Lecture 1

ADME

absorption, distribution, metabolism, elimination

goal of drug administration

achieve an effective drug concentration while minimising side effects

the therapeutic window

between too low concentration and too high concentration

dose range between effective dose and toxic dose

routes of administration

topical - onto surface of tissue

enteral - oral, sublingual, rectal (absorbed in intestines)

parenteral - IV, Intramuscular, Subcutaneous, other injection or infusion

IV vs oral administration

IV quickly reaches peak concentration but also comes down quickly vs oral slowly reaches peak and slowly declines

bioavailability

the fraction of the dose of a given drug that. is absorbed into circulation (into the bloodstream)

F (bioavailability) equation

F=AUC(oral)/AUC(IV)

numerator what looking at, always over IV

F of IV always = 1

oral administration

drugs must go through acidic stomach and then be absorbed at the intestinal wall
solubility important - H2O soluble molecules are not readily absorbed at the gut wall

factors that influence solubility

1. hydrogen bond formation - if can form hydrogen bond with water tends to be more soluble

2. ionization - charged (ionized) molecules are more H2O soluble and so not well absorbed

oral bioavailability

the fraction of the oral dose that is absorbed unaltered

depends on intestinal absorption, enzymatic metabolism in intestinal wall and liver

crossing intestinal wall

lipid soluble drugs diffuse passively across membranes

some drugs actively transported across membranes by transporters that are part of other biochemical processes

drug transport

transporters have a finite capacity so reach a maximum rate/limit irrespective. ofthe concentration of drug present

drugs compete for the same transporter - can be a source of drug interactions

pKa and ionization

when pH=pKa then it will be 50% ionized and 50% unionized

weak acidic drugs will be ionized in high pH such as intestines

basic drugs will be relatively at equilibrium in intestines so well absorbed

strong acids or bases are always ionized, so poorly absorbed

interactions with antacids

drugs that reduce acidity of stomach affect the absorption of other drugs as it changes the ionization of the drug in the stomach

distribution

transport of the drug to its target after it has been absorbed

plasma protein binding

limits free drug available for distribution into tissues

source of drug interaction - if one drug binds this proteins more strongly it means there could be a higher free drug concentration of another drug - e.g. aspirin and diazepam

partitions

blood, extracellular fluid, body fat, CNS

volume of distribution

tells us how much of the drug stays in the blood vs how much distributions into other parts of the body

the hypothetical volume in which a drug would need to be uniformly dissolved to result in the same concentration as is observed in the plasma

small Vd - drug mostly stays in blood

large Vd - drug spreads out into tissues

volume of distribution calculation

Vd = A/C where A = amount of drug in body (dose) and C = plasma concentration

blood brain barrier

water soluble drugs do not enter the brain as they have to pass through cells

some drugs can be transported in

in some diseases brain cells become more permeable so drugs can enter which usually would not be able to

placental barrier

blood vessels for fetus and mother are separated by many layers - stops drugs reaching baby

so water soluble drugs and large drugs cannot pass through