Factors Affecting Renal Excretion of Drugs

Factors affecting drug excretion are:

1. Physicochemical Properties of Drugs: Various factors affect the physicochemical properties of drugs:
   i) Molecular Weight (MW): The excretion of drugs with large molecular weights is difficult, compared to that of drugs with smaller molecular weights. This is especially seen in case of glomerular filtration.
   ii) Lipid Solubility: The solubility of a drug in lipids is inversely proportional to its urinary excretion. For example, if A drug  is more soluble in lipids compared to drug B, then drug A will show increased volume of distribution and a decreased renal excretion as compared to that exhibited by drug B (increased lipid solubility of a drug increases its volume of distribution and decreases renal excretion).
   iii) Volume of Distribution: The volume of distribution of drugs (V_d)  is inversely proportional to their clearance. A drug that possesses a V_d large  shows poor excretion in urine, while drugs possessing a smaller V_d (restricted to blood) show sufficient excretion (higher rate of excretion).
2. Renal Blood Flow: Drugs that show increased perfusion falso show an increase in their excretion; this is especially significant for drugs that undergo excretion by glomerular filtration.
3. Binding Characteristics of Drugs: Drugs that are bounded to plasma proteins act as macromolecules, and their filtration by the glomerulus is not possible. Glomerular filtrate contains only those drugs that are unbound or free. Drugs that are protein-bound possess extended half-lives.
4. Drug Renal Clearance: It is the rate at which a drug is excreted by the kidney into urine comparative to the plasma drug concentration. Adequate renal function determines the renal clearance of several drugs and their metabolites.

In cases of impaired renal clearance,  t_½ of a drug may increase and the body may show the presence of toxic levels of the drug. Renal clearance is significant particularly for certain drugs which are:

i) Excreted mainly by the kidneys, and
ii) Possess limited therapeutic index (e.g. lithium, digoxin, and warfarin).
Diseases decrease renal clearance in the following two patterns:
i) Diseases that Decrease Renal Blood Flow: For example, congestive heart failure, haemorrhage, and cardiogenic shock.
ii) Diseases that Decrease Renal Excretion: For example, renal disease (e.g., glomerulonephritis) that may increase the half-life (t _½ ) of drugs.

1. Plasma Drug Concentration: Glomerular filtration and renal reabsorption are affected by the concentration of drug in plasma. If the drug is not protein bound, its glomerular filtration is directly proportional to its plasma concentration. In drugs showing renal reabsorption, excretion occurs only when concentration in glomerular filtrate is higher than reabsorption capacity.
2. Urine pH: For weakly acidic (pKa 3-7) or weakly basic (pKa 6-12) drugs, the degree of ionisation in tubular fluid depends on pH , for example:
   i) Methamphetamine (Weak Base, pKa 10): Renal excretion is 4 times faster in acidic urine than in alkaline urine because at lower pH , the ionisation is lower, reabsorption is less, and excretion of methamphetamine is more.
   ii) Phenobarbital (Weak Acid, pKa 7.4): Renal excretion is 7 times faster in alkaline urine. However, renal clearance is only a small fraction of total clearance.
   iii) Salicylic Acid (Weak Acid, pKa 3.5): This acid is mainly ionised at physiological pH. At pH 5.0, the amount of non-ionised form is 25 times of that present at pH 7.4 . In over dosage of aspirin, systemic alkali and tubular acidosis occurs that enhances tubular reabsorption and prolongs half-life of elimination. This can be reversed by giving systemic alkali and fluids and producing an alkaline urine with high flow rate.
3. Biological Factors: Various biological factors, like age sex and species, inffuence the drug excretion. Circadian rhythm also plays an important role. Females show 10%  lower renal excretion than males; in neonates, renal function is only 60-70% in comparison to adults; in elderly, renal function and hence renal excretion is reduced.
4. Pregnancy: The volume and composition of body fluids undergo significant changes in pregnant women. The plasma volume, the red cell mass, and the albumin mass increases. The plasma volume shows greatest increase (up to 40% ), and the hematocrit and plasma albumin concentration also increase. Total body volume also increases between 6-8 lines. Pregnancy significantly increases renal blood flow and GFR in very early pregnancy. GFR increases up to 50%  by the end of first trimester. Hence, plasma concentration of components handled by filtration falls; e.g., normal serum creatinine in pregnancy is about 40-50mmol/l.
5. Drug Interactions: Drug excretion is influenced by many drug interactions and involve the following effects:
   i) Forced diuresis,
   ii) Alteration in urine pH ,
   iii) Alteration in intrinsic clearance,
   iv) Alteration in renal blood flow,
   v) Alteration in binding characteristics, and
   vi) Alteration in active secretion.

If the drug is highly protein bound and if any other drug displaces it, excretion of such highly protein bound drug increases. For example, furosemide enhances the excretion of gentamicin by displacing it from its protein binding sites; the excretion of basic drugs is enhanced by the acidification of urine, (e.g., by drugs like ammonium chloride) and the excretion of acidic drugs is enhanced by the alkalinisation of urine (e.g., by drugs like bicarbonates).

Disease States: Renal excretion is an important route of excretion, and hence the excretion of drugs will be affected by renal impairment or renal dysfunction. Renal impairment can be caused by hypertension, diabetes, nephrotoxicity (by aminoglycosides, lead, or mercury), polynephritis (inflammation of kidneys), and hypovolemia.

ulimia For example, in uremia associated with decreased glomerular filtration and accumulation of fluids, renal excretion of drugs is reduced. Thus, half-life of the drug increases, thereby increasing its accumulation in body.