this ppt deals with different types of drug interactions with examples and highlights important principles in monitoring drug therapy....for better understanding of complexity of multiple drug usage (polypharmacy)

2. DRUG INTERACTIONS &
MONITORING OF DRUG
THERAPY
Prof. Dr. V. SATHYA NARAYANAN MD
SRMMCH& RC
CHENNAI, INDIA

3. OUTLINE
 What is a drug interaction ?
 Why study them ?
 Factors promoting them.
 Drugs likely to be involved.
 Types
 Some clinically important interactions.
 How to prevent them ?
 Monitoring drug therapy – why? , 3 types, TDM

4. WHAT IS A DRUG
INTERACTION?
 DRUG INTERACTIONS OCCUR
WHEN
 THE EFFECTS OF ONE DRUG
ARE ALTERED BY
 EFFECTS OF ANOTHER DRUG

6. A CLINICAL PROBLEM
 Miss. Jones was taking OVRAL tablets for her
contraception since 2 years. She developed
cough with fever and chest discomfort for 7 days
and been to her family physician, but her illness
not relieved by antibiotics prescribed, and was
persisting more than a month, she was referred
to a pulmonologist.
 there she was diagnosed as having pulmonary
tuberculosis and was prescribed Intensive short
course chemotherapy with INH, Rifampicin,
Pyrazinamide and ethambutol.

7. A CLINICAL PROBLEM
 She started taking ATT, got improved and was
feeling better.
 On her next week end,
improved Miss.Jones celebrated the time
with her boy friend Mr. Albert freely in a
resort with the support assured
by
continuous intake of OCPs ( OVRAL )

9. A CLINICAL PROBLEM
 After a couple of months, she noticed her missed
periods and rushed to her family physician, her
pregnancy was confirmed shockingly….
 What is the cause of pregnancy in spite of OCPs
?
 Which drug is the culprit in this drug interaction ?
 How this has happened ?
 WHO IS RESPONSIBLE ??!!
 How could have this been avoided?!!

11. WHY STUDY DRUG INTERACTIONS?
 According to WHO essential drug list 
if a physician prescribes
4 drugs for a patient 
64 million combinations possible
so IMAGINE……………………………

14. DRUG INTERACTIONS
 DRUG IS ADMINISTERED  RESPONSE
OCCURS
 WHEN THE SECONDDRUG
IS GIVEN 
 RESPONSE OF FIRST DRUG
IS ALTERED 
WHICH MEANS
 A DRUG INTERACTION OCCURRED

15. FACTORS PROMOTING DRUG
INTERACTIONS
Advanced age
Multiple medication ( the more, the higher ) –
US )
Acute severe illness
Poor renal, hepatic function
More than one prescribing doctor

21. DRUG INTERACTIONS
 PRECIPITANT DRUG –
The drug that precipitates an interaction
 OBJECT DRUG –
The drug whose action is affected

25. DRUG INTERACTIONS
 Drug interaction result in 
Increased effect or
decreased effect of the
object drug

Usually result in an ADR(harmful)
Some cases  beneficialdrug interaction

27. DRUGS LIKELY TOBE INVOLVEDIN
INTERACTION
 Steep dose response curve and a small
therapeutic index eg. Digoxin, lithium
 Drugs that are known enzyme inducers or
inhibitors
 Drugs that exhibit zero order kinetics eg.
Phenytoin
 Drugs used long-term eg. OCP
 Drugs that are highly protein bound

32. TYPES OF DRUG INTERACTIONS
 Interactions outside the body
 Interactions at site of absorption
 Interactions during distribution
 Interactions directly on receptors or body
systems
 Interactions during metabolism
 Interactions during excretion

35. TYPES OF DRUG
INTERACTIONS
 PHARMACEUTICAL INTERACTIONS
 PHARMACOKINETIC INTERACTIONS
 PHARMACODYNAMIC INTERACTIONS

37. INTERACTIONS OUTSIDE THE BODY
PHARMACEUTICAL INTERACTION
Physico chemical interaction
I.V fluids  When drugs are added  interactions
Too numerous to remember….
Precipitation
Dilution  Loss of stability
Incompatibility and loss of potency
Eg. Ampicillin, erythromycin are unstable INFUSE
WITHIN 2-4 h
Sodium nitro prusside is light sensitive

39. INTERACTIONS BEFORE
ADMINISTRATION
 Phenytoin precipitates in dextrose
solutions(e.g. D5W)
 Amphotericin B precipitates in saline
 Gentamicin + penicillins  loss of
antibiotic effect
 Thiopentone + succinylcholine or morphine
 Noradrenaline to NaHCO3 solution
 Heparin + penicillin/ gentamicin
 Insulin should not be given in the infusion
bag

