Drug interaction

1. Drug Interaction
1

2. 2
Content
 Definition
 Epidemiology
 Risk factor
 Out come of interaction
 Mechanism ofinteraction
Pharmacokinetic
Pharmacodynamic
 Drug-Food interaction
 Drug-Disease interaction
 Reference

3. Definition
• Drug interaction occur when the response of a patient to a
drug is changed by the presence of another drug, food, drink,
herb or by some environmental chemical agent.
• A drug whose activity is
affected by such
interaction
OBJECT DRUG
• The agent which
precipitates such a
interaction
PRECIPITANTS
3

4. Drug interaction includes
Drug –drug interaction
Food – drug interactions
•e.g. inhibition of several drugs by grapefruit juice
Drug – disease interactions
• e.g. worsening of disease condition by the drug
4

5. 5
Epidemiology
• Drug–drug interactions resulting in about 2.8% of all
hospitalizations
• In 2007, a meta-analysis of 23 clinical studies from around the
world revealed that drug–drug interactions cause approximately
0.054% of emergency room visits, 0.57% of hospital
admissions, and 0.12% of rehospitalizations
• There are 136.1 million emergency room visits and 34.1
million hospital admission in USA each year

6. Risk Factor
• Poly pharmacy
• Multiple pharmacies
• Multiple prescribers
• Genetic make up
• Specific populationlike e.g. females, elderly, obese, critically ill
patient, transplantrecipient
• Specific illness E.g. Hepatic disease, Renaldysfunction
• Narrow therapeutic index drug - Cyclosporine, Digoxin, Lithium,
Antidepressant, Warfarin
6

7. Outcomes of drug interactions
Synergism or additive effect of one or
more drugs
Antagonism or reduction of the effects of
one or more drugs
Alteration of effect of one or more drugs
or the production of idiosyncratic effects
or toxicity
7

8. INTERACTIONS
OUTSIDE THE
BODY
INSIDE THE
BODY
PHARMACO-
KINETICS
PHARMACO-
DYNAMICS
8

9. 9
INTERACTIONS OUTSIDE THE
BODY
• Interactions may occur outside the body even before it is
administered and is usually chemicalinteraction
• E.g. mixing the drugs in same syringe such as thiopentone
and succinylcholine interact – administered separately
• Carboxipenicillin inactivate aminoglycosides when mixed in
same syringe or infusion
• Quinupristin and dalfoprisin combination used as i.v.
infusion which is incompatible with N-saline – use 5%
dextrose
• Ampicillin, amoxicillin, phenytoin, sulphonamides, heparin
are unstable in acidic pH of 5% dextrose – avoided

10. Drug interactions inside the body
Pharmacokinetics Pharmacodynamics
10

11. Pharmacokinetic interaction
Absorption Distribution Metabolism Excretion
11

12. Pharmaco-
dynamic
interactions
12
Antagonistic
or Opposing
Additive/
Potentiation/
Synergy
Changes in
Drug
Transport
mechanism

13. 13
Pharmacokinetic
interactions

14. 14
ABSORPTION

15. • Changes in GITpH
• Complex and chelate
formation in theGIT
• GIT motility
• Toxic effects on the GIT
• Changes in gutflora
Altered
Gastro-
intestinal
tract
absorption
15

16. Changes in gastrointestinal pH
• Non-ionized > Ionized form
Antacids
Decrease the absorption
of Ketoconazole,
Itraconazole (acidic)
Proton pump
inhibitors
Histamine
H2-antagonists
16

17. Alkalinizing effects of antacids on the
gastrointestinal tract aretransient
The potential for interaction decreased by
leaving an interval of 2–3 hours between
antacid and potentially interacting drug
17

18. 18
Complex formation in the
gastrointestinal tract
• Certain drugs are liable to react with other drugs in the
gastrointestinal tract and form chelates and complexes that are
not absorbed

