Factors modifying drug actions & effects

1. FACTORS MODIFYING DRUGFACTORS MODIFYING DRUG
ACTIONS & EFFECTSACTIONS & EFFECTS

2. Lecture Outline
Factors Modifying Action of Drugs
• Drugs’ factors
• Hosts’ factors
Physiological Factors
Pathological Factors (Diseases)
Genetic Factors
• Environmental Factors
• Drug interactions
A multitude of host, drug & environmental factors
influence drug response. Understanding of these factors
can guide choice of appropriate drug & dose for
individual patient.

3. 1. Drugs’ factors
• Physical properties (physical state, crystal structure, size of
particulate solid drugs) determine their absorption and
bioavailability, as well - the power of the drug effect.
• Physico-chemical properties: lipophilicity, pK-value, the
Michaelis affinity constant (Km) - the affinity of an enzyme to
its substrate. When the value of Km is the high affinity of the
enzyme is low, and vice versa.
• Сhemical structure
• Drug dosage forms
• Dose: dosis pro dosi; dosis pro die; dosis pro cura (cursu)
• Repeated and prolonged drug administration: cumulation,
tolerance.

4. 2. Physiological Factors
• Age
• Sex
• Pregnancy
• Body weight
• Lactation
• Food

5. Sponsored
Medical Lecture Notes – All Subjects
USMLE Exam (America) – Practice

6. Drugs and Age of Patients
• Most drugs are developed and tested in young to
middle-aged adults
• Drug consumption is different
• Dosage regimen cannot be based on body weight or
surface area extrapolated from adult dosage
• Therapeutic disasters:
• Gray Baby Syndrom: chloramphenicol
• Thalidomide: Teratogenic effect
• Isotretinion (Accutane®): Teratogenic effect

7. Thalidomide prescribed as a sedative or hypnotic. Afterwards, it
was used against nausea and to alleviate morning sickness in
pregnant women. Thalidomide became an over the counter drug in
Germany on October 1, 1957. Shortly after the drug was sold in
Germany, between 5,000 and 7,000 infants were born
with phocomelia (malformation of the limbs). Only 40% of these
children survived. Throughout the world, about 10,000 cases were
reported of infants with phocomelia; only 50% of the 10,000
survived.
http://en.wikipedia.org/wiki/Thalidomide

8. AGE PERIODS
• Premature infants:< 36 weeks gestation
• Full-term infants: 36-40 weeks gestation
• Neonates: 1st 4 weeks post-natal
• Infants: 5-32 weeks post-natal
• Children : 1-12 years
• Adolescents: 12-16years
• Geriatrics: > 65 years

9. Changes in body proportions & composition with growth and
aging
From Puig M: Body composition and growth. In Nutrition in Pediatrics, ed. 2,
edited by WA Walker and JB Watkins. Hamilton, Ontario, BC Decker, 1996

10.  High body water: >70% of BW
 gastric acid secretion
 liver microsomal enzymes; limited
metabolic clearance: glucuronidation
pathway is not developed the first year
 plasma protein binding - increase in unbound
drug in serum
 Lower body fat: highly lipid-soluble drugs
distribution is diminished (diazepam)
 GFR & tubular secretion
 Immaturity of BBB in neonates.
2.1 Drugs in Neonates

11. PEDIATRIC PHARMACOLOGY
CHILDREN ARECHILDREN ARE
NOTNOT
SMALL ADULTS!SMALL ADULTS!
• Compliance problem
• Poor communication
• Inconvenient dosage forms
• Unpalatability
• Unreliable measurement
• Spillage, etc
• Medication dosage: BW
versus BSA

12. There are a few formulae for calculation of dose of
the children under 12 years.
• Clark's Rule =
(Weight of the child in kg /
150) X Adult dose
• Dilling's Formula=
(Age/20) X Adult dose
• Young's Rule=
(Age X Adult dose)/Age+12
• The dose required for the
age between 12 to 16
years will be from ½ to 2/3
of the adult dose.
• Dose of sodium bicarbonate
for a child of 6 years
• Adult dose of sodium
bicarbonate is 1g (1-4 g).
• Young’s Rule
the required dose will
be = 6 x 1/ (6+12) =
6/20 =0,3g

