Clinical pharmacy

1. Drug Interaction

2. Introduction:
 Drug interaction refers to the process of alteration in effect
of one drug that occurs after co-administration of the
another drug.
 It is an adverse or seldom a beneficial drug response
produced.
 The effects of drugs may be modified by food, smoking,
alcohol or environmental pollutants.
The components of a drug interaction are:
 Precipitant drug: The drug which causes the interaction .
 Object drug: The drug which is affected by the interaction.

3. Epidemiology
 The incidence of drug interaction was estimated 2.2-30%
in hospitalized patients and 9.2 -70.3% in ambulatory
patients (Clinical Pharmacy & Therapeutics; R. Walker, C
Edwards).
 A review of drug-drug interactions (DDIs) in hospital
admissions 0-2.8% (Jankel & Filterman, 1993)
 The Boston Collaborative Drug Surveillance Program
examined 83,200 drug exposures in 9,900 hospitalized
patients and identified 3,600 ADRs

4.  Causes of Drug Interactions (DIS)
 Improper knowledge of health care practitioner
 Unawareness of the health care practitioner
 Inappropriate dose; high, low and both
 Polypharmacy
 Use of non prescriptive medicine
 Drug abuse
 Patient non-compliance
 Individual variation of patients: Age, Genetic factor, Sex,
Disease state, Renal function, Hepatic functions, Alcoho
consumption, Smoking, Diet, Environment factor, Individual
variation etc.

5.  Factors contributing to the occurrence of drug
interaction
 1. Multiple prescriber.
 2. Multiple pharmacological effects.
 3. Use of non prescriptive medicine.
 4. Drug abuse.
 5. Patient non-compliance.

6.  Likelihood of DIs
 The likelihood of drug interaction can be classified as:
1. Established; Well proved
2. Probable; Likely, not well proved
3. Suspected; Might occur, some data might be available
4. Possible; Could occur, limited data available
5. Unlikely; Doubtful
 Predictability of drug interactions is done also as the
following manner:
1. HP; Highly predictable. (Interaction occurs in almost all
patients)
2. P; Predictable. (Interaction occurs in most patients )
3. NP; Not predictable. (Interaction occurs only in some
patients)
4. NE Not established. (Insufficient data available on which
to base estimate of predictability)

7. Drugs most commonly involved in the adverse
interactions
 Potent therapeutic agents
 Drugs with narrow therapeutic index
 Drugs with which a small decrease in plasma
concentration may result in the loss of therapeutic effect
Drugs with high risk of interaction
1. Concentration dependent toxicity
 Digoxin, Lithium,Warfarin
2. Steep dose-response curve (Narrow therapeutic
index)
Varapamil , Sulphonylureas, Levodopa
3. Patient dependent on therapeutic effect
Immunosuppressive, Glucocorticoids, Oral contraceptives

8. Susceptible patients
 Elderly
 Critically ill Undergoing complicated surgical procedures
 Children
 Pregnant women
 Patients with chronic condition as: Diabetes, HIV
infections , Asthma, Epilepsy ,High blood pressure

9.  Classification of DIs
A. Consequence wise
1. Beneficial drug interactions
 Frequency and severity of the object drug related s effects
is decreased, while the therapeutic effect is enhanced by
the co-administration
 Aspirin + Acetaminophen
 This combination is used for more antipyretic effect.
 (Levodopa + Carbidopa) Carbidopa is used along with
levodopa to minimize the systemic effect of levodo and to
increase the anti parkinsonian action.
 Co-trimoxazole (Sulfamethoxazole + Trimethoprim)
 This combination is used because microbes resistant to
one can be susceptible to the combination

10.  Antihypertensives:
 Beta-blockers and diuretics are given in combination, as
they are more effective when in combination.
 Antitubercular drug therapy:
 Combination therapy has proved to be much effective and
is treating tuberculosis.
 Isoniazid + Ethambutol + Rifampicin + Pyrazinamide Local
Anesthetics
 Minerals
 Iron is given in combination with Vitamin C since it
increases the absorption of Iron
 Calcium is given in combination with Vitamin D so as to
increase the absorption of Iron.
 Antidotes
 These are given for antagonizing the drugs in over

11. 2. Adverse drug interactions
Undesirable, unwanted and harmful alteration in
the effect of one drug by the presence of another
drug, food, drink or chemical agent

12. B) Site wise
1. In-vitro drug interactions
 These interactions occur during formulation and mixing of
drug and usually termed as incompatibilities.
I. Physical Interaction
 When two or more different chemicals/drugs are mixed,
their physical state or color may be changed, changes
may occur to all the constituents mixed together or of one
component mixed.
 E.g. Heparin and Protamine when mixed together, such
kind of interactions are observed.
II. Chemical interaction
 During mixing of two or more chemicals/drugs produce
altered product due to chemical reaction among them.
 E.g. Dopamine and Sodium bicarbonate, Furosemide and

