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Flashcards in Pharmacokinetics Deck (94):
1

definition of drug

a chemical entity that affects living protoplasm

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definition of medicine

a chemical entity used to treat, cure, prevent, or diagnose disease

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pharmacology definition

study of drugs

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how do we achieve goal of drug therapy/medicine?

must get adequate amounts of the drug to tissues so that the effect of the drug can be achieved while limiting the toxicity of the drug

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pharmacokinetics

describes what happens to a drug given to a patient. what the body does to the drug

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pharmacodynamics

THE BODY'S RESPONSE TO A given drugs. what the drug does to the body

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fundamentals of pharmacokinetics

AADME (administration, absorption, delivery, metabolism, excretion)

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enteral drug administration

oral, rectal, sublingual

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parenteral drug administration

IV, IM, Sub Q

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advantages of oral administration

ease of use, outpatient care, low cost

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disadvantages of oral administration

most complicated path and therefore most variable response, first pass effect

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first pass effect

the concentration of a drug is greatly reduced before it reaches the systemic circulation (hepatic vein to IVC). It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall

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enteropathic circulation

instead of taking portal vein to liver, some drugs are recycled back and forth within GI

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advantages of rectal administration

relative ease of use, outpatient care, low cost, no pH/food effects, tolerability

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disadvantages of rectal administration

(less) complicated path/variable response. (less) first pass effect

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advantages of sublingual administration

ease of use, outpatient care, *rapid onset of action (direct systemic absorption), bypasses stomach/intestine, *no first pass effect

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disadvantages of sublingual administration

expensive, taste, limited available formulations

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advantages of IV (IA) administration

bypasses stomach/intestine, no first pass effect, precise control of dose, rapid onset of action

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disadvantages of IV (IA) administration

invasive (IA especially painful), expensive, unintentional overdosing, inpatient/supervised

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advantages of IM/Sub Q administration

bypasses stomach/liver, aqueous solution=fast onset of action, non-aqueous solution=slow sustained response

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disadvantages of IM/Sub Q administration

invasive, expensive, requires absorption, supervised, impossible to remove

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transdermal administration

skin acts as rich absorptive SA, bypasses first effect, improved compliance, lipid solubility determines absorption

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topical drug delivery

delivering drug directly to site of needed action

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administration via inhalation

rapid delivery over large SA of respiratory tract, lung parenchyma is permeable to peptides, lower metabolism in lung tissue, molecular size must be small

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absorption definition

transfer of drug from the site of administration to systemic circulation

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which type of administration has complete absorption?

IV (100%)

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what does GI absorption depend upon?

blood supply, presence of food in stomach, presence of other meds in stomach, level of enterocyte metabolism, disease states, permeation principles, effect of pH

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permeation principles

passive diffusion, lipid diffusion, special carriers, endo/exocytosis

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ticks law of diffusion

movement from high to low areas of concentration

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how do water soluble drugs penetrate membrane via diffusion?

through aqueous channels. increased size diminishes absorption

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how of lipid soluble drugs penetrate membrane via diffusion?

through the membrane. size isn't an issue, but charge is

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henderson hasselbach principle for lipid diffusion

tells what proportion of drug will be in uncharged state at any given pH. easier for uncharged to pass membrane so most drugs are weak acids/bases

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where do weak acids vs bases generally get absorbed?

acids: stomach
bases: intestine

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carrier mediated absorption

energy dependent process requiring ATP. moves drugs against concentration gradient, saturable

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bioavailability

the efficiency of absorption. fraction of the administered drug that reaches the systemic circulation in an UNCHARGED form

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calculate bioavailability

area under curve for administration/area under curve for IV

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how does first effect affect bioavailability

reduces it since amount actually absorbed in systemic circulation is decreased by gut enterocytes and liver

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definition of distribution

process by which a drug REVERSIBLY leaves the blood stream and enters the interstitial and/or cells of a tissue

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what happens once a drug distributes?

enters one of three compartments or is sequestered

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where are drugs most commonly sequestered?

bone and adipose tissue (fetus if pregnant)

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three compartments a drug can distribute into

plasma, interstitial fluid, intracellular fluid

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ECF

plasma + interstitial fluid

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total body water

plasma + IF + ICF =42L

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what determines where a drug distributes?

blood flow, capillary permeability, hydrophobicity/lipophilicity of drug, binding to plasma proteins

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blood brain barrier

brain capillary endothelial cells are continuous via tight junctions and prevent substances from entering interstitium

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role of plasma proteins

sequester drugs in a nondiffusible form in the plasma. drugs bound to them are inactive, binding is reversible though.