40. TO AVOIDPHARMACEUTICAL
INTERACTIONS
 Give i.v drugs by bolus inj. If possible or via an
infusion burette
 Do not add drugs to solutions other than dextrose or
saline
 Some are unstable or light sensitive
 Avoid mixing drugs in the same infusion solution,
unless the mixture is going to be safe
 Consult manufacturers’ package inserts ( eg
dopamine )
 Mix the drug thoroughly and check for visible
changes

52. AT SITE OF ABSORPTION
 Direct chemical interaction in gut  decrease
absorption
 Eg. Chelation of Ca,
 Aluminium, magnesium, iron
 with tetracycline
 Tetracycline with milk form insoluble complexes
 Antacids + iron
 Prevented by doses are separated by at least 2
hours

58. GUT MOTILITY
 Opioids, anticholinergic drugs 
 reduce gastric motility 
 delay absorption, decrease absorption
 Purgatives 
 decrease time spent in small intestine 
 less absorption of adrenal steroids and
digoxin

61. ALTERATION IN GUT FLORA
Antimicrobial agents 
 destroy normal intestinal bacterial
flora  decrease bacterial
synthesis of
 vitamin K 

Potentiate oral anticoagulants

65. BENEFICIAL ABSORPTION
INTERACTIONS
 Metoclopramide hastens
absorption of analgesics in
migraine
 Charcoalbinds drugs in gut in
poisoning

67. AT THE SITE OF INJECTION
 Subcutaneous:
Adrenaline + local
anesthetics

69. INTERACTIONS DURING DISTRIBUTION
 Displacement of one drug by another drug
plasma protein binding sites 
increased circulating concentration 
increased effect of displaced drug
 Commonest precipitant drugs  sulfonamides,
salicylates
 Common object drugs  Warfarin,
Tolbutamide, Phenytoin

72. DISPLACEMENT REACTIONS
 can be avoided by
slow introduction
of
precipitant drug

74. DISPLACEMENT FROMTISSUE
BINDING
 Quinidine displaces digoxin 
 impair renal excretion of digoxin 
 plasma concentration of digoxin double

 digoxin toxicity.

77. INTERACTIONS DURING
METABOLISM
 Enzyme induction 
 Phenytoin, rifampicin
induce metabolism of
oral contraceptives 
contraceptive failure

80. Liver
Induction
Drug A induces the
body to produce more
of an enzyme to
metabolized Drug B
This reduces
the amount of
Drug B and
may lead to
loss of Drug
B’s
effectiveness
Inhibition
Drug A inhibits the
production of
enzymes to
metabolize Drug B
This increases the amount of
Drug B in the body and could
lead to an overdose or toxic
effects

81. MICROSOMAL ENZYME
INDUCERS
 decrease concentration of metabolized
drugs (phenytoin, OC Pills, warfarin,
carbamazepine)
 Barbiturates,
* Phenytoin, Carbamazepine
* Chronic Alcohol, Tobacco smoke
* INH, * Rifampicin
* Griseofulvin
* Occurs within few days

83. CP450 enzyme inhibitors
 Increase concentration of metabolized
drugs ( theophylline, warfarin, phenytoin )
(eg.) Cimetidine
Erythromycin
Quinolones
Omeprazole
ketoconazole
SSRIs

84. INTERACTIONS DURING
METABOLISM
Enzyme inhibition
 erythromycin inhibit the metabolism of
 theophylline  precipitation of toxicity
 Disulfiram with alcohol
 Cheese reaction  MAO inhibitors + tyramine 
hypertensive crisis

85. BENEFICIAL INTERACTIONS
 L-dopa + carbidopa
 Carbidopa inhibits peripheral decarboxylase
enzyme  increased levels of levodopa 
more goes to brain

86. TORSADES DE POINTES
Ketoconazole inhibits the metabolism of
terfenadine and precipitate arrhythmias

88. INTERACTION DURING EXCRETION
 Occur in kidney
 Competition for renal tubular secretion eg.
Probenecid and penicillin ( beneficial )

Chloroquine + probenecid ( harmful )
 Quinidine inhibit P glycoprotein  tubular
secretion of digoxin is inhibited  increased
digoxin concentration  digoxin toxicity

89. INTERACTION DURING EXCRETION
 Lithium with diuretics (frusemide and thiazide )

 Retention of lithium  lithium toxicity

92. PHARMACODYNAMIC
INTERACTIONS

94. PHARMACODYNAMIC
INTERACTIONS
 DIRECT – When 2 drugs act on same site or
on 2 different sites, but with the similar end
result
 INDIRECT – Some way the therapeutic effect
or toxic effect of the pricipitant drug alters the
effects of object drug, but not related and
themselves not interact

