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Pharmacokinetics: Drug Excretion

Topic 5. Pharmacokinetics: Drug Excretion. 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana . Faculty of Veterinary Medicine, Khon Kaen University. Topic Contents. Definition Routes of excretion Renal excretion Processes involved in renal excretion Ion trapping

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Pharmacokinetics: Drug Excretion

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  1. Topic 5 Pharmacokinetics: Drug Excretion 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana Faculty of Veterinary Medicine, Khon Kaen University

  2. Topic Contents • Definition • Routes of excretion • Renal excretion • Processes involved in renal excretion • Ion trapping • High and low renal clearance • Biliary excretion • Pulmonary excretion • Mammary excretion • Salivary excretion

  3. Drug Excretion Definiton The removal of a drug molecule from the body without chemical modification. Generally in urine, but occasionally in bile etc.

  4. Routes of excretion • Major routes • Renal (primary route) • Biliary  Feces • Pulmonary • Minor routesbut significance for other reasons • Mammary - Delivery to baby • Salivary - Drug monitoring

  5. Kidney Glomerular Fitration Rate (GFR) 125ml/min Urine 1ml/min Plasma flow 650ml/min Acid Base 99% of H20 + Lipid soluble drugs Filtration Active Secretion Reabsorption

  6. Processes involved in renal excretion: 1Filtration • Passive process (Pressure driven) • 20% of plasma volume is filtered • Small molecules - Yes • Large molecules – No • Most proteins not filtered. • Drugs which are extensively protein bound will also not be filtered.

  7. Processes involved in renal excretion: 2Active secretion • Energy requiring • Two separate mechanisms for acids & bases • Saturable • Possible interactions • Competition for transporters

  8. Processes involved in renal excretion: 2Active secretion • Acids • Furosemide • Penicillins • Probenecid • Bases • Quinine • Quaternary ammonium salts • Probenecid and penicillins share same mechanism. - Probenecid competes with penicillins. - Penicillin clearance reduced.

  9. Processes involved in renal excretion: 3Reabsorption • 99% of water is reabsorbed • Lipid soluble drugs reabsorbed along with the water. • Only very water soluble molecules can be efficiently excreted by the kidneys.

  10. Ion trapping Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline Urine Rest of body pH 8.0 pH 7.4 Non-ionized Non-ionized Ionized Ionized Barbiturate moves into urine - eliminated from body.

  11. Renal clearance • The volume of plasma completely cleared of a specific compound per unit time and measured as a test of kidney function. • In medicine, the clearance is a measurement of the renal excretion ability

  12. High renal clearance If renal clearance is greater than G.F.R. Ex. - G.F.R. = 600 ml/min - Renal clearance = 650 ml/min then there must be active secretion.

  13. Low renal clearance • If clearance is much less than G.F.R. then either: • Not filtered • Extensively reabsorbed • e.g. antipyrine, thiopental

  14. Biliary excretion Bile formed in large volumes in the liver Most of the water re-absorbed Concentrated bile stored in the gall bladder Bile secreted into the upper small intestine

  15. Biliary excretion • Similar to kidneys • Lipid soluble drugs filter initially, • but get re-absorbed along with the bulk of the water. • Not excreted efficiently. • Acids and bases have active secretion mechanisms • BUT • only works effectively if Mol Wt high enough. • Limit varies for different species. (>300-500 for humans)

  16. Biliary excretion • Most drugs’ Mol Wt too low for efficient biliary excretion. • Conjugation to glucuronide • often increases Mol Wt sufficiently for biliary excretion. • Acetate or glycine generally too small. • Bile is significant route of excretion for: • Glucuronide conjugates (e.g. morphine) • Limited number of ionised drugs with very high Mol Wt

  17. Entero-hepatic circulation Free Conjugates in bile Liver Free Conjugates Colon Small intestine Mainly bacteria in colon that hydrolyse the conjugates

  18. Pulmonary excretion Excretion via the lungs and breath. Significant route of excretion for some volatile molecules - especially anaesthetics (gas anesthesia).

  19. Mammary excretion - (milk) • No active secretion, just passive diffusion. • Concentration in milk reflects free concentration in blood (apart from ion trapping). • Milk is slightly acid (pH 7.0) compared to blood (pH 7.4).

  20. Erythromycin in milk Blood (pH 7.4) Milk (pH 7.0) Non-ionized Non-ionized Ionized Ionized Lipid Erythromycin concentrations approx 8 times higher in milk than blood.

  21. Drugs in milk -clinical significance • The effect of the drug on the baby • Tetracyclines - incorporated into teeth which become weakened and ‘mottled’. • Chloramphenicol - Bone marrow toxicity • Drug residues in milk products • Milk quality • Public health problems

  22. Excretion in Saliva • Significant because of possible use in drug monitoring. • Pharmacokinetic experiments often need serial blood samples (10 or more). Ethical approval? • Saliva sampling is non-invasive. • Neutral molecules • salivary concentrations do reflect free concentrations in plasma. • Ionised drugs are a problem. • Saliva pH is variable • variable degree of ion trapping.

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