L3 Principles Of Drug Action (1)

Drug effects are “quantified” by studying the relationshipbetween drug concentration (or dose) and the responseproduced by the drug. This relationship is described byconcentration-response curves

The effect of a given drugcan be measured in manydifferent ways

• The response measured isdetermined by the type ofexperiment being performed

There are three main typesof pharmacologicalexperiment

• experiments in vitro

• experiments in vivo

• experiments ex vivo

Drug effects are studied ona piece of tissue dissectedfrom an animal (or human),and kept alive outside thebody.

By far the most common typeof experiment, and includeexperiments on cells grown intissue culture

Responses that might bemeasured include changes inthe tension of a muscle,changes in the activity of anenzyme or changes in thesecretion of a hormone orneurotransmitter………..

• Drug effects are studied inthe living animal (or human)

• Include clinical trials

• Tightly regulated by theHome Office

• Responses that might bemeasured include increase inblood pressure; reduction inpain threshold; reduction inallergen-inducedbronchoconstriction……

• A tissue or organ is removedfrom an animal that has beentreated with a drug, and theeffects that drug has had onorgan function are tested invitro

• Again tightly regulated bythe Home Office

• Examples might includeexperiments to see whetherlong-term treatment with adrug induces liver damage oralters some aspect of brainbiochemistry

• For experiments in vitro,concentrations are expressedin Moles per litre i.e. Molar(M)

• 1 Mole of a drug contains 6.02x 1023 drug molecules andweighs the molecular mass, ingrams

• A 1 Molar solution contains 1Mole of a drug dissolved in 1litre of solvent

• Most importantly, a 1 Molarsolution of drug “X” willcontain the same number ofdrug molecules as a 1 Molarsolution of drug “Y”

Most drugs act at concentrations in the range 1 x 10-6M to 1 x10-12M ie they are very potent (see later)

• Bare in mind however that a 10-9 M solution of drug stillcontains 6.02 x 1014 or 602000000000000 drug molecules perlitre!

• Often pharmacologists will use the prefixes milli (m)- micro (µ)- and nano (n)- for 10-3 ,10-6, and 10-9 respectively

• Thus a 1 micromolar (µM) solution is the same as a 1 x 10-6 Msolution

It is not possible to use molar concentrations forexperiments in vivo, simply because the volume of thesolvent (eg blood) is not known

Drug doses in this type of experiment are expressedas weight of drug per weight of animal eg 1 mg per kg(1 mgkg-1)

This allows an approximate extrapolation of the dosefrom, for example, a 20 gram mouse to a 70 kg human

Indicates the maximumresponse a drug canproduce, i.e. the “top” ofthe concentrationresponsecurve.Increasing theconcentration of the drugproduces no greatereffect.

• Indicates the position ofthe curve on theconcentration axis

• Defined as “the Molarconcentration of a drugthat produces 50% of themaximum response for thatdrug”.

• Sometimes use otherpercentage values eg EC90or EC20

A vague but commonly used term, used to describethe concentration at which a drug is effective

A potent drug is effective in very small amounts

Often quantified using the EC50

• Remember that the lower the EC50 the more potentthe drug

Comparing EC50 values for two drugs with the sameaction allows us to calculate their relative potencies,described by the potency ratio (M)

• Drug ‘A’ is clearly morepotent than drug ‘B’. Youneed 20 times more of ‘B’ toachieve the same effect

M = EC50(test)/EC50(standard)

orLog M = logEC50(test) –logEC50(standard)

Determining the relative potency of different drugsis a key role of the pharmacologist

• A “bioassay” is any techniques where the potency of adrug is determined by measuring the biologicalresponse it produces

Pharmacologists have developed hundreds ofdifferent bioassays, ranging from cells in culture toclinical trials in humans to look at different aspectsif drug response

• Bioassays underpin the development of new drugs inthe pharmaceutical industry

• The simplest bioassay fordetermining the relativepotency of two drugs

• Makes use of the fact thatthe middle portion of thelog concentration- responsecurves are almost linear,and if the two drugs areacting by the samemechanism, then the linesshould be parallel

• ‘M’ can be obtained bycomparing two doses ofstandard (S1, S2) with twodoses of unknown (U1, U2)

The ratio between the toxic dose of a drug and thedose producing the desired therapeutic effect

The higher the therapeutic index the less chance ofthe drug producing toxic side-effects in therapeuticuse

An important concept, but actually very difficult toquantify. Sometimes defined asTherapeutic index = LD50/ED50

LD50 = lethal dose in 50% of population

ED50 = Effective dose in 50% of the population

• Pretty meaningless definition from a clinicalperspective. Death is a rather extreme side effect!

• In humans, Therapeutic index = TD50 /ED50 where TD50is the “toxic” dose in 50% of the population

• Wide person to person variation in the both toxic andbeneficial effects of drugs

• A drug can have different ED50’s depending on thedisease being treated eg aspirin against headache orarthritis

• Ethically no longer defensible to obtain LD50 values inanimals.