Pharmacokinetics Flashcards
what are the 4 main pharmacokinetic processes
1) absorption
2) distribution
3) metabolism
4) excretion
what is absorption
movement of the drug into systemic circulation
what is bioavailability
fraction of administered drug that reaches the systemic circulation unchanged
what route is associated with the highest and the lowest bioavailability
highest: IV (100%)
lowest: oral
If 70% of buprenorphine is metabolized by the liver in one pass, what is the oral bioavailability?
30%
the most rapid absorption is associated with what route
IV (essentially instantaneous)
faster absorption is associated with ___________ effect and _________ duration, whereas slower absorption is associated with _______________ effect and _________ duration
faster absorption is associated with stronger effect and shorter duration
slower absorption is associated with smaller effect and longer duration
what is the risk if absorption is too slow
may not reach MEC for desired effect (drug is being eliminated as it is being absorbed)
what are the two classifications of administration and what is the difference
enteral (goes through liver before entering systemic circulation) and parenteral (does not pass through liver before entering systemic circulation)
classify oral, IM, IV, and SQ as either parenteral or enteral
Enteral: oral
Parenteral: IV, IM, SQ
what is always a concern with oral drugs
emesis and GI irritation possible, so the drug may never reach the MEC due to vomiting
is sublingual route enteral or parenteral
parenteral (it is absorbed across the oral mucosa into the systemic circulation)
what type of drugs is SQ good for
insoluble, oily, or solid pellets (note: should not be chemically irritating)
how could you slow the absorption of an IM drug
form an oily suspension
what type of administration is suitable for large volumes of drugs
IV bolus injection
what is a major drawback of IV administration
need to administer slowly to prevent cardiac toxicity
what is the safest route of administration of irritating drugs
IV CRI
if you needed to deliver a drug to a specific site (ex. the testes) in high concentrations, what route of administration would you choose
topical
what is the difference between topical and transdermal
transdermal is absorbed into the systemic circulation from the skin to have actions elsewhere in the body; topical is meant to be absorbed and act on the site of administration
in what form is a drug more easily absorbed and what would this form be for a weak acid and weak base
more easily absorbed in unionized form (lipid soluble form); AH or B
in what form is a drug more easily excreted and what would this form be for a weak acid and weak base
ionized form (water soluble form); A- or BH+
Will a weakly acidic drug with a pKa of 4.4 be better absorbed from the stomach (pH = 1.4) or small intestine (pH = 6.4)?
stomach (because it will be in its unionized form, AH)
A weakly basic drug with a pKa of 8.4 is administered orally. Will it be better absorbed from the stomach (pH = 2.4) or small intestine (pH = 6.4)
small intestine (because more will be in its unionized form, B)
Assuming you want to maximize absorption, would most oral drugs be weak acids or weak bases?
weak acids
Do drugs accumulate on the side of the membrane where ionization is highest or lowest?
highest (aka BH+ or A-)
Will a base accumulate in an environment that is more acidic or more basic?
It will accumulate where it is BH+ therefore acidic
Will an acid accumulate in an environment that is more acidic or more basic?
It will accumulate where it is A- therefore basic
What is distribution
movement of the drug from systemic circulation into other tissues
what is the distribution pathway
blood plasma -> extracellular fluid -> cells
T/F only a small fraction of each dose reaches the target receptor sites
true (the rest accumulates where it isn’t needed or is excreted before it reaches target receptors)
what 4 factors influence drug distribution
1) physiochemical properties of the drug
2) anatomy and physiology of the animal
3) plasma protein binding
4) tissue drug binding
once a drug enters blood, how long does it take to distribute to the entire blood volume
1-2 minutes
in the short term, tissues that ____________ receive more drug; in the long term, tissues that _______________ receive drug as equilibrium between occurs
have higher blood flow; are larger but less well-perfused
what types of drugs enter the BBB well
highly lipid soluble and low protein-binding
T/F protein bound drug will not be distributed to tissues to produce the effect and instead will be excreted
F; they will not be able to enter tissues to produce a desired effect, but they will also not be excreted
what is the consequence of plasma protein binding on half-life and drug intensity
increases half-life but decreases intensity of effect
T/F protein/drug binding is a nonlinear, saturable process
T
The local anesthetic lidocaine is a weak base. It must diffuse into neurons to reach its target receptors. If infected tissue is more acidic than healthy tissue, would you expect lidocaine to be more or less effective in infected tissue.
