kk_factors affecting drug therapy 2014

8/10/2019 KK_Factors Affecting Drug Therapy 2014

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Dr. Kumaraswamy MBBS, MD

Ext: 2838KumaraswamyKademane@imu.edu.my

LEARNING OBJECTIVES

18.11.1 Categorise and explain thefactors affecting patient’s response todrug therapy with relevant examples(patient factors and drug factors)

DRUG ACTION IS VARIABLE

Variation in response to the same dose ofa drug between different patients and even

in the same patient on different occasionsis a rule rather than exception

DRUG THERAPY

Drug therapy involves a great deal morethan matching the name of the drug tothe name of a disease; it requiresknowledge, judgment, skill and wisdom,but above all a sense of responsibility.

DRUG RESPONSE

Factors related

to the drug

Factors relatedto the

individualpatient

FACTORS INFLUENCING DRUG RESPONSED R U GFA C T O R S

Route of administration

PD: efficacy, toxicity,therapeutic index

PK: ADMEPharmaceutical factors,

potency

PAT I E N TFA C T O R S

Pregnancy

Ethnicity

Genetic factors

Psychological factor

Pathological state

Tolerance

ROUTE OF ADMINISTRATION

Parenteral : more rapid, morepronounced and more predictableaction Eg; MorphineDifferent uses through different route

Magnesium sulphateorally causes purgation

Applied on sprained joints decreases swellingIntravenously produces CNS depression and

hypotension

EXAMPLE FOR EFFICACY

DiureticsFurosemide: highly efficacious diuretic

Maximum increase in urine output

Hydrochlorothiazide: moderate efficacy diureticModerately increased outputSpironolactone: low efficacy diuretic

Very less increase in urine output

POTENCY

The amount of drug required to produce agiven response (effect)

THERAPEUTIC INDEX/RATIO/WINDOW

Ratio between median toxic/lethal doseand median effective doseTherapeutic index=TD50/LD50

ED50“Margin of safety”

LD50/ED50

PENICILLINS HAVE WIDE THERAPEUTIC RATIO

1. The drug dose can be increasedwithout causing adverse effects.

2. Safe in elderly even if the renalclearance is less

• In the presence of impaired metabolism andexcretion of drugs

3. Safer in liver or kidney diseases

STREPTOMYCIN HAS NARROW THERAPEUTICINDEX

• As the excretion is less,plasma concentrationremains high

a lower dose to beused

• Once a day therapy is adequateto maintain the plasma conc.instead of twice a day therapy

a lower frequencyof administration

PHARMACOKINETIC INTERACTIONS

Drug absorption

1. If calcium and iron preparationsare given together there is reduced

absorption of both.2. If iron and vitamin C are giventogether there is improved ironabsorption

ABSORPTION CONTD..

3. Antacids bind to drugs givenconcurrently and prevent absorption

Avoid giving drugs

concurrently with antacids4. Cholestyramine – a lipid lowering drug,prevents absorption of fat. Avoid giving fatsoluble vitamins concurrently

DRUG METABOLISM: ENZYME INDUCTION

Enzymeinduction

• Induction (stimulation) of liver microsomal enzymes• Speeds up the metabolism of a drug given concurrently

Whathappens?

• There is reduced plasma concentration• Leading to therapeutic failure

Example

• Rifampicin (an anti TB drug) speeds up the metabolism ofoestrogen in the oral contraceptive pill.

• Contraceptive failure

Rifampicin, carbamazepine, alcohol

ENZYME INHIBITION

Enzymeinhibition

• Inhibition of liver microsomal enzymes results in increased

plasma concentration of another drug administeredconcurrently

Whathappens?

• Increased plasma concentration causes drug toxicity

Examples

• Erythromycin & grape fruit juice are liver enzyme inhibitors• If given with a statin(a lipid lowering drug) causes

rhabdomyolysis .

Chloramphenicol, ciprofloxacin,erythromycin

IN EFFECT

Increased plasmaconcentration by use ofenzyme inhibiting drugs:drug toxicity

Reduced plasmaconcentration by use ofenzyme inducing drugs:therapeutic failure

EXCRETION INTERACTION

Certain drugs interfere with renalclearanceProbenicid inhibits penicillin excretion thereby

increasing the duration of action of penicillinsSalicylates inhibit renal clearance ofmethotrexate: methotrexate toxicity

PHARMACODYNAMIC INTERACTION

SynergismIncreased effect

AntagonismDecreased effect

POTENCY

Potency is the drug dose (weight) that produces aneffect/Amount of drug that produces a givenresponse

• Different doses of different drugs of the

same class may produce the same effectExample; Drug class – corticosteroidsPrednisolone 5mg and dexamethasone 0.75mgproduce the same effect.

