Pharmacology Flashcards
Pharmacokinetics
effect of the body on the drug
AMDE
Absorption
Distribution
Metabolism
Elimination
Pharmacodynamics
effect of the drug on the body
- receptor binding
- signal transduction
- physiological effect
Phase 1
is it safe
what are kinetics
20-100 normals
all healthy - give to small group to see how it behaves in the body
Phase 2
Does it work
20-100 patients with disease
compare to placebo
Phase 3
How well does it work
randomized trial - compared to something that works or placebo
Phase 4
post marketing suveillance
drug with rare side effect - won’t find in first 3 phases
Bioavailibility
F
amount of drug that reaches systemic circulation
IV = 1
Factors that affect bioavailability
gastric emptying time/food
dissolution/disintegration
dosage form - elixer v tablets
first pass metabolism - drug interactions
chemical formulation
disintegration
fall apart - big bolus
starts to dissolve
dissolution
after disinitegration
makes it in solution
slowed by: acidity, large particle size, water insolubility
toxicokinetics
what happens if you take too much
drug distribution
where does a drug reside in body
what properties alter where drugs reside
what properties allow drugs to move through bio membranes
Apparent V(d)
1 compartment model
put a known amt of drug into the body (mg)
measure blood concentration (mg/L)
can find the size of the theoretical space the drug resides in
small Vd
more drug in the blood
large Vd
most drug is outside of the blood (in fatty compartments)
can be bigger than body
old faithful
drug mg/L = s x F x dose (mg)/Vd
risk assessment
diff for diff things
f = percent bioavailibility
1 compartment model
instantaneous distribution
2 compartment model
slow distribution into a certain region
i.e. water to fat, how drug moves from one to the next
alpha distribution
alope of absorption rate?
2 compartment model
can’t calculate elimination until equilibrium and distrbution evens out
i.e. digoxin - doesn’t work until it gets into your heart
when concentration is blood and heart is the same (equilibrium) can discuss elimination
may be high in blood (if IV) but not in heart because distribution is low
beta elimination
slope of elimination rate constant
need to wait until distribution and elimination even out
refers to beta elimination of first order process - elimination from the blood does not mean elimination from body
some drugs result in long lasting effects (suicide inhibition, irreversible changes)
lipophilicity
fat soluble drugs live in fat soluble compartments
don’t always work where you live
Log P
actanol/water partition coefficient
how much fat, how much water
Log D - adjusts for physio pH
protein binding
some drugs are highly bound to plasma proteins
acidic - albumin
basic - alpha 1 acid glycoprotein
only unbound drug can cross bio membranes
change in protein –> dramatic change in bio effect bc alter distribution
phenytoin
only biologically active when free
binds to albumin
if decreased albumin (sick) - drug level doesn’t change but goes out in tissues and body and you think you ahve a higher level than you do
pH and charge
charged molecules DO NOT cross bio membranes well
membrane are lipid, charges increase water solubility
important for weak acids and bases - shift amout charged as a function of pH
aspirin and membrane permability
weak acid
only passes in HA form, not in charged form
at low PH (sick, acidemic) - in HA form, more passes over membrane
Pka = 3
at higher pH (physio) - most is chargd form and doesn’t move across membrane, most is in blood
weak acid/base rules
pH
pH > pKa - deprotonated forms mostly A-, B (acids stay in blood, bases cross)
Lipid emulsion
couldn’t revive after overdose
gave a bolus of fat - cause drug to diffuse from tissue into blood because it became fatty - took all drug away from the heart
increase BP
Aspirin poisoning and alkinization
normally, acid in eq between tissues, plasma, urine
if make uring really basic, make aspirin become uncharged and drag it out of tissues
urine [ASA} increases as a function of pH
redistribution
drugs that move slowly into compartments move slowly out of compartments
extravascular compartment can serve as a reservoir to maintain high blood concentrations following chronic administration
Digoxin redistribution
digoxin overdose - lives in heart
give Fab - big and can’t leave blood but binds free digoxin and drags all of the drug into blood from heart
Biotransformation
phase I - redox - reactive species made
phase II - conjugation - reactive conjugates made
phase II - elimination
