Kinetics

what is absorption

transport of drug from the site of administration to systemic circulation

what drug specific factors affect absorption

solubility, pH, particle size, dissolution rate, route of administration

patient specific factors that affect absorption

age, blood flow at absorption site, GI content

conditions that affect blood flow

PAD, HF

is unionized or ionized drug better at absorbing?

unionized drug is more lipid soluble and uncharged so is better at crossing cell membranes

better at absorbing

passive diffusion

net movement of drug from an area of high to low concentration

most common

facilitated diffusions

• carrier or channel mediated transport

• does not require energy

• cannot transport against concentration gradients

active transport

carrier or channel mediated

requires energy/ATP

enables movement from low to high drug concentrations

what does ficks law describe

how substances move (diffuse) from an area of high concentration to an area of low concentration

what are transporters

membrane bound proteins that facilitate movement of molecules in and out of the cell

influx transporter

transports drugs into the cell

• bidirectional facilitated diffusion and do not require ATP

• OATP, OAT, OCT, PEPT

efflux transporter

transports drugs out of the cell

require ATP to function

P-gp, MRP, BCRP, BSEP, MATE

bioavailability

fraction of the dose that reaches systemic circulation and ranges between 0 and 1

what are the three types of bioavailability

• fraction absorbed

• intestinal bioavailability

• hepatic bioavailability

fraction absorbed

• fraction that is absorbed intact in the intestinal membrane

intestinal bioavailability (Fg)

the fraction of the drug in the enterocytes that escapes metabolism

hepatic bioavailability (Fh)

• the fraction that enters the liver and escapes first pass metabolism

dissolution

the process in which the oral dose dissolves into the GI fluid

• determined by hydrophilicity, lipophilicity, crystalline form of the drug, particle size

pH partition hypothesis

• a non-ionized species will more readily partition (preference) into a lipophilic solvent than an ionized species

• whether a drug is charged depends on pKa and pH of its environment

what is the point of drugs being prepared into salts

• improve wetting: how liquid spreads over drug and causes dissolution

• leads to faster dissolution and increased rate of absorption

what does the noyes-whitney equation describe

the rate of dissolution of a drug (how fast a drug dissolves in a liquid)

higher concentration of drug inside the higher the rate of dissolution

the rate of drug absorption is controlled by

the slowest step

when dissolution rate controls absorption which equation describes the rate

noytes-whitney equation

when the membrane penetration controls drug absorption, the rate is approximated by

Fick’s law

dissolution and membrane penetration are what kind of process

follow first order kinetics

a weak acid or base partially ionizes into its ions in what type of solution

an aqueous solution

what is percent ionization

amount of acid or base that dissociates into its ions at a specific concentration

strong acids and bases dissociate into its ions at a specific concentration so their percent ionization is 100%

drug distribution

how rapid and to what extent drug in plasma gets up taken by tissue

• cannot measure tissue concentration so plasma concentration is measured instead

• effect only occurs when a drug reaches site of action

drug distribution is driven by what

passive diffusion of the unbound drug

distribution phase

• after administration the plasma drug concentration is much higher than that in the tissues

• drives diffusion of drug into the tissue

post-distribution phase

equilibrium is established between tissue and plasma, ratio between concentrations rises and falls in parallel

waht is volume of distribution

reflects how a drug will distribute throughout the body

Vd is constant for a drug and is the ratio of drug in body and the plasma concentration at a specific time

causes of low Vd

• large

• hydrophilic

• plasma protein bound

• impermeable membranes

what are some implications of low Vd

• low dose to saturate plasma

• fast clearance: if free drug

• tissues receiving equal exposure (see same amount of drug everywhere

what are some causes of high Vd

small

hydrophobic

tissue protein bound (stronger affinity for proteins in tissues)

permeable membranes

implications of high Vd

• allows targeting of tissues

• can cause toxic buildup

• concentrated in specific tissues

is drug binding to plasma proteins reversible or irreversible

reversible

examples of proteins involved in protein binding

• albumin, AAG, and lipoproteins are primary plasma proteins involved in drug binding

what does the Michaelis-mention equation describe

the velocity of metabolism (speed of metabolism)

when the velocity is half of Vmax, Chu is equal to

Km (Michaelis-Menton constant)

when Chu > km

rate is a zero order process

when Chu « km

rate approximates a first order process

renal excretion

parent drug is excreted out of the body via the urine

liver metabolism

parent drug is converted into metabolites by the liver

once the drug is converted to its metabolites, it is considered eliminated

rate of elimination and the rate of metabolism are what type of process

first order processes

clearance is dependent on what

liver and kidney function and how efficient they can extract drug from plasma

units of volume/time

total clearance is = to

renal clearance + hepatic clearance

clearance is constant but can be altered by

disease, medication, changes in organ function

large elimination rate constant means

short half life

low elimination rate constant equals

long half life

t1/2 =

0.693/K

first pass effect

removal of drug by GI tract and liver prior to entering systemic circulation

hepatic clearance is based on what model

well-stirred model

drug molecules are assumed to be distributed homogeneously

assumptions of the well stirred model

• only unbound drug in the blood is subject to elimination

• no membrane transport barrier

• no concentration gradient of the drug within the liver

• the concentration of the drug within the liver is equal to that in the venous blood

• linear kinetics