13. Body Surface Area for Drug Dosage
• Calculations based on
the child’s weight are
inaccurate
• Physiological
differences (body
water, fat): larger doses
of some drugs on a
mg/m2 basis
 BSA is calculated from
height and weight
(nomogram)
 The surface area rule
is the most accurate
• Approximate child’s
dose =
Body surface area X adult
dose / 1.7

14. Calculation of Drug
Dosages, 7th Edition Ogden,
Sheila J
Nomogram image, p. 364,
Copyright Elsevier for C4203
Approximate
child’s dose =
Body surface
area of the child
X adult dose /
1.7

15. PEDIATRIC PHARMACOLOGY
•GIT absorption of ampicillin and amoxicillin is greater in
neonates due to decreased gastric acidity.
•Chloramphenicol – Gray-baby syndrome – (inadequate
glucouronidation of chloramphenicol with drug
accumulation).
•Sulfonamides – Hyperbilirubinemia & Kernicterus
•The children can tolerate iron, belladonna preparations
relatively better than adult but they can not tolerate
opium and morphine preparations except in very small
doses.

16. PEDIATRIC PHARMACOLOGY
• Tetracyclines - permanent teeth staining
• Corticosteroids - growth & development
retardation
• Antihistaminics - hyperactivity.
• Administration of drugs during the first year of
life can be a challenge due to rapid changes in
body size, body composition, and organ
function.

17. Intramuscular Injections
• Vastus lateralis is the preferred site for
children under the age of 3.
• Ventrogluteal site is the preferred site for
children over the age of 3.
– The child should be walking.
2007 Thomson Delmar Learning, a division
of Thomson Learning Inc.
Anterior view of the location of the
vastus lateralis muscle in a young
child.
Remember:Remember:
•Children are vulnerable.Children are vulnerable.
•Be kind and patient.Be kind and patient.
•Enjoy the children;Enjoy the children;
you will receive moreyou will receive more
than you give.than you give.

18. 2.2. GERIATRIC PHARMACOLOGY
• Elderly constitute 12% of the population but consume 31%
of prescribed drugs in US
• Elderly more sensitive to drugs and exhibit more variability in
response
• Altered pharmacokinetics
• Multiple and severe illnesses
• Multiple drug therapy and usage
• Poor compliance
• “Individualization of treatment is essential: each patient
must be monitored for desired responses and adverse
responses, and the regime must be adjusted accordingly”

19. Changes in Geriatric Patients
• body fat (25-30%) - reduces plasma levels of lipid
soluble drugs
• total body water by 25% - increases concentration
of water soluble drugs and intensity of response;
greater risk for dehydration
• concentration of serum albumin- malnourishment
decreases albumin and results in increased drug
levels
• Metabolism: hepatic functions in elderly and drug
levels increase (diazepam, theophylline)

20. Changes in Geriatric Patients
•Stomach pH ; blood flow ; decrease in gut motility
(slow onset)
•In the elderly, muscle decreases by 25%.
•Excretion: decline (40-50%) of renal function in
elderly may lead to higher
serum drug levels and longer drug half-life.
Reduced renal clearance of active metabolites may
enhance therapeutic effect or risk of toxicity (e.g.,
digoxin, lithium, aminoglycosides, vancomycin)

21. Pharmacodynamic Changes
•Alterations in receptor levels may change: Beta-blockers less
effective in the elderly patients.
•Age-related changes resulting in sensitivity to certain classes
of drugs place the elderly at risk for adverse drug reactions
•CNS depressants (e.g., benzodiazepines) resulting in delirium,
confusion, agitation and sedation
•Anticoagulants and hemorrhage e.g., in combination with
NSAIDs, salicylates.
•Alpha-blockers resulting in orthostatic hypotension
•Anticholinergic medications resulting in dry mouth,
constipation, urinary retention, blurred vision, confusion

