Pharmacokinetics Flashcards
what can leave the blood stream to go to the site of action?
free drug
what are the mechanisms of membrane penetration?
- passive diffusion
- carrier mediated transport - facilitated diffusion, active transport
- filtration
- Transcytosis
what does the henderson-hasselbalch’s equation determine?
extent of ionization
what is the henderson-hasselbalch equation for acidic drug and basic drug?
how are weak acids ionized?
donating proton
how are weak bases ionized?
accepting protons
In a low pH environment which is hard and easy to ionize? (acid or base)
easy - base
hard - acid
In a high pH environment which is hard and easy to ionize? (acid or base)
easy - acid
hard - base
which kind of drug in an acidic medium will be rapidly absorbed?
weak acid
less ionized -> more lipid soluble -> rapidly absorbed
what kind of drug in a basic medium will be rapidly absorbed?
weak base
less ionized -> rapidly absorbed
what will happen if a weak basic drug diffuses into an acidic medium?
will become ionized and accumulate in the environment
what happens with strong acids and strong bases in any kind of medium?
always ionized in body -> not lipid soluble -> cannot penetrate membranes by passive diffusion
How is a non-ionized weak acid distributed between compartments with different pH?
conc. same on both sides because it is freely diffusible
How is a ionized weak acid distributed between compartments with different pH?
depends on pH and pKa
How is the total concentration of a weak acid distributed between compartments with different pH calculated on each side?
sum of concentration of ionized and non-ionized form of drug
what is ion trapping?
acids accumulated in basic environment
bases accumulated in acidic environment
How does the urine become more acidic in drug excretion? What does this eliminate more of?
ammonium chloride increases -> the elimination of bases
How does the urine become more basic in drug excretion? What does this eliminate more of?
sodium bicarbonate increases -> the elimination of acids
what is P-gp? what does it do?
- Permeability glycoprotein (P-glycoprotein)
- uses ATP to pump out a wide variety of substrates across extra and intracellular membranes
- DRUG EFFLUX
what are the other names for P-gp?
MDRI or ABCBI
where is P-gp found?
- extensively distributed
- intestinal mucosa, hepatocytes, renal PT cells, adrenal gland, and capillary endothelial cells (compromising blood-brain barrier)
Define absorption
how drug enters body fluids and distributes throughout organism
what are the factors that modify absorption
solubility, dissolution, concentration, BF, absorbing surface, pH, contact time
Define bioavailability
amount of active drug available at site of action
variable = F
what type of drugs have a bioavailability of 100%
IV
Relationship between IV and oral administration of same drug
DoseIV = DosePO x F
what is the bioavailability affected by?
- decomposition/inactivation of drugs in intestine
- degree of absorption
- metabolism in wall of gut or liver
- transport of drug by P-gp back into lumen of gut
Define first-pass effect
initial metabolism of drug while passing through wall of gut and liver
what is the most common, convenient, and economical method of drug administration?
oral
what are disadvantages of oral medications?
-irritation to intestinal mucosa, emesis
-destruction of drugs by enzymes or low pH
-irregularities in absorption
-metabolism by intestinal flora
-absorbed drug exposed to liver
-gastric emptying time
-binding to food
what are the advantages and disadvantages for slow release formulation?
-slow, uniform absorption of drug for several hours
-absorption often irregular and erratic
when are drugs given parenteral?
when drugs cannot be given by enteral route
what are parental routes
IV, IM, SubQ, intraperitoneal, intraarterial, epidural
Define parenteral
outside the intestines
When is inhalation used for drugs?
gaseous anesthetics, aerosols, rapid absorption
where can topical drugs be applied?
skin, eye, nose, throat
Does topical drugs achieve local or systemic absorption?
systemic
what conditions affect distribution?
protein-binding capacity -> drug capacity -> constant free fraction
what form of drug and protein is active and inactive?
where can drugs accumulate in the body and act as a resevoir?
fat, tissues, bone
what does storage depots of drugs do to the drug?
decrease plasma levels and prolong half-lives
what are the sites of drug exclusion
CSF, ocular fluid, endolymph fluid, fetal fluid, pleural fluid
Equation of apparent volume of distribution
Calculate Vd
when do we see a large Vd?
drugs that distribute extensively or bind extensively
when do we see a low Vd?
drug mostly present in the plasma
what is the principal goal of biotransformation of drugs and xenobiotics (foreign compounds)?
promote elimination from the body
what are the qualities of most pharmacologically active drugs?
lipid soluble, unionized or partially ionized, strongly bound to plasma proteins, not readily excreted by kidney, tend to remain in body for a long time unless liver metabolizes them and kidney excretes them
Define phase 1 reaction
convert lipid soluble parent compounds to more polar metabolites (less lipid soluble)
Are most phase 1 metabolites excreted?
yes only some undergo phase 2 rxns before excreted
what are the two phase 1 reactions?
non-microsomal (non-inducible)
microsomal (inducible)
How are non-microsomal phase 1 rxns metabolized
esterases and amidases, monoamine oxidases, alcohol and aldehyde dehydrogenases
How are microsomal phase 1 rxns metabolized
P450
what does phase 2 synthetic reactions result in?
larger molecular weight, increased polarity, mostly inactive
what is the only microbial phase 2 rxn? Is this inducible or non-inducible?
Glucuronidation, inducible rxn
List phase 2 rxns
glucuronidation, acetylation, glutathione conjugation, glycine conjugation, suldation, methylation, water conjugation
which phase reaction introduces or unmasks certain functional groups?
Phase 1 - OH, SH, NH2, etc.
what is enterohepatic circulation of drugs
increases 1/2 life of drug
conjugate from liver metabolism goes back into SI via bile -> colon/rectum, bacteria in gut combines conjugate to form drug and it goes back into liver
what contributes to renal excretion of drugs and drug metabolites?
glomerular filtration, active tubular secretion or reabsorption, passive diffusion across tubular epithelium
what is clearance?
measure of capacity of body to remove drug
Systematic clearance equation
rate of elimination equation
what two variables does clearance relate?
rate of drug elimination to its plasma concentration
what is the 1/2 life equation?
what is the kinetics of first order elimination?
-exponential
-constant proportion of drug eliminated in a unit time
what is the first order elimination equation?
Define half life
time required to change amount of drug in body by 50%
Define zero order elimination
constant amount is eliminated in a unit time
which order of elimination is associated with amount?
zero order
which order of elimination is associated with proportion?
first order
how many 1/2 lives does it take to obtain a steady state plasma level
5
when does the biologic effect happen?
After steady state
what is the relationship of concentration of steady state to dose and clearance?
Css directly proportional to dose
Css indirectly proportional to clearance
how long do you have to wait before determining plasma steady state levels of the drug in the body?
5 half lives
how many half lives does it take to eliminate most of the drug?
5 half lives
what will shortening the dosing interval do to the steady state concentration
raise it
what will lengthening the dosing interval do to the steady state concentration?
gradual dec of plasma level and lower steady state
Is the time to reach steady state levels related to the size of the dose?
no
Define loading dose
dose used to reach immediate therapeutic conc.
what is the loading dose equation
loading dose = Vd x TC
TC (target conc.) = Css
what is the dosing rate and elimination rate equation?
what is the maintenance dose equation?
what are the P450 inducers?
rifampin, barbiturates, phenytoin, glucocorticoids, st johns wort
what are the P450 inhibitors
CYP3A4 inhibitors
cimetidine, ketoconazole, diltiazem, erythromycin, verapamil, fluoxetine