phase II can happen before phase I, can skip a phase or 2
Phase I
prepare lipophilic drugs for the addition of functional groups or add the groups - convert to active/inactive/less active/prodrug to drug
oxidation
hydrolysis
reduction
dehydrogenation
dealkylation
Oxidation
primarily CYP450
Phase I
hydrolysis
phase 1
i.e. aspirin
ASA + H2O –> Salicylic acid (effect) + acetic acid (inactive)
alcohol metabolism
3 phase I reactions, no phase II
ethanol –> acetylaldehyde –> acetic acid (easily eliminated, not active)
ethanol –> acetyl aldehyde: CYP2E1, ADH (alcohol dehydrogenase, CATALASE
acetylaldehyde –> acetic acid : ALDH (aldehyde dehydrogenase)
Phase II
Conjugation
after Phase I or parent drug itself
enhance solubility allowing increased renal and other pways to elimination
detoxification - reduce toxic effects of parent/metabolized drug
Glucuronidation
most common phase II
addition of glucuronic acid
helps drug get out - doesn’t always make it inactive
morpine: add in diff spots, metabolites still a little active, some pain relief but not a lot
CYP450
cytochromes - class of hemoproteins that transfers electrons between oxidized Fe3+ and reduced Fe2+ forms of iron
predominatly responsible for Phase I drug metabolism
CYP450 location
on smooth ER
most in liver
some in kidney
some in intestine (in enterocytes of SI - contribute to “first pass” metabolism)
First pass metabolism
the concentration of a drug is greatly reduced before it reaches the systemic circulation
After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus greatly reduces the bioavailability of the drug.
CYP450 Substates
drugs, chemicals, hormones that undergo biotransfrmation via CYP450
depends on Km - if small, enzyme requires only a small amount to become saturated
CYP450 Inhibitors
alters enzyme activity resulting in decreased metabolism of substrate
most common cause of drug-drug interactions
can result in increased or decreased bioavailaiblity of a drug
i.e. grapefruit
CYP450 Inducers
alters enzyme activity causing increased metabolism of substrate
nuclear receptor mediated! gene transcription - more enzymes, more activity
enhance druge effect beceuase increasted activity of prodrug to active druge
decrease effect by enhanced elimination
Km
concetration of substrate at which 50% max activity of the enzyme
small Km - substrate only needs a small amt of substrate to be saturated
large Km - need a lot to reach max V
for substrate of CYP450 enzyme
alcohol metabolism and enzymes
low Km - ADH - at low amount, use ADH
high Km - CYP2E1 - in alocholics, use mostly, metabilize better at high concentrations
substrate selectivity
depends on many properties
i.e. S-warfarin and R-warfarin - work in diff CYP450
Simvastatin and Grapefruit
lowers cholesterol but can cause liver and muscle damage
grapefruit juice in small intestine - inhibits CYP34A mediated first-pass metabolism - cause serious liver and muscle problems because severe statin toxicity
Extensive metabolizers
considered normal
normal amt of enzyme and ddrug response
Intermediate Metabolizers
at least one gene isn’t working normally
less enzyme than normal
may be less response OR more side effects
Poor metabolizers
variants in both genes
much less enzyme/not at all
high risk for side effects, or may need higher drug if it needs to be broken down before it works
Ultrarapid metabolizers
extra copies of CYP genes –> more enzymes than normal
may break some drugs down so quickly that don’t work at usual doses
may neeed a lower dose if it has to be metabolized before it works
pharmacogenomics
enzyme activity is different in different regions
i.e. codeine, needs to be broken down into morphine to work, no effect for poor metabilizers, toxic effect for ultrarapid metabolizers
P-glycoproteins
sit on cell surface and actively pump drug out of cell
ATP
can move drugs against concentration gradient
has inducers and inhibitorsactivel extrudes drugs back into intestinal lumen, also BBB, kidneys, liver bile ducts
if inhibit - more intracellular = toxicity
Acetaminophen Metabolism
PHASE II - sulfation/glucuronidation –> detox and elim
PHASE I - oxidation via CYP450 to NAPQI –> phase II to detox and elim
at therapeutic concentrations - Phase II reactions
if overdose - make too much NAPQI, can’t detox - toxicity to hepatocytes, poisn liver - centrally located holes in cells
Mu opioid receptor
GPCR
hyperpolarizes post-synaptic neurons
inhibits presynaptic nt release
affinity
abilinty of drug to bind its biological compartment
how it gets on its receptor
Kd = [L][R]/{LR]
Ka = 1/[Kd}
low Kd
high affinity!