22. Effects of Aging on Volume of Distribution (Vd)
Aging Effect Vd Effect Examples
⇓⇓ body waterbody water ⇓⇓ Vd for hydrophilicVd for hydrophilic
drugsdrugs
ethanol, lithium
⇓⇓ lean body masslean body mass ⇓⇓ Vd for for drugsVd for for drugs
that bind to musclethat bind to muscle
digoxin
⇑⇑ fat storesfat stores ⇑⇑ Vd for lipophilicVd for lipophilic
drugsdrugs
diazepam, trazodone
⇓⇓ plasma proteinplasma protein
(albumin)(albumin)
⇑⇑ % of unbound or% of unbound or
free drug (active)free drug (active)
diazepam, valproic acid,
phenytoin, warfarin
⇑⇑ plasma proteinplasma protein
((αα11-acid glycoprotein)-acid glycoprotein)
⇓⇓ % of unbound or% of unbound or
free drug (active)free drug (active)
quinidine, propranolol,
erythromycin, amitriptyline

23. Polypharmacy Defined
• Treatment with multiple medications (> 5
meds per regimen) for a variety of conditions
and symptoms that include excessive or
unnecessary medications that place the
patient at risk for an adverse drug reaction.
Balance between avoiding excessive or
unnecessary use of medications and
providing beneficial therapies.

24. Increased incidence of chronic conditions as the
• Diabetes
• Hypertension
• Heart Failure
• Ischemic Heart Disease
• Asthma/COPD
• Arthritis
• Alzheimer’s Disease
• Urinary problems

25. Adverse Drug Reactions in Geriatrics
• Seven times more likely in elderly
• 16% of hospital admissions
• 50% of all medication-related deaths
• Drug accumulation secondary to reduced
renal function
• Polypharmacy : dangerous practice (drug-drug
interactions)
• Greater severity of illness
Cont.

26. • Presence of multiple pathologies
• Increased individual variation
• Inadequate supervision of long-term therapy
• Poor patient compliance
Reasons for non-compliance include complex
drug regimens, intentional non-adherence,
and dementia and cognitive impairment.

27. Start with a low dose and titrate slowly
• Simplify regimen (once or twice daily dosing)
• Consolidate medications
• Use of blister packs, pill boxes, calendars,
watches, other reminders
• Reduce costs (e.g., generics, pill splitting)

28. 2.3. SEX
• Females body size ; D
• Testosterone the rate of biotransformation of drugs
• metabolism of some drugs in female (Diazepam)
• Females are more susceptible to autonomic drugs
(estrogen inhibits choline estrase)
• Gynaecomastia is ADR occuring only in men
(metoclopramide, chlorpromazine, digitalis)
• Antihypertensive drs (clonidine, beta-blockers,
diuretics) interfere with sexual function in males.

29. 2.4. Drug Therapy During Pregnancy
Drug treatment in
pregnancy is complicated
mainly by two aspects:
•general concerns do exist
regarding potentially
harmful effects of drugs on
the embryo. The fear of a
second disaster as with
thalidomide
still present;
• physiological changes
occuring during
pregnancy may have an
influence on
pharmacokinetics and
pharmacodynamics and
subsequently efficacy of
drugs.

30. 1/3 to 1/2 of pregnant women take at least one
prescription drug and most take more
• Some used to treat pregnancy side effects
–Nausea
–Pre-eclampsia
–Constipation
• Some medications used to treat chronic disorders
–Hypertension
–Diabetes
–Epilepsy
–Cancer
–Infectious Diseases
• Drugs of abuse

31. Pregnancy
•GI transit time is prolonged by about 30-50%. This
could alter the rate and amount of absorption and the
plasma concentration of drugs, which are either given
as slow release forms or those, which are metabolised
in the gut wall.
•Vd almost doubles during the later course of
pregnancy; slight increment in renal clearance.
• treatment failures with ampicillin in pregnancy can
be due to lower plasma concentrations.

