Introduction:
Kidneys are a pair of bean-shaped organs located in the retroperitoneal area on either side of the body. Each kidney measures about four to five inches in size. The main function of the kidney is to filter blood. It is estimated that the whole blood in the body passes through the kidneys about forty times a day to get filtered. Other functions include maintaining the water-electrolyte balance and acid-base balance in the body. Once the blood reaches the kidney, along with filtration of the wastes, the salt, water, and electrolyte levels are adjusted, after which the blood re-enters circulation. The drugs and the medications that are taken for various reasons will alter kidney function.
How Is the Drug Dose Related to Its Clinical Effect?
Any drug administered goes through the following mechanism; initially, it gets absorbed by the body, which is then distributed in the blood, undergoes metabolism, reaches the kidneys, gets filtered, and the rest is excreted in the urine.
Based on the dosing interval, the concentration of the drug in the blood varies. The drug will be effective till its half-life and lose its action after that period. Hence, the half-life period of the drug is important for the duration of the effectiveness of the drug.
What Are the Determinants of the Dose and Concentration of the Drug in the Blood?
The factors that determine the dose and concentration of the drug are as follows:
1. Rate of Absorption: It is the pharmacokinetic property of the drug that denotes the way the drug is absorbed from the bloodstream into circulation. It is an important parameter as it determines the time and magnitude at which the drug reaches its peak concentration in the blood. The factors that influence drug absorption include:
-
Diseases That Cause Delayed Drug Emptying - The rate of absorption of the drug is determined by the rapidity with which the stomach empties the drug.
-
Physicochemical Properties of the Drug - The pharmacological effect of the drug depends on the physical and chemical properties of the other chemical agent that it interacts with in the gastrointestinal tract.
-
Intestinal Motility - Increased intestinal motility will accelerate the rate of drug absorption. But in the case of slowly absorbed drugs like Digoxin, increased intestinal motility would result in poor absorption.
-
Renal Dysfunction - Studies report that renal dysfunction affects the rate of drug absorption by the intestine and intestinal motility.
2. Rate of Distribution: The rate of distribution of the drug is an important factor, as it determines the amount of drug available in the blood to elicit the drug's effect. The factors that influence drug distribution include:
-
Systemic pH - An increase in the systemic pH would decrease the solubility of the drug.
-
Disease States - This may decrease the binding of the drug to the plasma proteins such as albumin and alpha-1 acid glycoprotein.
-
Protein Binding - It is the amount of drug that binds with the plasma proteins present in the blood.
-
Renal Dysfunction - Studies report that renal dysfunction affects drug distribution by inducing and altering the systemic pH.
3. Elimination: The drug is eliminated from the body by three mechanisms: metabolism, excretion, or dialysis.
-
Metabolism- It mainly takes place in the liver and the proximal convoluted tubules of the kidney.
-
Excretion - This is mainly through the bile juices, and a few drugs like anesthetic gases and paraldehyde are eliminated through the lungs.
-
Dialysis - This is a special mode of drug excretion; the water-soluble drugs of low molecular weight will be eliminated by this process.
How Does Renal Dysfunction Affect the Pharmacological Properties of the Drug?
The normal functioning of the kidneys is essential for the effectiveness of the drugs, as renal dysfunction has an impact on all the pharmacokinetic properties of the drug, such as absorption, distribution, and elimination.
Renal Dysfunction and Drug Absorption: Absorption is the first and prime step for the drug to reach blood circulation. In the case of renal dysfunction, the normal absorption of the drug is affected. It is because, in patients with renal failure, there will be decreased mesenteric blood flow. Mesenteric arteries are the main blood vessels that carry blood and oxygen to the intestine. As the intestines are responsible for drug absorption, the decreased mesenteric blood flow would decrease the absorption of the drug in the intestine.
Renal Dysfunction and Drug Distribution: The main component of the serum that helps in drug distribution is the plasma proteins. Once the drug is absorbed into the circulation, it binds with the plasma proteins, namely, albumin, beta-globulin, and acid glycoprotein. In renal diseases, the degree of drug binding to the plasma protein is decreased due to uremia (increased uric acid level in the blood) and hypoalbuminemia (decreased serum albumin), thereby affecting the half-life of the administered drug.
Renal dysfunction would result in systemic acidosis as a result of uremia or renal tubular acidosis, thereby altering the systemic pH. In this condition, the binding of drugs to the plasma protein is not affected, but the distribution of the drug to the target tissue is considerably reduced.
Renal Dysfunction and Drug Elimination: Eliminating the drugs from circulation is one of the key roles of the kidneys, as their main function is filtration. In patients with renal diseases, this process is affected due to the poorly functioning glomeruli and the number of nephrons (functional unit of the kidney), resulting in poor elimination of the drugs. As a consequence of this, the drug gets deposited in the kidneys leading to drug toxicity.
Can Changes Occur in the Properties of Drugs Due to Kidney Problems or Kidney Failure?
The drugs that show changes in their normal pharmacological behavior are as follows:
-
Propranolol is normally eliminated by the metabolic transformation in the liver and excreted in the urine. In patients with renal failure, the hepatic elimination of Propranolol is decreased, thereby increasing the bioavailability of the drug.
-
Drugs such as Cloxacillin, Chlorpropamide, and Pindolol show decreased intestinal absorption in patients with renal failure.
-
In patients with renal tubular acidosis and renal failure, there is decreased calcium absorption in the intestine due to the inadequate hydroxylation of vitamin D3.
-
Drugs such as Warfarin, Phenytoin, Salicylates, Tthiopentone, and Diazoxide, show distribution-related changes in patients with renal failure. As in such patients, the degree of plasma protein binding is poor, causing the decreased distribution of drugs in the blood and to the target tissues.
-
Hypoalbuminemia caused due to renal failure can affect the binding of drugs, such as Warfarin and Phenytoin, thereby increasing the amount of free drugs in plasma.
-
An antiarrhythmic agent such as Procainamide is usually eliminated by the kidneys. In patients with renal failure, Procainamide settles in the kidney causing toxicity.
-
Pain-relieving medication such as Pethidine, usually eliminated by the kidneys, can accumulate in the kidney due to its poor elimination capacity resulting in seizures.
-
Drugs such as Iodipamide, Probenecid, and high-dose salicylates induce uricosuria (excretion of uric acid in the urine) in patients with renal dysfunction by decreasing the reabsorption of uric acid by the kidneys.
Conclusion:
Renal dysfunction can affect the pharmacological property of the drug by affecting its rate of absorption, distribution, and excretion. Proper knowledge about the changes in the drug properties in patients with renal dysfunction would help alter the drug dosage accordingly and decrease the advent of complications and drug toxicity.