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32 Cards in this Set
- Front
- Back
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What is a half life? |
the time taken for the plasma concentration to fall by half. the time taken for the amount of drug in the body to fall by half. it increases as the elimination rate constant increases. |
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What happens to half life as clearance increases |
it decreases |
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what happens to half life as the volume of distribution increases |
it increases |
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After a single dose of a drug which has a half-life of 12 hours, what percentage of the dose is still in the body after 1 day? |
25% |
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During a constant rate intravenous infusion of a drug with an elimination rate constant of 0.173 per hour, the plasma drug concentration will be what percentage of steady state after 16 hours. |
steady state after 16 hours so half life is about 4 hours table on page 19 gives us the answer of 93.75 |
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half life determines |
bde the time to reach steady state the duration of action after a single dose the fluctuation in plasma drug concentration during a dosing interval |
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What are the major routes of drug elimination from the body? |
excretion as unchanged drug by the kidneys
and
elimination by metabolism in the liver |
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What is hepatic extraction ratio |
the fraction of the drug entering the liver in the blood which is irreversibly removed/extracted during one pass of blood through the liver |
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range of possible values of hepatic extraction ratio |
0 to 1 |
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Which two factors determine the clearance of a drug by the liver? |
rate of delivery of drug to the liver determined by the hepatic blood flow
the efficiency of removal of drug which is presented to it (the extraction ratio)
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what is the equation for hepatic clearance? |
CL(H) = Q(H) * E(H)
Q is hepatic blood flow E is hepatic extraction ratio |
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What are the two overall determinants of hepatic clearance ? |
the efficiency of drug delivery in the blood (blood flow)
efficiency of drug removal from the blood (extraction ratio) |
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Blood enters the liver via |
the portal vein |
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blood exits the liver and travels to |
the systemic circulation via the hepatic vein |
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extraction ratio = |
unbound fraction * intrinsic clearance/
blood flow + unbound fraction * intrinsic clearance |
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What is unbound fraction? |
tells us how tightly the drug is bound to proteins and cells in the blood. It is only unbound drug which is available for diffusion into the liver cell. There are exceptions. |
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What is intrinsic clearance? |
The intrinsic ability of the liver to remove or metabolise drug in the absence of restrictions imposed on drug delivery to the liver cell by blood flow and protein binding. It is hepatic clearance if blood flow was unlimited and all drug unbound. It tells us how active the liver drug metabolising enzymes are with that particular drug. |
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CL int = |
Vmax/Km
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What is Vmax |
maximal velocity of the reaction at saturation substrate concentration - the maximal rate at which the enzyme can convert the drug ot a metabolite. |
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What is Km? |
Michaelis-Menten constant and expresses how tightly the enzyme binds the drug substrate. The lower the value - the tighter the binding. It is a dissociation constant. |
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How are orally administered drugs absorbed? |
Through the gut lumen into the portal circulation. They must pass through the liver before reaching the systemic circulation. This is a first pass or pre systemic extraction. |
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High clearance drugs |
alprenolol glyceryl trinitrate propanolol lignocaine morphine |
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Intermediate clearance drugs |
desipramine nortryptyline quinidine paracetamol |
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low clearance drugs |
warfarin tolbutamide theophylline diazepam phenytoin carbamazepine
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the extraction of drugs by the liver is determined by three things |
the fraction of drug unbound in the plasma, the intrinsic activity of the drug metabolising enzymes with the drug as substrate liver blood flow |
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for low hepatic extraction ratio drugs |
the hepatic systemic clearance is only determined by protein binding and enzyme activity |
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for high hepatic extraction ratio drugs |
the hepatic systemic clearance is determined by hepatic blood flow. |
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what are the main determinants of clearance of a low hepatic extraction ratio drug |
intrinsic clearance and protein binding |
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The main determinant of the hepatic clearance of a high hepatic extraction ratio drug |
hepatic blood flow |
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the hepatic intrinsic clearance of a drug is determined by |
the maximal rate at which it can be metabolised by the drug metabolising enzyme
the tightness of binding to the drug metabolising enzyme. |
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For drugs such as warfarin with a low hepatic extraction ratio, a twofold increase in the activity of the drug metabolising enzymes will approximately"- |
double each of hepatic clearance, hepatic extraction ratio and hepatic intrinsic clearance |
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For a high hepatic extraction ratio drug, a halving of hepatic blood flow will approximately:- |
half the hepatic clearance |
