A 50-year-old man with edema is given furosemide 80 mg orally to improve his edema. In order to be familiar with pharmacokinetics of the drugs , which one of the following statements regarding volume of distribution ( V _d ) of a drug is CORRECT?

Simply V _d (also called the apparent volume of distribution ) refers to the distribution of a drug in body compartments, which include plasma, water, red blood cells, and tissue or organ binding. V _d is not a real but a theoretical volume. It is defined as the ratio of total amount of drug in the body to its concentration in plasma, or
The following example gives an idea of V _d of a drug:

The patient receives a bolus of 500 mg of a drug intravenously, and 1-h later the plasma concentration of the drug is 20 mg/L. The V _d of the drug is:
This means that the V _d for this drug is 25 L, or the drug is distributed in 25 L (0.36 L/kg in a 70 kg subject).

A drug that is highly protein-bound (mostly to albumin) remains in plasma. Water-soluble drugs remain in the extracellular fluid space, and have a small V _d . The V _d increases, if the patient has edema, ascites, or infection. In such cases, the plasma concentration of a particular drug is decreased. As a result, usual doses of a drug will result in low plasma concentrations. When total body water decreases as in volume depletion, the plasma concentration of a drug increases, but the V _d is decreased. Lipid-soluble drugs have a high V _d because the drug can penetrate the cell membrane and accumulate in adipose tissue. The increase in V _d causes low plasma concentration of the drug. Thus, an inverse relationship exists between V _d and plasma concentration. Certain drugs such as chloroquine bind to liver DNA or tetracyclines to bone. Patients on these or similar drugs have tissue concentrations several times higher than blood concentrations, and improper dosing may cause severe adverse reactions. Thus, option E is correct.

A 46-year-old woman with hepatitis C cirrhosis and ascites is on furosemide 80 mg/day and spironolactone 200 mg/day. Her serum albumin is 2.4 g/dL. Regarding volume of distribution ( V _d ) of furosemide, which one of the following choices is CORRECT?

Furosemide is highly albumin-bound (90–95 %). In a normal individual with serum albumin concentration of 4.2 g/dL, furosemide is bound to albumin, and <5–10 % of the drug is free. Therefore, the V _d of furosemide is about 3.4 L. In a hypoalbuminemic patient, the amount of free drug is extremely large, and therefore, the V _d is large or increased. Thus, choice B is correct, and other choices are inappropriate.

Many drugs are bound to albumin. Which one of the following statements regarding drug-albumin binding is CORRECT?

All of the statements are correct regarding the drug-albumin binding. Binding of a drug to albumin is mostly a reversible process that is dependent on the concentration of drug and albumin. Pharmacologically, the drug-albumin complex has three important implications. First, it is the free (unbound) drug that has a pharmacologic effect. Second, only the free drug that distributes into various tissues of the body, and can influence drug’s V _d , and finally, the bound fraction of the drug acts as a reservoir in the vascular compartment where dissociation of the drug-albumin complex provides free drug availability for further action and subsequently elimination from the body.

A 40-year-old obese woman is being treated with vancomycin for methycillin-resistant Staphylococcus aureus . She has an albumin concentration of 2.1 g/dL. Which one of the following statements regarding vancomycin in hypoalbuminemic obese patient is FALSE?

Obesity is associated with altered pharmacokinetic properties of several antibiotics, including vancomycin. Studies have shown that the V _d increases in obesity due to hydrophilic nature of vancomycin even in the presence of normal albumin levels. Thus, answer C is false. Clearance of vancomycin is increased in obesity. Also, binding of vancomycin to proteins is increased in obese patients, thus making less availability of unbound drug. Initial dose of vancomycin should be based on the total body weight to achieve adequate therapeutic levels, and subsequent dosages are dependent on trough levels. It has been shown that obese patients >100 kg in weight and those who receive >4 g/day are at increased risk for vancomycin-induced nephrotoxicity.

Regarding vancomycin adverse effects , which one of the following choices is CORRECT?

Vancomycin-induced nephrotoxicity has been well established with both the first- and second-generation preparations of the drug. The incidence of vancomycin-induced AKI may be related to several factors, including staphylococcal epidemic, health-care associated pneumonia, osteomyelitis due to prosthetic hard-wares, drug abuse, diabetes, etc., and the development of methicillin-resistant Staphylococcus aureus . On renal biopsy, acute tubulointerstitial nephritis is commonly demonstrated as a cause of AKI. Combination of vancomycin and aminoglycosides is more nephrotoxic than either drug alone.

Red man syndrome is an idiopathic infusion reaction of vancomycin. It is a hypersensitivity reaction characterized by flushing, erythema, and pruritus in the upper body, neck, and face. Hypotension, muscle spasm, and chest tightness may also occur.

Vancomycin-induced thrombocytopenia is rather rare, but several cases have been reported. Thrombocytopenia is due to the development of antiplatelet antibodies, and severe bleeding can occur. Thus, choice E is correct.

