Drug Interaction

dr. Tri Widyawati, MSi, PhD

1
 Do we
really need to
study drug
interactions?
2
 3
www.fda.gov
 Lethal Combination of Tramadol and
Multiple Drugs Affecting Serotonin
Ripple MG. et al. Am J For Med Path. 21(4):370-4,2000

• The threshold for seizures is lowered by

tramadol. In addition, the risk for seizure is
enhanced by the concomitant use of tramadol
with selective serotonin reuptake inhibitors or
neuroleptics.
• The cause of death in this individual was
seizure activity complicating therapy for back
pain and depression
4
5
“…drug interactions represent 3-5% of
preventable ADRs and are an important
contributor to ER visits and hospital
admissions.” < JAMA 1995;274(1):35–43>

“…elderly patients with digoxin

toxicity were 12 times more likely
to have been treated with
clarithromycin” < JAMA 2003;289 (13):1652>
6
Potential Drug Interactions
Number of Number of
Interactions
Drugs Interactions
1 0
2 A+B 1
3 A+B A+C 3
B+C
A+B A+C
4 A+D B+C 6
B+D C+D
7
 Patients in high risk of drug interactions

• Polypharmacy people (elder)

• Hepatic disorders • Renal disorders • Genetic factors

8
 Definition
• Drug interactions occur when one drug
modifies the actions of another drug in the
body
• A drug interaction occurs when either the
pharmacokinetics or the pharmacodynamics
of one drug is altered by another
• “Alteration either in the pharmaco-dynamics
and/or kinetics of a drug, caused by
concomitant drug treatment, dietary factors
or social habits such as tobacco and alcohol”
9
Outcomes of Drug Interactions: Adverse
• Toxicity
– Torsade de pointes: terfenadine, astemizole, cisapride
– Rhabdomyolyis: HMG-CoA reductase inhibitors
(antihiperlipidemia)
– Hypotension: calcium channel blockers,
sildenafil (Viagra®)
– Excessive sedation/respiratory depression:
benzodiazepines
• Drug resistance
• Therapeutic failure
10
Outcomes of Drug Interactions: Beneficial

• Additive desirable pharmacodynamic

effects:
Combination antiretroviral therapy
– Use of 2NRTIs + PI or NNRTI
•  potency
•  resistance

• Penicillin : probenicid is a competitive

inhibitor for tubular secretion
11
 Types
• Drug - drug interactions.
• Herbal - drug interactions.
• Food - drug interactions.
• Drink - drug interactions.
• Pharmacogenetic interactions.

12
 Mechanisms
Pharmacokinetics :
 Absorption interactions
 Distribution interactions
 Metabolism interactions
 Excretion interactions
Pharmacodynamics :
 Synergistic interactions
 Antagonistic interactions

13
Pharmacokinetic Interactions

14
 Absorption interactions
Mechanisms :
Altered local pH.
Altered bacterial flora.
Formation of drug chelates or insoluble
complexes.
Altered GIT motility.
P-glycoprotein transporter

15
 Altered local pH
• Some drugs are absorbed from stomach (acidic
media), so when this media become neutral or
alkaline, this will affect the absorption of drug.
• Vice versa
Drug (A) Drug (B) Effect
NaHCO3 Aspirin Dissolution rate (aspirin)   absorption
rate 
Antasid Penicillin G, Solubility drug B   total absorption 
Erythromycin
Antasid Fe Gastric pH   absorption of Fe 

Vitamin Fe Gastric pH   absorption of Fe 

C
16
 Altered bacterial flora
• Bacterial flora has a marked role in
metabolization of some drugs.
• Long term antibiotics may kill normal flora and
affect drug absorption.
• Ex :
erythromycin and digoxin

17
 Formation of drug chelates or insoluble
complexes
Drug (A) Drug (B) Effect

Tetracycline Cation multivalent (Ca2+, Chelating   absorption of

Mg2+, Al3+ in antacid, Ca2+ tetracycline and Fe2+
in milk, Fe2+ in Fe
preparation
Digoxin, Kaolin-pektin Drug (A) absorbed by drug (B)  
Lincomycin absorption of drug (A)

18
 Altered GIT motility
• Some drugs increase or decrease GIT motility 
increase/decrease time of absorption and absorbed
amount.

