Pharmacokinetics Flashcards
what is the goal of drug therapy?
deliver and maintain therapeutic, yet non-toxic, concentration of the most appropriate drug in the target tissue and achieve the therapeutic objective without adversely affecting the patient
what is a dose?
a specific amount of a drug taken at one time
what is a dosage?
an amount- mg/kg- at a specific interval for a specified amount of time, by a given route
what is the difference between topical and transdermal application of a drug?
topical is not supposed to go systemic- not systemic concentrations
transdermal is supposed to have an impact systemically
why is formulation important?
the specific formulation or salt of an active ingredient can markedly change its characteristics
ceftiofur has different formulations for different species/different routes of injection
what does formulation change?
pharmacokinetic properties
not pharmacodynamic properties
what route of administration is the most accurate dosing?
intravenous
what happens in intramuscular or subcutaneous administration?
must be absorbed into systemic circulation
cannot be irritating formulation
what is the safest route of administration?
oral
also most variable
true/false: overall drug exposure can be a lot lower in oral administration
yes
not all gets into blood stream
what is the major site of absorption of oral drugs?
duodenum
what are the sources of variability for oral drugs?
species
diet
food consumption
GI disease
what should you think about with topical medications?
goal is to have drug stay at site of application
high local concentrations
safer, but can get local reactions and might go systemic
what is pharmacokinetics?
disposition of drugs in the body
description of movement of a drug over time through the body
what is the underlying assumption of pharmacokinetics?
a relationship exists between the pharmacological or toxic response to a drug/chemical and the concentration of the drug in an easily measurable compartment
what is the shape of the drug clearance in IV administration of a drug?
exponential
does IM always have the highest peak in the time-concentration curve?
not always- depends on drug
what does the area under the time-concentration curve reflect?
how much drug is in circulation and how long it stays there
at ______________________, the amount of drug we are giving is equal to the amount of drug the body is eliminating per unit time
steady state
what are the physiologic processes of a drug in the body?
absorption
distribution
metabolism
excretion
what are the physical factors of the drug that affect absorption?
solubility: GI or at site of injection
chemical stability
feed
formulation
ability to cross membranes
what are the modifying factors of absorption?
contact time
surface area
blood flow to site of absorption
from plumb’s drug handbook: “oral systemic antibiotics should not be administered in patients with septicemia, shock, or other grave illnesses, as absorption of the drug from the GI tract may be delayed or diminished.” why does it say this?
blood flow to the intestines may be decreased
how does the solubility of drugs affect their distribution?
stay in systemic or interstitial fluid if water soluble
enter cells or go into fat or lipid environments if sufficiently lipid soluble
what are important factors in distribution of a drug?
binding to plasma or red cell proteins
ability to cross membranes
blood flow to tissues
tissue solubility or binding of the drug
what can the ability to cross membrane barriers influence?
how much is absorbed
rate of absorption
access to certain body spaces
whether a drug can be found intracellularly
what are the primary blood proteins that can bind to drugs?
albumin
lipoproteins
alpha 1-acid glycoprotein
what is the most important way for drugs to cross barriers?
passive diffusion
what determines lipophilicity?
size
presence of polar groups
ionization
an acid is non-ionized in ________________________; a base is non-ionized in _________________________
acid environment
basic environment
what is ion trapping?
a drug will be “trapped” at a higher concentration were it is most ionized
what are the active transport mechanisms for a drug crossing a membrane?
carrier-mediated active transport
transport pumps
what active transport mechanism for a drug crossing a membrane follows the concentration gradient and which one goes against it?
carrier-mediated follows the gradient
transport pumps pump against it
where are transport pumps found?
normal membranes: intestinal wall, blood-brain barrier, renal tubules, placental membranes
cancer cells
bacteria
what is P-glycoprotein and where is it found?
a transport protein
intestinal epithelium
blood-brain barrier
renal tubules
what makes up the blood-brain barrier and how does this affect drugs?
tight junctions
no intracellular pores or pinocytotic vesicles
active efflux transport proteins
highly lipophilic drugs tend to enter central nervous system
compromised during inflammation
true/false: water-soluble drugs tend to have a wider distribution
false: lipid soluble drugs do because they cross membranes more readily
what is the main objective of enzymatic biotransformation?
convert lipid-soluble drugs into more polar, less lipid soluble metabolites that are more easily excreted
what are the pharmacodynamic consequences of drug metabolism?
loss of pharmacological activity
maintenance of activity through pharmacologically active metabolites
formation of pharmacologically active compound from non-active prodrug
formation of toxic metabolites
what is the major site of biotransformation?
liver
what catalyzes the majority of Phase I reactions?
cytochrome P450 system
what happens in phase I or functionalization reactions?
parent drug is converted to a more polar metabolites through oxidation, reduction, or hydrolysis
what does insertion of oxygen by cytochrome P450 do?
creates wide variety metabolic transformations and polar metabolites
what are the clinical implications of cytochrome P450?
drug interactions: inhibition (decreased elimination) vs induction (increased elimination)
liver disease
genetic variation in P450 levels
infectious disease can affect activity
what is one group of dogs with lower drug metabolizing capacity?
sight hounds
what are phase II or conjugation reactions responsible for?
increasing water-solubility of a product by conjugation with endogenous substrates
what is one important thing phase II reactions do with detoxifying phase I metabolites?
glutathione conjugation
what are the types of conjugation reactions undergone in phase II?
glucuronidation
sulfate conjugation
acetylation
glutathione conjugation
methylation
what species is deficient in glucuronidation of some drugs?
cats
what species do no acetylate or are low?
dogs do not acetylate
cats are low
why is glutathione conjugation important?
very important in protecting agains reactive toxic metabolites
how do you calculate the rate of renal excretion?
