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57

N.M.’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.

48 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.

49-51

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).

58

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

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

p. 43

p. 44

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 ACE inhibitor, and another drug, a thiazide diuretic, each act

by a different mechanism of action to lower blood pressure, producing an

exaggerated hypotensive effect.

CASE 3-1, QUESTION 4: The intern asks you to explain the pharmacodynamic interactions that 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.

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 morphine for the pain management.

In a telephone conversation, N.M. expressed to a friend that she felt depressed. As a result, her friend

brought her a bottle of St. John’s-wort.

As the pharmacist on the multidisciplinary team your role is to assess therapy and make recommendations as

needed. Provide appropriate recommendations regarding N.M.’s therapy, 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 moderateto-severe pain. Several studies have identified acetaminophen as a culprit drug in

potentiating the effects of warfarin.

66 Patients who take four 325-mg acetaminophen

tablets per day for longer than a week were more likely to have an INR above 6.0

than those who did not take acetaminophen.

There is no evidence for a pharmacokinetic interaction between acetaminophen

and warfarin.

67 However, acetaminophen is metabolized by CYP2E1 producing the

metabolite N-acetyl-p-benzoquinone-imine (NAPQ1). NAPQ1 oxidizes vitamin Khydroquinone (KH2), the “active” form of vitamin K, and directly inhibits vitamin Kdependent carboxylation. 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 N.M. 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 US 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 treatment of depression. It has also been shown to

lower patient INR values and potentially decrease warfarin’s effectiveness.

68,69

Although this interaction is probably due to the induction of CYP2C9, the degree of

induction is unpredictable due 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 N.M.’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 N.M. 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 N.M.’s depression and to evaluate

therapeutic options that would provide the least risk of drug interactions, as well as

psychosocial treatment.

CASE 3-1, QUESTION 6: Pravastatin, the medication that N.M. was taking prior to admission, is not

available on the hospital’s formulary list. Therefore, the medical intern prescribes the formulary-preferred agent

rosuvastatin postsurgery. He receives an electronic health record drug interaction alert regarding the statin and

warfarin and asks you how this should be managed.

Rosuvastatin is not metabolized extensively by the CYP 450 system

(approximately 10% with CYP2C9 and CYP2C19 being the primary isoenzymes

involved). However, the combination of rosuvastatin and warfarin has resulted in an

increase in the INR and hence increasing risk of bleeding.

34-36 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 N.M., 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. In this instance, pravastatin,

which has limited CYP metabolism and is primarily excreted unchanged in the urine,

may be the optimal choice. Otherwise, rosuvastatin may be used but more frequent

monitoring of the INR is recommended until a stable INR has been reached. Table 3-

5 provides a summary of the metabolism of HMG-CoA reductase inhibitors. Refer to

Chapter 8 Dyslipidemias, Atherosclerosis, and Coronary Heart Disease for more

information on the use of statins, including drug interactions.

CASE 3-2

QUESTION 1: J.A. is a 69-year-old previously healthy male who was 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

Heparin 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’s IV infusion for hypotension secondary to septic shock

Vitals: T 101°F HR 105 RR 20 BP 95/60

Laboratory values: ABG: pH 7.30 /pCO2

42/pO2

80/CO2

19/Sao2

90% on mechanical ventilation: Assist

control RR 20 tidal volume 400 mL PEEP 10 FiO2

50%

Na+ 138 mEq/L WBC 14.600 × 103μ

/L

K+ 4.8 mEq/L Poly 80 %

Cl− 98 mEq/L Bands 12 %

HCO

3

− 19 mEq/L Hgb 9.0 g/dL

BUN 45 mg/dL Hct 28 %

SCr 1.8 mg/dL (baseline SCr

1.0 mg/dL)

Platelets 202 × 103μ

/L

Glucose 142 mg/dL AST 105 U/mL

Serum phosphate 0.9 mg/dL 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% to 90% of receptors blocked) or

the desired clinical effect (e.g., accepting ventilation and not over breathing the ventilator), with the lowest dose

of neuromuscular agent necessary.

71,72

Describe J.A.’s risk factors for drug interactions.

p. 44

p. 45

Table 3-3

Common Mechanisms of Pharmacokinetic Drug Interactions

1,3,6,16,31–33,37,59–64

Mechanism Example

Pharmacokinetics:

administration/absorption

Drugs that alter the pH of

the stomach can affect

Itraconazole requires an acidic gastric pH to become

soluble; absorption may be decreased if a patient is taking

absorption of other drugs a drug that increases gastric pH such as a PPI or H2

-