Less effective.
Rationale:
1) to diffuse into tissues, lidocaine needs to be in its unionized form (aka B)
2) in an acidic environment, lidocaine will be in the BH+ form, which is ionized
Explain: Mepivacaine is a weak base used for equine nerve blocks that diffuses better in tissues than other local anesthetics because it has a lower pKa
pH is greater than pKa - favours the B form, which makes it easier to diffuse into tissues
From a pharmacokinetic point of view, what are the two compartments of the body
1) vascular compartment
2) everything else
a higher Vd indicates
more drug has left the bloodstream and entered tissues
if some drug has been distributed to other tissues, Vd will be ____________ than blood volume
greater
how do we express Vd
L/kg BW or mL/kg BW
drugs with a small Vd may require _________ doses to be effective
larger
drugs with a large Vd may take _______ time to excrete
longer (the drug needs to be in the blood to be delivered to an organ of elimination)
You would expect a water-soluble (ionized) drug to have a ________ Vd, whereas you would expect a lipid-soluble (unionized) drug to have a ___________ Vd
small to intermediate; high
What would be more readily excreted in the urine, a drug with a pKa of 7.4 that is a weak acid or a weak base? Assume blood pH = 7.4 and urine pH = 5.4
weak base; want it to be in its ionized form in the urine (BH+ vs AH)
What is another word for metabolism
biotransformation
define metabolism
any chemical change made to a drug from the body
what are the two goals of metabolism and what is the exception?
1) make drug more water soluble
2) make drug inactivated
Exception: pro-drugs that must be metabolized into their active form
what is the main location of drug metabolism
liver
what are phase I reactions? what are phase II reactions?
phase 1: non-synthetic “functionalization”
phase 2: biosynthetic “conjugation”
phase I reactions inactivate drugs mainly by what mechanism
oxidation
in comparison to the parent molecule, phase 1 metabolites are usually more (2)
water-soluble and chemically reactive
phase II metabolites are usually (3)
polar, inactive and readily excreted
what dietary component of phase II metabolism are cats deficient in
glucuronic acid
cats are deficient in many transferases for phase II metabolism, which has what consequence
they have difficulty metabolizing many drugs and they therefore reach higher concentrations and have longer duration of action
what is the normal process of acetaminophen metabolism and how does this differ in the case of toxicity
normally: undergoes phase II metabolism by conjugation to glucuronic acid or sulphate
overdose: conjugation pathways overwhelmed -> metabolized via phase I metabolism by P450 enzymes into highly reactive NAPQI -> liver failure
you have a cat present with acetaminophen toxicity - what is your first step?
administer a source of glutathione -> get the phase II conjugation pathways working again
what are 6 factors that impact the rate of drug metabolism
1) enzyme induction and inhibition
2) multidrug therapy
3) distribution
4) age
5) genetics
6) disease
A food/drug constituent increases the activity of a hepatic enzyme. What effect will this have on drug action and rate of drug metabolism?
decreases the drug action by increasing the rate of drug metabolism
what are the organs involved in elimination
kidney, liver, lungs, intestinal tract, other (sweat, milk, tears)
T/F glomerular filtration is a non-saturable and non-selective process
T
a constant ________ of drug in the body is eliminated per unit tme
fraction
after how many half-lives have we essentially eliminated all of the drug
4-5
what is steady state
when plasma concentration of drug varies between two set levels without any accumulation
steady state is achieved within how many half-lives for any regular dosing regimen
5
why is a steady state reached and the plasma concentration doesn’t continually go up
kidneys filter a constant fraction of drug per time; a situation is reached within the dosing regimen where the amount administered per dose is equal to the amount cleared by the kidneys, so the values stabilize
how do we minimize fluctuations in drug concentration
giving small doses frequently (ex. a CRI)
if rate of drug administration is doubled, what happens to the steady state drug concentration, Css
doubles
how can you reach Css instantly
give a loading dose, wait 1 half-life and then give normal dose
In the case of renal failure, what happens to drug half life and why
increases, because the rate of excretion decreases
how are some drugs excreted by the liver
undergoing phase II metabolism followed by active excretion into bile -> into gut -> eliminated in feces
T/F enterohepatic recycling depends on route of administration
F; just depends on secretion of the drug into the bile
what is drug response proportional to
concentration of free drug at the target organ
how do we express clearance
volume (because it will not change based on the concentration of drug)
