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DETERMINANTS OF DETERMINANTS OF PHARMACOLOGIC PHARMACOLOGIC

EFFECTEFFECTDrug therapy is the major Drug therapy is the major

intervention available for the intervention available for the amelioration and palliative care of amelioration and palliative care of disease. The predominant role of disease. The predominant role of

pharmacotherapy in the pharmacotherapy in the management and prevention of management and prevention of

disease necessitates a clear disease necessitates a clear understanding of factors that understanding of factors that

influence the response to influence the response to xenobiotics.xenobiotics.

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XenobioticXenobiotic is a term used to refer is a term used to refer to any compound to which the body to any compound to which the body is exposed but which is foreign to is exposed but which is foreign to the body. This could be a drug or the body. This could be a drug or

environmental chemical. environmental chemical. Importantly, those principles that Importantly, those principles that

govern the disposition of and govern the disposition of and response to chemicals are the same response to chemicals are the same with which we are concerned as it with which we are concerned as it

relates to drugs.relates to drugs.

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PRIMARY MEANS TO PRIMARY MEANS TO QUANTIFY DRUG QUANTIFY DRUG

EFFECTEFFECT•ONSETONSET

•DURATION DURATION •INTENSITYINTENSITY

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Evaluation of the onset, Evaluation of the onset, duration and intensity duration and intensity of xenobiotics leads to of xenobiotics leads to the observation of an the observation of an

important reality about important reality about pharmacologic effect:pharmacologic effect:

VARIABILITYVARIABILITY

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The figure below illustrates the variability in response to one drop of phenylephrine 30 mg/ml instilled into the conjunctival sac of 39 subjects.

Data from Bertler and Smith, Clin Sci 40:403. 1971.

0 5 10 15

1.0-1.5

2.0-2.5

3.0-3.5

4.0-4.5

Increase in pupil diameter,

mm

Number of Subjects

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The figure above illustrates the variability in response to intramuscular atropine 0.02 mg/kg in a group of 27 subjects. Data from Smith and

Rawlins, Variability in Human Drug Response, 1973, p. 1-2.

0 5 10 15

-10 to 0

10 to 20

30 to 40

50 to 60

Change in Heart Rate

Number of Subjects

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PHARMACOLOGIC EFFECT

DRUG SPECIFICConcentration-effect Relationship

Site of Biological Effect

Disposition of the Drug

Potency of the Drug

PATIENT SPECIFIC

Environmental ExposurePsychological Condition

Genetic ConstitutionOrgan FunctionEnzyme Activity

REGIMEN SPECIFICDosage Form

FrequencyRouteDose

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DRUGSDRUGSVSVS

DRUG PRODUCTSDRUG PRODUCTS

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II. CRITICAL NATURE OF THE II. CRITICAL NATURE OF THE CONCENTRATION-EFFECT CONCENTRATION-EFFECT RELATIONSHIPRELATIONSHIP

Reproduced from: Nies AS, Spielberg SP. Principles of Therapeutics, In: Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 9th edition, Hardman JG, Limbird LE, Molinoff PB, Ruddon RW (eds). McGraw Hill, San

Francisco, 1996, p. 47.

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Reproduced from: Edwards DJ, Svensson CK, Visco JP, Lalka D. Clinical Pharmacokinetics of Pethidine. Clinical Pharmacokinetics

7:421-433, 1982.

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Atropine Dose (mg/70 kg)

0.5 1 2

Pe

rce

nt

inc

rea

se

or

de

cre

as

e

0

20

40

60

80

Effect of varying doses of atropine (SC) in man. The (+) and (-) values refer to increase or decrease.Redrawn from: Riker WF. Contributions to medicine research inPharmacology. Some aspects of dosage. JAMA 179:355, 1962.

Salivary secretion (-)

Micturition speed (-)

Heart rate (+)

Accomodation (-)

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Reproduced from: Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics, 4th edition, Lea & Febiger, 1991, p. 178.

