3. BASIC PRINCIPLES
The kidneys play an important role in the disposition of many drugs
It is important to design specific pharmacotherapeutic regimens for patients with renal impairment
Numerous other factors associated with kidney disease predispose patients to potential drug
toxicity by altering the pharmacokinetic? disposition and the pharmacodynamics? effects of drugs
Refers to what the body does to a drug
Describes what the drug does to the body
Absorption
Distribution
Metabolism
Elimination
Uremia affect drug efficacy and toxicity
4. Effect of Renal Failure on Drug Disposition
BIOAVAILABILITY The rate and extent to which an administered drug reaches the systemic circulation
limited data are available describing altered bioavailability
Several factors can potentially affect drug absorption in patients with kidney disease
Could be impaired in uremia by nausea, vomiting, diarrhea, gastritis, and edema of the gastrointestinal tract
Neuropathy Affect Gastric and intestinal motility, as well as gastric emptying time
Increase gastric ammonia increased gastric pH, which may affect the bioavailability of drugs that require
an acidic environment for absorption
such as ferrous sulfate
5. Effect of Renal Failure on Drug Disposition
BIOAVAILABILITY The rate and extent to which an administered drug reaches the systemic circulation
limited data are available describing altered bioavailability
Several factors can potentially affect drug absorption in patients with kidney disease
Patients with end-stage renal disease (ESRD)
Use oral phosphate binders, such as sevelamer and lanthanum carbonate
Use calcium-containing antacids Neutralize hydrochloric acid in the stomach and increase gastric pH
Impair the absorption of other medications
6. Effect of Renal Failure on Drug Disposition
PROTEIN BINDING
The extent to which a drug exerts its pharmacologic effects is related to the amount of free or unbound drug
Renal failure often have alterations in plasma protein binding increase the amount of unbound drug
Most important for highly protein-bound acidic drugs (>80%)
Basic drugs ?
Increase in the free fraction, the total drug concentration necessary to exert the
desired pharmacologic effect is lower than that needed under normal conditions
Need dose modification
7. Effect of Renal Failure on Drug Disposition
PROTEIN BINDING
Hypoalbuminemia a common complication of renal failure
Acidic rather than basic drugs are bound to albumin, their protein binding tends to be altered
Patients with uremia accumulate acidic by-products inhibit binding or displace acidic drugs from albumin
binding sites
structural conformation of albumin is altered in renal disease
reduce the number or affinity of binding sites for drugs
Increase the amount of unbound drug
9. Effect of Renal Failure on Drug Disposition
VOLUME OF DISTRIBUTION (Vd)
The “volume” or size of a compartment necessary to account for then total amount of drug in the body
if it were present throughout the body at the same concentration as that found in plasma
Decrease in the plasma protein binding of highly protein-bound drugs, such as phenytoin, leads to
an increase in the apparent Vd
Digoxin
Is a unique exception in that its vd is decreased in renal disease
This is attributed to a decrease in myocardial tissue uptake of digoxin
decrease in the myocardial or tissue to serum concentration ratio
10. Effect of Renal Failure on Drug Disposition
ELIMINATION
Depends on the amount of drug normally excreted unchanged in the urine and the degree of renal impairment
As kidney disease progresses, the kidney’s ability to excrete uremic toxins diminishes
The ability to eliminate certain drugs that are renally excreted also decreases
No modification of dose
?
Accumulate, potentially leading to an increase in the pharmacologic effect and toxicity
11. Effect of Renal Failure on Drug Disposition
ELIMINATION
The kidney eliminates drugs primarily by filtration or active secretion
Characteristics of a drug that determine its ability to be filtered
Molecular weight (MW) Affinity for protein binding
low protein binding or displaced from proteins in the
setting of renal disease are filtered more readily
Molecules with a high MW are not readily filtered
because of their large size
12. Effect of Renal Failure on Drug Disposition
ELIMINATION
Organic anion transporters (OATs) facilitate the uptake of small organic
anions into renal tubular cells
Decreased OAT activity
Decrease the renal secretion of various drugs
methotrexate, nonsteroidal antiinflammatory drugs,
and acetylsalicylic acid
Measuring creatinine clearance (CrCl) can estimate the
ability of the injured kidney to eliminate drugs
13. Effect of Renal Failure on Drug Disposition
ELIMINATION
Metabolic enzymes have been found within renal tissue, and may play a role in the metabolism of some drugs
The nonrenal clearance of drugs (e.G., Acyclovir) decreases in patients with renal impairment
believed to be caused by a decrease in “renal” metabolism
Excipients used to formulate medications should be considered ?
14. Pharmacodynamics and Renal Disease
Clinical observations report that patients with renal disease are more sensitive to various drugs
Morphine
Associated with increased neurologic depression in patients with renal failure
Potentiate the CNS-depressant effects of uremia
Alteration in the permeability of the blood–brain barrier
Higher CNS levels of morphine and morphine-6-glucuronide
?
15. Pharmacodynamics and Renal Disease
Nifedipine
Which at similar unbound plasma concentrations has an increased antihypertensive effect in patients with renal disease ?
The dose of nifedipine may need to be adjusted in patients with renal disease because of changes in drug effects
rather than pharmacokinetic alterations
Warfarin not significantly altered in renal failure
Patients with renal failure who are prescribed warfarin have a higher incidence of hemorrhagic complications
Platelet dysfunction from uremia
Drug–drug interactions from concomitant medications
16. Summary
The pharmacokinetic the pharmacodynamics are altered in renal failure
Modification of dose is crucial in sitting of renal failure
Creatinine clearance can estimate the ability of the injured kidney to eliminate drug
The nonrenal clearance of drugs (e.G., Acyclovir) decreases in renal impairment
Many patients are treated with multiple medications, which may require even greater
attention to dosage adjustment
18. Reference
Caroline S Zeind & Michael G Carvalho (2017) Applied Therapeutics (Koda Kimble and Youngs
Applied Therapeutics), 11th edn., US: LWW.
Karen Whalen (2018) Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series),
7th edn., US: Wolters Kluwer Health.
Editor's Notes
Four pharmacokinetic properties determine the onset, intensity, and duration of drug action
calcium-containing antacids used by patients with renal failure for GI symptoms and hyperphosphatemia
improvement in protein binding after removal of uremic by-products by hemodialysis.
Drugs that are not highly protein bound (e.g., gentamicin, isoniazid) have little
change in their Vd in renal disease.
MW (>20,000 Da)
Organic anion transporters (OATs) are predominantly found in the basolateral membrane of the renal tubules. OATs facilitate the uptake of small organic anions into renal tubular cells