32. Pregnancy
Plasma concentration/time profile of ampicillin, once after i. v. administration of
500 mg after delivery (= week 0, no pregnancy) and at week 40 of gestation;
note, that a dose of 935 mg has been given at week 40 to achieve a
comparable Cmax and AUC.
P. Thurmann, Drug treatment in pregnancy. Pharmaca
Jugoslavica. 2000;38:59-63.

33. Pregnancy
• Progesterone influences biotransformation
of drugs, metabolised by CYP3A4 (methyprednisolone).
• The microsomal oxidation of carbamazepine
to it's active metabolite doubles during pregnancy.
• Cardiac output  GFR and renal elimination of
drugs.
• Lipophilic drugs cross placental barrier
& slowly excreted.

34. The concept of teratology
•One of the most important factors determining the sensitivity of
the embryo is the gestational age:
•During the first 2 weeks (blastogenesis) the law of all-or-none
applies.
•During day 15 to 60 malformations maybe induced, depending on
the exact date of exposure (organo-genesis, embriogenesis). Birth
defects are known to occur in 3-5% of all newborns.
Teratogenesis (teras, meaning 'monster' or 'marvel‘)
•Sensitivity to drugs decreases during the foetal period (after 9
week), later exposure to xenobiotics may induce functional defects
or growth retardation.

35. Effects of Teratogens at Specific Stages of Fetal
Development

37. Thalidomide (1957–1961)

38. In 1962,
the United States Congress
enacted laws requiring tests
for safety during pregnancy
before a drug can receive
approval for sale in the U.S.
USA: 17
babies

39. Thalidomide is racemic: it contains both left- and right-handed
isomers. The (R) enantiomer is effective against morning sickness.
The (S) is teratogenic and causes birth defects. The enantiomers
can interconvert in vivo. The (S) enantiomer intercalates (inserts)
into the DNA in G–C (guanine – cytosine) rich regions.
(S)-thalidomide (R)-thalidomide

40. Drugs with documented teratogenic or
embryotoxic effect
P. Thurmann, Drug treatment in pregnancy. Pharmaca
Jugoslavica. 2000;38:59-63.

41. FDA pregnancy category
•A - Controlled studies in women fail to demon-strate a
risk to the fetus in the first trimester, and the possibility
of fetal harm appears remote (only 8 drugs: folic acid,
vit A, vit C, vit D in physiol. D)
•B - Animal studies do not indicate a risk to the fetus
and there are no controlled human studies, or animal
studies do show an adverse effect on the fetus but
well-controlled studies in pregnant women have failed
to demonstrate a risk to the fetus (250 medicines;
penicillins, erythromycin, metthyldopa, lansoprazole).
Cont.

42. •C - Studies have shown that the drug exerts animal
teratogenic or embryocidal effects, but there are no
controlled studies in women, or no studies are
available in either animals or women. However,
potential benefits may overweight the potential risk
(700 drs; atenolol, aminophylline).
•D - Positive evidence of human fetal risk exists, but
benefits in certain situations (e.g., life-threatening
situations or serious diseases for which safer drugs
cannot be used or are ineffective) may make use of the
drug acceptable despite its risks (phenytoine,
metotrexate, doxiciclin, enalapril, cyclophosphamide).
Cont.

43. •X - Studies in animals or humans have
demonstrated fetal abnormalities or there is
evidence of fetal risk based on human
experience, or both, and the risk clearly
outweighs any possible benefit (statins,
dinoprost).
Whereas categories A to C define the
degree of risk, categories D and X
offer a risk-benefit evaluation.

44. Some recommended drugs for selected indications
during pregnancy
P. Thurmann, Drug treatment in pregnancy. Pharmaca
Jugoslavica. 2000;38:59-63.

