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75 Cards in this Set
- Front
- Back
what factors affect drug distribution?
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(1) reversible movement between blood and tissues (2) water volumes (3) volume of distribution drug factors (4) volume of distribution physiological factors (5) rate of distribution
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how does the reversible movement between blood and tissues affect drug distribution?
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drug remaining in compartments have prolonged drug action, toxicity, depots, residues
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where do water volumes affect drug distribution?
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(1) intracelular (2) interstitial (3) plasma (4) blood cells
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what drug factors affect the volume of distribution?
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(1) lipid solubility (2) pH-pKa relationship (3) plasma protein binding (4) intracellular protein binding
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how does lipid solubility of a drug affect the volume of distribution?
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lipid solubility is more important for intracellular vs extracellular and some special tissue sites have additional tissue layers (blood-brain barrier, prostate/testes, joint, placenta/mammary gland, ocular compartments) that drugs must penetrate
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how does the pH-pKa relationship affect the volume of distribution?
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only unionized drug fraction will diffuse freely and thus distribute and only unbound or free drug fraction will diffuse freely and thus distribute
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how does plasma protein binding affect volume of distribution?
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drugs bound to plasma proteins will not be distributes as extensively
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how does intracellular protein binding affect volume of distribution?
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drug will want to be distributed in those organs and there are specific receptors or transport systems
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name some examples of specific receptor tissues and and drugs that rely on intracellular protein binding to affect volume of distribution?
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tetracyclince to bone, chlorinated pesticides to adipose tissue, aminoglycosides to kidney proximal tubules
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the intracellular protein binding of tetracyclince to bone, chlorinated pesticides to adipose tissue, aminoglycosides to kidney proximal tubules affects what?
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volume of distribution
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tetracyclince to bone, chlorinated pesticides to adipose tissue, aminoglycosides to kidney proximal tubules affect the volume of distribution via what mechanism?
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intracellular protein binding
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what physiological factors affect the volume of distribution?
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(1) tissue perfusion and mass of tissue (2) ratio of blood flow to tissue mass or perfusion rate (3) transcellular tissue compartments (4) tissue-specific transport processes (5) plasma and tissue protein binding (6) factors that alter plasma protein concentrations (7) plasma protein binding
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how does tissue perfusion and mass of tissue affect volume of distribution?
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well-perfused tissue takes up drug more rapidly and larger tissue mass has more drug binding sites
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what is another term for the ratio of blood flow to tissue mass?
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perfusion rate
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what is another term for perfusion rate?
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the ratio of blood flow to tissue mass
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what are the units of perfusion rate?
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ml/min/ml tissue
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what organs have a high perfusion rate?
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brain, kidney, heart, endocrine, liver
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what happens in organs with high perfusion rates?
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have a very rapid rise or rate in drug concentration and must be monitored for toxicosis
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what organs have a low perfusion rate?
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muscle, skin, fat, bone
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what happens in organs with low perfusion rates?
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have a greater capacity to increase extent of drug distribution
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how do transcellular tissue compartments affect volume of distribution?
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have additional membranes and potential pH differences
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how do tissue-specific transport processes affect volume of distribution?
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by selectivly transporting drugs against a gradient
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what are examples of tissue-specific transport processes that affect volume of distribution?
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blood-brain barrier and active drug efflux
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what are examples of tissue-specific transport processes at the blood brain barrier?
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glucose, transferrin, L-amino acids
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what are examples of tissue-specific transport processes with active drug efflux?
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P-glycoprotein associated transport system
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how do plasma and tissue protein binding affect volume of distribution?
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when the drug is free in blood or bound in tissue it has physiological effects
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name common plasma and tissue proteins that affect volume of distribution?
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albumin, alph1-acidic glycoproteins, hormone transport proteins, lipoproteins
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what does albumin bind that affects volume of distribution?
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binds neutral and weakly acidic drugs
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what does alpha1-acidic glycoproteins bind that affects volume of distribution?
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binds basic drugs
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what does hormone transport proteins bind that affects volume of distribution?
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bind steroids
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what does lipoproteins bind that affects volume of distribution?
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bind very lipophilic pesticides
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what type of interactions are plasma and tissue protein binding?
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reversible noncovalent interactions resulting in a dynamic equilibrium
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what are plasma and tissue protein binding dependent on?
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drug-protein affinity and drug concentration and protein concentration
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what law does plasma and tissue protein binding follow?
