FMS Week 4 Flashcards
Pharmacology
albumin
plasma protein binding agent for mostly neutral/acidic drugs
Significance of gefitinib and EGFR mutations
only 10% of patients respond to gefitinib due to somatic mutations around the ATP-binding pocket of the EGFR tyrosine kinase domain
DR = ([Rt][D]/(Kd + [D]))
Version of Michaelis-Menten that relates drug receptor binding to affinity, total number of receptors, and body concentration
what physiochemical properties of drugs affect distribution out of the plasma?
lipid solubility (partition coefficient) and pKa of the drug
β2AR polymorphisms and albuterol response
Homozygotes for Arg-16 in β2AR gene are 5.3x (and heterozygotes 2.3x) more likely to respond to albuterol
what is an example of a covalent bonding drug?
aspirin
what is the therapeutic window of a drug?
the range of concentrations between the minimum therapeutic concentration and the toxic concentration
what factors affect clearance of a drug?
greater volume of distribution and higher elimination constants increase clearance
TPMT
enzyme associated with thiopurine inactivation, overactive in over-metabolizers leading to decreased active (cytotoxic) products
structural changes of hydroxylation
RCH2CH3 to RCH2CH2OH
t{1/2} = 0.693(Vd)/CL
formula for the half-life of a drug based on the clearance (which is a function of the elimination constant)
what is the latency of a drug?
the time from administration to therapeutic concentration
what are spare receptor agonists?
when maximal response is achieved without using all of the receptors (intrinsic activity greater than 1)
what factors affect GI absorption?
surface area, GI pH, GI motility/gastric emptying, blood flow
how much non-interstitial, extracellular water is there in the body?
3L in a 70kg man (20% of extracellular water) in the plasma
what is the duration of a drug?
the time that blood concentrations stay in the therapeutic window
how would you calculate the desired dose of a medication?
Dose= Volume of distribution X therapeutic concentration
what form of bases can pass through lipid membranes?
unprotonated weak bases
most common phase II mechanism?
glucuronidation
what is the intrinsic activity of an antagonist?
zero
t{1/2} = 0.693/k
Formula for the half-life of a drug based on the elimination constant
define volume of distribution
the volume of fluid needed to contain the administered amount of drug at the concentration measured in blood or plasma (V=amount administered/concentration measured)
what factors decrease the rate of passive diffusion?
thickness of the membrane, concentration on “inner” side of the membrane
inhibitors of CYP
cimetidine, erythromycin, ketoconazole, chloramphenicol, acute alcohol, grapefruit juice
what is true of the drug concentration [D] in first-order drug metabolism?
It is small; less than the metabolism constant (Km)
D = D{0}^e-kt
Rate equation for the AMOUNT of drug present in the body at a given time after administration
how do drugs permeate across placental barrier?
the placenta is highly permeable via simple diffusion
what type of transport is involved with endogenous compounds?
facilitated diffusion
how would the plasma concentration and half-life of a drug compare for an undermetabolizer vs a hypermetabolizer?
the plasma concentration would be higher and the half-life would be longer for an undermetabolizer
what are the 2 key microsomal enzymes?
NADPH-cytochrome p450 reductase and cytochrome P450
define pharmacokinetics
actions of the body on drugs
what are the types of microsomal metabolism induction?
phenobarbital-like (more enzyme) and Polycyclic hydrocarbon-like (decreasing metabolism)
What is ED50?
the dose at which 50% of the population reaches the desired effect
what form of acids can pass through lipid membranes?
protonated weak acids
what is the quantitative definition of affinity?
the concentration of drug (Kd) at which ONE-HALF of total receptors are bound by the drug; molar qty, (lower value = greater affinity)
margin of safety
the 1% toxic dose/ 99% effective dose
less than 1 would be less safe, greater than 1 would be more safe
TI = TD50/ED50
Formula relating therapeutic index to the 50% toxic and effective doses
C = (Q/kVd) * (1- e^kt)
formula for concentration of a drug in the body following infusion for an amount of time
what is the role of intestinal enzymes in free drug action?
glucuronides may be hydrolyzed by intestinal or bacterial β-glucuronidase to be reabsorbed
how does blood/urine acidity affect excretion?
acidic urine (relative to blood) will take in basic drugs for excretion and relatively basic urine will take on acidic drugs
what is true of the of the drug concentration [D] in zero-order drug metabolism?
it is relatively high; often unpredictable
how do drugs permeate across the blood-brain barrier?
primarily through ATP-driven drug efflux pumps on the luminal plasma membrane
what mechanisms contribute to extrarenal clearance?
hepatic metabolism and biliary excretion
characteristics of plasma protein binding
reversible, nonselective, & competetive
how much body water belongs to erythrocytes?
3L (about 10% of intracellular water)
what are the cardiovascular factors of drug distribution?
cardiac output and regional blood flow
globulins
plasma protein binding agent for basic drugs
MD = LD - (LD)e^-kt
Formula for calculating the maintenance dose needed based on the size of the loading dose and time since administration
inducers of CYP
phenobarbital, phenytoin, polycyclic hydrocarbons, chronic alcohol, St. John’s wort
what is the ratio of extracellular water to intracellular water in the body?
