Drug Interactions and

Adverse Drug Reaction

Mustofa
Department of Pharmacology and Therapy
Faculty of Medicine, Gadjah Mada

Definition
Drug interaction is the modification of
the effect of one drug (the object drug)
by the prior concomitant administration
of another (precipitant drug).

Outcomes of drug interactions

1)
2)
3)
4)

Loss of therapeutic effect

Toxicity
Unexpected increase in pharmacological activity
Beneficial effects e.g additive & potentiation (intended)
or antagonism (unintended).
5) Chemical or physical interaction
e.g I.V incompatibility in fluid or syringes mixture

Drugs Removed from or Restricted in the

U.S. Market Because of Drug Interactions

Terfenadine (Seldane)February 1998

Mibefradil (Posicor)
June 1998
Astemizole (Hismanal)
July 1999
Grepafloxacin (Raxar)
October 1999
Cisapride (Propulsid)
January 2000
Cerivastatin (Baycol)
August 2001
Levomethadyl (Orlaam) August 2003

* Restricted

Contribution of Drug Interactions to the

Overall Burden of Preventable ADRs

Drug interactions represent 35% of

preventable in-hospital ADRs
Drug interactions are an important
contributor to the number of ER visits
and hospital admissions
Leape LL et al. JAMA 1995;274(1):3543.
Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959963.

Risk Factors for Drug Interactions

High Risk Patients
Elderly, young, very sick, multiple disease
Multiple drug therapy
Renal, liver impairment

High Risk Drugs

Narrow therapeutic index drugs
Recognised enzyme inhibitors or inducers

Classification of Drug Interactions

Pharmacokinetic
in drug absorption,
distribution, metabolism
or excretion

Pharmaceutic

Pharmacodynamic
of pharmacological effect at standard
drug concentrations
or
of pharmacological effect resulting from
altered pharmacokinetic exposures

in out of the body

All drugs known to humans are
poisons, only the amount or dose
determine the effects.

Paracelsus,14901541

Pharmaceutical Interactions
Interactions that occur prior to systemic
administration.
For example incompatibility between two drugs
mixed in an IV fluid. These interactions can be
physical (e.g. with a visible precipitate) or chemical
with no visible sign of a problem

Example pharmaceutic interactions

Phenytoin precipitates in IV dextrose solutions.
Amphotericin precipitates in IV saline
Gentamicin is physically/chemically incompatible
when mixed with most beta-lactam antibiotics,
resulting in loss of both antibiotics effects

Pharmacokinetic Drug Interactions

One drug alters the rate or extent of
absorption, distribution, metabolism or
excretion of another drug.
A change in blood concentration causes
a change in the drugs effect.

Site of Pharmacokinetic Interactions

Absorption

Distrition

Example

Change in absorption from GI tract

Alterations in pH
Complex formation with ions
Interference w/transport protein (i.e. P-gp)
Pre-systemic enteric metabolism

TetracyclinewithAntacid

Change in distribution free drug

Protein binding drug deplacement

WarfarinwithTMP/SMX

Metabolism Changes in hepatic metabolism

Rifampisinwithotherdrug
Interference with transport proteins
Interference with phase I or II drug metabolism

Excretion

Decreased/Increase renal excretion

Interference with glomerular filtration, tubular Penisilinwithprobenesid
secretion or other mechanisms

Absorption Interaction
Change in gastrointestinal pH
Ketoconazole needs acidic conditions in gut

Drug binding in GI tract

E.g. tetracycline and calcium

Change in gastrointestinal flora

Antibiotics with OCs

Change in GI motility due to mucosal demage

Metoclopramide and digoxin

Malabsorption caused by other drugs

Orlistat (Xenical) and fat soluble vitamins

Altered pH
The non-ionized form of a drug is more
lipid soluble and more readily absorbed
from GIT than theionized form does.
Antiacids
pH

pKa=pH+log(HA/A-)
pKa=pH+log(BH+/B)

H2 antagonists
Decrease the tablet
dissolution of
Ketoconazole (acidic)

pH

Therefore, these drugs must

be separated by at least 2h
in the time of administration
of both .