96. INTERACTIONS DIRECTLY ON
RECEPTORS
 Precipitant drug alters the effect of
the object drug at its site of action
 SYNERGISM eg. Alcohol and diazepam
 ANTAGONISM eg. Naloxone – Morphine

99. SOME DIRECT
PHARMACODYNAMIC
INTERACTIONS
 Alcohol + other CNS depressants ( like
antihistamines)
 Aminoglycosides, quinidine + depolarising
skeletal muscle relaxants
 Verapamil + betablockers
 Halofantrine + antiarrhythmic drugs 
prolongation of QT interval
 Sildenafil + nitrates  fatal hypotension
reported

100. INDIRECT PHARMACODYNAMIC
INTERACTIONS
 Aspirin has antiplatelet effect promote warfarin
induced bleeding
 Thiazide diuretics  hypokalemia  digoxin
toxicity, risk of arrhythmias
 NSAIDs impair antihypertensive effect of beta
blockers
 NSAIDs  gastric ulcer  promote warfarin
induced bleeding
 Thiazide + sulfonylureas

102. PKINTERACTION THAT RESULT FROMPD
EFFECT
 Diuretics  sodium loss 
 Lithium retention 
 lithium toxicity

104. DRUG-FOOD INTERACTIONS
 Milk
 Grapefruit juice – inhibits the metabolism of
phenytoin
 Cheese reaction
 Garlic, ginseng, ginger increases bleeding
with anticoagulants
 Fruits rich in potassium  facilitate
hyperkalemia

106. Centers for Education &
Research on Therapeutics™
Drug-Herbal Interactions
St. John’s Wort with:
–Indinavir
–Cyclosporine
–Digoxin
–Tacrolimus
–Possibly many others

108. Centers for Education &
Research on Therapeutics™
After St. John’s Wort

109. Food-Drug Interactions
 Some drugs lead to ↓ BIO in the fed state and
a risk of treatment failure (tetracycline,
indinavir, bisfosfonates…)
 A lot of drugs lead to ↑↓ BIO , but no major
changes in clinical effect (pravastatin,
phenoxymethylpenicillin, furosamide…)
 Some drugs lead to ↑ BIO and increased drug
effect. Usually desirable but may be a risk of
toxicity (albendazole, griseofulvin, saquinavir,
halofantrine*…)

111. DRUG+DISEASE
INTERACTIONS
 HEPATIC DISEASE
 RENAL DISEASE
 VARIENT ANGINA
 ASTHMATICS
 DIABETES MELLITUS
 PEPTIC ULCER

112. Centers for Education &
Research on Therapeutics™
Monahan BP et al. JAMA 1990;264(21):2788–2790.
Case 1: Torsades de Pointes

113. Centers for Education &
Research on Therapeutics™
Monahan BP et al. JAMA 1990;264(21):2788–2790.
Ventricular Arrhythmia (Torsades de
Pointes) with Terfenadine Use
 39-year-old female Rx with terfenadine 60
mg bid and cefaclor 250 mg tid × 10 d
 Self-medicated with ketoconazole 200 mg
bid for vaginal candidiasis
 2-day Hx of intermittent syncope
 Palpitations, syncope, torsades de pointes
(QTc 655 msec)

114. Centers for Education &
Research on Therapeutics™
Monahan BP et al. JAMA 1990;264(21):2788–2790.
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Day of Administration
TerfenadineTerfenadine
CefaclorCefaclor
KetoconazoleKetoconazole
MedroxyprogesteroneMedroxyprogesterone
SymptomaticSymptomatic
HH

115. Centers for Education &
Research on Therapeutics™
Adapted from: Sinoway L, Li J. J Appl Physiol 2005;99:5–22.
Case 2: Rhabdomyolysis

116. Centers for Education &
Research on Therapeutics™
Kahri J et al. Rhabdomyolysis in a patient receiving atorvastatin and fluconazole. Eur J Clin
Pharmacol 2005;60:905–907.
Rhabdomyolysis:
Atorvastatin & Fluconazole
 76-year-old male with Hx of chronic atrial
fibrillation and aortic stenosis
 Initial prescription medications:
– Bisoprolol
– Digoxin
– Warfarin
– Doxicycline
– Fucidic acid
– Prednisolone
– Esomeprazole
– Pravastatin
– Fluconazole