Drug (A) Drug (B) Effect

morphine like Paracetamol GET >>  absorption time of
drugs drug B >>
metoclopramide Paracetamol, GET <<  absorption time of
propanolol drug B <

19
 Drug absorption:
effect of inhibition of P-gp
P-gp action:
reduced absorption
of substrate

Inhibitor: Inhibition of p-gp

Ex. grapefruit juice  More drug enters
= ↑ absorption

Hansten, PD. Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distributioin: Focus on H1-Receptor
Antagonists. Clin Drug Invest 21 (8):587-596, 2001. Posted to Medscape 8/1/01
 Interactions
Based on Distributions & Binding

21
 Distribution interactions

• There is an important factor :

Vd
• Protein binding interactions :
- unbound molecules remain free and
pharmacological active.
- bound molecules are pharmacological inactive.
• Some drugs may compete others for binding to
protein depending on affinity and concentration.

22
 Distribution interactions
Only drugs with low Vd will be affected.
•Ex :
Warfarin (99% bound) and Phenytoin (90%
bound)

23
2 units 18 units

AA A A A AAAAAAAAAAAAAAAAA Vd=20/2=10

Vascular
Compartment Extravascular compartment of the body

BBBBB B Vd=20/18=1.1
BBBB BB
BBB

18 units 2 units

Vd = Amount of drug in the body

Concentration in the blood
24
 Mefenamic
acid Albumin-Warfarin Warfarin level  Bleeding

Sulphonamide Albumin-Tolbutamide Tolbutamide level  Hipoglycemia

25
 Interactions
Based on Metabolic Clearance
• Most drugs are chemically altered within Liver
• Hepatic metabolism has two pathways :
– Phase 1 (modification)
– Phase 11 (conjugation)

26
CYP450 most important isoenzymes responsible
for liver metabolism.

27
isoform CYP450.doc
28
Types of drug metabolism interaction
1. Enzyme induction:
• Onset slow (days – 2weeks).
• Increase the dose or frequent of administration
2. Enzyme inhibition:
• Most common than enzyme induction
• Takes 2-3 days
• Decrease drug metabolism  increase the
serum concentration

29
30
– If serum levels within therapeutic ranges so it is
not clinically important.
– Some drugs can be metabolized by more than one
of CYP450 isoenzymes, so the reaction may be not
clinically important.

31
  Inhibition of drug metabolism   effect of the object
drug  toxicity

Eg : inhibitor CYP1A2   toxicity risk of klozapin and

teofilin.

 Inhibition of enzym  effect 

 Inhibition of prodrug metabolism   active drug  
therapeutic effect
 Eg : analgetyc and toxic effect of codein  result of
convertion of codein to morphine by CYP2D6

32
 Induction of enzyme  effect 
Drug that metabolism by CYP3A4 or CYP2C9  induction
of enzim.
Especially : FPE >> by CYP3A4 at intestinal walls and hepar
 serum concentration of object drug <<.

 Induction of enzym  toxic metabolite

Eg. : convertion of analgetyc acetaminofen to non-toxic and
toxic metabolite.
Enzyme inductor   toxic metabolite and hepatotoxicity
risk

33
 Interactions
Based on Metabolic Clearance
• Drug that reduce hepatic blood flow  reduce
the clearance of other drugs metabolized in
the liver
Eg. propranolol + morphine

34
 Excretion Interaction
• Most drug are excreted in Urine or Bile.
• Some drugs are reabsorbed from renal tubules
or enterohepatic recirculation.
• Some drugs are excreted in acidic urine, so
changing urine pH will affect there serum
level.
• These interaction is rare.

35
 Interactions during excretion
Excretion by bile and enterohepatic circulation

Drug (A) Drug (B) Effect

Probenecid Rifampicin, Excretion of drug B by bile duct   effect of drug
Indometacin B
Neomycin, Oral Drug (A) suppressed intestinal bacteria  inhibit
Rifampicin contraception enterohepatic circulation of drug B   effect of
drug (B)

36
 Interactions during excretion
Tubular secretion
Drug (A) Drug (B) Effect
Probenecid Metothrexate, Penicillin,
Indometacin, Dapson Drug A inhibit drug B
secretion in tubular 
Furosemide Gentamycin,
sefalosporin clearens drug B  
effect/toxicity drug B 

37
 Interactions during excretion
Altering of pH urinary
Drug (A) Drug (B) Effect
Base drug : Amonium chloride (drug B) pH urinary   clirens of
amfetamin, efedrin, drug A  effect of drug A 
quinidine
Bic-nat, asetazolamide (drug B) pH urinary   clirens of
drug A  effect of drug A 
Acid drug : Bic-nat, antasid (drug B) pH urinary   clirens of
salicylate, (Al(OH)3 and Mg()H)2 drug A   effect of drug A 
fenobarbital

