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Pharmacokinetics (Excretion (Renal Clearance (Total Urine Excretion =…
Pharmacokinetics
Excretion
Excretion is when a molecule is expelled in liquid, solid or gaseous waste
Renal Clearance
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Only drugs free in the plasma are cleared by the kidneys - those bound to proteins have little exposure to renal clearance
Water soluble molecules are eliminated by glomerular filtration and larger ones eliminated by active tubular secretion
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In renal impairment, choose drugs which are eliminated by the liver instead and avoid nephrotoxic drugs
Weak acidic drugs are cleared faster is urine is alkali and vice versa. For aspirin overdoses, patient is given sodium bicarbonate to make urine more alkali
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Hepatic Clearance
3/4 of blood supply is from portal vein, 1/4 is from hepatic artery
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Liver will produce more enzymes to clear a low HER drug (low HER drugs are effective as drugs as they have low first pass metabolism)
In liver failure, 70% of the liver must be lost for drug metabolism to be effected
Hypoalbuminaemia leads to increased free plasma levels of lipid soluble drugs - accumulation can lead to toxicity
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With IV infusion, it takes 4-5 half lives to reach 95% of steady state
A drug with slow elimination will take a long time to reach steady state and will accumulate in the plasma until elimination rate rises to match drug infusion
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If a drug has a long half life, it will take a long time to reach steady state so a loading dose is given to shorten the time to steady state
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Distribution
Lipid soluble drugs are only active in intracellular fluid e.g. steroids, paracetamol
Volume of distribution = total amount of drug in body ÷ concentration of drug in plasma . This is the volume (L) that the drug would occupy if it was distributed through all the compartments as if they were all plasma - value is much higher than reality
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Drugs can bind reversibly or irreversibly to proteins in plasma/tissue. Binding lowers the free concentration of the drug and acts as a depot store
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Lipid soluble drugs pass easily from blood to brain, water soluble drugs enter slowly. Efflux transporters protect the brain by removing drugs back to circulation
= The process by which the drug is transferred reversibly from the general circulation to the tissues
If the drug has a high Vd, then it will have a low plasma concentration
Metabolism
Elimination = The removal of a drug's activity from the body. Can involve metabolism and/or excretion
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Large bowel flora metabolise phase 2 products
and the drug is freed from glucuronic acid. The
drug is then able to re-diffuse into the gut before
going back to the liver again. This enterohepatic
circulation can prolong the action of some drugs
Bioavailability
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As an IV drug has a bioavailability of 1, the oral dose must be 10x higher than the IV dose
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Pharmacodynamics
- Summative: Effect equals the sum of the parts
- Synergism: Effect is greater than the sum of their parts e.g. paracetamol and ibuprofen/morphine
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- Antagonism: Drugs are opposed e.g. morphine + naloxone
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- Potentiation: Drug A makes drug B more powerful but drug B does not make drug A more powerful e.g. probenecid (malaria) makes penicillin more powerful
Kinetics
First Order
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An increase in concentration of a drug will result in a higher rate of diffusion from plasma to tissue
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Zero Order
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This occurs when an enzyme system that removes the drug is saturated - the rate of removal is now constant and is unaffected by an increase in concentration
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