45. 2.5. Drug Therapy during Breast Feeding
Drugs get through breast milk and can effect infant
•Little research done on this aspect because of dangers
involved in these studies - Adverse effects are described
(penicillin, tetracycline)
•Concentration of drugs differ in milk. Lipid soluble drugs
are in higher concentration; Milk is weakly acidic: weak
bases are concentrated.
• Generally most drugs are in too low a concentration to be
harmful to infant.
•Some drs can lead to toxicity in the child if enter the milk
in pharmacological quantities - laxatives.
Cont.

46. Some drugs are contraindicated because of known
risk: nicotine, amphetamines, lithium, marijuana,
anticancer drugs.
Some drugs to be avoided: amiodarone, TTC,
quinolones, aspirin, benzodiazepines.
The infant should be monitored if betalytics
(bradycardia), corticoids (infants´adrenal functions) or
lithium (intoxication) are prescribed to mother.
Others: metronidazole gives milk an unpleasant taste;
bromocriptine and diuretics suppress lactation.

47. Lactation Risk Categories – LRC)Lactation Risk Categories – LRC)

48. Goodman & Gilman's The Pharmacologic
Basis of Therapeutics - 11th Ed. (2006)
Goodman & Gilman's The Pharmacologic
Basis of Therapeutics - 11th Ed. (2006)

49. L1 – safest: Paracetamol, Ibuprofen, Epinephrine.
LACTATION RISK CATEGORIES (LRC) (Hale, 2004; 2008):
L2 – safer: Diclofenac, Fentanyl, Cetirizine,
Omeprazole, cephalosporins.
L3 – moderately safe: Acarbose, Acetylsalicylic acid,
Indometacin, Codeine, Morphine, Midazolam, Triazolam,
Acebutоlol, Dimetinden.
L4 – hazardous: Colchicine, Lithium, Ergobrevine,
Ergotamine.
L5 – contraindicated: ACE inhibitors (enalapril etc.)

50. PRCsPRCs LRCsLRCs
AA:: controlled studiescontrolled studies
show no riskshow no risk
BB:: no evidence of risk inno evidence of risk in
humanshumans
CC:: risk cannot be ruledrisk cannot be ruled
outout
DD:: positive evidence ofpositive evidence of
riskrisk
XX:: contraindicated incontraindicated in
pregnancypregnancy
L1L1:: safestsafest
L2L2:: safersafer
L3L3:: moderately safemoderately safe
L4L4:: possibly hazardouspossibly hazardous
L5L5:: contraindicatedcontraindicated

51. 2.6. Species and race
•Rabbits are resistant to atr; rats & mice – to digitalis.
•Afro-americans require higher and mongols – lower D
of atr & ephedrine to dilate their pupil.
•Beta-blockers and ACE inhibitors are less effective as
antihypertensive in afro americans.
•Around 80% of Asian people have a variant of the
gene coding for the enzyme alcohol dehydrogenase.
Alcohol flush reaction (also known as Asian flush
syndrome, Asian flush) is a condition in which an
individual's face or body experiences flushes or
blotches as a result of an accumulation of
acetaldehyde.

52. 3. Pathological Factors
Diseases cause individual variation in drug response
• Renal and liver insufficiency are the
main modulators of drug effect.
• Renal failure decreases drug
elimination.
• Liver failure decreases drug
metabolism

53. 3.1. Renal Disease
Renal excretion is reduced in relation to GFR -
raised plasma levels
• tubular function
• Plasma albumin
•Drugs (and their metabolites) excreted predominantly
by the kidney accumulate in renal failure:digoxin-
lithium- gentamycin- penicillin.
•Risk of toxicity after usual doses: aminoglycosides,
digoxin, lithium, enalapril, atenolol, methotrexate
•CLcr
– essential in deciding on an appropriate dose regimen

