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gapcom 4/6 Drug Elimination (X)


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what are routes of removal of drug from body?
mainly through kidney, major organ of excretion, into the urine. liver contributes to drug loss through metabolism and/or excretion into the bile. also, the bile (specifically steroids & CTH agents), intestine, the lung, or milk in nursing mothers. A patient in renal failure may sometimes benefit from a drug that is excreted by this pathway into the intestine and feces rather than through the kidney. Some drugs may also be reabsorbed through the enterohepatic circulation, thus prolonging their half-life.
what are three types of drug elimination that occurs in the kidneys?
relative balance of filtration, secretion, and reabsorption rates determines the kinetics of drug elimination by the kidney. also effected by the drug metabolism (phase 1/2 reactions)
1. glomerular filtration - free drug enters glomerular filtrate
2. proximal tubular secretion - active secretion
3. distal tubular reabsorption - passive reabsorption of lipid-soluble un-ionized drug whuch has been concentrated so that the intraluminal conc > conc in perivascular space.
excretion - leaving collecting duct is ionized, lipid-insoluble drug into urine.
explain glomerular filtration.
-drugs enter kidney through renal arteries which divide into glomerular capillary plexus. free drug flows through capillary slits into Bowman's space as part of glomerular filtrate.
- glomerular filtration rate (125 ml/min) is normally about 20% of renal plasma flow (66 ml/min).
note: lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate
what causes the drug to be more rapidly excreted
-enhancing blood flow, inc glomerular filtration rate, and decreasing plasma protein binding
-underlying these above is inc delivery of drug to glomerulus.
explain proximal tubular secretion.
drugs not transferred into glomerular filtrate leaves glomeruli through efferent arterioles, which divide to form capillary plexus surrounding nephric lumen in the proximal tubule. secretion primarily occurs in the proximal tubules by 2 energy requiring active transport systems: 1.for anions, 2.for cations. both systems show lo specificity, so competition btw drugs for carriers can occur
explain distal tubular reabsorption. what is ion trapping?
-as drug moves toward DCT, its conc inc and exceeds that of perisvascular space. If uncharged, drug may diffuse back into systemic circulation.
ion trapping is manipulating the pH of the urine to inc the ionized form of the drug in the lumen to minimize amount of back-diffusion (hence, clearance of an undesirable drug) ex. phenobarbitol OD, given bicarbonate, which alkalinizes the urine
explain what phase I and II reactions do to effect drug metabolism in the body.
-when drug conc in filtrate > then conc in perivascular space. to minimize reabsorption, drugs modified by making more polar using these 2 rxns.
phase I rxns - involve either the addition of hydroxyl groups or the removal of blocking groups from hydroxyl,carboxyl, or amino groups
phase II rxns - use conjugation with sulfate, glycine, or glucuronic acid to inc drug polarity. the conjugates are ionized, and the charged molecules cannot back-diffuse out of the kidney lumen.
how do you calc plasma clearance? what is the unit
clearance = amt renal plasma flow * extraction ratio. bc both normally invariant over time, so clearance is constant. plasma clearance expressed as vol of plasma frmo which all drug appears to be removed in a given time - for ex. ml/min
what is and how calc the extraction ratio?
ratio is decline of drug conc in the plasma from the arterial to the venous side of the kidney. the drugs enter the kidneys conc at C1 and exit the kidneys at conc C2. so extraction ratio = C2/C1.
what is and how calc the excretion ratio?
excretion rate (mg/min) = clearance ml/min * plasma concentration mg/ml.
how do you calc half-life of drug?
elimination of a drug usu follows first-order kinetics. t1/2=ln 0.5/ke = 0.693*Vd / CL where ke=the first order rate constant for drug elimination from the total body; CL=clearance. presents in linear graph when log drug conc versus time.
what is total body clearance?
systemic cleraance (CLtotal) is the sum of the clearances from the various drug metabolizing and drug eliminating organs.

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