What factors affect the transfer of drug to various sites within the body?
molecular size, degree of ionization, lipid solubility, protein binding, amount of blood flow to the tissue, concentration gradient of the drug across the membrane
What is pharmacokinetics
concentration of a drug during the processes of absorption, distribution, metabolism, or biotransformation and elimination from the body
what the body does to the drug
how does molecular size affect distribution?
the smaller the molecule, the more likely it is to cross cell membranes
What are SLCs? What do they do?
solute carrier transporters – control passive movement of solutes down their electrochemical gradient
What are ABCs? What do they do?
ATP binding cassette transporters – active pumps requiring energy derived from ATP
How does ionization affect lipid solubility?
the ionized (charged) form is water soluble
the nonionized (uncharged) form is lipid soluble
When the pH = pKa…..
charged and uncharged forms exist in equal amounts
What is ion trapping?
The uncharged part of the drug can cross into the tissue membrane and then the charged portion cannot move back out.
The degree of protein binding for a drug is proportional to…
its lipid solubility
*the more lipid soluble it is the more it is protein bound
How can you overcome protein binding of a drug?
Add another agent that competes for the same protein binding sites. This will lead to an increase in fraction of free agent of the 1st drug.
What happens to drug concentrations when plasma proteins are low?
total drug concentration is lowered but unbound concentrations of the drug are not affected.
What is bioavailability?
the extent to which a drug reaches its effect site after its introduction into the circulatory system
What are some factors that affect bioavailability?
age, sex, pathology, pH, blood flow, temperature, etc.
Describe the compartments in the 2-compartment model/
central compartment - (vessel rich) consists of intravenous fluids, and highly perfused tissues like the brain, heart, kidney, liver, lungs.
peripheral compartment - (vessel poor) composed of muscle, fat, bone
How can drugs exit the central compartment?
via distribution to the tissues or via metabolism and excretion
What is Vd?
volume of distribution proportionally relates the amount of drug in the body to the serum/plasma concentration
Why is it important to recognize the volume of distribution?
it will help you to determine loading doses of drugs to achieve steady-state concentrations
How can you calculate Vd?
dose of drug / plasma concentration of drug
What is the volume of the plasma compartment?
4L
What is the volume of the interstitial fluid?
10L
What is the volume of ECF?
plasma volume + interstitial fluid = ECF
4L + 10L = 14L
What is the intracellular fluid volume?
28L
What is Total Body Water volume?
plasma + IF + ICF = TBW
4L + 10L + 28L = 42L
If a drug has a small Vd…. is it lipid soluble?
no – likely water soluble and contained to the plasma
When might a drug have a large Vd?
if it is lipid soluble, unbound to plasma proteins, etc. it will cross into cell membranes and have a large Vd
What factor can supercede all other factors when it comes to how a drug behaves in the body?
structure/stereochemistry
What is a chiral center?
a carbon atom with 4 different, asymmetrical bonds
As the # of carbons in a molecule increases, so will the # of…
possible stereoisomers
What is an enantiomer?
stereoisomers with non-superimposable mirror images of each other
What does the Alpha Phase of the plasma concentration curve represent?
initial dispersal of the drug into the tissue compartments from the central compartment
steep slope of the curve if the drug is lipid soluble
What does the Beta phase of the plasma concentration curve represent?
represents concentration falling exponentially because of elimination of the drug from the body.
usually has a more gradual slope
What is goal of drug metabolism?
change lipid-soluble agents into more water-soluble forms that can be excreted by the kidneys
What is first-order kinetics?
drug is cleared at a rate proportional to the amount present in the plasma
What is zero-order kinetics?
even at a therapeutic level, the drug overwhelms the body’s ability to excrete or metabolize it. Available enzymes for metabolism are saturated. So a constant amount of drug is cleared regardless of the plasma concentration
What are phase 1 reactions of metabolism?
hydrolysis, oxidation, reduction resulting in increased polarity of the drug molecules
What are phase 2 reactions of metabolism?
conjugation - drug or metabolite added to endogenous substances like glucuronic acid, sulfonic acid or acetic acid.
What enzyme class catalyzes oxidation reactions?
cytochrome P450
What are microsomal enzymes?
reside in the hepatic smooth ER that are responsible for the biotransformation of numerous agents
What is enzyme induction?
increasing enzyme activity by stimulating the enzymes over a period of time by repeated exposure to a drug or chemical
Why is it important to consider enzyme induction when giving drugs?
helps you determine dosing intervals because this increased ability to clear drugs will lead to a reduction in the half-lives of many agents
What is the elimination 1/2 life?
time necessary for the plasma concentration of a drug to drop by 50% after a rapid bolus injection
In a practical setting, when is a drug effectively cleared from the plasma?
after 4-5 half lives, or about 95% clearance.
Clearance of a drug is directly proportional to _____ and inversely related to ______ and _______.
the dose of the agent; the agent’s 1/2 life; concentration in the central compartment
What are the two main organs for clearance of drugs?
liver and kidneys
How is clearance mathematically determined?
clearance = blood flow x extraction ratio
When can the BBB be overcome by a drug?
large doses, head injuries and hypoxemia
elimination 1/2 time is independent of…..?
the dose of the drug delivered
What is the 1st Pass Effect?
drugs absorbed from the GI system enter portal circulation and can be extensively extracted and metabolized before they reach the effect site
What are the 3 most common plasma proteins drugs bind to?
albumin (acids)
lipoproteins
Alpha-1 acid glycoproteins (bases)
If hepatic extraction for a drug is greater than ____, it’s clearance will depend on hepatic blood flow
0.7
What is capacity-dependent clearance?
when the extraction ratio is low, a decrease in protein binding or an increase in enzyme activity will increase clearance of the drug.
not really affected by hepatic blood flow
How can you determine the therapeutic index of a drug?
Ratio of LD50 to ED50