filtration+secretion-reabsorption
what can pass through glomerular filtration?
free drugs
non-protein drugs- limited by size of pores
true/false: monoclonal antibodies are likely to be cleared by glomerular filtration
false: proteins will not
what is secreted by tubular secretion?
acidic and basic substances
can be very efficient
what method of reabsorption is most important in tubular reabsorption?
passive
pH can affect because only unionized drugs are reabsorbed
what is enteral?
via the gastrointestinal tract
what is parenteral?
routes other than enteral
what is the first pass effect?
the loss of drug degraded during its first passage through the liver and intestinal wall after absorption from the GI tract
what is enterohepatic recirculation?
process by which drug metabolites are excreted in bile, then the parent drug is reabsorbed from the gut
how does enterohepatic recirculation affect a drug in the body?
increases absorption phase
greater exposure of intestine to drugs
can create a series of plasma peaks as the drug recirculates
can increase overall bioavailability
what is the systemic dose equation?
the oral dose administered multiplied by the bioavailability (F)
how do you calculate bioavailability?
bioavailability (F) of oral= Area under the curve of oral divided by the area under the curve of IV
what should you think about with bioavailability?
greatest impact when bioavailability is low
if do rectal administration, 50% of circulation from rectal region bypasses the liver
first pass effect can be a site of drug interactions
Maropitant (Cerenia) is dosed at 1mg/kg SC, IV or 2-8mg/kg PO. given this information alone, what would you predict its bioavailability is?
much less than 100%, maybe 50% or less
why are mathematical pharmacokinetics helpful?
allows us to describe what happens
predicts time to onset, magnitude, and duration of effect
helps us design drug dosage regimens
helps us to predict the magnitude of a change in drug concentrations in a patient
the decrease in drug concentration is exponential-____________________________________________
a fixed fraction is lost with each unit of time
what does the distribution phase of the drug plasma concentration over time graph show?
the time where the drug is distributed to the tissues- an initial steep decline in concentration
what is half-life?
time it takes for drug concentration to drop 50%, or time it takes for half of the drug to be eliminated from the body
t1/2
in five half-lives, over ____ of the drug is eliminated
95%
in ten half-lives, over ____ of the drug is eliminated
99.9%
reference point for contamination of food products
what is apparent volume of distribution (Vd)?
the conceptual volume in which the drug would have to be dissolved to achieve the concentration (Co) observed in the plasma
relates the total amount of a drug in the body to the plasma concentration of that drug
what are the equations for calculating Vd and Co?
Vd=dose/Co=mg/kg/mg/ml=ml/kg
Co=dose/Vd
dose=Co x Vd
how do you calculate plasma concentration of a drug?
amount of drug in body divided by volume of distribution (ml)
dose of drug (mg/kg) divided by volume of distribution (ml/kg)
does Vd indicate penetration into specific sites?
no
what is clearance (Cl)?
conceptual: volume of plasma or blood that would have to be completely cleared of drug to account for its removal per unit of time
a proportionality constant that reflects the rate at which drug is cleared from the plasma
what makes up drug clearance?
hepatic clearance+renal clearance+other routes
what makes up drug elimination?
drug metabolism and drug excretion
at steady state, ________________ and __________________ are equal
rate of elimination and dosing rate
what is dosing rate?
dose of drug per unit time
what is the equation for clearance at a steady state?
rate of elimination/Css
Css=average steady state drug concentration
what is the equation for clearance after a single injection?
Cl=dose/AUC
AUC= area under the curve
clearance is _____________ of concentration of drug in the blood
independent
what is drug elimination?
amount of drug cleared from the blood per unit time
Cl x drug concentration
clearance predicts the __________________________________________ in multiple dosing
average steady state plasma concentration
what is zero order kinetics?
drug elimination processes become saturated and a fixed amount is cleared per unit time
can lead to overdose/more toxic effects
what is the slope of the drug concentration over time?
-k or Kel
what is the equation for half-life using the slope of the concentration over time graph
t1/2=0.693/Kel
=0.693(Vd/Cl)
what are the primary parameters of pharmacokinetics?
volume of distribution and clearance
half-life is the most useful secondary parameter
half-life is ________________ on Cl and Vd, but Cl and Vd are ________________
dependent
independent
how long does it take to achieve steady state?
five half-lives
time is independent of dosage
when will drug accumulation occur?
when dosing interval is less than 2 half-lives
the shorter the interval, the more significant the accumulation
if the dosing interval is greater than ______________, accumulation of the drug is negligible
3-5 half-lives
why would we give a loading dose?
to reach therapeutic concentrations more quickly
may still take 5 half-lives to reach stable steady state concentrations
what is the equation for loading dose?
loading dose= Vd x desired concentration
duration of drug action is extended by ______________ when the dose is doubled
one half-life
what does it mean for two drugs to interact with inhibition?
decreased elimination- toxicity
what does it mean for two drugs to interact with induction?
increased elimination- loss of therapeutic effect
when you change the formulation of a drug, does pharmacodynamics or pharmacokinetics or both change?
pharmacokinetics changes
pharmacodynamics does not
what would impact blood flow to the site of absorption?
sick animals may have reduced blood flow to intestine and decreased absorption
dehydrated animals/low blood pressure might have reduced subcutaneous and intestinal blood flow
how prominent are changes in protein binding?
clinically significant effects relatively rare
what drugs interact with cytochrome P450?
Phenobarbital: induces
Ketoconazole: inhibits
what is the first pass effect?
loss of drug degraded during its first passage through the liver after absorption from the GI tract
what is enterohepatic recirculation?
process whereby drug metabolites are excreted in the bile amd then the parent drug is re-absorbed from the gut