38
 Interaksi Farmakodinamik

• Interaksi yang berdasarkan efek atau

aksi yang searah

• Interaksi yang berdasarkan efek yang

berlawanan arah
 Interaksi Farmakodinamik yang
searah
• 1. Addisi atau Sumasi Synergism
Efek obat yang merupakan
gabungan antara dua obat
1-Addition 2+2=4
2. Supra addisi
Bila efek obat yang diperoleh
lebih besar dari gabungan kedua 2-Potentiation 2+2=5
obat
= potensiasi
3. Potensiasi
Bila penggunaan satu obat akan
menambah efek atau kerja dari
obat yang lain
 Interaksi Farmakodinamik yang
berlawanan arah
• Bila penggunaan dua obat
menghasilkan efek yang lebih kecil dari
kedua obat tersebut.
• Antagonism (Opposing)
acute pain Strong opioid
pain decreases or goes away ± NSAID ±
adjuvant analgesic

NSAID ± SEVERE
adjuvant analgesic
± weak opioid
(codein)

MODERATE
paracetamol
or NSAID ± chronic pain
adjuvant analgesic
pain persists or increases
MILD
PAIN
Opioids
Alpha-2 agonists

Local anesthetics
Opioids
Alpha-2 agonists

Local anesthetics

TRAUMA
Local anesthetics
Anti-inflammatory
drugs
PRE-SYNAP OPIOIDS POST-SYNAP
µ1
NMDA
INHIBITION

Glu
ACTIVATION
Subs.P
M1 NK-1
2 PAIN

Adr 2
CLONIDINE

ACh INHIBITION

GABA GABA

MIDAZOLAME
 Supra Adisi (Synergy)

Ketoprofen2
Diclofenac2 Paracetamol

Morphine1
Metamizol Piroxicam2
Carbachol2

Meloxicam2

1.Miranda H.F., Silva.E., Pinardi G;Synergy between the antinociptive effects of morphine
and NSAIDs; Canadian Journal of Physiology & Pharmacology, 2004.
2. Miranda H.F., Siereralta, Pinardi G; Carbachol interactions with NSAIDs,
Canadian Journal of Physiology & Pharmacology, 2002.
 How to overcome an interaction ?
Is the the Using
Using the dose
interaction alternative will
space will solve
clinically solve the
the interaction?!
important?! interaction?!

No Yes Yes

Yes No No

•Binding interactions can be avoided if the two drugs are taken an hour or two apart
• Tetracyclines: Do not take milk, iron preparation or indigestion remedies at the same
time of day as this medicine
If the previous solutions don’t work ?!!!
Adjust drug dosage with monitoring of drug level and physiological functions

46
 Online Drug Interaction
Checker
http://reference.medscape.com/drug-
interactionchecker
,,,,,,,
https://online.epocrates.com/u/1300/MultiChe
ck?ICID=search-DDI
,,,,,,
http://www.drugs.com/drug_interactions.html

47
 Refferences

Omar, A.Drug interaction, ppt.

E-mail: tw_rozan@yahoo.com

48
49
ADVERSE DRUG
REACTIONS
dr. Tri Widyawati, MSi, PhD
 Paracelsus (1493-1541)

• “All substances are poisons; there is

none which is not a poison; the right
dose differentiates a poison and a
remedy.”
• Key Principle of Pharmacology
No drug has a single action.
 Adverse Drug Reactions (ADR)
Harm associated with the use of a given
medications

OR
• Unwanted or harmful reaction experienced
after the administration of a drug or
combination of drugs under normal
conditions of use
• ADR= significant morbidity & mortality
• Range from mild reactions
(drowsiness, nausea, itching& rash);
disappear after discontinuation of drug
OR
• Severe reactions (respiratory
depression, neutorpenia, hepatocellualr
injury, hemorrhage, anaphylaxis
ADR most common in

• Women
• Elderly (>60 y old)
• Very young (1-4 y)
• Patients taking more than one
drug
 Classification of ADR
 Rawlin & Thompson classification ABCD
 Traditional classification A&B
About 80% of ADR----Type A reactions

1) Type A Reactions
a) Related to pharmacological action of drug
Extensions of the principal pharmacological action
of the drug
b) Predictable
Relatively easily predicted by preclinical and clinical
pharmacological studies
c) Common
Type A reactions not serious---common
d) Dose-dependent
Usually dose dependent

 www.mcqsinpharmacology.com
 Type A reactions (classes)
i) Toxicity of overdose (Drug overdose)
An adverse drug reaction caused by excessive dosing

e.g., hepatic failure with dose of paracetamol

Headache with antihypertensives
hypoglycemia with sulfonylurea;

 www.mcqsinpharmacology.com
 ii) Side Effects
Nearly unavoidable secondary drug effect
produced by therapeutic doses