54. Prescribing for patients with renal disease
• Check the renal status
• CLCR
• Consider how the drug is eliminated
• if non-renal elimination accounts for less than 50% of
total elimination, than dose reduction will probably
be necessary
• monitor therapeutic and unwanted effects
• when appropriate also TDM
• use potentially nephrotoxic drugs - with special
care
• aminoglycosides, NSAIDs, ACEI

55. Nephrotoxicity
Reduction of GF:
• NSAID – decreased PGI2 – vasoconstriction of afferent
arteriole
• ACEI – decresed AGII – dillatation of efferent arteries
• renal vasoconstriction – cyclosporin, amphotericin
Chronic interstitial nephritis, papillary necrosis
(phenacetin, NSAID)
Tubular damage (MTX)
Praecipitation (sulphonamides)

56. There is no reliable biomarker describing hepatic
impairment.
In chronic liver disease :
• serum albumin is the most useful index of drug
metabolizing capacity or prothrombin time also
shows a moderate correlation with drug clearance of
drugs.
• such indices of hepatic function serve mainly to
distinguish the severly affected from the milder cases
(in contrast to serum cr or Clcr in renal impairment).
3.2. Liver disease

57. Influence of liver disease
• Altered pharmacokinetics
a) increased bioavailability
- reduced first-pass metabolism
- decreased first-pass activation of pro-
drugs
b) decreased protein binding
c) decreased elimination
• Altered drug effect
• Worsening of metabolic state

58. Liver Disease
• Prolong duration of action = ↑ (t1/2).
• Plasma protein binding for warfarin,
tolbutamide; adverse effects.
• Hepatic blood flow clearance of morphine,
propanolol.
• Impaired liver microsomal enzymes -
diazepam- rifampicin- theophylline

59. Prescribing for patients with liver diseasePrescribing for patients with liver disease:
• if possible, use drugs that are eliminated by routes
other than the liver
• response and untoward effects should be monitored
(and therapy adjusted accordingly)
• predictable hepatotoxins (cytostatic drugs) should
only be used for the strongest of indications
• avoid drugs that interfere with hemostasis
(anticoagulants, aspirin)

60. Drug-induced
hepatotoxicity
Jiwon Kim. An Overview of Drug-Induced Liver Disease
US Pharm. 2005;11:HS-10-HS-21.
http://www.uspharmacist.com/index.asp?show=article&page=8_1634.htm

61. 4. Genetic Factors
• Pharmacogenetics is the study of the relationship b/w
genetic factors and drug response.
• All key determinants of drug response (transporters,
metabolizing enzymes, ion channels, receptors with their
couplers and effectors are controlled genetically.
• Pharmacogenomics is the use of genetic information to
guide the choice of drug & dose on an individual basis.
• It intends to identify individuals who are either more likely
or less likely to respond to a drug, as well as those who
require altered dose of certain drug.

62. Genetic Factors
• GENETIC POLYMORPHISM
The existence in a population of two or
more phenotype with respect to the
effect of a drug.
• Idiosyncrasy abnormal drug reaction due to genetic
disorder.
• Acetylation.
• Oxidation.
• Succinylcholine apnea.
• Glucose 6-phosphate dehydrogenase deficiency.

63. Genetic Factors
• Polymorphism of N-acetyl transferase 2 gene
results in rapid & slow acetilator status
(acetyl transferase - non-microsomal).
• Isoniazid, sulphonamides, procainamide, etc.
• Slow acetylator phenotype - isoniazid
peripheral
neuropathy; procainamide-induced lupus.
• Rapid acetylator phenotype - hepatitis.

64. •Pseudocholinesterase deficiency Succinyl
choline (Sk. muscle relaxant)
•Succinylcholine apnea due to paralysis of respiratory
muscles.
•Malignant hyperthermia
By succinyl choline due to inherited inability to chelate
calcium by sarcoplasmic reticulum.
abnormal Ca release, muscle spasm, temp.
Genetic Factors

65. Genetic Factors
•Deficiency of Glucose–6 phosphate
dehydrogenase (G-6-PD)
G-6-PD deficiency in RBCs is responsible for
hemolytic anemia upon exposure to some
oxidizing drugs.
•Antimalarial drug: primaquine, quinine.
•Long acting sulphonamides, nalidixic acid.
•Fava beans ( favism).