A 46-year-old man with cirrhosis due to hepatitis C and chronic kidney disease (CKD) stage 3b is admitted for fever, elevated white blood cell (WBC) count, and bacteremia. He was admitted with similar diagnosis 3 months ago, and was successfully treated with penicillin-related antibiotics. He is now started on high doses of penicillin products with improvement in fever and WBC count. While he is being planned for discharge, the nurse noticed seizure activity, which lasted for 3 min. What is the next appropriate step in the management of his seizure activity that is CORRECT?

In the above patient, reducing penicillin dosage to <6 g/day (option C) is appropriate. Other options are incorrect.

A 26-year-old woman with recurrent urinary tract infection is admitted for acute pyelonephritis. Urine culture shows E. coli, which is sensitive only to gentamicin. Her renal function is normal. After a loading dose, she is maintained on therapeutic doses of gentamicin. Ten days later, she develops hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalcemia with normal blood pressure. Which one of the following syndromes has been described with the use of gentamicin ?

Gentamicin and other aminoglycosides have been shown to induce a Bartter-like syndrome characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalcemia, normal serum creatinine levels, and normal blood pressure. Gentamicin, a polyvalent, cationic molecule, is thought to activate the extracellular calcium sensing receptor (CaSR) in the thick ascending limb of Henle’s loop. Thus, aminoglycoside treatment can lead to abnormalities that resemble those seen in patients with autosomal dominant hypocalcemia, which is caused by mutations in the CaSR gene. This condition is also termed type V Bartter syndrome (option B). Calcimimetic agents can improve this syndrome.

Although Gitelman syndrome has also the same biochemical characteristics as Bartter syndrome, it is differentiated from Bartter syndrome by hypocalciuria. Liddle and Gordon syndromes are characterized by hypertension. Thus, option B is correct.

A 60-year-old man with sepsis, requiring intubation, developed Candida albicans infection after a prolonged course of antibiotics. He is on amphotericin B. Which one of the following adverse effects of amphotericin B is CORRECT?

Amphotericin B disrupts cell membrane integrity, leading to leakage of cell contents. It causes electrolyte (hypokalemia and hypomagnesemia), acid–base (dRTA due to backleak of H ⁺ into the distal tubule cell), and tubular (NDI due to inhibition of vasopressin action) abnormalities. Thus, E is correct. Acute tubular necrosis is also common due to renal vasoconstriction and reduced renal blood flow. Adequate hydration of patient with normal saline may prevent acute kidney injury. Many of the electrolyte, acid–base, and tubular disorders may persist for a period of time even after amphotericin B is discontinued.

A patient is treated for vancomycin-resistant Enterococcus faecium with linezolid 600 mg twice a day. Which one of the following acid accumulation is MOST likely to occur with linezolid therapy ?

Many case reports have documented that patients treated with linezolid can develop severe high anion gap metabolic acidosis due to lactic acid production. Although it is unclear, mitochondrial toxicity has been suggested as the underlying mechanism for lactic acid production. Thus, option C is correct.

Food intake affects drug absorption. Which one of the following food and drug interactions is FALSE?

Except for option D, other options are correct. It is well established that food intake and phosphate binders reduce iron and tacrolimus absorption, whereas absorption of cinacalcet increases with food intake. High fat meal has been shown to increase sirolimus absorption.

In many clinical trials of chronic kidney disease (CKD) and hemodialysis ( HD) patients, the participation of a clinical pharmacist has some positive impact on which one of the following clinical measures:

Only a few trials addressing the benefit and impact of clinical pharmacy services in CKD and HD patients have been published. Most of these studies have reported that involvement of a clinical pharmacist has a positive effect on decreased hospital rates, improving Hgb levels in many CKD patients, improvement in overall quality of life in HD patients, and increased medication-related knowledge. Thus, choice E is correct. It is of interest to note that none of the studies reported a negative impact of pharmacists’ involvement on patient care.

A 36-year-old woman with medullary sponge kidney is admitted for urinary tract infection with E. coli which is sensitive to aminoglycosides only. Her eGFR is 49 mL/min. After a loading dose of gentamicin, which one of the following dose schedules minimizes nephrotoxicity ?

In patients with low GFR (<60 mL/min), once daily dose has been shown to minimize nephrotoxicity compared to other dosage schedules. In this patient with CKD 4, the appropriate dose is once daily. Thus, choice C is correct.

An 18-year-old woman with soft-tissue sarcoma is consulted for a persistent electrolyte abnormality and weakness. She is on ifosfamide. Which one of the following electrolyte abnormalities is the MOST likely cause of her weakness?

Ifosfamide is an alkylating agent used for treatment of soft-tissue sarcomas. It causes proximal renal tubular acidosis and Fanconi syndrome. Ifosfamide-induced hypokalemia is the most likely electrolyte abnormality, causing muscle weakness. Thus, option C is correct.

Which one of the following drugs is associated with renal tubular acidosis (pRTA) ?

All of the above drugs have been shown to cause pRTA with different mechanisms.