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law of mass action where the concentration of protein and the concentration of drug sum to the concentration of protein bound drug
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illustrate the law of mass action?
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[P] + [D] > [PD]
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in plasma and tissue protein binding what is k1?
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forward association constant
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in plasma and tissue proteing binding what is k2?
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reverse association constant
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in plasma and tissue protein binding what does Ka stand for?
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association constant
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in plasma and tissue protein binding illustrate Ka?
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Ka = [PD]/[P]{D]
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in plasma and tissue proteint binding what happens if the Ka is large?
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most of the drug is bound and large dose may be needed for effect
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in plamsa and tissue protein binding what happens with multiple drugs?
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competition may occur (ex warfarin and phenylbutazone) and the drug with the highest Ka will displace the other drug and increase the free drug concentration of the drug with lower Ka
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in plasma and tissue protein binding what happens if tissue Ka is larger?
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little drug will stay in plasma
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in plasma and tissue protein binding what happens if plasma Ka is larger?
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more drug will stay in plasma
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in plamsa and tissue protein binding when does physiological effect occurs?
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when drug is free in blood or bound in tissue
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in plasma and tissue protein binding what factors alter plasma protein concentrations?
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(1) reduced serum albumin (2) increased alpha1-acid glycoprotein (3) changes in body temp or acid-base balance
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in plasma and tissue protein binding what causes reduced serum albumin?
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malnutrition, pregnancy, age, cancer, liver abscess, renal disease
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in plasma and tissue protein binding what causes increased alpha1-acid glycoprotein?
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age, inflammation, infection, obesity, renal failure
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in plasma and tissue protein binding what affect do changes in body temp or acid-base balance have?
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alter binding
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in plasma and tissue protein binding, when is it clinically important?
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when [bound drug] > 90% because a physiologic change (drug intoxication or disease) in [free drug] will be pharmacologically significant
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what does the rate of distribution depend on?
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tissue perfusion and membrane permeability
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what does the apparent volume of distribution reflect?
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dilution of drug in body
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what factors determine the apparent volume of distribution?
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dose, plasma water, body water
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how can we illustrate the apparent volume of distribution of a drug?
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dose (mg/kg) = [plasma] (mg/L) x Vd (L/kg)
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what is the average amount of plasma water?
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50mL/kg (0.05 L/kg)
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what is the average amount of body water?
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600 mL/kg (0.6 L/kg)
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what happens when apparent volume distribution is 0.05 to >250L/kg has protein binding?
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the drug can occupy space greater than physiologically available water volume
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what determines the extent of distribution?
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lipophilicity and plasma/tissue protein binding
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what does Vd stand for?
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volume of distribution
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what is the Vd for drugs confined to plasma?
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0.05 L/kg
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what do drugs confined to a plasma with a Vd of 0.05 L/kg include?
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drugs that are strongly bound to proteins or whose molecular size is too large to cross capillary wall (heparin, insulin)
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what are examples of drugs that are strongly bound to proteins or have molecular size that is too large to cross capillary walls?
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heparin and insulin
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what is the Vd for drugs distributed in extracellular compartment?
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0.2-0.4 L/kg
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what do drugs distributed in extracellular compartment with a Vd or 0.2-0.4 L/kg include?
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polar compounds (tubocurarine, gentamicin) with low lipid solubility
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for drugs distributed in extracellular compartment, where else will drug be?
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some drug will still be in blood with some minor protein binding in plasma and tissues
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what is the Vd for drugs distributed throughout body water?
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0.55 L/kg
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what do drugs distributed throughout body water with a Vd of 0.55 L/kg include?
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(1) relatively lipid soluble drugs that cross cell membrane, (2) drugs that can bind outside of plamsa and body fat so Vd >>>Vd for body water (3) such drugs can reach fetus, brain, other transcellulr comparments (4) extensive drug tissue binding results in very large Vd
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what does extensive drug tissue binding result in?
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very large Vd
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what is Vd useful for?
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predicting where drug is distributed and calculating dose needed for desired plasma concentration
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how do we predict the effect of plasma and tissue binding on Vd?
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Vd = Vp + Vtw(fup/fut)
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what does Vp stand for?
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plasma water (constant)
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what does Vtw stand for?
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total water (constant)
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what does fup stand for?
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fraction unbound in plasma
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what does fut stand for?
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fraction unbound in tissue
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what does incrased plasma binding result in?
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decreased Vd
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what does increased tissue binding result in?
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increased Vd
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