Drug Excretion PDF

Drug Excretion  Elimination It is the irreversible loss of drug from the systemic circulation by metabolism and/or excretion Elimination of drugs occur by one or both of: Metabolism Excretion. It is the process of a...

Drug Excretion  Elimination It is the irreversible loss of drug from the systemic circulation by metabolism and/or excretion Elimination of drugs occur by one or both of: Metabolism Excretion. It is the process of a It is irreversible loss of conversion of one the unchanged form of chemical species to the drug in urine, bile, another chemical feces, and other body species fluids.  Elimination Rate Renal excretion and metabolism mainly are first-order processes for over 90% of all drugs Elimination that is not first order results in nonlinear pharmacokinetics Elimination Rate Is the mount of drug eliminated in a unit time. According to First-Order Elimination 1. (–dX/dt): rate of decrease of drug in the body over time 2. K: First order elimination rate constant 3. X: mass (amount) of drug in the body at time t Elimination rate of drug at any time dependent on elimination rate constant the amount of drug in the body  Elimination Rate t1/2: Elimination half life is the time interval required to eliminate 50% of the amount of drug present in the body at the beginning of the interval.  Elimination Rate Elimination Rate = Metabolism Rate + Excretion Rate (– dX/dt) = K X = Km X + Kr X 1. (–dX/dt): rate of decrease of drug in the blood over time 2. X: mass (amount) of drug in the blood at time t 3. K: First order elimination rate constant 4. Kr: First order excretion rate constants 5. Km: First order metabolic rate constants K = Kr + Km  Clearance definitions 1. Clearance is fundamental (independent) pharmacokinetic parameter for elimination. 2. It is a proportionality constant describing the relationship between the rate of elimination and the plasma concentration 3. Clearance is expressed in terms of the volume of plasma containing drug that is eliminated per unit time. 4. The hypothetical volume of blood (plasma or serum) or other biological fluids from which the drug is totally and irreversibly removed per unit time The units for clearance are (mL/min) but most often (L/h).  Clearance is the most useful pharmacokinetic parameter available for the evaluation of the elimination mechanism and of the eliminating organs (kidney and liver). The larger the clearance, the more efficient is the eliminating organ (kidney and liver). Renal clearance (Clr). The clearance of drug (a fraction of total clearance) for a drug that is removed from the blood (plasma/serum) by the process of renal excretion. Metabolic clearance (Clm). The clearance of drug (a fraction of total clearance) for a drug that is removed from the blood (plasma/serum) by the process of metabolism, from whatever metabolic organ. Hepatic clearance (ClH). The clearance of drug (a fraction of total clearance) for a drug that is removed from the blood (plasma/serum) by the process of hepatic metabolism; the liver is the organ responsible for most metabolism of drugs. Systemic clearance (Cls) or total body clearance (TBC). This is the sum of all individual organ clearances that contribute to the overall elimination of drugs. Hence, systemic clearance is often partitioned into renal (Clr) and non-renal (Clnr) clearance (often equated with hepatic clearance,Ch). Cls = Clnr + Clr  Equation for systemic clearance Cl = K V when various physiological factors change, clearance and volume of distribution may vary independently of each other (clearance will not change if distribution changes and volume of distribution will not change if clearance changes). K is more correctly viewed as being dependent upon the values of Cl and V. A small clearance and a large volume of distribution will promote …… elimination and a ….. half-life. a) rapid / long b) rapid / short c) slow / long d) slow / short Another equation for systemic clearance is for intravenous bolus administration As the plasma drug concentration decreases during elimination, the rate of drug elimination, –dX/dt, will decrease accordingly, but clearance will remain constant. Clearance will be constant as long as the rate of drug elimination is a first-order process (Clearance remains independent of the dose administered).  