Basic principles of metabolism

what is pharmacokinetics?

what the body does to the drug

what is pharmacodynamics?

what the drug does to the body

define pharmacokinetics

time course and movement of a drug:

into (absorption) - across physiological barriers

around (distribution) - to reach its target tissues

out of (elimination)

the body

outline the principle of pharmacokinetics

the drug’s ability to access its target is limited by:

metabolism: body inactivates the drug (enzymatically)

excretion: body gets rid of the drug (via kidney or in the faeces)

why do we need pharmacokinetics?

tells us the correct dose of each drug which is needed to reach the target site at a concentration high enough to cause an effect but low enough to avoid side effects

what knowledge does a drug PK data give us?

which dose to give

which administration route to choose

how often to give a dose (frequency)

which administration formulation to choose for a drug

where do we gain information about drugs PK data?

through experiments done as part of drug development research

drug discovery - identifies target site, new drug synthesis

preclinical experiments - in vitro and in vivo, testing drug activity, side effects/efficacy

clinical trials - phases I to III

drug approval - phase IV observation - 10-15 years

what does ADME stand for?

absorption, distribution, metabolism, elimination

define absorption

a drug enters the blood flow

mass transfer process that involves the movement of unchanged drug molecules from the site of administration into the blood stream

define distribution

once a drug reaches the bloodstream, it will get distributed across different compartments in the body

define metabolism

after being distributed, the drug will reach sites where it is metabolised in its active or inactive form

define elimination

drug is excreted from the body and passed out via excretion organs (liver, kidney, skin, lungs)

in which ways can drugs be transported across membranes?

active transport, passive diffusion, facilitated passive diffusion, endocytosis

outline cell membrane structure

consist of phospholipids (2 hydrophobic tails harbouring a phosphate group)

many integral proteins in membrane which are amphipathic (with both polar and non-polar groups)

which molecules are cell membranes permeable and impermeable to?

permeable to small non-polar molecules

impermeable to molecules with high polarity, high molecular weight or conformational freedom

outline simple diffusion across membranes

transcellular route is used spontaneously

no involvement of any membrane protein

slowest step of the absorption process

large molecules will diffuse more slowly than smaller ones

outline the kinetics of simple diffusion

follows first order kinetics

instantaneous rate at which the concentration of a drug diminishes at the site of absorption is at any moment proportional to the remaining concentration of the drug in the site of absorption

linear - helps to sustain a concentration gradient

does not apply in condition which reduce extent of absorption (eg, physical excercise)

define facilitated diffusion

process of spontaneous passive transport of drugs across a biological membrane via specific transmembrane integral proteins

state 2 types of transmembrane proteins

channel and carrier

outline how channel proteins are involved in facilitated diffusion

form open pores in membranes

small molecules also pass between adjacent cells connected as tight junctions

outline how channel proteins are involved in facilitated diffusion

bind specific drugs and as a consequence undergo conformational changes that allows molecules to pass through

which molecules pass across membranes via facilitated diffusion?

sugars, amino acids, nucleosides

name the 3 different active transporters

uniport, antiport, symport

describe uniport active transport

mediate the transport of a single drug/substance

facilitate the mode of diffusion accelerating a reaction that is already thermodynamically favourable

allows transport of non-diffusible substances across the membrane at a much higher rate than passive diffusion

molecules are never in contact with the hydrophobic core of the membrane

eg,

describe antiport active transport

ability to couple the movement of one substance with another against the concentration gradient

eg, Na+/Ca2+ antiporter in cardiac muscles - 3 Na+ ions required to transport Ca2+

describe symport active (co) transport

ability to transport two different substances simultaneously

eg, Na+/glucose symporter - movement of each is independent of the other (dependent on its own concentration gradient, but uses same membrane protein)

name some parameters that influence absorption

physiochemical properties of the drug (eg, hydrophilic, lipophilic, size, acidity)

pharmaceutical dosage form (eg, sustained release forms)

anatomical and physiological characteristics (eg, body weight, age)

administration route (systemic or topical)

how can a drugs journey be represented on a graph?

plasma concentration versus time curve

need to study relationship between plasma concentration achieved and time after a single oral dose from the given dosage form

look at both the rate and extent of absorption

define a dose of a drug

a specific measured amount of drug (in mg or micrograms) needed to achieve a specific plasma concentration

define plasma concentration

the amount of drug which reaches the blood stream, gets distributed in the body and thus achieves a specific plasma concentration

this specific concentration reaches the target site and has a pharmacologic effect

what defines the absorption phase?

when absorption>elimination

what defines the elimination phase?

when elimination>absorption

give an example of routes of administration that result in fast and slow absorption

fast - intravenous

slow - dermal

what is D_L?

initial dose

what is C_p?

plasma concentration

what is C_max?

maximum plasma concentration

what is T_max?

time to reach maximum plasma concentration

what is V_D?

volume distribution

state the equation for D_L?

V x C

what does the area under the curve (AUC) of C_P against time graph represent

actual body exposure to drug after administration of a dose

what is AUC expressed in?

mg*h/L

state the equation for AUC

D x F/ C_L

D = initial dose, F = bioavailability, C_L = clearance

for IV injections AUC = C₍₀₎/gamma

C₍₀₎ = extrapolated plasma concentration, gamma = elimination rate constant

define bioavailability

the amount of drug reaching circulatory system from delivery system used

for oral administration and for IV what does bioavailability depend on?

oral - absorption rate

IV - 100% (administered directly into circulation)