19. Quinolones/
Ciprofloxacin
Antacids
Containing
Aluminium
or
Magnesium
Dramatically
reduces levels
of Quinolones/
Ciprofloxacin
Levodopa,
Levodopa/
Carbidopa
combination,
Methyldopa
Iron
supplement
s
Reduces
absorption
19

20. • Interaction can be prevented if the antibacterialis not
given until at least 6 hours after theantacid
• reduce the absorption of
antibacterials – azithromycin,
quinolones, rifampicin, tetracyclines
Antacids
• Reduce the absorption of
bisphosphonates – alendronate,
clodronate, etidronate
Calcium
20

21. 21
•Most chelation and adsorption interactions can be
prevented by separating doses of the interacting
drugs by a period of several hours

22. 22
Gastrointestinal motility
•Drugs that influence gastric emptying or
gastrointestinal motility can affect the absorption of
other drugs

23. bioavailability of levodopa by as much as
50%
Anticholinergic
• Delay gastric emptying andreduce
drugs
• Increases gastric emptying and increases
absorption rate of paracetamol
• Also accelerates absorption propranolol,
mefloquine, lithium and cyclosporin
Metoclopramide
23

24. Toxic effects on the gastrointestinal tract
Absorption of some drugs may be reduced due to
damage of the small intestine
Absorption of phenytoin and verapamil can be
reduced by 20–35% in patients taking cytotoxic
drugs such as methotrexate, carmustine, or
vinblastine for treatment of malignant disease
24

25. Changes in gut flora
Large bowel
Small bowel
Stom-
ach
25

26. 26
• Drugs that are metabolised to some extent by the gut flora
include sulfasalazine and levodopa
• Evidence suggest that ampicillin may reduce the effects of
sulphasalazine by reducing the gut bacteria that act on
sulphasalazine to release sulphapyridine and 5-aminosalicylic
acid

27. DISTRIBUTION
27

28. Main mechanism behind such interactions is displacement
from protein binding sites
Drug displacement interaction is defined as a reduction in
plasma protein binding of one drug caused by presence of
another which competes for the same binding sites, resulting
in an increased free or unbound concentration of displaced
drug
28

29. 29
• Displacement makes more unbound (free) drug available for
metabolism of glomerular filtration, displaced drug can
normally distribute out of the plasma compartment, increased
unbound drug concentrations are usually only transient, and,
do not give rise to altered pharmacological effects in the
patient

30. Phenylbutazone,
Salicylates,
Sulphonamides
Displace
Tolbutamide
from binding site
Cause
hypoglycaemia
Salicylates,
Indomethacin,
Phenytoin and
Tolbutamide
Displace warfarin
Cause
haemorrhage
30

31. METABOLISM
31

32. METABOLIC
PROCESS
PHASE I
REACTIONS
Oxidation,
hydrolysis or
reduction
Hepatic mixed
function oxidase
system
cytochrome P450is
most important
PHASE II
REACTIONS
Conjugation ofdrug
(or productof phase
I metabolism) with
substances such as
glucuronic acid,
sulphate, orglycine
32

33. 33
• Sub-families of P450 isoenzymes are responsible for most of
the metabolism of commonly used drugs CYP1, CYP2, and
CYP3 in humans
• Isoforms (CYP1A2, CYP2C9, CYP2C19,CYP2D6, CYP2E1,
and CYP3A4) are involved in the metabolism of a large
proportion of drugs
• Importance of these enzymes for drug interactions is enzyme
inducers and inhibitors and may affect the metabolism of
selected drugs

34. Enzyme induction
Enzyme induction usually develops over a
period of several days or weeks
Effect generally persists for a similar period
following withdrawal of the enzyme-inducing
agent
34

35. • Rifampicin
• Tobacco
smoke
• Phenytoin
• Rifabutin
• Ethanol
(chronic)
• Griseofulvi
n
• Barbiturate
s
• Carbamaze
pine
Some enzyme
are
inducers
35

