exam 3 Flashcards
ADME stands for
Absorption, Distribution, Metabolism, Excretion
Characteristics determined by concentration vs time profile
Onset, duration, intensity
Time between administration and pharmacological effect
Onset
How high the concentration is
Intensity
Length of time above MEC
duration
Minimum effective concentration
MEC
The study of the absorption, distribution, biotransformation, and elimination of xenobiotics
Pharmacokinetics
The study of the molecular, biochemical, and physiological effects of xenobiotics and their mechanisms of actions
Pharmacodynamics
Patho, pharmacodynamics, pharmacokinetics make up
pharmacotherapeutics
Most rapid onset route
Intravenous
Slowest onset route
Oral
Routes of administration
Ingestion, Inhalation, Dermal, Parenteral
IV, SC, IM, Intraperitoneal equal what route
Parenteral
Reduction of absorption impacts
intensity and duration
Reduction of speed of entry impacts
Onset
AI phenobarbital to hydroxyphenobarbital
Hydroxylation
AA procainamide to N-acetylprocainamide
acetylation
IA codeine to morphine
demethylation
AR
acetaminophen to reactive metabolite
Major routes of excretion
Renal (kidney) is primary
Biliary (feces)
Other routes of excretion
Pulmonary, salivary, mammary
Which antibiotic is a better choice in a patient with renal failure?
The one eliminated in bile not urine
Barriers that may reduce amount of drug that reaches site of action
gut wall metabolism, degraded in stomach, dose distributing away from target tissue, can’t enter membranes, enzymes
The fate of a drug once it enters the systemic circulation
Disposition
A chemical that is normally foreign to the body includes drugs, occupational chemicals, environmental compounds
Xenobiotic
___ percent of problems used to be from ADME, now its ___ percent
40%, 10%
___ barriers like the BBB can significantly reduce the amount of drug that enters the site of action
Tissue
Morphine is a metabolite of codeine and this metabolite is responsible for the analgesic effect when codeine is administered. In a patient who has a genetic defect such that they cannot metabolize codeine, the magnitude of pain relief would be expected to be _____ compared to normal patients.
Decreased
Factors that determine movement of a drug across membranes
Characteristics of membrane, mechanism of passage, swell time, physiochemical characteristics, pH of microenvironment, surface area
Why does most oral drug absorption occur in the small intestine?
Inner wall of small intestine covered by folds of kerckring plicae circulares, surface contain tiny villi and microvilli that increase surface area
food transit time in mouth
1 min
food transit time in esophagus
4- seconds
food transit time in stomach
2-4 hours
food transit time in small intestine
3-5 hours
food transit time in colon
10 hours to days
Carrier mediated transport examples
Facilitated diffusion and active transport
95% of drugs are absorbed by
passive transcellular diffusion
Transcellular permeability can be increased by
removing charged ionized groups, increasing lipophilicity, reducing size
The passive movement of drug through lipid membranes driven by concentration gradient
Transcellular diffusion
The passive movement of drug between cells via tight junctions driven by concentration gradient
Paracellular diffusion
A carrier mediated process that involves a transport protein which moves drug with a concentration gradient
facilitated diffusion
A carrier mediated process that involves a transport protein which moves drug against a concentration gradient
active transport
A process in which a cell engulfs and internalizes a particle
Endocytosis
Primary site of absorption after oral administration because of high surface area
small intestine
altered by food or drugs, influences extent and rate of drug absorption
gastrointestinal transit time
carrier mediated is different than passive because its
saturable and subject to drug drug interactions
Selectively move substrates across cell membranes
transporter proteins
remove drugs from cells that have entered via passive diffusion, can reduce the amount of drug that accumulates in certain tissue such as the brain
Efflux transporters
Slowing gastric emptying would be expected to have which effect on the absorption of a drug absorbed by passive diffusion?
it will take longer to reach peak concentration
Which moves mechanisms down a concentration gradient?
Paracellular, transcellular, facilitated diffusion
Co-administration of an inhibitor of the efflux protein p-glycoprotein would have what effect on the oral absorption of a drug that is a substrate for pgp?