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volume of distribution

a hypothetical volume of fluid into which a drug is disseminated prior to elimination. (bioavailable dose)/(concentration in plasma)

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small Vd after drug is displaced from plasma protein binding site...

concentration in plasma is high=increased risk of toxicity

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large Vd after drug is displaced from plasma protein binding site...

drug can distribute into other compartments and risk of toxicity is low

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value of Vd if drug is distributed throughout total body water

0.6 L/Kg

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Large Vd tells drug is distributed...

throughout entire body (water soluble, easily distributed, small molecule)

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Small Vd tells drug is distributed...

within plasma.

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drugs only distributed in plasma

large molecular weight or binds tightly to plasma proteins, too big to pass into IF or not free to do so

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drugs distributed to ECF

low molecular weight, hydrophilic, can move through endothelial slit junctions into IF.

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drugs distributed throughout total body water

drug has low molecular weight, lipophilic, can move through cell membrane and slit junctions, distribute into huge volume, water soluble

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drugs distributed to tissues

drug bound receptors or carrier mechanism, drug sequestered in bone or fat tissue

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elimination

metabolism + excretion

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metabolism/biotransformation primary purpose

inactivate drug. achieved by converting drug into more excitable form (polar compound)

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prodrugs

require biotransformation to become activated

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where does the majority of drug metabolism take place?

liver (but really any cell with mitochondria)

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phase 1 drug metabolism

oxidation via cytochrom P450. primary mode of metabolism, difficult to saturate

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phase 2 drug metabolism (not always sequential)

couples endogenous substrate to a drug or to its phase 1 metabolite. CONJUGATION. (acetylation, methylation, etc)

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CYP

cytochrome P-450 system. major catalyst of drug and endogenous compound oxidations

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most common CYP families

1,2,3

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which specific CYP protein is responsible for many drug metabolisms

CYP3A4

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rifampin

drug used in treatment of TB. side effect=orange fluid. increases activity of CYP3A4, therefore decreasing the efficacy of drugs dependent on phase 1 (breaks them down quicker, St Johns Wort too)

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grapefruit juice

decreases activity of CYP3A4 in GI endothelial cells, thereby increasing timespan/concentration of dependent drugs

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polymorphisms in CYP family genes

increased copies of genes leads to faster metabolism of dependent drugs (CYP2D6 example)

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consequence of reduced metabolism

toxicity, death

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consequence of increased metabolism

loss of efficacy

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inhibition of gastric endothelial cell CYP3A4 activity results in...

increased absorption of orally administered drugs

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enterohepatic circulation

biliary excretion

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functional unit of the kidney

nephron

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three processes of renal excretion

glomerular filtration, active tubular secretion, passive tubular reabsorption

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amount of drug excreted by the kidney

the sum of the amount filtered and secreted minus the amount reabsorbed

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elimination

metabolism & excretion. the process whereby the body terminates drug action

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what is the rate of elimination called?

clearance

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what is clearance proportional to?

concentration of the drug

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first order kinetics

when clearance is DIRECTLY proportional to the concentration of the drug

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zero order kinetics

capacity limited excretion, elimination is saturable.

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kinetics at low drug concentrations

first order

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kinetics at high drug concentrations

zero order (saturable)

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half life of drug

the time required to eliminate half of the amount of drug in the body or to reduce the plasma concentration by 50%

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how is half life of drug calculated?

from the plasma concentration curve following administration of a single dose of the drug

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how many half lives for first order kinetics to eliminate >90% of drug?

4

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steady state concentration

when rate of accumulation is equal to the rate of elimination

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how long does it take to reach steady state?

4-5 half lives (think inverse of elimination: i.e. how long to reach >90%/plateau)

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what is the steady state concentration directly proportional to?

drug dose administered per unit of time and the elimination half life

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will a drug administered by continuous infusion reach steady state at different time than drug administered intermittently?

no, they will both reach it at the same time, but intermittent drug plasma level will just flucuate

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loading dose

a dose that saturates. used when it is necessary to rapidly achieve a therapeutic plasma concentration. commonly used with antibiotics and anticoagulants

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maintenance dose

given to establish or maintain a desired steady state concentration

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impact of liver disease on pharmacokinetics

reduced phase 1 metabolism and reduced albumin

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impact of renal failure on pharmacokinetics

reduced GFR and secretion

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impact of heart failure on pharmacokinetics

volume expansion, reduced circulation