36. 36
• Enzyme induction usually results in a reduced pharmacological
effect of the induced drug but where active metabolites are
responsible for a drug’s effect the reverse may occur

37. Barbiturates,
phenytoin,
carbamazepine
and rifampicin
CYP2C9 WARFARIN
If phenytoin
administered
Anticoagulant
effect over
To maintain the
the same effect
to patient the period the dose of
stabilised
on warfarin
of several weeks warfarin
If enzyme inducing drug is withdrawn enzyme activity returns to
normal, with a risk of haemorrhage unless the warfarin dose is
correspondingly reduced
37

38. 38
Examples of interactions due to enzyme induction
Drug affected Inducing agent Clinical outcome
Carbamazepin
e
Lamotrigine Increased concentrationsof epoxide metabolite
leading totoxicity
Hormonal
contraceptives
Rifampicin Therapeutic failure ofcontraceptive
Rifabutin Additional contraceptive precautionsrequired
Carbamazepine
Ciclosporin Phenytoin Decreased ciclosporin levels with possibility of
transplant rejection
Carbamazepine
Paracetamol Alcohol
(chronic)
In overdose, hepatotoxicitymay occur at lower
doses
Corticosteroids Phenytoin Increased metabolism with possibilityof
therapeuticfailure
Rifampicin

39. Enzyme inhibition
Inhibition of drug metabolism may
result in exaggerated and prolonged
responses and increased risk of toxicity
inhibition is more rapid than induction
as soon as sufficient concentrations of
the inhibitor appear in theliver
39

40. • Antiviraldrugs
• Indinavir
• Ritonavir
• Saquinavir
40
• Antifungal drugs
• Fluconazole
• Itraconazole
• Ketoconazole
• Miconazole
• Antidepressants
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Antibacterials
• Ciprofloxacin
• Erythromycin
• Isoniazid
some enzyme
are
inhibitors

41. • Other
• Disulfiram
• Dextropropoxyphe
ne
41
• Rheumatological
drugs
• Allopurinol
• Azapropazone
• Phenylbutazone
• Gastrointestinal
drugs
• Cimetidine
• Cardiovascular
drugs
• Amiodarone
• Diltiazem
• Quinidine
• Verapamil
some enzyme
are
inhibitors

42. Cimetidine
reduces theophylline clearance
serious convulsions and cardiac
arrhythmias
dose of theophylline may need
to be reduced
42

43. • Cimetidine prolongs the t1/2
phenytoin, nitrazepam,
diazepam, warfarin, and
theophylline
• enzyme inhibitors, including macrolides cause the accumulation of
drugs, prolong the QT interval and cause arrhythmias most
characteristic is torsades de pointes
oxidative drug
--
-- metabolism
43

44. 44
Drugs that can prolong the QT interval
• Mechanism is drug-induced blockade of the repolarizing
potassium channels
Antiarrhythmic
drugs
Amiodarone, sotalol, quinidine, disopyramide
Antihistamines Terfenadine, astemizole
Antiinfectives Erythromycin (especially intravenous use),
halofantrine, some quinolones
Psychiatric
drugs
Amisulpride, haloperidol, sertindole,
thioridazine, pimozide
Others Cisapride

45. metabolism of cyclosporin is inhibited
by diltiazem, verapamil, azole
antifungal agents, erythromycin and
clarithromycin
Interactions have been used as a cost
saving device in organ transplant
patients, aim of using a lower dose of
cyclosporin to achieve
immunosuppression
45

46. EXCRETION
46

47. Most interactions involving elimination or
excretion occur in kidneys
Interactions can occur when drugs interfere
with kidney tubule fluid pH, active transport
systems, or blood flow to the kidney thereby
altering the excretion of other drugs
47

