Chapter 2

Pharmacodynamics

What the drug does to the body

Action and Effect of drug

Effect: Response resulting from interactions between drugs and molecules in body. It is a result of the drug action. Such as Noradrenaline Blood pressure raise Vascular smooth muscle contract Vasoconstriction

Action: Initial response of leading to the drugs observed effects. It is fashion processes which drug brings about the molecules response in organism(body).

Such as: interaction between adrenaline and receptorNoradrenaline -receptor vasoconstriction blood pressure raise heart rate decrease(Reflex response to blood pressure changes)

Analysis of drug effectBasic expression of drug effect

Excitation: increasing or raising of function Adrenaline: blood pressure Inhibition: decreasing of function Insulin: blood glucose Benzodiazepines: Sedative-Hypnotic actionSame drug may produce different effects on various tissues and organs

SelectivitySelectivity is relativeHigh selectivity: high pharmacological activityLow selectivity: wide pharmacological activity, may be more side reactionSuch as Morphine: distribution in kidney, but target organ is CNS Atropine: low selectivity , wide action, more side reaction

RangeSensitiveQuestion: If a drug has high specificity, can we say the drug has good selectivity?

Therapeutic effect

etiological treatment

symptomatic treatment

Adverse reaction Conceptall the reactions that can bring out the uncomfortable or painful reaction, and have no relationship with the aim of administration, are called adverse reaction.

side reaction: is the inherent property of drugs, it appears at the clinical dosage because of the selectivity of the drugs.

toxic reactionWhen dosage was excessive or drugs are concentrated in certain tissue, there will be harmful responses which are serious and can be avoid.

residual effectafter effectwhen the administration ceased, the concentration of drug in the plasma would decrease below the threshold concentration, but there still would resist some residual pharmacological effect withdrawal reaction when the administration ceased the symptoms of original disease would be aggravated ,rebound reaction

allergic reactionhypersensitive reaction characters

immunoreaction (hapton)Having no relationship with dosageHaving no relationship with inherent effectPharmacological antagonist having no efficacy on it when poisoning

(idiocyncrasy)

Dose-effect relationship

(Dose-response relationship)

Dose effect relationshipeffect of the drug increases or decreases followed by the change of the drug dose or concentration

Dose-response (dose-effect) curve

Dose response curve...

According to the properties of effectgraded responseThe effect was changed continuously, could be expressed by concrete number or maximal ratio, eg. BpHRDose-effect relationshipeffect intensity for y-axis, Dose/concentration for x-axisrectangle hyperbolaLog Dose/concentration for x-axis symmetrical s curve

quantal response/all-or-none responsepharmacological effect was not followed by continuous dosage changes, but expressed by quantitative change.Positive or negativeall or noneDose-effect relationshipFrequency for y-axisdose for x-axisnormal distribution curveCumulative positive ratio for y-axis dose for x-axis long tai s curveCumulative positive ratio for y-axis logD for x-axis symmetrical s curve

Dose-response (dose-effect) curvePharmacological effects

minimal effective dosethe dosage could elicit the minimal effect, also could be called threshold dosemaximal effectEmaxefficacyEC50the concentration could elicit 50 percentage of maximal effectpotencythe relative concentration or dose could elicit equivalent effect (50% Emax), smaller the value is, more intensive the potency isslopevariation of drug

Drug efficacy, EmaxThe ability of a drug to elicit a maximal responseAlso called intrinsic activity of a drug (receptor theory)

Graded Dose-ResponseSlope ASlope B

Drug potencyA measure of the amount of drug required to obtain a particular response

50% of animal population tested10 mg20 mg

Dose-response curves% of population tested

ED50: Median effective doseED50 (median effective dose):The dose of a drug that produces a specified, desired effect in 50% of the animal population tested

LD50: Median lethal doseLD50 (median lethal dose):The dose of a drug that produces death in 50% of the animal population tested

NO DRUG IS RISK-FREEAll drugs are associated with undesirable or harmful effects at some dose or plasma concentration

Drug plasma concen-trationSubtherapeutic levelsTherapeutic levelsToxic levels

Therapeutic index (TI)TI = LD 50 ED50

The ratio of the dose producing a lethal effect in 50% of the test population (LD50) to the dose producing a specified desired effect in 50% of the test population (ED50)

Narrow therapeutic index10 mgED5025 mgLD50

Certain safety factorLD1 ED99

The ratio of the dose producing a lethal effect in 1% of the test population (LD1) to the dose produced a specified desired effect in 99% of the test population (ED99)

Overlap between effective and toxic drug plasma levelsLD1ED99

safety marginLD5~ED95

The distance of the dose producing a lethal effect in 5% of the test population (LD5) to the dose produced a specified desired effect in 95% of the test population (ED95)

Dose (units)ED95LD5ED50LD502060TI compared with Safety Margin% of animal population tested

Drug v.s. Receptor

Receptorreceptor is a macromolecular substance that may be a protein or an enzyme which is located on cell membrane or in cell plasma. It could recognize the minim chemical substances and bound with them.