117. Centers for Education &
Research on Therapeutics™
Kahri J et al. Eur J Clin Pharmacol 2005;60:905–907
Rhabdomyolysis in Association with
Atorvastatin and Fluconazole Use
 Pravastatin dosage increased from 40mg to
80mg/day
 Pravastatin changed to Atorvastatin 40mg
 After 7 days – Extreme fatigue
 After 3 weeks – Hospitalized for dyspnea
– Creatinine 1.36
– CK 910 I.U.
 Dx: Renal Failure and DEATH

118. Centers for Education &
Research on Therapeutics™
Weeks
Fluconazole
Pravastatin 80mg
Pravastatin 40 mg
Atorvastatin
Fatigue
Dyspnea & CK 910
Death
Fatal Rhabdomyolysis

120. SOME CLINICALLY IMPORTANT
DRUG INTERACTIONS
 Alcohol + metronidazole
 Gentamicin + furosemide
 Local anesthetics + adrenaline
 Theophylline + macrolides, quinolones
 Insulin + betablockers
 Oral contraceptives + rifampicin, phenytoin,
carbamazepine
 Betablockers + cold remedies

121. SOME CLINICALLY IMPORTANT
DRUG INTERACTIONS
 Alcohol + other CNS depressants
( antihistamines, opioids, neuroleptics,
Benzodiazepines)
 Fibrates + statins  myopathy
 Betablockers + verapamil
 Lithium + SSRIs  Serotonin syndrome
 Nitrates + sildenafil
 Ciprofloxacin + NSAIDs

122. SOME CLINICALLY IMPORTANT
DRUG INTERACTIONS
 Oral contraceptives + ampicillin, tetracyclines,
co-trimoxazole

128. Centers for Education &
Research on Therapeutics™
*These programs are not endorsed by the FDA
Drug-Drug Interaction Prevention:
A Stepwise Approach
1. Take a medication history
(AVOID Mistakes mnemonic)
2. Remember high-risk patients
• Any patient taking ≥ 2 medications
• Patients Rxed anticonvulsants, antibiotics,
digoxin, warfarin, amiodarone, etc.
3. Check pocket reference or PDA
4. Consult pharmacists or drug info specialists
5. Check up-to-date computer program
• Medical Letter Drug Interaction Program*
• www.epocrates.com* and others

129. Centers for Education &
Research on Therapeutics™
A Good Medication History:
AVOID Mistakes
 Allergies?
 Vitamins and herbs?
 Old drugs and OTC? (as well as current)
 Interactions?
 Dependence? Do you need a contract?
 Mendel: Family Hx of benefits or
problems with any drugs?

131. MONITORING THERAPEUTIC
EVENTS
 AEDs --- seizure frequency
 Antianginal drugs --- frequency of attacks
 Diuretics in edema – body weight
 IN THE POPULATION
 Immunization – survey
 Smoking – CAD
 Losing weight – CAD, DM

133. MONITORING THE PHARMACODYNAMIC
EFFECTS OF DRUGS
 Surrogate markers –
 blood glucose, HBA1C – DM
 Prothrombin time as INR
 FEV1, Peak flow rate – in bronchial asthma
 Tumour markers in cancers
 As a guide to drug therapy
 May not correlated precisely with the
therapeutic effect

135. MONITORING DRUG
PHARMACOKINETICS
 Plasma concentration measurement – TDM
 MAY BE A GUIDE TO DRUG THERAPY TO
FOLLOWING DRUGS ( PROVEN )
 Aminoglycoside antibiotics ( eg gentamicin )
 Anticonvulsants ( phenytoin, carbamazepine )
 Digoxin
 Lithium
 Theophylline
 Ciclosporin
 SOMETIMES  TCAs, antiarrhythmics

136. MONITORING DRUG
THERAPY
 Fortherapeutic effect
1. Poor patient compliance
2. If large inter-individual variation
3. Failure of response
4. Drug interaction reducing the concentration

137. MONITORING DRUG
THERAPY
 Forpreventing toxicity
1. Drugs with zero order kinetics
2. Narrow therapeutic index
3. Toxic drugs in renal failure
4. Poisoning
5. Drug interaction likely raising the
concentration

141. SUMMERY
 Drug interactions can be harmful or beneficial
 Expect it when you use more drugs and in high-
risk patients
 Know about PC, PK, PD interactions to prevent
them
 Aware of Drug-food interactions
 Aware of drug-disease interactions
 Monitoring drug therapy will be useful in
knowing the therapeutic outcome and
preventing toxicities

142. The young physician starts life with 20 drugs for each
disease, and the old physician ends life with one drug
for 20 diseases
Sir. William Osler 1849 - 1919