Lipid solubility :weak acids and weak bases

HA <==> H+ + A[ UI ]

[I]

pKa=pH+log(HA/A-)
ASPIRIN pKa = 4.5 (weak acid)
100mg orally

0.1 = [ I ]
Stomach
pH = 2

99.9 = [ UI ]

Blood
pH = 7.4

[ UI ]

Aspirin is reasonably absorbed

from stomach (fast action)

B + HCl <==> BH+ + Cl[ UI ]

[I]

pKa=pH+log(BH+/B)
STRYCHNINE pKa = 9.5 (weak base)
100mg orally

99.9 = [ I ]
Stomach
pH = 2
0.1 = [ UI ]

Blood
pH = 7.4

[ UI ]

Strychnine not absorbed until

enters duodenum

Grapefruit Juice and Felodipine

Hours after Dose

Hours after Dose

Dresser GK, et al. Clin Pharmacol Ther 2000;68(1):2834.

Mediated by alterations in gastric emptying

or gastrointestinal transit

11
10

9
8

7
6
GRT
(hr)

3
2
1

Fasting

Fed

Effect of food on
gastric residence time
(GRT) of the
Heidelberg capsule
administered to
healthy male (circles)
and female (squares).
Reproduced from: Mojaverian
P et al. Effect of food on the
absorption of enteric coated
aspirin: Correlation with
gastric residence time. Clin
Pharmacol Ther 41:11-17,
1987.

Influence of food on salicylate absorption

Altered intestinal bacterial flora

In 10% 0f patients receive digoxin..40% or more
of the administered dose is metabolized by the intestinal flora

Antibiotics kill a large

number of the normal
flora of the intestine
Increase digoxin conc.
and increase its toxicity

Drug binding in GI tract form complexation or chelation

Tetracycline interacts with iron preparations or milk
(Ca2+) form unabsorpble complex
Antacid (aluminum or magnesium) hydroxide
decrease absorption ciprofloxacin by 85% due to
chelation

Effect of ferrous sulfate (325 mg) on plasma levodopa and carbidopa

concentrations after ingestion of Sinemet (100/25) in patients with
Parkinson's disease. Concentrations shown are mean values without
(tirangles) and with (circles) ferrous sulfate administration simultaneously.
Adapted from Campbell NRC et al: Br J clin Pharmacol 30:599-605, 1990

Effect of Antacids on Iron Absorption from a Multivitamin.

Antacid was ingested immediately after multivitamin ingestion.
Data from: O'Neil-Cutting MA, Crosby WH. The effect of
antacids on the absorption of simultaneously ingested iron.
JAMA 255:1468- 1470, 1986.

Drug induced mucosal damage

Antineoplastic agents :
Cyclophosphamide
Vincristine
Procarbazine

Inhibit absorption
of several drugs
eg., digoxin

Altered motility
Metoclopramide
(antiemitic)

Increase absorption of
cyclosporine due
to the increase of
stomach empting time

Increase the
toxicity
of cyclosporine

Drug Interaction in Distribution

Protein Binding Drug Displacement
Drug B

Plasma

Tissue

Drug A
protein bound

Drug A
free

Drug A
free

Drugs A and B both bind to the same plasma protein

Displaced protein binding

It depends on the affinity of the drug to plasma protein.
The most likely bound drugs is capable to displace others.
The free drug is increased by displacement by another drug
with higher affinity.
Phenytoin is a highly bound to
plasma protein (90%),
Tolbutamide (96%), and
warfarin (99%)
Drugs that displace these agents are
Aspirin
Sulfonamides
phenylbutazone

Interactions in Drugs Metabolism

Nearly always due to
interaction with Phase I
enzymes, rather than Phase II
Commonly due to cytochrome
P450 enzymes which have
highly variable activity and, in
some cases, are genetically
absent or over-expressed

