important to assess F.D.’s depression and
to evaluate therapeutic options that would provide the least risk of
drug interactions, as well as psychosocial treatment.
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CASE 3-1, QUESTION 6: The medical team would like to resume F.D.’s
medications that she was taking before admission. However, when the medical
resident enters the order into the computer, they receive an electronic health
record drug interaction alert regarding the statin and warfarin. How should this
be managed?
Fluvastatin is metabolized extensively by the CYP system,
primarily by CYP2C9 and to a lesser extent by CYP3A4 and
CYP2C8. Fluvastatin is also a substrate for the transport protein
OATP1B3. OATP transports statins from the blood to the liver for
metabolism or excretion into the bile and feces. The combination of
fluvastatin and warfarin has resulted in an increase in the INR, hence
increasing the risk of bleeding.
3,35,36
In addition to this, fluvastatin
when coadministered with phenytoin has been reported to increase
phenytoin serum concentrations.73 Each of the statin agents is
metabolized by different CYP isoenzymes and to different degrees
(Table 3-5). The goal of lipid management is to prescribe an agent
with the least side effects and at the lowest effective dose. If a
patient, such as F.D., requires a drug that interacts with statin
metabolism (CYP), switching to a statin that has a more favorable
elimination profile may be the best option. For example, pravastatin
is a good alternative because its elimination is not dependent on
CYP metabolism and is eliminated 20% by the renal route.74 F.D. has
minor renal dysfunction with a creatinine clearance of 70 mL/minute;
pravastatin would not require dose adjustment unless F.D.’s
glomerular filtration rate (GFR) drops <30 mL/minute.75 However, if
fluvastatin is continued with warfarin therapy more frequent,
monitoring of the INR is recommended until a stable INR has been
reached. It is vital to monitor the patient’s INR during initiation and
discontinuance of fluvastatin therapy.73 Table 3-5 provides a
summary of the metabolism of HMG-CoA reductase
inhibitors.
36,74,76,77
Refer to Chapter 8, Dyslipidemias, Atherosclerosis,
and Coronary Heart Disease, for more information on the use of
statins, including drug interactions.
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Table 3-5
Transport, Metabolism, and Excretion of HMG-CoA Reductase
Inhibitors (Statins)
CYP, cytochrome P450 isoenzyme; OATP, organic anion transporting polypeptide;
P-gp, P-glycoprotein.
a
Efflux transporter, P-gp prevents oral absorption of statins and OATP facilitates
hepatic uptake of statins from the blood → drugs that inhibit these transporters
may ↑ statin plasma concentrations.
Sources: Adapted from Wiggins BS, Saseen JJ, Page RL 2nd, et al.
Recommendations for management of clinically significant drug-drug interactions
with statins and select agents used in patients with cardiovascular disease a
scientific statement from the American Heart Association. Circulation.
2016;134:e468–e495. PL detail-document. Clinically significant statin drug
interactions. Pharmacist’s Letter/Prescriber’s Letter. April 2012. Scripture CD,
Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet.
2001;40(4):263–281. Hatanaka T. Clinical pharmacokinetics of pravastatin. Clin
Pharmacokinet. 2000;39(6):397–412.
CASE 3-2
QUESTION 1: J.A. is a 69-year-old previously healthy male admitted to the
medical intensive care unit (ICU) with lower left lobe pneumonia, and he has
developed septic shock. His hospital course for the first 18 days of admission
consisted of a worsening bilateral pneumonia characterized by profound
hypoxia and acute respiratory distress syndrome (ARDS). J.A. is currently
deeply sedated and receiving neuromuscular blockade to manage his ARDS,
high peak inspiratory pressures (PIPs), and low oxygen saturation (Sao2).
