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8/10/2019 KK_Factors Affecting Drug Therapy 2014
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Dr. Kumaraswamy MBBS, MD
Ext: [email protected]
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LEARNING OBJECTIVES
18.11.1 Categorise and explain thefactors affecting patient’s response todrug therapy with relevant examples(patient factors and drug factors)
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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
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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.
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DRUG RESPONSE
Factors related
to the drug
Factors relatedto the
individualpatient
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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
Age
Pregnancy
Ethnicity
Genetic factors
Psychological factor
Pathological state
Tolerance
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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
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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
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POTENCY
The amount of drug required to produce agiven response (effect)
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THERAPEUTIC INDEX/RATIO/WINDOW
Ratio between median toxic/lethal doseand median effective doseTherapeutic index=TD50/LD50
ED50“Margin of safety”
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LD50/ED50
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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
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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
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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
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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
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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
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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
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IN EFFECT
Increased plasmaconcentration by use ofenzyme inhibiting drugs:drug toxicity
Reduced plasmaconcentration by use ofenzyme inducing drugs:therapeutic failure
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EXCRETION INTERACTION
Certain drugs interfere with renalclearanceProbenicid inhibits penicillin excretion thereby
increasing the duration of action of penicillinsSalicylates inhibit renal clearance ofmethotrexate: methotrexate toxicity
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PHARMACODYNAMIC INTERACTION
SynergismIncreased effect
AntagonismDecreased effect
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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.
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PHARMACEUTICAL FACTORS
Dosage forms
Absorbedfaster
Drug absorptionthrough GIT
Excipient
Solids Liquids
Tablets,capsules
Disintegration,
Dissolution in the
GIT
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O A S A
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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
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GFR
• 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
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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
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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
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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
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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
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RACE
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
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GENETICS
1. Drugtransporters
2.Drugmetabolising
enzymes
3. Drugreceptors/
targets
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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
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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
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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
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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
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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
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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!
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