Elimination Two principal organs responsible for drug elimination are the Kidney it is the primary site for removal of a drug in a chemically unaltered or unchanged form (i.e., excretion) as well as for metabolites. liver. It is the primary organ where drug metabolism occurs. Excretion by organs other than kidneys such as lungs, salivary glands and sweat glands is known as nonrenal excretion.  Kidney Urinary excretion is also called “Renal excretion”, because kidneys is the organ responsible for excretion of drugs and molecules in urine. The kidney is the main excretory organ for the removal of metabolic waste products and plays a major role in maintaining the normal fluid volume and electrolyte composition in the body. To maintain salt and water balance, the kidney excretes excess electrolytes, water, and waste products while conserving solutes necessary for proper body function The kidney consists of functional units called nephrons  Nephron anatomy & physiology Bowman’s capsule (Glomerulus) Distal tube Proximal tube Henle’s loop urine Nephron anatomy & physiology Bowman’s capsule (Glomerulus) Water, ions, and small molecules are filtered out of the blood to the tubular lumen Glomerular filtration urine Nephron anatomy & physiology Proximal tube Acidic and Basic molecules are transferred from blood to tubular lumen by non-selective transporters Active tubular secretion urine Nephron anatomy & physiology The longer loops of Henle allow for a greater ability of the nephron to reabsorb water, thereby producing more concentrated urine. Henle’s loop urine  Nephron anatomy & physiology Distal tube Lipid soluble, non-polar, small molecules are reabsorbed from tubular lumen to blood by passive diffusion Passive tubular reabsorption urine  Renal Excretion Processes The kidney consists of functional units called nephrons, in which the following physiological renal excretion processes take place: 1. Glomerular filtration 2. Active tubular secretion 3. Passive tubular reabsorption  Renal Excretion Processes 1) Glomerular filtration: The kidneys receive approximately 25% of the cardiac output, or 1.2–1.5 L of blood per minute. Approximately 10% of this volume (i.e., 120–150 mL) is removed every minute as it passes through the glomeruli of the kidneys. the rate being called as the glomerular filtration rate (GFR). In the glomerulus, the blood is subjected to hydrostatic pressure, which forces plasma water and small solutes, including most drugs, through the capillary membrane and into the renal tubule.  Renal Excretion Processes 1) Glomerular filtration: Glomerular filtration is a unidirectional process by which small molecules including undissociated (nonionized) and dissociated (ionized) drugs are readily filtered from the blood through the glomerulus of the nephron. large size components can not be filtered through the glomerular membrane, which implies that blood cells, plasma proteins and plasma protein- bound drugs can not cross into the tubular filtrate  Renal Excretion Processes 1) Glomerular filtration: Glomerular filtration rate (GFR) is measured by renal clearance of a drug that is eliminated primarily by filtration only (ie, the drug is neither reabsorbed nor secreted) Therefore, the renal clearance of inulin or creatinine is a measure of the glomerular filtration rate (GFR). The clearance of inulin will be equal to the GFR, which is equal to 120 ml/min. If a drug does not bind to plasma proteins and it is small enough to be filtered in the glomerulus, its clearance by only glomerular filtration is equal to the GFR ClGF = GFR ClGF : is clearance by glomerular filtration.  Renal Excretion Processes 1) Glomerular filtration: if a drug is bound completely (100%), its clearance by glomerular filtration will be zero. If, on the other hand, a drug is 70% bound to the plasma proteins (fu = 0.3), only 30% of the drug in the plasma will be filtered and ClGF = fu. GFR = 0.3 x 120 = 36 ml/ min  Renal Excretion Processes 1) Glomerular filtration: Glomerular filtration of drugs is directly related to the free or nonprotein-bound drug concentration in the plasma. As the free drug concentration in the plasma increases, the glomerular filtration for the drug increases proportionately, thus increasing renal drug clearance for some drugs.  