it will bind a greater number of a particular receptor at a lower concentration than a low affinity drug
high Kd
low affinity
Potency
all will ultimately have the same effect but which has ED50 at the lowest dose
Efficacy
effect is notbinding
once binding occurs what is the effect
EC50
median effective concentration
how much is needed for 50% max effect - find where effect is 50% and drop down
full agonist
provides max effect at given receptor
partial agonist
same efficacy but can never get 100%
neutral antagonist
drug that sits on R and does nothing
if have agonist, can occupy and prevent agonist from working
inverse agonist
if constituitively active - does opposite - gives decreased signaling up to 100%
reversible inhibition
noncovalent binding
i.e. ibuprofen
irreversible
permanent alteration
i.e. aspirin at COX1
competitive inhibition
A and I acting at same site
as increase antagonist - act at same site + reversible
mass action - inhibits less - shift EC curve to the right! have to give more agonist
noncompetitive inhibition
allosteric - binds and takes it out - doesn’t mater if increase [agonist]
pseudo-irreversible also
pseudo-irreversible inhibition
competitive (bind at same site) but noncompetitive! binds so tightly that it looks like non comp
Varenicline
smoking cessation drug
partial agonist!
withdrawl attenuation: stronger potency but partial agonist - relieves craving and withdrawl
blocks nicotine induced domaminergic activation: partial agonist - if take nicotine with it, block reward
tolerance
adaptation such that exposure to a drug induces changes that result in a decrease of one or more effects over time, or the nee for a higher dose to maintain an effect
many mechanisms: desensitistation, internalization, downregulation
Therapeutic Index
LD50/ED50
average!
therapeutic window
window between efficacy and no toxicity
ED50-LD1 (where 1 person dies)
Warfarin TW
very small TW - experiemental! keep between 2-3 need to test
between benefit and hemorrhage
chirality implications
in a chiral environment, stereoisomers may have steroselective protein binding, transport, receptor, enzyme interactions —-> diff effects
i.e. Methodone is chiral
spare receptors
when EC50 < Kd
between the biologican resoinse you want and all of the receptors that are avaiable
if EC50 = Kd - if you remove one receptor you will decrease efficacy
major centers of elimination
Kidney and liver
diffusion
break in membrane bilayer - passive
how big, soluble
kidney elimination
FIRST ORDER
filtration process
how much drug is in concentration, in the system - into kidneys!
more in blood –> more scooped out - certain PERCENTAGE of total drug (dilution of remaining drug passes through the kidney again)
percent/time concentration dependent
first order kinetics
percent/unit time
concentration dependent
first order k(e)
slope of the line when drawn in natural logs
how much you are removing - percent/time
half life equation
.693/k(e)
elimination constant!
how much it takes for 1/2 of drug to be gone
helps to dose medication correctly
liver enzymes
ZERO ORDER
limited number of enzymes - a certain amount of a drug can be broken down by unit time
doesn’t matter how much there is - concentration independent
Michaelis Mentin
enzymes - when concentration of drug is low - function based on blood flow and metabolize a certain percent per time (FIRST ORDER) and then when get overwhelmed (massive overdose) they switch to ZERO ORDER and are at capacity - metabolize a certain amount
Clearance
analogous to the Vd - amount of blood that is totally removed of a drug in a unit of time
Cl = rate of elimination/Cp (plasma concentration)
vol/time
total body clearance is sum total of all routes of elimination
Steady State
when drug concentration remains relatively constant over time
absorbtion and elimiation rates are equal!
SS = absorption/elimination = rate in/rate out
usually - 5 half lives to get steady state
Tau
dosing interval!
how often you have to give a drug over a period time
heodialysis
first order process (like kidneys!)
blood in, drug out
remove certain amt in 4 hours
factors favoring elim: small Vd, low protein binding, water soluble, molecular weight is small
calculate how long patient needs to stay on HD to bring drug concentration down to an acceptible amount
charcoal
decrease amount of drug absorbed
enters enterohepatic ciruclation
if IV drug - can still leave through feces