The inhibitor will increase the amount of drug absorbed
which of the following would not increase transcellular permeability? remove ionized groups, decrease lipophilicity, reduce molecular size
decreasing lipophilicity
under passive diffusion rate of transport increases as concentration _____
increases
move solutes out of the cell
efflux transporters
Consequences of efflux transporter p glycoprotein
Limited drug absorption, enhanced drug elimination, limited distribution
For large molecules, depend on particle size, frequently used for nanoparticle drug delivery
endocytosis
The movement of drug molecules across biological membranes into various tissues in the body
Distribution
The movement of drug molecules across vascular endothelial cells and into interstitial space
Transvascular transport
A transvascular transport process driven by pressure
Convection
A transvascular transport process driven by a concentration gradient
Diffusion
The concentration of a drug within a tissue due to pH differences that lead to ionization of the drug in the tissue environment
drug trapping
The initial movement of drug from highly perfused tissues to poorly perfused tissues
Redistribution
slower distribution, driven by pressure, convection
perfusion
driven by concentration gradient, diffusion
permeability rate limited
binding of drug to plasma protein
restricts distribution
most drug in tissue is bound to
nonspecific sites and not receptors
only ___ is phamacologically active
free drug
different ph environments causes
drug trapping
BBB properties
tight junctions, negative head groups, high pgp concentration
how drugs enter cns
existing transporter, directly to CNS, disruption of BBB, appropriate physiochemical properties
efflux activity can be so extensive drug in brain doesnt reach
measurable concentrations
___ molecules dont cross membrane to fetus
large polar
driving force for convection
pressure
driving force for diffusion drug movement
concentration gradient
A drug that is only distributed into vascular space will exhibit a monoexponential blood concentration vs time curve after intravenous administration t of f
true
Which drug is most likley to undergo transvascular transport via convection
the biggest dalton one
A decrease in plasma protein binding will result in an
increase in amount of drug in tissue (only free drug crosses)
A change in the structure of a drug molecule such that is is no longer transported by pgp will have what effect on CNS concentration?
higher cns concentration (pgp only transports out bc its efflux)
Kidney route excretion process
GABEPVDC
Mechanisms of renal excretion
Filtration, active tubular secretion, tubular reabsorption, biotransformation
Determinants of filtration
MW <5000, number of nephrons, protein binding, renal blood flow
Filtration happens in
glomerulus of bowmans capsule
test for renal disease
if protein in urine then its a sign of disease
Active tubular secretion location
Proximal convoluted tubule
active tubular secretion graph
linear then hits a max
drugs that under go ATS an exhibit
Stereoselective renal secretion
clearance vs mw relationship
indirect
dose and urinary excretion relationship
indirect
The active transport of drug from blood to renal tubule in proximal tubule
active tubular secretion
Movement of solute from inside renal tubule back into the blood
tubular reabsorption
reabsorption of drug from small intestine after drug has been excreted through bile into intestine
enterohepatic recirculation
food stimulates release of bile with drug in it
dose dumping
Primary routes of drug excretion
renal and hepatic
secondary routes of drug excretion
pulmonary, salivary, mammary
Most important mechanisms of renal excretion
filtration, active tubular secretion, tubular reabsorption sometime biotransformation
glomerular filtration is largely influenced by
molecular size and plasma protein binding
Drugs which undergo active tubular secretion exhibit
saturation at high concentration and subject to competition
tubular reabsorption is passive and driven by
concentration gradient and ph sensitive
carrier mediated tubuar reabsorption
process is saturable
hepatic elimination involves
metabolism and biliary excretion
when a part of a dose is eliminated before entering circulation
first pass effect
pgp and mdr1
actively secrete drug from hepatocyte into bile
primary factors determining biliary secretion are
molecular weight and polarity
Which is most likely subject to competitive drug drug interactions
tubular secretion
As mw increases in renal elimination, filtration
decreases
plot mw and drug excreted in bile
direct relationship
Effect of enterohepatic recirculation on half life of a drug
increases half life
decrease in plasma protein binding in glomerular filtration results in
increase of renal elimination
which vitamin undergoes bioactivation in the kidney
vitamin d
phase 1 metabolism
biotransformation of xenobiotics that includes oxidation, hydroxylation, to introduce or expose a functional group
phase 2 metabolism
involves conjugation with a polar group yielding a polar metabolite that can be excreted in bile or urine influenced by availability of co substrate
Most important organ where biotransformation takes place
liver
frequently but not always subsequent to phase 1
phase 2
two components in cytochrome p450 system
cyp450 reductase and cyp450
indentification of cyp450 important for predicting
drug drug interactions
cyp450 generates
reactive oxygen species with detrimental cellular effects
critical determinant in ability to bind to cyp450 and binding affinity
geometric shape/conformation
potent inhibitors of cyp450 that serve as sixth axial ligand for iron in heme
nitrogenous compounds
covalent binding renders cyp450 inoperable and new cyp450 must be synthesized to restore metabolism
mechanism based inhibitors, suicide inhibition
induction of metabolism results from
activating transcription factors
when drugs induce the same cyp450
autoinduction
inducers of drug metabolizing enzymes exhibit
cross talk
increases polarity and size of drug molecules and reduces pharmacologic effect
phase 2 metabolism
variablity in diet, other drugs, disease, environment can be more important than
genetic variability
which pathway increases mw
phase 2
which pathway results in metabolite eliminated in bile
phase 2
Which inhibits cyp4a4
ritonavir
what type of cyp450 inhibitor produces the longest lasting inhibition
mechanism based inhibition
inducers of cyp450 are selective for one enzyme or enzyme family t o f
false
