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

-

blocker

Induction or inhibition of

CYP enzymes in the

gastrointestinal (GI) tract

Grapefruit juice inhibits intestinal CYP 3A4 potentially

increasing the bioavailability of CYP 3A4 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 (e.g., 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

Physiochemical

inactivation

Mixing a furosemide solution with an acidic solution (i.e.,

with midazolam) decreases the pH sufficiently to cause

furosemide precipitation and reduced availability when

administered intravenously

Pharmacokinetics:

distribution

Interaction between two

highly protein-bound

drugs (e.g., 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 organic

transporting peptides

(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 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

occur until 10–14 days

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 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

Table 3-4

Common Mechanisms of Pharmacodynamic Drug Interactions

65

Mechanism Example

Pharmacodynamics Additive—two or more

medications with

comparable

pharmacodynamic effects

result in an exaggerated

and/or toxic response

Administration of thiopental and midazolam during induction.

Midazolam reduces the amount of thiopental required for

anesthesia

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

p. 45

p. 46

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,

for example, P-gp;

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

clearance.

73,74

Table 3-5

Metabolism of HMG-CoA Reductase Inhibitors (Statins)

Statins

a

Isoenzyme Comments

Lovastatin CYP3A4 substrate Caution drugs that significantly inhibit its metabolism (potent

CYP 3A4 inhibitors)

Simvastatin CYP3A4 substrate Caution drugs that significantly inhibit its metabolism (potent

CYP 3A4 inhibitors)

Atorvastatin CYP3A4 substrate Metabolized by CYP 3A4 but less than lovastatin and

simvastatin

Fluvastatin CYP2C9 substrate Metabolized primarily by CYP2C9 and to a lesser extent by

CYP3A4 and CYP2D6

Pravastatin Excreted primarily

unchanged in urine

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).

Adapted from Pharmacist’s Letter/Prescriber’s Letter, “Clinically Significant Statin Drug Interactions,” August

2009, Volume 25, Number 250812 and Pharmacist’s Letter/Prescriber’s Letter, “Characteristics of the Various

Statins,” June 2010, Volume 26, Number 260611.

70

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.