pharmacokinetics
what body does to drug
pharmacodynamics
what drug does to body
pharmacogenetics
influence of one gene on drug
pharmacogenomics
influence of entire genome on drug
what are 2 ways to get toxic effects?
drugs going to unintended targets or overdose of therapeutic drugs
spermeation
movement through or around cells which limit size
-drugs have to be of certain size and shape to be absorbed and bind to certain receptors
efficacy
effect of drugs
- same effect b/w 2 drugs –> same efficacy
- nothing to do with []
potency
amount of drug to get an effect
-least concentration –> most potent
what is the best type of drug to give?
one with least potency and takes a higher dose to have effect
-easier to manipulate and regulate
steps in pharmacokinetics
- absorption
- distribution
- metabolism
- excretion
absorption
- polar molecules more easily absorbed (biotransformation in liver)
- no rxn with receptor if bound to carrier
- tight junctions (fast), lipophilic, facilitated or active transport, or endo/exocytosis (slow)
distribution
volume of distribution = amount of drug in body relative to [] in blood - measure space available to house the drug
metabolism
biotransformation by the liver - more polar and water soluble through conjugation to be excreted in urine
- phase 1 and 2 enzymes
- some drugs not metabolized
excretion
- elimination - rate of removal from circulation
- clearance - body’s ability in removing drug
agonist
bind to same site as ligand to have same effect
antagonist
- competitive - binding to same site to block ligand (no response)
- non-competitive - bind to other site to elicit effect
allosteric activator vs. inhibitor
- activator - bind to other receptor site increasing receptor response
- inhibitor - bind to other site decreasing response
partial agonist
sometimes called antagonist
- agonist on its own
- antagonist in presence of other substrate
therapeutic index
Toxic/lethal does divided by effective dose
-bigger number –> better drug
tolerance
down regulating receptors after therapeutic effect takes place
- decrease receptor –> decrease effect
- may have to increase dose
- protective response
barriers to absorption
- cell membrane - small (paracellular; lipophilic (diffuse); hydrophilic and charged (transporter)
- capillaries - easier to get drugs across (larger pores)
- blood/brain - protection; need transporter
- placenta - only lipophilic drugs across
1st pass metabolism
oral –> GI –> hepatic portal vein –> metabolized by liver (protection)
- occurs before interacting with receptor
- can decrease availability in circulation and less reaches active site
- skip by using another method besides oral
- bioavailability good indication
- proteins and lipids have high 1st pass - do not take orally
bioavailability
% of drug that ends up in circulation after 1st pass metabolism
-IV (most) > transdermal > IM and subQ > rectal > oral and inhalation
large, polar, lipophilic drug
do not take orally
- take IV or IM
- harder to be absorbed, 1st pass metabolism, more broken down
non polar, uncharged drugs
more easily absorbed - take orally
henderson-hasselbach equation
pH = pKa + log10 ([A]/[HA])
- uncharged molecules better absorbed than charged
- more acidic –> more uncharged
- more basic –> more charged
- equal charged and uncharged when pH = pKa
ion trapping
- gastric juice (pH 2) –> convert to uncharged form –> better absorption
- plasma (pH 7) –> reconvert to charged form –> ion trapping
- ex. aspirin being absorbed in stomach
- ex. methamphetamine in urine - can change pH of urine to excrete faster
drug bound to protein
cannot exit to peripheral tissues or bind to receptor
- acts as reservoir
- drug maintained in central compartment
- liver damage –> less albumin –> more free drug and higher effect
lipophilic/fat soluble drugs
bypass 1st pass metabolism bc they enter lymphatic circulation then head to periphery 1st
-end up in adipose tissue compartment
partition coefficient
ratio of solubility of a substance in water to a lipophilic, non-polar solvent
- determine how hydrophilic/hydrophobic something is
- larger number –> more hydrophobic
volume of distribution
measure of space in body to contain drug
Vd = amount of drug/plasma []
-low # –> drug in central compartment
-high # –> drug in peripheral compartment and has longer half life (not metabolized or excreted)
one vs. two compartment model
administer drug –> central –> peripheral –> metabolized and excreted by liver and kidneys in central increasing [] in peripheral (reservoir) –> drug reenters central to reach equilibrium
what is the goal of phase 1 and 2 rxns
make something more polar –> better excretion
- CYP enzymes in liver (can activate or deactivate drug)
- phase 1 = oxidize
- phase 2 = conjugate
CYP enzymes
needed by phase 1 rxns
- lipophilic, mainly in the ER membranes, Low specificity and react with a lot of molecules breaking them down
- can inactivate a drug or activate a prodrug
phase 2 rxns
conjugation
- not CYP dependent
- make more water soluble than phase 1
- oxidative stress can decrease GSH levels
what can hydrolysis during phase 1 lead to?
toxicity of drug - best to excrete it before reaching phase 1
acetaminophen
broken down into metabolite –> excreted by GSH or other conjugators or go down toxic path
- excess acetominophen –> induce CYP2E1 –> toxic pathway
- EtOH also induces CYP2E1 –> immediate toxicity
CYP3A/4
metabolize 50% of drugs in phase 1
glucoronidation
metabolize 25% of drugs in phase 2
competitive inhibition of drugs
reduce metabolism when 2 drugs competing for the same site
- prodrug not metabolized fast enough to have effect
- real drug not broken down into inactive –> toxic
- can be substrate and inhibitor at same time
inducers vs. inhibitors
inducers - increase CYP enzyme and metabolism
-ex. rifampin, carbamazepine, ethanol
inhibitors - downregurate CYP decreasing activity
-ex. erythromycin, grapefruit, cimetidine
elimination vs. excretion
elimination = remove drug by excretion or or biotransformation (drug --> metabolite) excretion = removal of intact drug
ion trapping
pH changes across 2 different tissues that traps an ion in one of the tissues
- weak acid - uncharged if pH below pKa –> can get across
- weak base - charged if pH is above pKa –> cannot get across (trapped)
enterohepatic circulation
where lipophilic drugs end up
- another compartment, not much enter circulation
- reservoir for lipophilic drugs that can leak back into circulation causing effect
clearance
ability of organs to eliminate drug from the body
-region of body that is cleared of a drug
half life (t1/2)
time required to reduce the drug in the body by half during elimination
zero order rxn
- elimination rate CONSTANT - not dependent on drug []
- half life CHANGES - longer half-life with more drug
- linear
- ex. PEA (phenytoin, ethanol, aspirin)
1st order rxn
- elimination rate dependent on drug [] –> faster with more drug
- half life CONSTANT
- exponential
- 95% of drug eliminated in 5 half lives
impact of infusion and bioavailability
- increase infusion rate –> increase []
- equal infusion but half bioavailability –> lower [] but longer duration
- half infusion rate, same bioavailability –> decrease [] and duration
maintenance dose rate
plasma drug concentration x clearance x time divided by bioavailability
-maintain dose in plasma - keep at equilibrium
loading dose
plasma drug concentration x Vd divided by bioavailability
-given to overcome lag period
half life equation
0.7 x Vd divided by CL