Phases of Metabolism Pathway

Absorpsi
FASE I

Metabolisme
Ekskresi
FASE II

Metabolit aktif

Obat
Metabolit
nonaktif
Oksidasi (SitP450)
Oksidasi
Reduksi
Hidrolisis
Hidrasi
Isomerasi
Dll

lifofilik

Konjuga
t
Konjuga
t
Glukoronidasi
Sulfasi
Metilasi
Asetilasi
Konjugasi as.
amino
Konjugasi
glutation
Konjugasi as.
lemak
Kondensasi

hidroofili
k

Phase I - Drug Oxidation

Tamoxifen metabolism

Goetz et al, J Clin Oncol 2005; 23

Spectrum of Consequences of
Drug Metabolism

Inactive products
Active metabolites
Similar to parent drug
More active than parent
New action unlike parent

Toxic metabolites

Microsomal Enzymes
Cytochrome P450
Flavin mono-oxygenase
(FMO3)

CYP450 Nomenclature
Family

CYP2D6
Genetic Family

Specific Gene

Genetic sub-family
NOTE: This nomenclature is genetically based; it does not imply
chemical specificity

Major Human CYP450 Isoforms

CYP1A2
CYP2B6
CYP2C8
CYP2C9
CYP2C19

CYP2D6
CYP2E1
CYP3A4
CYP3A5
CYP3A6

CYP450 Activity in the Liver

Relative Importance of
P450s in Drug Metabolism
CYP2E1

Relative Quantities
of P450s in Liver

CYP1A2

CYP2C

CYP1A2
CYP2C

CYP3A
CYP2D6
CYP2E1
CYP3A

CYP2D6

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

Enzyme characteristics
% drugs metabolised by enzyme

3A4
2D6
1A2
2C9
2C19

2E1

60%
25%
15%
Small no. but significant interactions
Small no. but significant interactions
?

Cytochrome P450 3A
Responsible for metabolism of:
Most calcium channel blockers
Most benzodiazepines
Most HIV protease inhibitors
Most HMG-CoA-reductase inhibitors
Most non-sedating antihistamines
Cyclosporine

Present in GI tract and liver

CYP 450 System Definitions

Substrate:
Drug is metabolised by the enzyme system
Inducer:
Drug that will increase the synthesis of CYP450
enzymes
Inhibitor
Drug that will decrease the metabolism of a
substrate

CYP3A Inducers
Carbamazepine
Rifampin
Rifabutin
Ritonavir
Phenobarbitone
Cigarette smoke

Enzyme Induction
Leads to production of more enzyme, usually
after 3-4 days of exposure to inducer
Most CYPs are inducible but not CYP2D6
Time course of interaction depends on halflife of inducer.
Rifampicin has short half-life and induction
apparent with 24 hours
Phenobarbitone has longer half life so time to
complete induction takes longer

Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations

and prothrombin time. From: Cucinell SA, et al. Lowering effect of phenobarbital on
plasma levels of dicumarol and diphenylhydantion. Clinical Pharmacology & Therapeutics
6:420-429, 1965.

Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. NEJM 304:1466, 1981.

Enzyme Inhibition
Often rapid, reversible and relatively short acting.
E.g. erythromycin and cyclosporin
NB erythromycin is a substrate and an inhibitor of
CYP 3A4
May be prolonged due to long half- life of drug.
E.g. amiodarone and S-Warfarin
NB amiodarone is an inhibitor of CYP2C9 but not a
substrate for this CYP

CYP3A Inhibitors
Ketoconazole
Itraconazole
Fluconazole
Cimetidine
Clarithromycin
Erythromycin
Troleandomycin
Grapefruit juice

NOT Azithromycin

Effect of cimetidine on the clearance on diazepam (D),

desmethyldiazepam (DZD), chlordiazepoxide (CZD) and
oxazepam (OXM). CZD values are x10, while OXM values are
1/10. Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. Clin
Pharmacokinet 7:23, 1982.

