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Class excretion of drugs

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Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.

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Excretion is a process whereby drugs are transferred from the
internal to the external environment
Excretion, along with m...

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Kidney is the primary organ of removal for most drugs
especially for those that are water soluble and not
volatile.
The th...

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Class excretion of drugs

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Class excretion of drugs

  1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.
  2. 2. Excretion is a process whereby drugs are transferred from the internal to the external environment Excretion, along with metabolism and tissue redistribution, is important in determining both the duration of drug action and the rate of drug elimination. Principal organs involved Kidneys, Lungs, Biliary system, Intestines Saliva and Milk. EXCRETION OF DRUGS
  3. 3. Kidney is the primary organ of removal for most drugs especially for those that are water soluble and not volatile. The three principal processes that determine the urinary excretion of a drug glomerular filtration, tubular secretion, and tubular reabsorption (mostly passive back-diffusion)
  4. 4. The ultrastructure of the glomerular capillary wall is such that it permits a high degree of fluid filtration while restricting the passage of compounds having relatively large molecular weights. This selective filtration is important in that it prevents the filtration of plasma proteins (e.g., albumin) that are important for maintaining an osmotic gradient in the vasculature and thus plasma volume. Several factors, including molecular size, charge, and shape, influence the glomerular filtration of large molecules. All unbound drugs will be filtered as long as their molecular size, charge, and shape are not excessively large.
  5. 5. Urinary excretion of drugs (i.e., weak electrolytes) is the extent to which substances diffuse back across the tubular membranes and reenter the circulation. The movement of drugs is favored from the tubular lumen to blood, partly because of the reabsorption of water The concentration gradient thus established will facilitate movement of the drug out of the tubular lumen, given that the lipid solubility and ionization of the drug are appropriate. The pH of the urine (usually between 4.5 and 8) can markedly affect the rate of passive back-diffusion. Acidification increases reabsorption (or decreases elimination) of weak acids, such as salicylates, and decreases reabsorption (or promotes elimination) of weak bases, such as amphetamines.
  6. 6. A number of drugs can serve as substrates for the two active secretory systems in the PCT Actively transfer drugs from blood to luminal fluid, are independent of each other; one secretes organic anions, and the other secretes organic cations. The secretory capacity of both the organic anion and organic cation secretory systems can be saturated at high drug concentrations. Each drug will have its own characteristic maximum rate of secretion (transport maximum,Tm).
  7. 7. Organic Anion Transport Organic Cation Transport Acetazolamide Acetylcholine Bile salts Atropine Hydrochlorothiazide Cimetidine Furosemide Dopamine Indomethacin Epinephrine Penicillin G Morphine Prostaglandins Neostigmine Salicylate Quinine
  8. 8. Some substances filtered at the glomerulus are reabsorbed by active transport systems found primarily in the proximal tubules. Active reabsorption is particularly important for endogenous substances, such as ions, glucose, and amino acids, although a small number of drugs also may be actively reabsorbed. The probable location of the active transport system is on the luminal side of the proximal cell membrane.
  9. 9. The rate of urinary drug excretion will depend on the drug’s volume of distribution, its degree of protein binding, and the following renal factors: 1. Glomerular filtration rate 2. Tubular fluid pH 3. Extent of back-diffusion of the unionized form 4. Extent of active tubular secretion of the compound 5. Possibly, extent of active tubular reabsorption
  10. 10. Bile flow and composition depend on the secretory activity of the hepatic cells that line the biliary canaliculi. As the bile flows through the biliary system of ducts, its composition can be modified in the ductules and ducts by the processes of reabsorption and secretion, especially of electrolytes and water. For example, osmotically active compounds, including bile acids, transported into the bile promote the passive movement of fluid into the duct lumen.
  11. 11. Hence, drugs with molecular weights lower than those of most protein molecules readily reach the hepatic extracellular fluid from the plasma. Group A - concentration in bile and plasma are almost identical (bile–plasma ratio of 1). Ex. Glucose, and ions such as Na, K, and Cl. Group B - ratio of bile to blood is much greater than 1, usually 10 to 1,000. Ex. bile salts, bilirubin glucuronide, procainamide Group C - ratio of bile to blood is less than 1, for Ex. insulin, sucrose, and proteins. Biliary Excretion