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Relationship between seizure control Relationship between seizure control and plasma phenytoin concentration.and plasma phenytoin concentration.

PhenytoinConc (mg/L) # Patients

# Pts withoutseizuresduring 2months

% SeizureFree

0 to 9.9 95 41 43

10 to 19.9 33 24 72

>20 20 19 95

(Data from Lund L. Biological Effects of Drug in Relation to Their Plasma Concentration. Davies DS, Pritchard BNC (Eds), MacMillan Press, 1973, p. 227.)

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Relationship Between Phenytoin Relationship Between Phenytoin Serum Concentration and Gingival Serum Concentration and Gingival

HyperplasiaHyperplasiaGrade of

Hyperplasia # of PtsPhenytoin Conc

(mg/L)

0 75 3.0

I 26 3.8

II 99 9.5

III 27 18.4

(Data from: Kapur et al. Dev Med Child Neurol 15:483, 1973.)

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Reproduced from: Gibaldi M. Reproduced from: Gibaldi M. Biopharmaceutics and Clinical Biopharmaceutics and Clinical PharmacokineticsPharmacokinetics, 4, 4thth edition, 1991, p. 356 edition, 1991, p. 356

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Reproduced from: Shargel L, Yu ABC. Reproduced from: Shargel L, Yu ABC. Applied Biopharmaceutics & Applied Biopharmaceutics & PharmacokineticsPharmacokinetics, 4, 4thth edition, 1999, p. 510. edition, 1999, p. 510.

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Effect

Log Concentration

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Frequency of plasma phenytoin concentrations in a group of ambulatory patients, all of whom

were receiving 300 mg per day.

0 20 40

<5.0

10-14.9

20-24.9

>30

Plasma Phenytoin (mcg/ml)

Percent of Patients

(Data from: Koch-Weser J. Eur J Clin Pharmacol 9:1-8, 1975)

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Reproduced from: Galinsky RE, Svensson CK. Basic Pharmacokinetics, In: Gennaro AR Reproduced from: Galinsky RE, Svensson CK. Basic Pharmacokinetics, In: Gennaro AR (ed), (ed), Remington: The Science and Practice of Pharmacy, 20Remington: The Science and Practice of Pharmacy, 20thth edition, 2000, edition, 2000, p. 1128 p. 1128

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The foregoing can be The foregoing can be summarized to note important summarized to note important

facts related to drug effect:facts related to drug effect:• There is significant variability in There is significant variability in

drug responsedrug response• Pharmacologic response is Pharmacologic response is

dependent, in large measure, on dependent, in large measure, on the concentration of drug achieved the concentration of drug achieved at the site of actionat the site of action

• There is significant variability in There is significant variability in the drug concentration achieved the drug concentration achieved after a standard dose of a drugafter a standard dose of a drug

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What conclusion do we What conclusion do we draw from these facts?draw from these facts?

Variability in drug concentration makes a

major contribution to the observed variability in pharmacologic effect.

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Drug in dosage form

ReleaseRelease

Drug particles in body fluids

Dissolution

Drug in solutionDegradation

Absorption

Liver

Excretion

GI

Central Compartment

Free Bound

Distribution

PeripheralTissues

Pharmacologic effect

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PharmacokineticsPharmacokineticsThe study of the absorption, The study of the absorption, distribution, biotransformation distribution, biotransformation and elimination of xenobiotics.and elimination of xenobiotics.

PharmacodynamicPharmacodynamicssThe study of the biochemical The study of the biochemical and physiological effects of and physiological effects of xenobiotics and their xenobiotics and their mechanisms of actionsmechanisms of actions

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Drug in dosage form

ReleaseRelease

Drug particles in body fluids

Dissolution

Drug in solutionDegradation

Absorption

Liver

Excretion

GI

Central Compartment

Free Bound

Distribution

PeripheralTissues

Pharmacologic effect

Pharmacodynamics

Biopharmaceutics

Pharmacokinetics