Excretion Interactions
Drug A increases or reduces the excretion
(usually renal) of Drug B.
Blood levels of B fall below or rise above
normal therapeutic range.
Becomes either ineffective or toxic.

Mechanism of Excretion Interactions

Mechanisms of urinary excretion:
- Simple filtration
- Active secretion
Mechanisms for active secretion
- Acids
- Bases
Active secretion mechanisms have limited capacity.
e.g. One acid drug may saturate the acid drug
active secretion mechanism. Another acid drug
will then be secreted less efficiently

Active Tubular Secretion

Urine pH

Renal clearance of salicylate in 11 yo child with rheumatic fever treated

with an antacid. Data from Levy G, Lampman T, Kamath BL, Garrettson
LK. Decreased serum salicylate concentrations in children with rheumatic
fever treated with antacid. N Engl J Med 293:323-325, 1975.

Excretion Interaction lithium + thiazides

Probable mechanism:
Thiazides cause diuresis and initial sodium loss.
Compensatory sodium retention in proximal
tubules.
Proximal tubules do not distinguish sodium
from lithium.
Lithium also retained and accumulates.

Excretion Interaction
methotrexate and NSAIDs
Methotrexate and NSAIDs
NSAIDS can decrease renal blood flow
by inhibition of renal prostaglandins.
Reduced clearance of MTX and active
(toxic) metabolite

Pharmacodynamic Drug
Interactions
One drug causes a change in patient
response to another drug without
altering that drugs pharmacokinetics
Eg increase toxicity of digoxin caused by diuretic
induced hypokalaemia
Additive effects of alcohol and benzodiazepines
Beta-blocker given with beta-agonist

Classifications of
Pharmacodynamic Interactions
Additive (1+1 = 2)
Increased bone marrow toxicity of ZDV + GCV
Synergistic (1+1 = 3)
HAART effect greater than additive
monotherapy
Antagonistic (1+ 1 = 0 or 0.5)
ZDV and D4T reduces antiviral effect
Potentiating (1 + 0 = 2)

* Prevention of drug interaction

1) Monitoring therapy and making adjustments
2) Monitoring blood level of some drugs with narrow
therapeutic index e.g., digoxin, anticancer agents
etc
3) Monitoring some parameters that may help to
characterize the the early events of interaction
or toxicity e.g., with warffarin administration, it
is recommended to monitor the prothrombin time
to detect any change in the drug activity.
4) Increase the interest of case report studies to
report different possibilities of drug interaction

Adverse Drug Reactions

Definition :
An ADR is any unwanted effect
resulting from a drugs use in
treatment.

WHO Definition of ADRs

Any noxious, unintended, undesired
effect of a drug which occurs at doses
used for prophylaxis, diagnosis, or
therapy, excluding therapeutic failures,
intentional and accidental overdose and
drug abuse, and does not include AEs
due to errors in drug administration.

Incidence of ADRs

ADRs are always under reported

ADRs are the 4th-6th largest cause for mortality in the
USA1
ADRs account for approximately 10% of hospital
admissions

1.
2.
3.

Norway 11.5%, France 13.0% UK 16.0%2

ADRs increase the length of hospital stay and

medical costs
15-20% of hospital budget may be spent dealing with
drug complications3
Lazarou et al.JAMA 1998, 279(15) 1000-5
Safety of Medicines. WHO/EDM/QSM/2002.2
White et al. Pharmacoeconomics,1999,15(5) 445-458

Possible Causes of Adverse Reactions

Intrinsic factors of the drug
Pharmacological
Idiosyncratic
Carcinogenicity, Mutagenicity
Teratogenicity
Extrinsic factors
Adulterants
Contamination
Underlying medical conditions
Interactions
Wrong usage

How knowledge about ADRs is created?

animal experiments
clinical trials
epidemiological
methods
Observational studies
case reports
case series