  12. 12. The physicochemical properties of most drugs are sufficiently favorable for passive intestinal absorption that the compound will reenter the blood that perfuses the intestine and again be carried to the liver. Such recycling may continue (enterohepatic cycle or circulation) until the drug either undergoes metabolic changes in the liver, is excreted by the kidneys, or both. This process permits the conservation of such important endogenous substances as the bile acids, vitamins D3 and B12, folic acid, and estrogens ENTEROHEPATIC CIRCULATION
  13. 13. Drugs that Undergo Enterohepatic Recirculation Indomethacin Methadone Amphetamine Metronidazole Estradiol Morphine 1,25-Dihydroxyvitamin D3 Phenytoin Estradiol Polar Glucuronic Acid Conjugates Polar Sulfate Conjugates Mestranol Sulindac
  14. 14. Any volatile material, irrespective of its route of administration, has the potential for pulmonary excretion. Gases and other volatile substances that enter the body primarily through the respiratory tract can be expected to be excreted by this route. No specialized transport systems are involved in the loss of substances in expired air; simple diffusion across cell membranes is predominant. The rate of loss of gases is not constant; it depends on the rate of respiration and pulmonary blood flow. The degree of solubility of a gas in blood also will affect the rate of gas loss. Gases such as nitrous oxide, which are not very soluble in blood, will be excreted rapidly, that is, almost at the rate at which the blood delivers the drug to the lungs.
  15. 15. Sweat and Saliva Minor importance for most drugs. Mainly depends on the diffusion of the un-ionized lipid-soluble form of the drug across the epithelial cells of the glands. Thus, the pKa of the drug and the pH of the individual secretion formed in the glands are important determinants of the total quantity of drug appearing in the particular body fluid. Lipid-insoluble compounds, such as urea and glycerol, enter saliva and sweat at rates proportional to their molecular weight, presumably because of filtration through the aqueous channels in the secretory cell membrane.
  16. 16. The ultimate concentration of the individual compound in milk will depend on many factors, including the amount of drug in the maternal blood, its lipid solubility, its degree of ionization, and the extent of its active excretion. The physicochemical properties that govern the excretion of drugs into saliva and sweat also apply to the passage of drugs into milk. Since milk is more acidic (pH 6.5) than plasma, basic compounds (e.g., alkaloids, such as morphine and codeine) may be somewhat more concentrated in this fluid. In general, a high maternal plasma protein binding of drug will be associated with a low milk concentration. A highly lipid-soluble drug should accumulate in milk fat.
  17. 17. Enzymatic elimination of drugs primarily First Order Kinetics (Michaelis-Menton) Elimination half life t 1/2 = 0.693/k Elimination is dependent upon concentration, but almost 97% will be eliminated after 5 half-lives Initial concentration 1 mg% One half life 0.5 mg% Two half lives 0.25 mg% Three half lives 0.125 mg% Four half lives 0.0625 mg% Five half lives 0.03125 mg% or 0.96875 mg% (97%) eliminated
  18. 18. First Order Elimination [drug] decreases exponentially w/ time Rate of elimination is proportional to [drug] Plot of log [drug] or ln[drug] vs. time are linear t 1/2 is constant regardless of [drug] Zero Order Elimination [drug] decreases linearly with time Rate of elimination is constant Rate of elimination is independent of [drug] No true t 1/2
  19. 19. Half-life is the time taken for the drug concentration to fall to half its original value The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.
  20. 20. Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
  21. 21. Ability of organs of elimination (e.g. kidney, liver) to “clear” drug from the bloodstream. Volume of fluid which is completely cleared of drug per unit time. Units are in L/hr or L/hr/kg Pharmacokinetic term used in determination of maintenance doses. Volume of blood in a defined region of the body that is cleared of a drug in a unit time. Clearance is a more useful concept in reality than t 1/2 or kel since it takes into account blood flow rate. Clearance varies with body weight. Also varies with degree of protein binding
  22. 22. Dose rate = target Cpss *CL/F Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24 Rate of drug elimination=(Vmax)(C)/Km+C C-plasma concentration, Vmax-maximum rate of drug elimination, Km=plasma concentration Maintenance Dose = CL x (Steady State plasma concentration)CpSSav CpSSav is the target average steady state drug concentration
  23. 23. VD is a theoretical Volume and determines the loading dose. Clearance is a constant and determines the maintenance dose. CL = k VD. CL and VD are independent variables. k is a dependent variable. F-bioavailability Volume of Distribution = Dose_______ Plasma Concentration
  24. 24. An established relationship between concentration and response or toxicity A sensitive and specific assay An assay that is relatively easy to perform A narrow therapeutic range A need to enhance response/prevent toxicity

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