An HIV patient sees his primary care physician for management of disease. His eGFR is <60 mL/min. Which one of the following antiretroviral drug categories/agents needs dosage adjustment in patients with CKD 3-5?

Except for nucleoside and nucleotide reverse transcriptase inhibitors, other categories of antiretroviral drugs do not require dosage adjustment in CKD 3–5 patients.

A 42-year-old woman with CKD 4 complains of depression due to her kidney disease during routine follow-up. She is started on fluoxetine, one of the selective serotonin reuptake inhibitors (SSRIs) . Which one of the following adverse effects of SSRIs is expected to see in this patient?

SSRIs cause hyponatremia due to syndrome of inappropriate antidiuretic hormone (SIADH) and increased upper GI tract bleeding. The latter effect is frequently seen with concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs). The bleeding tendency is related to deficiency of platelet serotonin, resulting in decreased platelet aggregation.

Hypertension and SIADH are caused by serotonin-norepinephrine reuptake inhibitor such as duloxetine, whereas seizures are caused by norepinephrine-dopamine reuptake inhibitor (bupropion). It is advisable to avoid duloxetine in CKD patients with hypertension. Dosage reduction is needed for bupropion in patients with CKD 4–5.

Which one of the following vaptans is available as intravenous preparation ?

Of the above vaptans only conivaptan is available as an intravenous preparation. Only conivaptan and tolvaptan are available in the United States. Conivaptan is a combined V1 _a /V2 receptor antagonist. V1 _a receptors are present in hepatocytes and splanchnic circulation. Use of conivaptan in cirrhotic patient is expected to cause splanchnic vasodilation, and cause an increase in portal pressure. Thus, option C is correct.

Lithium is used widely to treat bipolar and depressive disorders. It has a narrow therapeutic and toxic range. Which one of the following lithium-induced nephrotoxicities is CORRECT?

Lithium is filtered at the glomerulus, and reabsorbed mostly in the proximal tubule. A fraction of lithium is reabsorbed in the distal nephron via ENaC. Lithium causes nephrogenic diabetes insipidus, resulting in urinary concentrating defect and polyuria as well as hypernatremia. Prerenal azotemia is not uncommon. Use of loop and thiazide diuretics and ACE-Is/ARBs and NSAIDs aggravate lithium toxicity. Hydration with normal saline initially improves blood pressure, volume status, and azotemia. Subsequent fluid administration depends on serum [Na ⁺ ]. Amiloride treatment blocks ENaC uptake of lithium with improvement in polyuria and urinary concentrating ability. Dialysis is indicted to improve lithium toxicity. Thus, option E is correct.

A 55-year-old man with multiple myeloma is admitted for paraparesis. An MRI of the spinal cord is normal. Neurologic exam shows muscle weakness of the lower limbs with tendinous areflexia and absence of pyramidal syndrome. His medications at the time of admission include dexamethasone 4 mg Q6H and thalidomide 200 mg/day. Blood pressure and pulse rate are normal. Except for serum K⁺ of 8.4 mEq/L, the other laboratory tests are normal. What is the MOST likely cause of this hyperkalemia and sudden paraparesis?

Thalidomide is being used by some investigators as the first-line treatment of multiple myeloma. In both dialysis and CKD patients, thalidomide has been shown to cause severe hyperkalemia, which may be related to either cell lysis or cellular shift. Thus, option C is correct. Both steroid use and remission of multiple myeloma are unlikely causes of hyperkalemia. Also, pseudohyperkalemia has not been reported with thalidomide. Severe volume depletion may cause hyperkalemia by limiting delivery of glomerular filtrate to the distal nephron, but this patient does not have either renal insufficiency or volume depletion.

A 32-year-old woman with tubulointerstitial disease has serum [K⁺] of 5.1 mEq/L without any EKG changes. She is on K⁺ diet. Which one of the following is NOT associated with exacerbation of her serum [K ⁺ ]?

Except for licorice (causes hypokalemia), all other medications inhibit ENaC, and cause hyperkalemia. Nafamostat is a serine protease inhibitor that is used in acute pancreatitis and disseminated intravascular coagulation.

A 46-year-old Indian woman with type 2 diabetes for 12 years is found to have a serum [K⁺] of 5.8 mEq/L, [HCO₃ ⁻] 24 mEq/L, and glucose 100 mg/dL on a follow-up visit. One month ago her serum [K⁺] was 4.2 mEq/L. Her eGFR is 48 mL/min, which is stable for the last 1 year. She is on glipizide (5 mg/day) and sitagliptin (50 mg/day). She denies taking any dietary supplements or NSAIDs. The only complaint is fatigue. Which one of the following is NOT a cause of her hyperkalemia ?

Except for oral hypoglycemic agents, all other food supplements cause hyperkalemia. Noni juice contains 56 mEq/L and raw coconut juice 44.3 mEq/L of K ⁺ . COX-2 inhibitors cause hypoaldosteronism, whereas alfalfa is rich in K ⁺ . Thus, option D is correct.

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