Flashcards in Pharmacokinetics Deck (94):
definition of drug
a chemical entity that affects living protoplasm
definition of medicine
a chemical entity used to treat, cure, prevent, or diagnose disease
study of drugs
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
describes what happens to a drug given to a patient. what the body does to the drug
THE BODY'S RESPONSE TO A given drugs. what the drug does to the body
fundamentals of pharmacokinetics
AADME (administration, absorption, delivery, metabolism, excretion)
enteral drug administration
oral, rectal, sublingual
parenteral drug administration
IV, IM, Sub Q
advantages of oral administration
ease of use, outpatient care, low cost
disadvantages of oral administration
most complicated path and therefore most variable response, first pass effect
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
instead of taking portal vein to liver, some drugs are recycled back and forth within GI
advantages of rectal administration
relative ease of use, outpatient care, low cost, no pH/food effects, tolerability
disadvantages of rectal administration
(less) complicated path/variable response. (less) first pass effect
advantages of sublingual administration
ease of use, outpatient care, *rapid onset of action (direct systemic absorption), bypasses stomach/intestine, *no first pass effect
disadvantages of sublingual administration
expensive, taste, limited available formulations
advantages of IV (IA) administration
bypasses stomach/intestine, no first pass effect, precise control of dose, rapid onset of action
disadvantages of IV (IA) administration
invasive (IA especially painful), expensive, unintentional overdosing, inpatient/supervised
advantages of IM/Sub Q administration
bypasses stomach/liver, aqueous solution=fast onset of action, non-aqueous solution=slow sustained response
disadvantages of IM/Sub Q administration
invasive, expensive, requires absorption, supervised, impossible to remove
skin acts as rich absorptive SA, bypasses first effect, improved compliance, lipid solubility determines absorption
topical drug delivery
delivering drug directly to site of needed action
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
transfer of drug from the site of administration to systemic circulation
which type of administration has complete absorption?
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
passive diffusion, lipid diffusion, special carriers, endo/exocytosis
ticks law of diffusion
movement from high to low areas of concentration
how do water soluble drugs penetrate membrane via diffusion?
through aqueous channels. increased size diminishes absorption
how of lipid soluble drugs penetrate membrane via diffusion?
through the membrane. size isn't an issue, but charge is
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
where do weak acids vs bases generally get absorbed?
carrier mediated absorption
energy dependent process requiring ATP. moves drugs against concentration gradient, saturable
the efficiency of absorption. fraction of the administered drug that reaches the systemic circulation in an UNCHARGED form
area under curve for administration/area under curve for IV
how does first effect affect bioavailability
reduces it since amount actually absorbed in systemic circulation is decreased by gut enterocytes and liver
definition of distribution
process by which a drug REVERSIBLY leaves the blood stream and enters the interstitial and/or cells of a tissue
what happens once a drug distributes?
enters one of three compartments or is sequestered
where are drugs most commonly sequestered?
bone and adipose tissue (fetus if pregnant)
three compartments a drug can distribute into
plasma, interstitial fluid, intracellular fluid
plasma + interstitial fluid
total body water
plasma + IF + ICF =42L
what determines where a drug distributes?
blood flow, capillary permeability, hydrophobicity/lipophilicity of drug, binding to plasma proteins
blood brain barrier
brain capillary endothelial cells are continuous via tight junctions and prevent substances from entering interstitium
role of plasma proteins
sequester drugs in a nondiffusible form in the plasma. drugs bound to them are inactive, binding is reversible though.
volume of distribution
a hypothetical volume of fluid into which a drug is disseminated prior to elimination. (bioavailable dose)/(concentration in plasma)
small Vd after drug is displaced from plasma protein binding site...
concentration in plasma is high=increased risk of toxicity
large Vd after drug is displaced from plasma protein binding site...
drug can distribute into other compartments and risk of toxicity is low
value of Vd if drug is distributed throughout total body water
Large Vd tells drug is distributed...
throughout entire body (water soluble, easily distributed, small molecule)
Small Vd tells drug is distributed...
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
drugs distributed to ECF
low molecular weight, hydrophilic, can move through endothelial slit junctions into IF.
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
drugs distributed to tissues
drug bound receptors or carrier mechanism, drug sequestered in bone or fat tissue
metabolism + excretion
metabolism/biotransformation primary purpose
inactivate drug. achieved by converting drug into more excitable form (polar compound)
require biotransformation to become activated
where does the majority of drug metabolism take place?
liver (but really any cell with mitochondria)
phase 1 drug metabolism
oxidation via cytochrom P450. primary mode of metabolism, difficult to saturate
phase 2 drug metabolism (not always sequential)
couples endogenous substrate to a drug or to its phase 1 metabolite. CONJUGATION. (acetylation, methylation, etc)
cytochrome P-450 system. major catalyst of drug and endogenous compound oxidations
most common CYP families
which specific CYP protein is responsible for many drug metabolisms
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)
decreases activity of CYP3A4 in GI endothelial cells, thereby increasing timespan/concentration of dependent drugs
polymorphisms in CYP family genes
increased copies of genes leads to faster metabolism of dependent drugs (CYP2D6 example)
consequence of reduced metabolism
consequence of increased metabolism
loss of efficacy
inhibition of gastric endothelial cell CYP3A4 activity results in...
increased absorption of orally administered drugs
functional unit of the kidney
three processes of renal excretion
glomerular filtration, active tubular secretion, passive tubular reabsorption
amount of drug excreted by the kidney
the sum of the amount filtered and secreted minus the amount reabsorbed
metabolism & excretion. the process whereby the body terminates drug action
what is the rate of elimination called?
what is clearance proportional to?
concentration of the drug
first order kinetics
when clearance is DIRECTLY proportional to the concentration of the drug
zero order kinetics
capacity limited excretion, elimination is saturable.
kinetics at low drug concentrations
kinetics at high drug concentrations
zero order (saturable)
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%
how is half life of drug calculated?
from the plasma concentration curve following administration of a single dose of the drug
how many half lives for first order kinetics to eliminate >90% of drug?
steady state concentration
when rate of accumulation is equal to the rate of elimination
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)
what is the steady state concentration directly proportional to?
drug dose administered per unit of time and the elimination half life
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
a dose that saturates. used when it is necessary to rapidly achieve a therapeutic plasma concentration. commonly used with antibiotics and anticoagulants
given to establish or maintain a desired steady state concentration
impact of liver disease on pharmacokinetics
reduced phase 1 metabolism and reduced albumin
impact of renal failure on pharmacokinetics
reduced GFR and secretion