48. Changes in urinary pH
• Passive reabsorption of drugs depends on the extent towhich
the drug exists in the non-ionised lipid-soluble form
At alkaline pH weakly acidic drugs, exist
as un-ionised lipid insoluble molecules
unable to diffuse and lost in the urine
clearance of these drugs is increased if
the urine is made more alkaline
48

49. Urine alkalinisation may be used as increasing
drug elimination in salicylate poisoning
Acidification of urine has been used to increase
amphetamine elimination
49

50. Changes in active renal tubule excretion
Drugs which use the same active transport system in kidney
tubules can compete with one another for excretion
Onset and offset of this inhibitory effect is rapid and
concentration dependent, due to its competitive nature
Probenecid may be given to increase the serum concentration
of penicillins by delaying their renal excretion
50

51. Changes in renal blood flow
Blood flow through the kidney is partially controlled
by the production of renal vasodilatory prostaglandins
mechanism underlying this interaction is not entirely
clear
51

52. If an NSAID is prescribed for a
patient takinglithium
synthesis of prostaglandinsis
inhibited
renal excretion of lithium is reduced
with a rise in serum levels
serum levels should be closely
monitored
52

53. Drug-Transporter Proteins
Drugs cross biological membranes by passive
diffusion and by transporter proteins
most well known is P-glycoprotein, an efflux
pump found in cell membranes
pumping actions of P-glycoprotein can be
induced or inhibited by some drugs
53

54. Induction of intestinal P-glycoprotein by rifampicin causes
digoxin to be ejected into the gut more, resulting in reduced
digoxin levels
Verapamil inhibit activity of P-glycoprotein, andincrease
digoxin levels
P-glycoprotein inhibition may have a greater impact on drug
distribution than on drug absorption.
54

55. Pharmacodynamic
Interactions
55

56. • Antagonistic or Opposing Interactions
• Additive Effect/Potentiation/Synergy
• Interactions Due to Changes in Drug Transport
Mechanisms
• Interactions Due to Disturbances in Fluid and
Electrolyte Balance
• fairly common but may not always be recognised
Pharmacodynamic interactions generally
involve
56

57. Antagonistic or Opposing Interactions
drug with an agonist action at a particular receptor type will
interact with antagonists at that receptor
Specific antagonists may be used to reverse the effect of
another drug at receptor sites
opioid antagonist naloxone and the benzodiazepine antagonist
flumazenil
57

58. Additive Effect/Potentiation/Synergy
• If two drugs with similar pharmacological effects are given
together, the effects can be additive
Additive or synergistic interactions
Interacting drugs Pharmacological effect
NSAID and warfarin Increased risk of bleeding
ACE inhibitors and K-sparing diuretic Increased risk of hyperkalemia
Verapamil and beta-adrenergicantagonists Bradycardia andasystole
Neuromuscular(NM) blockers and
aminoglycosides
Increased NM blockade
Alcohol andbenzodiazepines Increased sedation
Thioridazine andhalofantrine Increased risk of QT interval
prolongation
Clozapine andcotrimoxazole Increased risk of bone marrow
suppression

59. Interactions Due to Changes in Drug
Transport Mechanisms
One drug may interfere with the uptake and
transport of another to intracellular sites ofaction
Antihypertensive effects of adrenergic neurone
blocking drugs such as guanethidine is prevented or
reversed by tricyclic antidepressants
59

60. Interactions Due to Disturbances inFluid
and Electrolyte Balance
Potentiation of the effects of digoxin by diuretics which
decrease plasma potassium concentrations
ACE inhibitors have a potassium-sparing effect, and
concurrent use of potassium supplements or potassium
sparing diuretics lead to hyperkalaemia
60
•Changes in electrolyte balance may alter the effects
of drugs, acting on myocardium, neuromuscular
transmission and kidney

61. 61
DRUG - HERB INTERACTIONS
• Most well-known and documented example is the interaction
of St John’s wort (Hypericum perforatum) with different drugs
• Herb can induce CYP3A4, and can also induce P-glycoprotein

