The document discusses drug interactions, defining it as when the pharmacological activity of one drug is altered by the concomitant use of another drug. It describes the main types of interactions as pharmacokinetic, involving effects on absorption, distribution, metabolism and excretion, and pharmacodynamic, involving effects on pharmacological activity. The key mechanisms of pharmacokinetic interactions are induction or inhibition of drug-metabolizing enzymes and displacement from plasma protein binding. Food and herbs can also cause interactions.

2. DRUG INTERACTIONS
BY: AMNA SAMIN
CMS # 25780
M PHIL PHARMACOLOGY
RIPHAH INSTITUTE OF PHARMACEUTICALS SCIENCES

3. CONTENTS:
• Definition
• Epidemiology
• Risk factor
• Out come of interaction
• Mechanism of interaction
a. pharmacokinetic
b. pharmacodynemic

5.  DEFINITION
Drug interaction is a situation in which a substance affects the activity of a
drug when both are administered together. this action can be synergistic
or antagonistic or a new effect can be produced that neither produces on
its own.
When the effects of one drug is changed by the presence of other drug,
herb, food, drink.
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.

6. However, interactions may also exist between drugs and foods (drug-
food interactions), as well as drugs and medicinal
plants or herbs (herb-drug interactions). People taking antidepressant
drugs such as monoamine oxidase inhibitors should not take food
containing tyramine as hypertensive crisis may occur (an example of
a drug-food interaction). These interactions may occur out of
accidental misuse or due to lack of knowledge about the active
ingredients involved in the relevant substances.

7. Types of Interactions:
• Drug-drug interactions.
• Drug-food interactions.
• Chemical-drug interactions.
• Drug-laboratory test interactions.
• Drug-disease interactions.

8. 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.

9. Object & Precipitant:
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”

10. Epidemiology
• In Harvard medical practice study of adverse event 8%
were consider to be due to drug interaction.
• US community pharmacy study revealed 4.1 % incidence of drug
interaction in hospitalized patient.
• Australian study found that 4.4% of all ADR , which resulted in
hospital due to interaction

11. Risk Factors:
• Poly pharmacy
• Multiple prescribers.
• Multiple pharmacies.
• Genetic make up.
• Specific population like e.g. females , elderly, obese, malnourished ,
critically Sick patient , transplant recipient.
• Specific illness e.g. Hepatic disease, Renal dysfunction.
• Narrow therapeutic index drugs like,
Cyclosporine, Digoxin, Insulin, Lithium , Antidepressant, Warfarin.

12. Onset of drug interaction :
It may be seconds up to weeks for example in case
of enzyme induction, it needs weeks for protein synthesis, while
enzyme inhibition occurs rapidly.
The onset of action of a drug may be affected by the half lives of
the drugs e.g., cimitidine inhibits metabolism of theophylline.
Cimitidine has a long half life, while, theophylline has a short one.
When cimitidine is administered to a patient regimen for
Theophylline, interaction takes place in one day.

13. Mechanisms of drug interactions
Pharmacokinetics Pharmacodynamics
• 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.

14. PHARMACOKINETIC INTERACTIONS:
Modifications in the effect of a drug are caused by differences in
the absorption, transport, distribution, metabolization or
excretion
These changes are basically modifications in the concentration of
the drugs. In this respect two drugs can be homergic if they have
the same effect in the organism and heterergic if their effects are
different.

15. 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

16. ABSORPTION INTERACTIONS
It mainly includes:
• Alteration in GI pH.
• Alteration in gut motility.
• Alteration in GI enzymes.
• Complexations and Chelation.
• Alteration of GI micro flora.
• Malabsorption syndrome.

17. 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

18. e) Alteration in Gut motility:

19. Alteration in GI enzyme:
defined as an alteration in the absorption,
distribution, metabolism or excretion of one drug by another. This is
the most common type of drug interaction. pharmacodynamics –
where the drug affects the action or effect of the other drug.
CYP450 family is the major metabolizing enzyme in phase I
(oxidation process).