Medications:
Propofol IV infusion and fentanyl IV infusion for sedation and analgesia
Cisatracurium IV infusion for neuromuscular blockade—goal is to improve
oxygenation (Pao2/FIO2 ratio)
Pantoprazole IV for stress ulcer prophylaxis
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Heparin subcutaneous (SC) and pneumatic compression boots for deep
venous thrombosis (DVT) prophylaxis
Hydrocortisone IV for corticosteroid insufficiency in critical illness
Amikacin IV and imipenem/cilastatin IV for day 5 treatment of a multidrug-
resistant organism
Norepinephrine and vasopressin IV infusions for septic shock secondary to
pneumonia
Ophthalmic ointment to lubricate eye while on prolonged neuromuscular
blockade
Lactated Ringer IV infusion for hypotension secondary to septic shock
Vitals: T 101 °F (38.33 °C), heart rate (HR) 105, respiratory rate (RR) 20, BP
95/60
Laboratory values: arterial blood gas (ABG): pH 7.30/PCO2 42/PO2 80/CO
2
19/Sao2 90% on mechanical ventilation: Assist control RR 20, tidal volume
400 mL, positive end-expiratory pressure (PEEP) 10, FIO2 50%.
Na
+
138 mEq/L White blood cell
count (WBC)
14,600 ×
103 μL
K
+
4.8 mEq/L Poly 80%
Cl
−
98 mEq/L Bands 12%
HCO
3
−
19 mEq/L Hemoglobin (Hgb) 9.0 g/dL
Blood urea
nitrogen (BUN)
45 mg/dL Hematocrit (Hct) 28%
Serum creatinine
(SCr)
1.8 mg/dL (baseline SCr
1.0 mg/dL)
Platelets
202 × 10
3
μL
Glucose 142 mg/dL Aspartate
transaminase (AST)
105 U/mL
Serum phosphate 0.9 mg/dL Alanine
transaminase (ALT)
85 U/mL
J.A.’s train-of-four (TOF) is 0/4. A peripheral nerve stimulator, the TOF, is a
clinical tool used to monitor neuromuscular blockade. The TOF Scale includes
the following: 0/4 indicates that no twitch elicited, neuromuscular blocker agent
occupies 100% of postsynaptic nicotinic receptors, and a 100% blockade,
whereas 4/4 indicates that <75% of the postsynaptic nicotinic receptors are
blocked. The goal of neuromuscular therapy is to achieve an adequate
neuromuscular blockade, a TOF of 1/4 or 2/4 (80%–90% of receptors blocked)
or the desired clinical effect (eg, accepting ventilation and not over breathing the
ventilator), with the lowest dose of neuromuscular agent necessary.
78,79
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What are J.A.’s risk factors for drug interactions?
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 (eg, changes in
physiologic pH and body temperature, electrolyte imbalances, organ
failure), as well as the multitude of medications prescribed as
treatment. Patients in ICU 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
owing to the following: hypoperfusion from shock, increased
stomach pH from PPI and histamine blocker therapy, decreased GI
motility, or drug effect on carrier proteins, for example, P-gp
Decreased SC absorption owing to the following: edema,
vasopressor therapy, or disease-induced peripheral
vasoconstriction
Increased volume of distribution (Vd) for hydrophilic medications
owing to increased total body water from fluid resuscitation and
third spacing
Altered free drug fraction owing to increased α-acid glycoprotein
from systemic inflammation and decreased albumin plasma
concentrations
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 clearance.
80,81
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.
82
This effect is most pronounced in patients who are hypovolemic.
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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 as follows.
Patient Risk Factors
Age: 69 years old—altered pharmacokinetics and pharmacodynamics
Renal dysfunction: baseline SCr 1.0 mg/dL and current SCr 1.8
mg/dL—decreased renal clearance
Mild hepatic dysfunction: AST 105 U/mL and ALT 85 U/mL—
decreased metabolism
Pneumonia: T 101 °F (38.33 °C), WBC 14.6 × 103 μL, poly 80%,
bands 12%—increased catabolism
Hypotension (result of shock): BP 95/60 on norepinephrine,
vasopressin, and lactated Ringer solution—decreased clearance
Hyperthermia: T 101 °F (38.33 °C)—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 to the liver and kidneys
Mechanical ventilation: decreased cardiac output
Other Risk Factors
Polypharmacy: risk of adverse drug interaction increases with
multiple medications
Duration of hospital stay: 18 days—susceptible to hospital-acquired
conditions and subsequent drug therapy
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