Renal Excretion Processes 2) Active tubular secretion: It is an active transport process. as such, active renal secretion is a carrier mediated system that requires energy input, because the drug is transported against a concentration gradient from the blood capillaries across the tubular membrane to the tubule (proximal tubule) The carrier system is capacity limited and may be saturated.  Renal Excretion Processes 2) Active tubular secretion: There are two active processes, with low degree of specificity for tubular secretion 1. Organic anion transporter : it transports organic acids e.g. Penicillins 2. Organic cation transporter : it transports organic bases e.g. Morphine Active secretion is unaffected by change in pH or protein binding since the bound drug rapidly dissociates the moment the unbound drug gets excreted  Renal Excretion Processes 2) Active tubular secretion: Protein binding influences the elimination of a half-life of the drug that is excreted solely by glomerular filtration. In contrast, protein binding has very little effect on elimination of a half-life of a drug excreted mostly by active secretion, because there is a rapid transport of the unbound drug (free drug) and rapid dissociation of the drug-protein complex. For example, dicloxacillin, although extensively bound to the plasma protein and not subject to hepatic metabolism, is rapidly eliminated by active secretion.  Renal Excretion Processes 3) Tubular re-absorption: As the filtrate moves through the proximal tubule and the loop of Henle, water is reabsorbed back into the systemic circulation. When the filtrate reaches the distal tubule, about 80% of the filtered water has been reabsorbed. (only about 1–2 mL of the 125 mL of the filtrate reaches the bladder) a) As a result, the concentration of drugs in the filtrate becomes higher than that in the blood in the surrounding capillaries, and drugs diffuse along their concentration gradient back into the systemic circulation.  Renal Excretion Processes 3) Tubular re-absorption: Lipophilic drugs will readily pass through the tubular membrane and be reabsorbed back into the circulation. polar drugs e.g. gentamicin and digoxin, are unable to do this. Such drugs will therefore be excreted unchanged in the urine. This highlights the importance of hepatic metabolism in producing more polar, less lipophilic molecules that are much less susceptible to tubular reabsorption.  Renal Excretion Processes 3) Tubular re-absorption: Tubular re-absorption may be active or passive process: 1) Active Tubular Reabsorption: It is commonly seen with endogenous substances or nutrients that the body needs to conserve e.g. electrolytes, glucose, vitamins. 2) Passive Tubular Reabsorption: (done in the distal tubule) It is common for exogenous substances including drug Lipid-soluble drugs are reabsorbed from the lumen.  Renal Excretion Processes 3) Tubular re-absorption: If a drug is completely reabsorbed, then the value for the clearance of the drug is approximately zero. For drugs that are partially reabsorbed without being secreted, clearance values are less than the GFR of 120 mL/min. Reabsorption results in increase in the half life of the drug  Renal Excretion Processes The appearance of drug in the urine is the net result of filtration, secretion, and reabsorption processes. If a drug is only filtered and all the filtered drug is excreted into the urine, then Rate of renal excretion = Rate of filtration  Renal Clearance The appearance of drug in the urine is the net result of filtration, secretion, and reabsorption processes.  Renal Clearance Example1:. Although it is not possible to know exactly how much tubular secretion and/or reabsorption occurs, it is clear that tubular reabsorption must exceed any tubular secretion by 70 mL/min.  Renal Clearance Example2: 300 = 120*80\ 100 + CLs - reabsorprption 204=CLs - reabsorption Calculating renal clearance (Clr) 1. Ku is the urinary excretion rate constant (h-1) 2. V is the apparent volume of distribution 1. (Xu)∞ is the mass or amount (e.g., mg) of drug excreted (unchanged form only) in urine at t = ∞ and 2. (AUC)0 ∞ here is the area under the plasma concentration versus time curve (mg L-1 h) from t = 0 to t = ∞  Factors affecting renal clearance 1) Kidney perfusion 1) The kidneys receive a large blood supply (approximately 25% of the cardiac output) 2) Increasing blood flow to the kidneys increases renal clearance. 