Post-Marketing
Surveillance (PMS)
prescription event
monitoring
cohort studies

intensive hospital
monitoring

case-control studies
record-linkage
meta-analysis

Classification of ADRs
Type A (Augmented ) reactions
Reactions which can be predicted from the
known pharmacology of the drug
Dose dependent, can be alleviated by a dose
reduction
E.g. Bleeding with anticoagulants,
bradycardia with beta blockers, headache
with nitrates, postural hypotension with
prazosin

 Type B (Bizarre) reactions

Cannot be predicted from the

pharmacology of the drug
Not dose dependent, host dependent
factors important in pre-disposition
E.g. anaphylaxis with penicillin,
anticonvulsant hypersensitivity

 Type C (Chemical) reactions

Biological characteristics can be predicted from the
chemical structure of the drug/metabolite
E.g. paracetamol hepatotoxicity
Type D (Delayed) reactions
Occur after many years of treatment. Can be due to
accumulation
E.g. Secondary tumours after treatment with
chemotherapy, teratogenic effects of phenytoin
taken during pregnancy, analgesic nephropathy,
tardive dyskinesia with antipsychotic agents

 Type E ( End of treatment) reactions

Occur on withdrawal especially when
drug is stopped abruptly
E.g. withdrawal seizures on stopping
phenytoin, adrenocortical insufficiency
on withdrawal of steroids.

Characteristic type A & B of ADRs

Common Adverse Reactions

Respiratory depression
Opiates, barbiturates, general anaesthetics
Anaphylactic Shock
Antibiotics, Opiates, barbiturates, blood/blood products,
snake/spider antivenom, blockers
Nausea / Vomiting
Anticonvulsants, general anaesthetics, opiates, decongestants,
antihistamines, antihypertensives, antihypertensives,
peripheral/central vasodilators, oral contraceptives

 Constipation
Opiates, anti muscarinics, Tricyclic anti depressants,
Hypertension
Sympathomimetics, corticosteroids, oral contraceptives,
MAOIs, CNS stimulants
Hypotension
Calcium channels blockers, diuretics, general anaesthetics,
opiates, benzodiazepines, antipsychotics, antiarrhythmics

 Rash
Antibiotics, benzodiazepines, lithium, aspirin
Dry mouth
Opiates, antimuscarinics, antihistamines
Drowsiness/sedation
Opiates, benzodiazepines, antihistamines, general anaesthetics,
tricyclic antidepressants

How to recognize ADRs

Since ADRs may act through the same
physiological and pathological pathways as
different disease, they are difficult and
sometimes impossible to distinguish

Drug administered
Pt develops a new condition/symptoms
Drug suspected?
Yes
Check literature
Documented ? (for the product
or similar class of products)
Yes
Highly suggestive of ADR

Not documented in literature

Drug continued

Drug discontinued

Worsening of symptoms

Symptoms improve

Any other possible causes?

Concomitant therapy
Underlying conditions

(+ve dechallenge)
Drug restarted
Symptoms recur
(+ve rechallenge)

Term related ADRs

Adverse Drug Reactions
Side Effects
Idiosyncratic Reactions
Drug Dependence
Toxicology

Side Effects
An unwanted effect of the drug related to its action at
other sites in the body

Muscarinic Blockers : Atropine

Blockers : Propanolol

Muscarinic Blockers : Atropine

Pharmacology: Non-selective muscarinic antagonist
Indications: Bradycardia, enuresis, peptic ulcer
Side Effects
Urinary retention
(M3 blockade)

Tachycardia
(M2 blockade)

Someone taking atropine for enuresis, tachycardia is a side

effect
Someone taking atropine for bradycardia, urinary retention is a
side effect

 Blockers : Propanolol
Pharmacology: Non selective antagonist
Indications : Hypertension (1 blockade)
Side Effects
Bronchospasm
(2 blockade)

Hypoglycaemia
(2 blockade)