20. A drug may induce the enzyme
that is responsible for the
metabolism of another drug or
even itself e.g. Carbamazepine
(antiepileptic drug ) increases its
own metabolism.
Phenytoin increases hepatic
metabolism of theophylline
Leading to decrease its level &
Reduces its action

21. CONT..
Cytochrome P450 is a very large family
of haemoproteins (hemoproteins) that are characterized by
their enzymatic activity and their role in the metabolism of a
large number of drugs.[
CYP450 most important iso-enzymes responsible for liver
metabolism.
CYP 3A4
CYP 2D6
CYP 2C8

22. c) Complexation or chelation

23. Cont:
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, sulpho-methoxazole, warfarin with cholestryamine
leads to reduced absorption due to binding

24. Alteration in GI micro 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.
.
Increase digoxin conc
and increase its toxicity
Antibiotics kill a large number of the normal flora of
the intestine

25. MALABSORPTION SYNDROME
Malabsorption syndrome refers to a
number of disorders in which the small
intestine can't absorb enough of certain
nutrients and fluids.
e.g. Vitamin A, B12, Digoxin with
Neomycin or colchicine's leads to
inhibition of absorption due to
Malabsorption.

28. Drug-induced mucosal damage

29. Displaced protein binding:
It depends on the affinity of the drug to plasma protein. The most
likely bound drugs is capable to displace others.
e.g. Phenytoin is a highly bound to plasma protein (90%),
Tolbutamide (96%), and warfarin (99%)
Drugs that displace these agents are Aspirin Sulfonamides
phenylbutazone.

30. • The free drug is increased by displacement by another
drug with higher affinity

33. 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.
e.g. 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)

34. 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)

36. First Pass Metabolism:
Oral administration increases the chance for liver
and GIT metabolism of drugs leading to the loss of
a part of the drug dose decreasing its action. This
is more clear when such drug is an enzyme
inducer or inhibitor.
e.g. Rifampin lowers serum con. of verapamil level
by increase its first pass . Also Rifampin induces
the hepatic metabolism of verapamil

37. Excretion Interactions:
Renal excretion
Human kidney nephron.
Only the free fraction of a drug that is
dissolved in the blood plasma can be removed
through the kidney. Therefore, drugs that are
tightly bound to proteins are not available for
renal excretion, as long as they are not
metabolized when they may be eliminated as
metabolites

38. CONT:

39. Cont:
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

41. Bile excretion
Bile excretion is different from kidney excretion as it is always
involves energy expenditure in active transport across the
epithelium of the bile duct against a concentration gradient.
This transport system can also be saturated if the plasma
concentrations of the drug are high. Bile excretion of drugs
mainly takes place where their molecular weight is greater than
300 and they contain both polar and lipophilic groups.

42. 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.
These are of two types
1.direct pharmacodynamics interactions.
2.Indirect pharmacodynamics interactions

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

44. 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.

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

46. FOOD- DRUG INTERACTIONS.
Tryamine rich food (cheese, liver, yeast product) and MAO inhibitors
(Phenelzeline etc) leads Fatal risk of hypertensive crisis enhanced
metabolism.

47. Cont:
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.

49. Cont:
• Grapefruit juice and Terfenadine
• Grapefruit juice and cyclosporin
• Grapefruit juice and felodipine
• Grapefruit contains : furanocoumarin compounds
that can selectively inhibit CYP3A4

50. Liquorice:
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)

51. CHEMICAL DRUG INTERACTION:

52. Drug Laboratory Interactions:
Multiple prescription medications can have an
affect on laboratory testing. The most common
medications that alter laboratory values are
antibiotics, psychotropic medications, anti-
hypertensive medications and hormones.

53. DRUG DISEASE INTERACTIONS.
A drug-disease interaction is an event in which a drug that is intended for therapeutic
use causes some harmful effects in a patient

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

55. 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.
5.Avoid complex therapeutic regiments when possible.
6.Educate the patient.
7.Monitor therapy.

56. Beers Criteria:
The Beers Criteria for Potentially Inappropriate Medication Use in
Older Adults, commonly called the Beers List. Which are guidelines
for healthcare professionals to help improve the safety of prescribing
medications for older adults. They
emphasize deprescribing medications that are unnecessary, which
helps to reduce the problems of polypharmacy, drug interactions,
and adverse drug reactions, thereby improving the risk–benefit
ratio of medication regimens in at-risk people.

58. http://reference.medscape.com/drug-interactionchecker
https://online.epocrates.com/u/1300/MultiCheck?ICID=search-DDI
http://www.drugs.com/drug_interactions.html

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