• intensity is dose dependent

• Occur immediately after initially taking drug or
may not appear until weeks after initiation of
drug use

• E.g., sedation with antihistamines

 www.mcqsinpharmacology.com
 iii) Secondary Effects
Secondary pharmacological effect

• E.g., development of diarrhea with antibiotic

therapy due to altered GIT bacterial flora
• Orthostatic hypotension with a phenothiazine

 www.mcqsinpharmacology.com
 iv) Drug Interactions
When two drugs taken together & they effect
each other’s response pharmacologically or
kinetically

• E.g., one drug slow metabolism of 2nd drug

blood conc.= toxicity

• Theophylline toxicity in presence of

erythromycin
 www.mcqsinpharmacology.com
 2) Type B Reactions
Unrelated to known pharmacological actions
of drug
Unpredictable
Often caused by immunological &
pharmacogenetic mechanisms
Unrelated to dosage
Comparatively rare & cause serious illness or
death
 www.mcqsinpharmacology.com
• Results (more likely) in withdrawal of marketing
authorization
• Often not discovered until after drug is
marketed
• Both environmental & genetic factors =
important in this reaction

 www.mcqsinpharmacology.com
 Type B Reactions (classes)
i) Drug Intolerance
Lower threshold to normal pharmacological
action of a drug
e.g., tinnitus (single average dose of aspirin)

ii) Hypersensitivity (immunological reaction)

Immune mediated response to a drug agent in
sensitized patient
e.g., anaphylaxis with penicillin

 www.mcqsinpharmacology.com
 iii) Pseudoallergic Reaction

 Direct mast cell activation & degranulation by drugs

(opiates, vancomycin & radiocontrast media)

 Clinically indistinguishable form Type I

hypersensitivity but not involve IgE (non immunologic
reactions)

 www.mcqsinpharmacology.com
 iv) Idiosyncratic Reactions
• An uncommon & abnormal response to drug
• Usually due to genetic abnormality
• Affect drug metabolism & receptor sensitivity
• Harmful even fatal, appear in low doses

E.g., Anemia (hemolysis) by antioxidant drugs (G6PD

deficiency)
Paralysis due to succinylcholine (enzyme deficiency)

 www.mcqsinpharmacology.com
 3) Type C (chronic) Reactions
• Associated with long-term drug therapy
• Well known and can be anticipated
• Adaptation occurs = discontinuation of
drug=abstinence syndrome

E.g. opoids, alcohol, barbiturates

 www.mcqsinpharmacology.com
 4) Type D (delayed) Reactions
 Carcinogenic & teratogenic effects
 Delayed in onset
 Very rare
Carcinogenic Effect
Medication lead to cancer; take >20 y to develop
Teratogenic Effect
Drug- induced birth defects

 www.mcqsinpharmacology.com
 Sign & Symptoms of ADR
• Mild, moderate, severe or lethal
• Sign & symptoms manifest soon after 1st dose or only
after chronic use
e.g., Allergic reactions occur soon after drug is
taken usually 2nd time ( itching, rash, eruption,
upper or lower airway edema with dyspnea &
hypotension)

Idiosyncratic reactions=any unpredicted symptom

 www.mcqsinpharmacology.com
 Mechanisms of ADR
Type A =non immunological, reversible with reduction
of dose, non serious, extension of pharmacological
effects
Type B
Biochemical mechanism unrelated to pharmacological
Immunologic = Hypersensitivity (Type I, II, III, IV)
OR
Non immunologic (direct)= Pseudoallergic,
idiosyncratic, intolerance

 www.mcqsinpharmacology.com
Mechanism of Type B Reactions
i) Often mediated by a chemically reactive
metabolite

Non detoxification of metabolite

Direct cytotoxicity

Direct tissue damage + necrosis

 www.mcqsinpharmacology.com
 Drug Hypersensitivity (allergic)
Reaction
• Common form of adverse response to drugs

Classification (Gell & Coombs)

Type I reactions (IgE-mediated)
Type II reactions (cytotoxic)
Type III reactions (immune complex)
Type IV (delayed, cell mediated)

 www.mcqsinpharmacology.com
 What should raise
our suspicion of an ADR?

A symptom :
• appears soon after a new drug is started
• appears after a dosage increase
• disappears when the drug is stopped
• reappears when a drug is restarted (do not
deliberately rechallenge!)
 Remember!

“All health-care professionals have a

responsibility to inform colleagues
about clinically important adverse drug
reactions that they detect, even if a
well-recognised or causal link is
uncertain.”

Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and
management. Lancet 2000; 356: 1255-59
76