1:2 (14L to 28L in a 70kg man)
what are the characteristics of carrier-mediated transport?
can occur against concentration gradient, has competitive inhibition for similar substrates
formula for loading dose for a given route of administration?
loading dose=
(V(d) * C)/F
F=bioavailability
structural changes of sulfoxide formation
R1SR2 to RSOR2
what is the intrinsic activity of an agonist?
greater than zero
what is an antagonist?
has no intrinsic activity itself, but interferes with the binding of a ligand (endogenous or agonist)
describe the biotransformation effects of the liver
products have generally lower biological activity, and are more polar (facilitating excretion)
Difference between desensitization and down-regulation
Desensitization is rapid, the result of receptor phosporylation, and results in decreased affinity
Down-regulation is slower, is the result of receptor turnover, and results in decreased receptor numbers
list the routes of drug administration
PO, IV, IM, SC, rectal, inhalation, sublingual, intrathecal, transdermal
Re = γ([Rt][D])/{Kd + [D])
version of michaelis-menten that relates receptor response to intrinsic activity, receptor concentration, body concentration, and affinity
what factors affect affinity of a ligand to its receptor?
number of interacting sites, types of forces involved
structural changes of desulfuration
R1CSR2 to R1COR2
how much body water does a normal 70kg man have?
42L (60% of body weight)
G6PD deficiency results in what? by what mechanism?
hemolysis, inability to process oxidative stressors
where does first-pass metabolism occur?
the liver, and to a lesser extent the intestinal epithelium
what is the difference between noncompetetive antagonists and inverse agonists?
Noncompetetive antagonists bind to ligand-dependent receptors away from the ligand binding site to inhibit
Inverse agonists bind to ligand-independent receptors to inhibit their constitutive activity
what classes of drugs are metabolized by CYP2D6?
antidepressants, antiarrhythmics, beta blockers, and analgesics
ATP-binding cassette (ABC)
3 families (B,C, &G) of P-gp transporters involved in carrier-mediated transport
components of Glucuronidation
Phase II metabolism; microsomal enzyme UDP glucuronosyl transferase and donor uridine 5’-disphosphate (UDP) glucoronic acid
rasburicase
drug that leads to increased peroxides from uric acid breakdown, which causes hemolysis in people with G6DP deficiency
what types of drugs are associated with facilitated diffusion?
analogs of endogenous compounds
what is an agonist?
a drug that mimics the effects of the endogenous ligand for a receptor (has intrinsic activity)
what is the significance of fat reservoirs on drugs?
may affect onset and duration of action
what types of permeation is associated with lipid-soluble drugs?
passive diffusion
what is the relationship between renal function and plasma half-life of a drug?
plasma half-life increases exponentially with decreasing renal function
what factors increase the rate of passive diffusion?
area of the membrane, concentration on “outer” side of the membrane
what factors determine bioavailability of a drug?
Physiological (first pass metabolism, blood flow), Physiochemical (drug solubility), Biopharmaceutical (tablet dissolution, particle size)
V = Vmax[D]/(Km+[D])
Michaelis-Menten equation for determining the RATE of drug concentration at a given body concentration
MD = (CL * Css)/F
Formula for calculating the maintenance dose needed based on clearance, steady-state concentration, and bioavailability
how much of the extracellular water in the body is interstitial?
about 80% (11L in a 70kg man)
what is the usefulness of partial agonists?
tend to be safer (does not elicit maximal response even at maximum receptor binding); intrinsic activity is less than 1
what disease factors might affect drug metabolism?
chronic liver disease (hepatitis, cirrhosis, cancer), decreased hepatic blood flow (cardiac dysfunction), pulmonary/thyroid disease
C = C{0}^e-kt
Rate equation for determining CONCENTRATION of a drug at a given time after administration
define the effect of partition coefficient on absorbtion
greater partition coefficient indicates faster absorbtion (function of lipid solubility)
structural changes of deamination
RC(NH2)HCH3 to RCOCH3 +NH3
what types of drugs are associated with endocytosis/exocytosis?
a few very large or impermeant substances
typically how long does it take for plasma concentration to plateau after first dose?
about 4 half lives
what are thiopurines used for?
autoimmune conditions, leukemias, and organ transplant rejection prevention
define pharmacodynamics
actions of drugs on the body
what is the role of P-glycoproteins?
they oppose absorption of certain molecules. Found in GI tract, liver, kidney, blood/barrier etc.
what is typically true of the rate of metabolism (V) in first-order drug metabolism?
it is generally less than 10% of the Vmax, and it is directly proportional to the concentration [D]
TPMT
Enzyme that leads to inactive metabolites of thiopurines
enterohepatic cycling
water-soluble drugs are eliminated in feces (via bile), lipid-soluble drugs are reabsorbed
what is true of the rate of drug metabolism (V) in zero-order drug metabolism?
V= Vmax; the rate cannot go any faster
structural changes of dealkylation
RNHCH3 to CNH2O
rank the types of bonding from strongest to weakest
Covalent, Ionic, Hydrogen, Hydrophobic, Van der Walls
what receptor is associated with codeine?
mu-opioid receptor
Define bioavailability
fraction of unchanged drug that reaches systemic circulation (AUC of administration route/ AUC of IV)
how are glucuronides eliminated?
in the bile
Describe tamoxifen metabolism
Prodrug for endoxifen, metabolized by CYP2D6, higher metabolism leads to better disease-free survival in breast cancer
what type of drugs are associated with passive diffusion through aqueous filled pores?
very small molecules
G6PD deficiency?
assoated with haemolytic anaemia due to decreased antioxidant capacity (less than 60% enzyme activity), somewhat x-linked recessive expressivity (many genetic variants)
what are the 4 pharmacokinetic processes?
ADME; absorption, distribution, metabolism, elimination
