Pharmacokinetics/Pharmacodynamics

Answer: B

Increasing the concentration of an antibiotic at an

infection site is most important (Answer B is correct).

Although case reports describe the use of intraven-

tricular antibiotics in the treatment of meningitis, they

have not shown superiority (Answer A is incorrect).

Although there is the potential to reduce vancomycin-

induced nephrotoxicity, no studies have compared

the nephrotoxicity of intraventricular antibiotics with

that of intravenous antibiotics, likely because this is

not the rationale for their use (Answer C is incorrect).

Ototoxicity could also be reduced, but this was not the

intent of the locally instilled antibiotics (Answer D is

incorrect).

Three studies have documented an increase in digoxin

absorption when the gastric pH is increased, with

two studies noting the cause of increased gastric pH

from a proton pump inhibitor (Answer D is correct).

However, no studies have shown a decreased absorp-

tion of carvedilol (Answer A is incorrect), ciprofloxacin

(Answer B is incorrect), or diazepam (Answer C is

incorrect).

Answer: A

A decrease in the ionization of a drug allows the drug

to pass more easily through membranes. Increasing the

ionization would decrease the Vd by decreasing its abil-

ity to pass through membranes. A weak acid would be

less ionized in a more acidic environment. The patient

is likely in diabetic ketoacidosis with a definite acidosis.

Ciprofloxacin (a weak acid) is less likely to be ionized

and would have an increased Vd (Answer A is correct;

Answers B–D are incorrect).

Answer: C

Levofloxacin has a large Vd. The increase in interstitial

fluid volume caused by 6 L of crystalloids would increase

the Vd of hydrophilic drugs but would not appreciably

affect the Vd of a drug like levofloxacin, which already

has a large Vd (Answer C is correct). Tobramycin, dap-

tomycin, and cefepime have relatively small Vd values

and are increased in patients with increased interstitial

volumes (Answers A, B, and D are incorrect).

Answer: B

Morphine is a high extraction ratio drug. Mechanical

ventilation can decrease cardiac output and thus

decrease liver blood flow. The decrease in liver blood

flow is inversely proportional to the unbound steady-

state concentration. Therefore, it both decreases the

hepatic blood flow and increases the unbound concen-

tration (Answer B is correct). The effects of mechanical

ventilation on cardiac output would likely decrease

oxygen delivery (Answer A is incorrect). Cytokines

affect intrinsic clearance but would not affect the con-

centration of a high extraction ratio drug (Answer C is

incorrect). Mechanical ventilation can indirectly affect

the unbound concentration (Answer D is incorrect).

Answer: B

This patient has sepsis, which is associated with an

increased production of inflammatory cytokines.

These cytokines can decrease the activity of the CYP

enzymes and decrease intrinsic clearance. In addition,

fluconazole inhibits CYP2C19 activity. Diazepam is

a low extraction ratio drug. The hepatic clearance of

diazepam is affected by changes in intrinsic clearance

(including CYP2C19 activity). The unbound steady-

state concentration would be increased, because of a

decrease in intrinsic clearance caused by the inflamma-

tory cytokines and CYP2C19 inhibition by fluconazole.

The increased unbound steady-state concentrations

would cause increased sedation (Answer B is correct).

There is no cause for an increase in intrinsic clearance

and a corresponding decrease in sedation (Answer A is

incorrect). There is no reason for this patient to have a

decrease in the unbound fraction of diazepam (Answer

C is incorrect). A decrease in albumin could occur with

sepsis and would result in an increase in the unbound

fraction of diazepam. The increase in unbound fraction

would not affect the unbound steady-state concentra-

tion, nor would it affect the level of sedation (Answer D

is incorrect).

Answer: D

Under normal conditions, the unbound steady-state

concentration for phenytoin is expected to be 10% of

the total concentration. Thus, a total concentration of

10-20 mg/L is equivalent to an unbound steady-state

concentration of 1-2 mg/L. When the unbound fraction