66. 5. Chronopharmacology
•The study of rhythmic, predictable-in-time differences in
the effects and/or pharmacokinetics of drugs. It
investigates the effects/side effects of drugs upon
temporal changes in biological functions or symptoms of a
disease as well as drug effects as a function of biologic
timing.
•Circadian Rhythm. A biological rhythm is an adaptive
phenomenon to predictable changes in environmental
factors linked to the rotation of the earth around its axis in
24 hours as well around the sun in 365 days.

67. Circadian rhythms are endogenously driven by
biological clocks found in single cells, flowers,
animals and men and in which "clock genes" are
expressed.
Mammalians circadian pacemaker resides in the
paired suprachiasmatic nuclei.

68. Types of rhythm
• Ultradian < 20 h
• Circadian ~ 24 h
• Infradian > 28 h
• Circaseptan ~ 7 days
• Circamensual ~ 30 days
• Circannual ~ 1 year

70. CVS
• BP rises about 20% immediately after awaking.
• 2 hrs after arising are the peak hrs for MI,
hemorragic stroke, thrombotic events.
• Reasons: physical activity
catecholamine level
platelet aggregation
vascular tone
intrisic thrombolytic activity

71. 5. Environmental Factors
Microsomal Enzyme Inducers
• Tobacco Smoke. Smokers metabolize drugs more
rapidly than non smoker.
• Pollutants are capable of inducing P450 enzymes,
such as hydrocarbons present in tobacco smoke,
charcoal broiled meat induce CYP 1A.
• Industrial workers exposed to some pesticides
metabolize certain drugs more rapidly than who are
non exposed. Polychlorinated biphenyls used in
industry, cruciferous vegetables also induce CYP 1A

72. Food-Drug Interaction
• Drug-food interactions may decrease absorption:
Calcium containing foods and tetracyclin
High fiber foods reduce absorption
• Drug-food interactions may increase absorption:
High calorie food more than doubles the absorption of
squinavir
• Drug may cause upset stomach if taken without food
–Choose alternative drug?
–Increase dose if taken with food?
–Take shortly before or after meal?

73. Food-Drug Interaction
• Grapefruit juice may inhibit metabolism of
certain drugs, raise the blood levels (co-
administration of grapefruit juice produce a
40% increase in blood levels of felodipine-
drug for hypertension), and lead to toxicity
level.
• Grapefruit juice may inhibits cytochrome
CYP3A isoenzyme and decrease metabolism of
certain drugs: One glass (200 ml) is sufficient.

74. REFERENCE
• FACTORS MODIFYING DRUG DOSE-RESPONSE RELATIONSHIP M. Imad Damaj,
http://www2.courses.vcu.edu/ptxed/m2/powerpoint/download/Damaj%20DR
%20Modification.PDF
• Body composition and growth. In Nutrition in Pediatrics, ed. 2, edited by WA
Walker and JB Watkins. Hamilton, Ontario, BC Decker, 1996
• Jiwon Kim. An Overview of Drug-Induced Liver Disease
• US Pharm. 2005;11:HS-10-HS-21.
• http://www.uspharmacist.com/index.asp?show=article&page=8_1634.htm
• http://www.medpharm-sofia.eu/
• P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.
• B. G. Katzung, Basic and Clinical Pharmacology, 12th ed., Appleton&Lange, 2012.
• H. P. Rang, M. M. Dale, J. M. Ritter, Pharmacology, 7th
ed., Churchill Livingstone,
2012.
• Lippincott's Illustrated Reviews Pharmacology, 4th EditionChapter 14
• Bailey DG. Grapefruit-medication interactions. CMAJ. 2013 Apr 2;185(6):507-8
• Journal of Chronotherapy and Drug Delivery (ISSN: 2249-6785)