Pharmacology E1 Flashcards
Controlled substances scheduling system
Schedule I – high potential for abuse; no accepted medical use (eg, heroin)
Schedule II – high potential for abuse; currently accepted medical use (eg, morphine)
Schedule III-V
Lesser potential for abuse
Schedule VI
All other prescription drugs
Pregnancy risk categories
Category A – studies fail to demonstrate risk to fetus in first trimester, no evidence of risk in later trimesters
(category B/C/D/X higher risk)
EC50
The molar concentration of an agonist that produces 50% of the maximal possible effect of that agonist, can be stimulatory or inhibitory
ED50
Dose of drug that produces, on average, a specific all-or-none response in 50% of a test population
if the response is graded –> dose that produces 50% of the maximal response to that drug
Antagonist
drug that reduces the action of an agonist, often acting by the same receptor
Competitive antagonism
Result: apparent dec in affinity, no change in maximal response
- binding of agonist and antagonist is mutually exclusive
- usually surmountable (with inc [agonist])
- shift to RIGHT
Noncompetitive antagonism
insurmountable
Antagonist could inactivate receptors, leading to dec in maximal response, but no change in affinity of the remaining receptors
LD50
dose of the drug that produces death in 50% of a population of test animals
Therapeutic Index
ratio of LD50 to ED50 (or LC50:EC50) –> relative indication of safety. Want a higher #
*need to avoid overlap between high end of therapeutic effect and low end of toxic effect, bc pts may req larger, potentially toxic doses
(want a wide window)
Therapeutic window
range of drug concentrations in blood which produce a therapeutic response without unacceptable toxicity
Efficacy
Efficacy = Fraction of Emax attained
partial agonist does not attain Emax
pKa of a drug
pH w/ [ionized form]=[non-ionized form]
acidic drug in pH < pKa –> mostly non-ionized (protonated)
basic drug in pH < pKa –> mostly ionized (protonated)
*uncharged forms readily pass thru membranes
An acidic drug with pKa of 5 will be in what form in blood, stomach?
blood: mostly ionized, non-protonated
stomach: mostly non-ionized, protonated
A basic drug with pKa of 5 will be in what form in blood, stomach?
blood: mostly non-ionized (non-protonated)
stomach: mostly ionized (protonated)
Kidney excretion of drugs
ionized drugs excreted, non-ionized reabsorbed
if acidify urine –> basic drugs excreted
if alkalinize urine –> acidic drugs excreted
Concerns for breast milk
When mother is taking basic drugs (narcotics), bc milk is more acidic, they will be concentrated in the milk
Volume of distribution
Vd=dose/Cp (units of vol)
relates amount of drug in body to [drug]plasma
not a real volume
related to lipid solubility but does not tell you where drug is
Loading dose
Dl=Vd * desired Cp
if any other routes, oral etc, include bioavailability
Dl=(Vd * Cp)/F
Clearance
Cl= dose rate/Cp (steady state)
measure of vol of plasma cleared of drug content per unit time
units of vol/time
Also:
Cl = dose / AUC
Cl = Vd x k
Cl = Q x E
weak acids, which form is nonionized/ionized?
protonated, non-ionized
non-protonated, ionized
weak bases, which form is nonionized/ionized?
non-protonated, nonionized
protonated, ionized
Sites of drug metabolism
*Liver Intestine Lungs Kidneys Placenta Plasma
first-pass metabolism
process by which some orally administered drugs are metabolized by the GI/liver such that only a fraction of what is administered reaches the systemic circulation
also called “pre-systemic extraction”
Microsomal enzymes
- Cytochrome P450 (CYPs)
- UDP Glucuronosyltranferases (UGTs)
others: NADPH-CYP reductase Glutathione S-tranferases Epoxide hydrolases Flavin-containing monooxygenases (FMOs) Carboxyl esterases Aldehyde dehydrogenases
Phase I Drug Metabolism
Phase I (more active change)
- CYP 450 (oxidation)*
- Alcohol & aldehyde oxidation
- Azo & nitro reduction
- Hydrolysis
Phase II Drug Metabolism
Phase II (more passive change) Glucuronidation* Acetylation Sulfate conjugation Methylation
Cytochrome P450 enzymes - most important quantitatively?