LigandLigandis the substance that can specially bind to receptor

a) Endogenous : transmitter, hormone, b) Exogenous

Properties of receptorsensitivityspecificitysaturabilityreversibilityMultiple-variation

Classical theoryoccupation theory

Only if drugs bound with receptor, the drugs could be activated which intensity was proportional with the number of occupative receptors. When all receptors were occupied, the effects were the maximal effect.

Interaction between receptor with drugaffinityis the capabilities that drug could bind with receptors, and can be expressed by the concentration at which reach 50% Emax

1954modified the effect that drugs could bind with receptors and be activated not only need affinity, but also need intrinsic activity. intrinsic activityis the information encoded in a drugs chemical structure causes the receptor to change accordingly when the drug is bound.

D+R DR E [RT]=[R]+[DR] KDKD,()

KD =[D][R][DR]

KD =[D] [RT]- [DR][DR]

[D] = 0 E = 0[D]>>> KD E=Emax

KD = [D] KDmol/L(50%)

E=[DR]=[D]Emax[RT]KD+ [D]

[DR]=50%[RT]

KDKD represents the concentration of free drug at which half-maximal binding is observed.The KD is the drug concentration for 50% saturation of the receptors. The KD is the dose of 50% for the maximal effect.The KD is inversely proportionate to the affinity of the drug . pD2 affinity index pD2 = -KD

KD pD2 affinity KD , pD2 affinity

Intrinsic activity

0 1

E=[DR]Emax[RT]

If affinity is equal, Emax depends on intrinsic activity

If intrinsic activity is equal, affinity depends on potency of drug

Endogenous ligand(e.g. endorphin on opoid receptor)Agonist(e.g. morphine on opoid receptor)Antagonist(e.g. naloxone on opoid receptor)Classification of drugs

Classification of drugs agonistFull agonistStrong affinityStrong intrinsic activity1

Partial agonistStrong affinityWeak intrinsic activity 0

antagonist

antagonistFull antagonistStrong affinityNo intrisic activity= 0

Partial antagonistStrong affinityWeak intrisic activity0

Competitive antagonistAgonist

Competitive antagonist:

Because antagonism is competitive, the presence of antagonist increases , the agonist concentration required for a given degree of response, and so the agonist concentration-effect curve shifts to the right.

The presence of different concentration of antagonist may paralleling shift concentration-effect curve of agonist to the right, Emax is not changed.

Antagonism index, pA2The intensity of antagonismWhen agonist was combined with antagonist, if the effects that doule agonist joined up with antagonist coud elicit were equal to the effect that only agonist without antagonist could elicit, the negative logarithm mol concentration of antagonist was pA2pA2antagonism

Noncompetitive antagonistAgonist

Irreversible antagonistAffinity&intrisic activityEmaxconcentration-effect curve shifts to the right. not parallel

Two State Receptor ModelResting state RActivated state R*Full effectpartial effectReverse effectno effectReverse AgonistResting state (Ri)actviated state (Ra)

Spare receptor: Not occupied receptors. Maximal effect can be elicited by a agonist at a concentration that not result in occupancy of the full complement of available receptor.Available receptor and spare receptor are not hidden or unavailable and when they are occupied they can be coupled to response.

Ligand-Gated ChannelsG Protein coupled receptorReceptor Tyrosine KinaseCytosolic Recptors other

receptor desensitizationreceptor-mediated responses to drugs and hormonal agonists often desensitize with time. After reaching an initial high level, the response gradually diminishes over seconds or minutes, even in the continued presence of the agonist. This desensitization is usually reversible.

Factors affecting drug responseDrug factorDrug properties:PreparationPhysiochemical propertiesAdministrationDrug in combination

Physiological factorsAgeWeightSexhyposensitivity

Psychological factors:placebowas made of the neural substances that had no special pharmacological activity, which shape was the same as real drug.

Placebo effectoften caused by psychological factors

Pathological factors:Heart diseaseHepatic diseaseRenal diseaseInnutritionBalance of base or acid disorderedElectrolytes disordered

Genetic factorsTimeLiving habits and environments