62. Effect of St John’s wort (Hypericum perforatum)
on ‘conventional drugs’
Drug Effect
Buspirone Additive CNS effects
Carbamazepine Reduced levels of single-dose carbamazepine, no significant
effect on multiple doses of carbamazepine
Digoxin Reduced digoxin levels; digoxin toxicity seen in onepatient
when St John’s wortstopped
Hormonal
contraceptives
Breakthrough bleedingand contraceptive failures reported
Indinavir Marked reduction in indinavirlevels
Irinotecan Decreased levels of the active metabolite of irinotecan
SSRIs Cases of the serotonin syndrome reported
Verapamil Reduced verapamil bioavailability
Voriconazole Reduced voriconazolelevels
Warfarin Moderate reductionin the effects of warfarin reported 62

63. 63
DRUG FOOD INTERACTIONS
• Due to presence or absence of food and simultaneous
consumption of food items, several interactions have occurred
• Most of them are not clinically relevant while some may be
serious(cheese reaction)

64. 64
1. Presence of food:
• Fatty food reduces the absorption of many drugs due to reduced
gastric emptying e.g. Thyroxine , Rifampicin
• Absorption of alendronate is reduced by orange juice, tea, or
coffee
• Therefore should be taken empty stomach
2. Milk:
• Reduces absorption of certain drugs e.g iron and tetracycline
due to presence ofcalcium
3. Grape fruit juice:
• Increases the absorption of cyclosporine
• Inhibits metabolism of phenytoin, terfenadine and amiodarone
leading to toxicity

65. 65
4. Cheese reaction:
• Severe hypertension may occur if a patient on MAO inhibitor
and consumed the food item prepared by fermentation as they
contain tyramine
• Cheese also contains tyramine and same reaction occurs with
cheese as well and this is called cheese reaction
5. Fruits rich in potassium:
• Sweet lime and mango may cause hyperkalemia when used with
potassium diuretics or ACE inhibitors or patients of chronic
renal failure

66. 66
DRUG DISEASE INTERACTIONS
• Presence of disease or in pathological states a drugmay
aggravate or precipitate thedisease
1.Hepatic disease:
Drugs which are completely metabolized, their concentration
increases in hepatic damage depending on the degree of liver
dysfunction
2.Renal disease:
Drugs which are eliminated unchanged, their concentration
increases in renal damage depending on the degree of renal
dysfunction

67. 67
3.Cardiovascular diseases:
a)Variant angina: Non-selective beta blockers may aggravate
the variant angina because they cause vasoconstriction of
coronary blood vessels
b)MI: Cardiac dysrhythmia may occur due to digoxin and
sympathomimetics
4.Respiratory diseases:
a)Asthmatic patients: Non selective beta blockers , aspirinand
indomethacin may precipitate the attack of bronchialashtma

68. 68
5. Endocrine diseases:
a)Diabetes mellitus: glucocorticoids cause hyperglycemia and
thus difficult to control diabetes mellitus
b)Thyroid disease: drug metabolism is reduced in
hypothyroidism while enhanced in hyperthyroidism
6.Other diseases:
a)Myasthenia gravis: made worse by quinine and quinidine.
Myasthenics are intolerant to competitive neuromuscular
blockers(d-tubocurarine) and aminoglycosides(gentamicin)
b)Migraine: during acute attack of migraine the delayed gastric
emptying and reduced intestinal motility lead to reduced
absorption of drugs

69. 69
CONCLUSION
• Drug interaction causes morbidity and occasionally mortality
• It is impossible to remember all known important interactions, but
keeping basic principles in mind can help clinicians minimise their
occurrence
• Drugs with a narrow therapeutic window (e.g. anticoagulants,
digoxin, lithium, immunosuppressives) are oftenimplicated
• pharmacokinetic interactions involved drugs which can induce or
inhibit hepatic cytochrome P450 enzymes; vigilance is required
when these areprescribed