13. 2. In-vivo drug interactions
Pharmacokinetic drug interactions
I. Drug interaction due to absorption
a. Adsorption, Chelation and other Complexing
mechanisms
 Tetracycline and Antacids,Ca+ion forming insoluble
complexes, chelates that can't be absorbed from the
mucosal layer of GIT.
 Some adsorbents may also cause the reduction in the
absorption of drugs e.g. Kaolin, Charcoal, Anion exchange
resins.
b. Change in Gl- pH
 Weakly acidic drugs are best absorbed at low pH e.g.
Salicylates.
 Antacids, Proton-pump inhibitors, H, blockers affect the

14. c. Alteration in gastric motility
 Opiates (Morphine, Codiene, Pethidine) reduce gastric
motility thus decrease absorption of another drug by
decreasing gastric emptying
 Metocloperamide increases gastric emptying thus increase
absorption of another drug
d. Alteration in normal flora of GIT
 10% Digoxin is inactivated by gut bacteria. Introduction of
broad-spectrum antibiotics decrease the gut bacteria,
hence increasing the levels of Digoxin

15. II. Drug interaction due to distribution
a. Drug displacement/Protein binding interaction
 Reduction in the extent of plasma protein binding of one
drug caused by the presence of another drug, resulting in
an increased free or unbound fraction of the displaced
drug
 If a patient taking Phenytoin is given another drug that
displaces it from its binding sites, free or unbound drug
increases.
b. Receptor binding
 Binding sites are significant in interactions
 e.g. Quinidine displaces Digoxin from binding sites in
skeletal muscle increasing serum concentration of Digoxin

16. III. Drug interaction due to Metabolism
 The concurrent administration of more than one drug may
lead to an alteration in metabolic rates.
Enzyme Induction
 Certain drugs induce enzyme systems causing more
metabolism of drug
 Approximately 400 drugs and chemicals are enzyme
inducers in animals and humans. Phenobarbital,
Phenytoin, Carbamazepine, Rifampicin are enzyme
inducers of clinical significance
Enzyme Inhibition
 Certain drugs inhibit enzyme system causing less
metabolism of drug, This likely results in increased serum
concentration of the object drug and if the drug has narrow
therapeutic index, the toxicity occurs very soon
 Ciprofloxacin and Norfloxacin inhibit CYP1A2 and ha been

17. IV. Drug interaction due to Elimination
 Most drugs are eliminated either through the bile or
through urine.
 Interactions occur when drugs interfere with kidney pH,
active transport mechanism or blood flow.
Changes in urinary pH
 A change in glomerular filtration rate (GFR), tubular
secretion, reabsorption, urinary pH etc can alter
elimination of the same drug.
 Urine alkalization and acidification is used as a mean of
increasing the elimination of drug in the poisoning with
Salicylates & Amphetamine
Changes in active renal tubular excretion
 Competition at the same active transport system in
tubules may occur with certain drugs

18. II. Pharmacodynamic drug interactions
 In this process one drug induces a change in patient's
response towards drug without altering the object drug's
pharmacokinetics, are known as pharmacodynamic drug
interactions.
Types of pharmacodynamic drug interactions
I. Additive reactions (A+A= 2A)
 If the effect of one drug doubles, on co-administering the
similar dose of another drug, it is said to be showing
additive effect.
 Two drugs with similar pharmacological effects when
given together, the effect may be additive
II. Synergestic reactions (A+A=>2A)
 If the effect of one drug becomes more than double, on
co-administering the similar dose of another drug, it is
said to be showing synergistic effect.

19. III. Antagonistic reactions (A + A =<A)
 If the effect of one drug becomes less than the effect of
the single drug, on co administering the similar dose of
another drug,
 Agonist and antagonist competition for the same
receptor site
 antagonists may be used to reverse the effect of another
drug at the receptor site e.g. Opioid vs. Naloxone,
Benzodiazepine vs. Flumezinil
IV. Indirect pharmacodynamic interactions
 There are many indirect pharmacodynamic interactions
of potential clinical significance.
 Eg. MAOIS and SSRIS, MAOIS and TCAS are
responsible for serotonin syndrome. It is caused by
excessive serotonin activity in CNS which causes

22. Clinical Significance of DIs
 Drugs that have small therapeutic index so that relatively
small quantitative changes at the target site, will lead to
substantial changes in effect, eg lithium
 Drugs that are exhibit saturable metabolism when small
interference with kinetics may lead to large alteration of
plasma concentration, eg phenytoin
 Drugs that are used long-term, where precise plasma
concentrations are required, egantiepilepsy drugs, lithium
 When drugs that may interact are used to treat the same
disease, for this increases their chance of being given
concurrently, e.g. theophylline and salbutamol given
for asthma may cause cardiac arrhythmia
 In patients with significantly impaired liver or kidney
function, for these are the principal organs that terminate
drug action
 In the elderly, for they tend to have multiple pathology,