Side effect may cause contraindication in

Asthmatics

Diabetics

Idiosyncratic reactions
A response to a drug which is unusual / unpredictable and
seldom observed in the population

Due to

Genetic Differences
in metabolism
Alcohol
Suxamethonium (neuromuscular blocker)
Propanolol ( blocker)

Immune Reaction
Hypersensitive immune response to a drug
Anaphylactic shock

Idiosyncratic Reaction : Suxamethonium metabolism

1:2000 individuals have an inherited defect in plasma pseudocholinesterase
Suxamethonium (depolarising neuromuscular blocker) has short duration of
action due to breakdown by cholinesterase and pseudocholinesterase
These people have an extremely slowed metabolism of depolarising
neuromuscular blockers (due to defect in pseudocholinesterase)

Prolonged paralysis (not good)

Idiosyncratic Reaction : Immune Reaction

Anaphylactic Shock
In some individuals a drug or its metabolite acts as an antigen
and produces an immune reaction

In most cases this is presented as a skin rash, fever,

oedema, joint inflammation (Type II, III and IV
hypersensitivity)

BUT
Some people have a severe immune reaction to some drugs = Anaphylactic Shock

Penicillin : Anaphylactic Shock

Within 20 min.
Hypotension
Breathing difficulties
Abdominal cramping
Oedema
Treatment:
Adrenaline administration
Vasoconstriction
Bronchodilation
Relax GI muscle

Drug Dependence
Physical Dependence:
Withdrawal of drug produces physical symptoms. Body
needs the drug for normal physiological function
(Heroin: within 4-6 hours)

Psychological Dependence:
Psychological cravings for a drug, overcome by the desire
to have a drug.

Tolerance
Decreased response to a drug over time necessitating a larger to
dose to achieve the same effect
Metabolic Tolerance:
Induction of hepatic enzymes increases metabolism
Behavioural Tolerance:
An individual can compensate for the the drugs effects
Functional Tolerance:
Compensatory mechanisms at the receptor, enzyme level

Opiates
Heroin, Morphine
Pharmacology: Endorphin Agonist ( ) in CNS
Physical Addiction: Physical withdrawal symptoms within 4-6 hours
Psychological Addiction
Metabolic, Behavioural and Functional Tolerance

Opiate Effect and .the physical withdrawal symptom

Numbness
Euphoria
Dryness of mouth
Constipation
Slow Pulse
Low Blood Pressure
Pin Point Pupils
Sluggish
Relaxed Muscles

becomes pain
becomes anxiety
becomes sweating
becomes diarrhoea
becomes rapid pulse
becomes high blood pressure
becomes dilated pupils
becomes restless insomnia
becomes muscle cramps
piloerection (cold turkey)

Opioid Dependency

The facts.after 10 years

3040% remain off opioids (most still report cravings)
40-50% active users or imprisoned
10-20% are dead

Toxicology
Study of the properties, effects and treatments of poisons
(including adverse reactions to drugs)

Industrial, Environmental and Agricultural Toxins

Carbon Monoxide
Sulphur Dioxide
Nitric oxide
Ozone
Halogenated Hydrocarbons
Aromatic Hydrocarbons
Chlorinated Hydrocarbons
Organophosphates
Dioxins
Carbamates
2-4-5 T
Heavy Metals
Industrial and Agricultural industries are a threat
Asbestos
because of long term exposure to low
concentrations of toxins

Domestic Toxins
Detergents
Bleaches
Solvents
Pesticides/Herbicides
Medications
Garden Plants
(Elephants Ear, Poinsettia, Philodendrons,
Chrysanthemums, Daffodil, Rhubarb, Tulip, Oleander, Foxglove)

Domestic Toxins
Higher chance of domestic poisoning than industrial and
environmental poisoning
Why ?
Wisdom and Technical Knowledge, Domestic safety significantly
less
Most common cause of poisoning
Failure to follow recommended safety practices

E-mail: far@bpfk.gov.my
www.bpfk.gov.my