Pharmacokinetics Flashcards
agonist
binds to a receptor and activates it
antagonist
binds to a receptos and inhibits it
Presence of a competitive antagonist does what to the dose-response curve of the agonist?
shifts it to the right but does not affect Emax because it takes higher concentrations of agonist to overcome a competitive antagonist, but it can still bind to all of the necessary sites once it has out-competed the antagonist
inert binding sites
bind to drug molecule with no effect - buffer drug concentrations
Two important plasma drug-binding proteins?
albumin and orosomucoid
aqueous diffusion
diffusion of small drug molecules through water-filled pores of capillaries from blood to extravascular space - governed by Fick’s Law.
Which tissues lack aqueous pores in their capillaries?
brain, testes
Lipid diffusion
passive movement of molecules through membranes and other lipid barriers - governed by Fick’s Law
transport via special carriers
transporter molecules move a substance across the membrane that cannot passively move through
transporters exist for ions, neurotransmitters, metabolites like glucose/amino acids, and foreign molecules like anticancer drugs
Clinical significance of transporters used for endocytosis of amine neurotransmitters (dopamine, norepinephrine, and serotonin) back into the pre-synaptic membrane?
many antidepressants inhibit these transporters, not allowing amine neurotransmitters back into the nerve endings they came from.
endocytosis of drugs
drug binds to receptor on cell membrane and the area of the membrane folds and internalizes the drug
Why is endocytosis so selective?
drug/molecule must bind with a specific receptor on the cell membrane
What does Fick’s Law tell us?
rate of movement of molecules across a barrier
What is the EQ for Fick’s Law and what does it indicate about drug absorption in different tissues?
rate: (concentration gradient) C1-C2 x (permeability coefficient/thickness) x area.
Tells us that tissues with more surface area will absorb drugs faster, and tissues with thin membrane barriers - (not very thick.)
What is the aqueous solubility of a drug related to?
its degree of ionization - this changes based on the pH of the environment
How can you find the fraction of drug molecules in ionized state?
Henderson-Hasselbalch:
log (protonated/unprotonted) = pKa - pH.
What is the importance of determining the pH and pKa of drug molecules?
the ionization of the drug depends on the pH of the tissue, such that the pH can determine how much of a drug is soluble in that tissue
In what pH is a weak base drug molecule more soluble?
low pH - acidic, donates a proton to the weak base, making it a charged molecule
bioavailability
amount of drug absorbed into systemic circulation/amount of drug administered = bioavailability by that route
What influences absorption from intramuscular and subcutaneous administration of a drug? why?
blood flow - maintains concentration gradient between tissue and blood vessel
How does size of an organ influence distribution into particular tissues?
larger organs are better at maintaining drug blood-tissue concentration gradient. Smaller tissues dissipate the concentration gradient - no where for the tissue drug concentration to go
What does high blood flow do to the rate of drug uptake?
increases rate of uptake in well-profused tissues
How does solubility of a drug in a particular tissue influence uptake?
If a drug is more soluble in a tissue, then the concentration in the area adjacent to the blood vessel will be lower, maintaining a more favorable concentration gradient.
How does binding of a drug to macromolecules in a tissue/compartment affect concentration of drug in different tissues? examples?
If a drug has high affinity for a macromolecules that is primarily present in a certain tissue or compartment, more of the drug will remain in that space. examples: warfarin binds to albumin and remains in the bloodstream, chloroquine binds to extravascular proteins so is not concentrated in the blood
What is Vd?
related amount of drug in the body to the amount in the blood
Where does drug metabolism occur primarily?
in the liver
elimination
conversion of a drug into a biologically inactive derivative/metabolite
prodrugs
inactive when administered and active when metabolized by the body - ex: levodopa, minoxidil
drugs that have active metabolites?
morphine, some benzodiazepines
What is the difference between first-order and zero-order elimination?
Drugs with first-order kinetics are eliminated at a slower rate as their plasma concentration decreases.
Drugs with zero-order kinetics are eliminated at a constant rate regardless of concentration.
Examples od drugs with zero-order elimination
ethanol, phenytoin (anticonvulsant), and aspirin at therapeutic or toxic concentrations
Loading dose
dose required to achieve a specific plasma concentration with a single dose of the drug.
Loading dose(in mg) = Cp(target plasma concentration) x Vd (volume of distribution)
Maintenance dose
dose required for regular administration to maintain a target plasma level - requires restoring the amount of drug that is lost to elimination (clearance, CL)
Maintenance dose (in mg/time) = Cp (target concentration) x CL (clearance)
therapeutic window
range between the minimum effective concentration and the minimum toxic concentration.
clearance
ratio of elimination of drug to concentration of drug in plasma. units of volume/time
Half-life
time required for amount of drug to fall by 50%
First-pass effect
elimination of a drug prior to it getting to the bloodstream
Steady state
rate of elimination = rate of administration
average total amount of drug in the body does not change over multiple dosing cycles