CYP3A4/5 - written as CYP3A (more than 50% of currently marketed drugs)
In both liver and intestinal mucosa
Most common conjugation rxn
Glucuronidation
Multiple UDP-glucuronosyltransferases
UGT1A1 & UGT2B7 most studied
Substrates: Lorazepam, Morphine, Zidovudine (AZT)
Prodrug
If the “drug” is inactive and the “metabolite” is active
exp. plavix, codeine
Acetaminophen and hepatotoxicity
Normally involves direct conversion to no n-toxic glucuronide metabolites
Small amount of clearance mediated by CYP450 enzymes –> yields toxic NAPQI (usually conjugated to glutathione, but only so much) –> hepatotoxicity
Risk fx for acetaminophen toxicity
Anything that inc bioactivation (inc specific CYP enzyme activity)
Anything that impairs detoxification
Anything that depletes glutathione levels
Sources in variability in drug metabolizing
*Genetics (polymorphisms such as CYP2D6, CYP2C19, acetylation, others)
*Other drugs
Disease states
Habits (smoking, exercise)
Diet
Environment
Age (+/-)
Gender (+/-)
Most important transporter, functions to protect body from unfavorable foreign substances
P-glycoprotein (P-gp), known as Multidrug resistance-associated protein (MRP)
Determinants of bioavailability
Cmax: peak-plasma concentration
Tmax: Time of peak concentration
AUC: area under the plasma concentration curve (systemic exposure)
measure of rate and extent of absorption
First order behavior
Rate of elimination –> proportional to Cp
Clearance –> independent of Cp, constant
- A constant FRACTION of drug removal per unit time.
*most drugs exhibit this
Zero order behavior
Rate of elimination –> independent of Cp, constant
Clearance –> dependent on Cp
- A constant AMOUNT of drug removal per unit time.
*usu occurs when elimination process is saturated
Inhibitors
dec enzyme activity leading to a dec in metabolite prod
plasma levels of parent drug –> inc
clinical effect –> enhanced
*opp for prodrug
Inducers
inc enzyme activity leading to increase in metabolite being made
plasma levels of parent drug –> dec
clinical effect –> diminished
*opp for prodrug
Important routes of drug administration
Oral (P.O.) Parenteral -subcutaneous (SC) -intramuscular (IM) -intravenous (IV)
Bioavailability
Fraction of drug absorbed systemically after extravascular vs. intravascular admin (F)
F=AUC(oral)/AUC(IV)
> 0.90 –> Better
0.02 –> crappy
Reasons for low bioavailability
Poor absorption Pre-systemic extraction (first-pass metabolism) -hepatic -enteric (CYP3A) Efflux transport (P-glycoprotein)
Two most common pharmacokinetic drug interactions
Absorption (binding/chelation vs pH related)
Metabolism (induction vs inhibition)
Aminoglycoside Kinetics (eg, gentamicin, tobramycin, amikacin)
Not absorbed orally
Poor lipid solubility
Little protein binding
Vd usually around 0.3 L/kg (low)
Metabolism - none
Excretion - primarily renal
Genetic polymorphisms
SNPs *frequent, don’t prod change usually
Indels *infrequent but higher likelihood of having functional effect
CYP450 polymorphisms
select alleles (CYP450 2C19*3) - European and East Asian population --> poor metabolizers Common substrates: omeprazole, plavix *prodrug, so will be more INACTIVE with this drug, bc cant convert it into active form via CPY enzymes
Whole gene polymorphisms
CYP450 2D6
- african Americans, europeans, Ethiopians*** –> ultraRAPID metabolizers
Exp: antidepressants, antipsychotics.
Codeine, tamoxifen –> both PRODRUGS, so this population will form active form FASTER –> more likely to have toxicity
^greater ant codeine –> morphine
Consequences of being poor metabolizer
Reduced first pass effect -inc oral bioavailability (inc frac of orally admin drug that reaches systemic circulation) -inc plasma levels Reduced metabolic clearance -inc half life -inc accumulation w/ repeated doses Alternate pathway metabolism Failure to activate prodrugs Not affected by inhibitors
Genetic changes that lead to impaired warfarin metabolism
CYP2C9 (pharmacokinetic) or VKORC1 (pharmacodynamic, responsible for clotting factor activation) alterations
60% of variability still explained by other factors (age, weight, comorbidities, etc)
If HLA genetic change involved… greater risk for
alergic rxn
would req pharmacogenetic testing
Barriers to pharmacogenetics testing in clinical practice
Resistance to abandon “trial & error” approach
Concern about genetic discrimination
Unfamiliarity with principles of genetics
Lack of outcomes data
Affordability
If both the infusion rate and the concentration at steady state are known, what can be determined?
Clearance