3) The renal blood flow is important in case of drugs excreted by glomerular filtration only and those that are actively secreted. In the latter case, increased perfusion increases the contact of drug with the secretory sites and enhances their elimination.  Factors affecting renal clearance 1) Kidney perfusion 4) Kidney perfusion is affected by: A. Age: blood flow is lower in neonates and in elderly humans than in adults. B. Diseases: kidney diseases, cardiac diseases, and impair blood flow to the kidney. In neonates, elderly, kidney, and cardiac diseases, renal clearance is slower than in healthy adults.  Factors affecting renal clearance 2) Renal activity Factors affecting renal activity affect renal clearance. In newborns, elderly, and kidney disease patients, renal activity is lower than that in healthy adults; thus renal clearance is expected to be slower in these populations. 3) Drug molecular size Decreasing molecular size increases renal clearance because only small molecules (< 500) are filtered by the glomerulus.  Factors affecting renal clearance 4) Protein binding Drugs that are highly bound to plasma protein have slow renal clearance because only free (unbound) drug is filtered by the glomerulus. Active tubular secretion operates efficiently for some protein bound drugs (e.g. penicillin) and inefficiently for other protein bound drugs. 5) Drug competitive inhibition Some drugs (e.g. probencid) retard the tubular secretion of other drugs (e.g. penicillin) by competition on the proximal tube transporters; thus decrease their renal clearance.  Factors affecting renal clearance 6) Urine pH (ionization) Urine pH ranges between 4.5 and 8. Urine pH affects renal clearance through alteration of tubular reabsorption of weak acidic and weak basic drugs. For weak electrolyte drugs, urine pH affect the ratio of non-ionized and ionized drug When urine is acidic, weak acids tend to be reabsorbed because it exists in unionized form that is lipid soluble; thus can cross the tubular membrane by passive diffusion. When urine is alkaline, weak bases tend to be reabsorbed because it exists in unionized form that is lipid soluble; thus can cross the tubular membrane by passive diffusion.  Factors affecting renal clearance 6) Urine pH (ionization) Overdosing with weak acids (e.g. phenobarbital, aspirin) is treated with sodium bicarbonate injection (sodium bicarbonate increases urine pH; thus promotes ionization of weak acids and prevent their reabsorption). Overdosing with weak bases (e.g. codeine, amphetamine) is treated with ammonium chloride injection (ammonium chloride decreases urine pH; thus promotes ionization of weak bases and prevent their reabsorption).  Factors affecting renal clearance 7) Drug lipid solubility Drugs that are lipid soluble have slow renal clearance because it is readily reabsorbed in the distal tubes by passive diffusion. 8) Solute concentration in urine Fluid intake decreases the concentration of the drug in the filtrate, thus reduces tubular reabsorption rate and increases renal clearance.  Hemodialysis 1) Hemodialysis or 'artificial kidney' therapy is used in renal failure to remove toxic waste material normally removed by the kidneys, from the patient's blood. 2) In the procedure blood is diverted externally and allowed to flow across a semi-permeable membrane that is bathed with an aqueous isotonic solution. 3) Small molecules including nitrogenous waste products and some drugs will diffuse from the blood, thus these compounds will be eliminated.  Hemodialysis This technique is particularly important with drugs which: a) are smaller (< 500) molecular weight b) are not tightly bound to plasma protein c) have a small apparent volume of distribution. d) have good water solubility Conversely drugs which are tightly bound or extensively stored or distributed into tissues are only poorly removed by this route, or process. Creatinine clearance is to be determined in a 55-year-old 65-kg female patient. Her urine was collected over a 24-h period, and the urinary concentration of creatinine was determined. The patient’s serum concentration of creatinine was measured at the beginning of the study. The data are as follows: Collection period: 0–24 h Volume of urine collected: 1050 mL Urinary creatinine concentration: 1.14 mg/mL Serum creatinine concentration: 1.0 mg/dL Determine creatinine’s clearance rate.