VARIOUS DRUG INTERACTIONS USEFUL ASPECT, MECHANISMS, NET EFFECT, REDUCING RISK OF INTERACTIONS, RESOURCES WHCH CAN HELP PHARMACEUTICAL STUDENTS.

1. DRUG
INTERACTION
S
PRESENTED BY: RAGHAV DOGRA
M.PHARM (ANALYSIS)
2016-2017

2. DEFINATION
 An interaction is said to occur when the effects of one
drug is changed by the presence of other drug, herb,
food, drink.
OR
 Drug interaction is defined as the pharmacological
activity of one drug is altered by the concomitant use of
another drug or by the presence of some other
substance.
 The Drug whose Activity is effected by such an
Interaction is called as a “Object drug.”
 The agent which precipitates such an interaction is
referred to as the “Precipitant”.

3. TYPES
 Drug-drug interactions.
 Drug-food interactions.
 Chemical-drug interactions.
 Drug-laboratory test interactions.
 Drug-disease interactions.
An interaction occurs when pharmacokinetics
or pharmacodynamics of drug are changed.

4. CAUSES
 Poly pharmacy
 Multiple prescribers
 Multiple pharmacies
 Genetic make up
 Specific population like E.g., females, elderly,
obese, malnourished, critically ill patient,
transplant recipient.
 Specific illness E.g. Hepatic disease, Renal
dysfunction,
 Narrow therapeutic index drug: Cyclosporine,
Digoxin, Insulin, Lithium , Antidepressant,
Warfarin etc.

5. MECHANISM OF DRUG
INTERACTION
 Pharmacokinetics involve the effect of a drug on
another drug kinetic that includes absorption
,distribution , metabolism and excretion.
 Pharmacodynamics are related to the
pharmacological activity of the interacting drugs
E.g., synergism , antagonism, altered cellular
transport effect on the receptor site.
PHARMACOKINETICSPHARMACODYNAMICS

6. THE NET EFFECT OF THE
DRUG INTERACTION :
• Generally quantitative i.e. increased or decreased
effect.
• Seldom qualitative i.e. rapid or slower effect.
• Precipitation of newer or increased adverse effect.

7. PHARMACOKINETIC
INTERACTIONS
 “These interactions are those in which ADME
properties of the object drug is altered by the
precipitant and hence such interactions are also called
as ADME interactions”.
 The resultant effect is altered plasma concentration of
the object drug.
These are classified as:
1.Absorption interactions
2.Distribution interactions
3.Metabolism interactions
4.Excretion interactions

8. ABSORPTION
INTERACTIONS
 It mainly includes:.
 Alteration in GI pH.
 Alteration in gut motility.
 Inhibition of GI enzymes.
 Complexations and adsorption.
 Alteration of GI micro flora.
 Malabsorption syndrome.

9. ALTERATION IN GI pH
 The non-ionized form of a drug is more lipid soluble
and more readily absorbed from GIT than the ionized
form does.
 Some drugs are absorbed from stomach (acidic media),
so when this media become neutral or alkaline, this will
affect the absorption of drug.
 E.g. Sulphonamides and Aspirin when given with
antacids leads to enhanced dissolution and BA.
 Ketoconazole or Tetracycline with antacid leads to
decreased dissolution and BA.

10. ALTERATION IN BACTERIAL
FLORA
 Bacterial flora has a marked role in metabolism of some
drugs.
 Long term antibiotics may kill normal flora and affect
drug absorption.
E.g. 40% or more of the administered Digoxin dose is
metabolized by the intestinal flora.
Antibiotics kills large population of Intestinal flora
thus increases the Digoxin concentration and chances of
toxicity.

11. COMPLEXATATION AND
CHELATION
 E.g. Tetracycline or fluoroquinolones like ciprofloxacin
with antacid or food containing divalent ions lead to
formation of poorly soluble chelates or complexes
which can not be absorbed.
 Cephalexin, sulphomethoxazole, warfarin with
cholestryamine leads to reduced absorption due to
binding

12. ALTERATION IN GUT
MOTILITY
 Some drugs usually alters the GIT emptying time by
altering the peristalsis of the gut hence leading to
defected absorption
 E.g. aspirin, levodopa, diazepam co-administered with
metoclopramide leads to rapid gastric emptying and
increased rate of absorption.
 Same drugs with atropine leads
to delayed emptying and
decreased absorption.

13. MALABSORPTION
SYNDROME
E.g. Vitamin A, B12, Digoxin
with Neomycin or colchicines
leads to inhibition of
absorption due to Malabsorption.

14. DISTRIBUTION INTERACTIONS

15. COMPETETIVE
DISPLACEMENT
 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 Valproic acid
(Phenytoin toxicity) Sulfonamides (hypoglycemia), Aspirin
(bleeding),

16. METABOLISM INTERACTIONS
 The effect of one drug on the metabolism of the other is
well documented. The liver is the major site of drug
metabolism but other organs can also do e.g., WBC,
skin, lung, and GIT.
 CYP450 family is the major metabolizing enzyme in
phase I .
 Hepatic metabolism has two pathways :
 Phase 1 (modification)
 Phase 11 (conjugation)

17. CONT..
 CYP450 most important iso-enzymes
responsible for liver metabolism.
 CYP 3A4
 CYP 2D6
 CYP 2C8

18. CONT..
 Enzyme induction:
A drug may induce the enzyme that is responsible for the
metabolism of another drug or even itself e.g.,
OBJECT DRUG PRECIPITANT DRUG INFLUENCE
Oral contraceptive,
coumarins, Tolbutamide
Barbiturates Decreased plasma level
leading to decreased efficacy
of object drug
Theophylline,
cyclosporine, oral
contraceptives
Phenytoin Decreased plasma level
leading to decreased efficacy
of object drug
Oral contraceptive,
coumarins, Tolbutamide
Rifampicin Decreased plasma level
leading to decreased efficacy
of object drug
N.B enzyme induction involves protein synthesis .Therefore, it needs time up to
3 weeks to reach a maximal effect