PHARMACEUTICAL FACTORS

Dosage forms

Absorbedfaster

Drug absorptionthrough GIT

Excipient

Solids Liquids

Tablets,capsules

Disintegration,

Dissolution in the

O A S A

NEWBORN BABIES ANDCHILDREN

• Less efficient

• GFR is 20% of the adultDrug elimination

• Half life of Gentamicin(an antibiotic) is longer

in the premature babythan in a full term baby

Half life of drugs

are longer

Drug doses are smaller in children(based on the weight of the child ) thanin adults

• GFR falls by 25% at 50 years and 50% by 75 years• Renal clearance of drugs is reduced and may lead

to toxicity

Half life ofdrugs

• Plasma elimination half life is prolonged• Impaired metabolism and clearance

Response

• Produce an exaggerated /altered effect• Antihypertensives produce more postural

hypotension due to impaired baroreceptorsensitivity

Physiological factors- drug therapyin elderly

Reduced plasma albumin andincreased total body water

• Increased cardiac output, increased

renal blood flow and increased GFR,increased hepatic metabolism – needhigher doses

Effect on the fetus – teratogenecity in the first 3 months. Lipid soluble drugs cross the placenta

• Some drugs are excreted in thebreastmilk in significant amounts – avoid

Physiological factors – pregnancy / breast feeding

PATIENT FACTORS- PATHOLOGICAL FACTORS

Decreased first passmetabolism

Increased bioavailability

Dose to be reduced toprevent drug toxicity

Decreased drugmetabolism/elimination

Increased plasmaconcentration

Dose/frequency need to bereduced to prevent toxicity

Liver disease

PATIENT FACTORS –PATHOLOGICAL FACTORS

Renaldisease

• Reduced excretion of the drug

• The dose and frequency to be reduced proportionately tothe creatinine clearance

Cardiacdisease

• Reduced drug absorption –poor blood supply to intestines• Reduced tissue perfusion, smaller volume of distribution

• Increased drug concentration to the brain and the heart

Thyroid

disease

• Slow metabolism in hypothyroidism• Rapid metabolism in hyperthyroidism

ETHNICITY

Chinese differ from Caucasians in alcoholmetabolism , producing

increased plasma acetaldehyderesulting in

flushing and palpitations.

Chinese are more sensitive to propranololthan Caucasians whereas, Afro-Caribbeansare less sensitive

Blacks require higher and mongolslower concentrations of atropine andephedrine to dilate their pupilBeta blockers are less effective in

AfricanIndians tolerate thiacetazone betterAplastic anemia due to chloramphenicolis less in India and china

GENETICS

1. Drugtransporters

2.Drugmetabolising

enzymes

3. Drugreceptors/

targets

PHARMACOGENETICS VS GENOMICS

Pharmacogenetics : the study of geneticbasis for variability in drug responsePharmacogenomics: use of genetic

information to guide the choice of drugand dose on an individual

GENETIC DEFECTS

Atypical pseudocholinesterase resultsin prolonged succinylcholine apneaG6PD deficiency causes hemolyticanemia with primaquine, sulfonamides

Low CYP2C9 leads to warfarin toxicityCYP2D6 abnormality: metoprolol,antidepressants and antipsychoticstoxicity

SOME MORE EXAMPLES

Abnormal Ca2+ release channel – malignant hyperthermia after halothanePolymorphism of N-acetyltransferase 2gene results in rapid and slow

acetylatorsIsoniazid, procainamide, hydralazine: LUPUSINH: fast acetylators – hepatitis

slow acetylators – neuropathy

TOLERANCE

Gradual decrease in the responsivenessto a drug OR Requirement of higherdose of a drug to produce a givenresponse

Eg: nitrate tolerance,Tolerance develops to sedative actions ofchlorpromazine but not to its antipsychoticTolerance develops to analgesic andeuphoric actions of morphine but not to itsconstipating and miotic actions

PSYCHOLOGICAL FACTORS

Efficacy is affected by patients belief,attitudes, and expectationsPlacebo: Inert substance; latin = I shallplease

Works psychologically rather pharmacologicallySome individuals respond to a placeboUsed as a control device in clinical trial of drugsUsed to treat patient who does not require adrugPlacebos might release endorphins in brain

PATIENT NON- COMPLIANCE

A major factor of therapeutic failure

25%-50% of patients fail to followinstructions on treatment

Patients may take only 50-90% of the prescribeddose orthey may not take the medicines at all!

kk_factors affecting drug therapy 2014

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