19. CONTD…
 Rifampicin increase metabolism of Ciclosporin by
inducing CYP 3A4

20.  Enzyme inhibition:
Most common than enzyme induction. This interaction
decrease drug metabolism and so increase its concentration
in serum. It takes 2-3 days.
OBJECT DRUG PRECIPITANT DRUG INFLUENCE
Tryamine rich food (cheese,
liver, yeast product)
MAO inhibitors
(Phenelzeline etc)
Fatal risk of hypertensive
crisis enhanced metabolism
Folic acid Phenytoin Decreased folic acid
absorption
Alcohol Disulphiram Disulphiram like reaction
due to acetaldehyde
coumarins Metronidazole Increased chances of
anticoagulation.
AZT, Mercaptopurine Allopurinol Increased antineoplastic
toxicity chances
Alcohol , Benzodiazepines,
warfarin
Cemetidine Increased blood level of
object drug

22. EXCRETION INTERACTIONS
 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.
 Major mechanisms of excretion interactions are-
 Alteration in renal blood flow
 Alteration of urine PH
 Competition for active secretions
 Forced diuresis

23. CONT….
 Change in Active Tubular Secretion:
 Change in Urine pH:
 Change in Renal Blood flow:
Antibiotics and
Methotrexate
Probenicid Elevated plasma level of
Probenicid and risk of toxicity
Procainamide , ranitidine Cimetidine Increased risk of Cimetidine
toxicity
Amphetamine, Quinidine Antacids, thiazides Increased passive
reabsorption basic drugs
Lithium carbonate NSAIDS Decreased renal clearance
of lithium

24. PHARMACODYNAMICS
INTERACTIONS
 It means alteration of the dug action without change
in its serum concentration by pharmacokinetic
factors.
 they occur when the effects of a drug are changed due
to presence of another drug at its site of action either
directly (on the same receptor) or indirectly (on
different receptor).
 Such interactions may be direct or indirect.
 1.These are of two types
 1.direct pharmacodynamics interactions.
2.Indirect pharmacodynamics interactions.

25. DIRECT INTERACTION
 Additive effect : 1 + 1 =2
 Synergistic effect : 1 +1 > 2
 Potentiation effect : 1 + 0 =2
 Antagonism : 1-1 = 0

26.  Antagonism:
The interacting drugs have opposing actions
Example: Acetylcholine and nor-adrenaline have opposing
Effects on heart rate.
 Addition or summation:
The interacting drugs have similar actions and the resultant
effect is the some of individual drug responses
Example: CNS depressants like sedatives and hypnotics,…etc
 Synergism or potentiating:
It is an enhancement of action of one drug by another
Example: Alcohol enhances the analgesics activity of aspirin.

28. INDIRECT INTERACTIONS
 In which both the object and the precipitant drugs
have unrelated effects. but the latter in Some way
alerts the effects but latter in some way alerts the
effects of the former.
 Example: salicylates decrease the ability of the
platelets to aggregate thus impairing the Homeostasis
if warfarin induced bleeding occurs.

29. HERBAL – DRUG INTERACTIONS
 St john's wort increase metabolism of ciclosporine by
inducing CYP 3A4.

30. FOOD- DRUG INTERACTIONS.
 Tryamine rich food (cheese, liver, yeast product) and
MAO inhibitors (Phenelzeline etc) leads Fatal risk of
hypertensive crisis enhanced metabolism.
 Tetracycline or fluoroquinolones like ciprofloxacin with
antacid or food containing divalent ions lead to
formation of poorly soluble chelates or complexes
which can not be absorbed.
 Grapefruit juice and Terfenadine
 Grapefruit juice and cyclosporin
 Grapefruit juice and felodipine
 Grapefruit contains : furanocoumarin compounds
that can selectively inhibit CYP3A4

31. CONT..
 Liquorice contain glycyrrhizin (glycyrrhizinic or
glycyrrhizic acid)
 Glycyrrhizinic acid is hydrolyzed in the intestine to
pharmacologically active compound glycyrrhetic acid
which inhibit 11 betahydroxysteroid dehydrogenase.
 This increase cortisol in kidney and act as aldosterone
(fluid retention, hypokalemia, hypertension)
 Ex:
 Liqourice and antihypertensive

32. Patients in high risk of drug
interactions
 Polypharmacy people (elder)
 Hepatic disorders
 Renal disorders
 Genetic factors

33. CONSEQUENCES OF DRUG
INTERACTIONS:
 The consequences of drug interactions may be:
• Major: Life threatening.
• Moderate: Deteriotion of patients status.
• Minor: Little effect.

34. REDUSING THE RISK OF DRUG
INTERACTIONS:
 1.Identify the patients risk factors.
 2.Take through drug history.
 3.Be knowledge about the actions of the drugs being
used.
 4.Consider therapeutic alternatives.
 5Avoid complex therapeutic regiments when possible.
 6.Educate the patient.
 7.Monitor therapy.

35. Resources
 Stockley’s Drug Interactions

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

37. APPS
https://play.google.com/
store/apps/details?id=com.
medscape.android&hl=en
………………….
https://play.google.com/
store/apps/details?id=com.
epocrates&hl=en