A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own.

2. OUTLINE
 DRUG INTERACTIONS -
INTRODUCTION
 DRUG – DRUG INTERACTIONS
 FOOD – DRUG INTERACTIONS
 DRUG- DISEASE INTERACTION

3. DO WE REALLY NEED
TO STUDY DRUG
INTERACTIONS?

4. DEFINITION
A drug interaction is a situation
in which a substance affects
the activity of a drug, i.e. the
effects are increased or
decreased, or they produce a
new effect that neither
produces on its own.

5. Effects of drug interaction
 Drug interaction can result in
 Increased effect – Additive or Synergistic effect
Increased therapeutic effect good
Increased toxic or adverse effect bad
 Decreased effect – Antagonistic effect
Decreased therapeutic effect bad
Decreased toxic effect good
 Drug interactions usually happen unexpectedly and result in
adverse drug reactions
 Drug interactions for good therapeutic effects are usually used
intentionally and their results are already known by physicians

6.  Synergistic drug-drug interaction : use of probenecid with
penicillins to block the renal tubular secretion of penicillin to
increase duration of action of penicillin.
 antagonistic drug-drug interaction : Ibuprofen enhances salt
retention by the body and the diuretic like furosemide gets the
body rid of the salt.

8. Outcomes of drug interactions
Desired (Beneficial
Effects)
undesired (Harmful
Effects)

9. Risk Factors for Drug Interactions
High Risk Patients
Elderly, young, very sick, multiple disease
Multiple drug therapy, Renal, liver impairment
High Risk Drugs
Narrow therapeutic index drugs e.g.(digoxin, warfarin,
theophylline)
Recognized enzyme inhibitors or inducers

10. Site of interaction:
 Outside the body.
 Inside the body.

11. Outside the body:
Incompatibilities: reaction of I.V drugs resulting in solutions
after mixing that are not longer safe for the patient alter
stability(change the PH) or structure leading to:
 Loss of drug activity.
 Formation of precipitates.
 Development of toxic product.

12.  Penicillin and aminoglycoside should never be placed in the
same infusion fluid because of formation of inactive complex.
 Protamine zinc insulin + soluble insulin lead to reduces the
immediate effect of the dose.
 With calcium – ceftriaxone precipitates in the lung and kidneys
premature neonates.
 Qunipristin and dalfopristin combination (antibiotics) used as
i.v. infusion is not compatible in N-saline so the infusion
solution should be prepare in 5% dextrose.

13. Drug Interactions Inside the body
 Pharmacokinetics drug interactions
 Pharmacodynamics drug interactions

14. Pharmacokinetics drug interactions
 Most drug interactions involve an alteration in the
pharmacokinetics of the drug.
 Probably no ‘overlap’ in the therapeutic effects of the two drugs.
 Difficult to predict
 Absorption.
 Distribution.
 Metabolism.
 Excretion.

15. Drug
absorption
Drug
excretion
Drug metabolism
(biotransformation)
CYP3A4, CYP2D6,
CYP2C9…
Drug
displacement
(protein-binding)
Transport of
the drug inside
the body

16. Drug Absorption
 Drug interactions can either delay the onset of
drug action or increase or decrease the amount
of drug absorbed.
 Rate of drug absorption is a concern when a fast
onset of absorption is necessary.
 An example of this would be analgesics. A rapid
response is often desired when the patient is in
pain.
 This is important because it can ultimately affect
drug levels.

17. Interaction at the site of absorption
1. Formation of drug Chelates or complexes.
2. Altered gut Flora
3. Altered GIT Motility.
4. Altered PH.
5. Drug induced Mucosal damage.
6. Malabsorption caused by other drugs.
7. Interaction other than in the Gut.

18. 1. Direct chemical interaction in the gut and formation of
drug Chelates or complex-
 Calcium (milk), iron, anti acid (Al or Mg hydroxide) + Tetracycline
insoluble complex.
 levothyroxine ,digoxine and some acidic drugs e.g warfarine +
Colestyramine decrease their absorption.
2. Altered intestinal bacterial flora
Antimicrobials may potentiates Oral Anticoagulant by reducing synthesis of
vitamin K.
In 10% 0f patients receive digoxin…..40% or more of the administered dose is
metabolized by the intestinal flora
Antibiotics kill a large number of the normal
flora of the intestine Increase digoxin conc. And increase its toxicity
3. Altered gut motility
Slowing of gastric emptying such as antimuscarinic drugs and opiate
analgesics
anticholinergics + acetaminophen Impact: delay in absorption of
acetaminophen

20. 4. Altered PH.
The non-ionized form of a drug is more lipid soluble and more readily absorbed
from GIT than the ionized form does
H-2 blockers, antacid + ketoconazole
Decrease gastric acid, dissolution of ketoconazole is decreased, resulting in
reduced absorption
Therefore, These drugs must be separated by at least 2h in the time of
administration.

22. 5. Drug-induced mucosal damage:
 Colchicine (which cause local Mucosal damage) can decrease absorption of poorly
absorbed drugs e.g. (phenytoin)
6.Malabsorption caused by other drugs:
Orlistat (Xenical) Inhibits pancreatic lipases, preventing hydrolysis of ingested fat
Orlistat (Xenical) + fat soluble vitamins(A,D,E,K) malabsorption of Fat-soluble
vitamins
7. Interaction other than the gut
Addition of vasoconstrictors e.g adrenalin to local anesthetics delay absorption and
prolong local anesthesia.

23. Distribution
 When the drug leaves the systemic
circulation and moves to various parts of the
body
 Drugs in the bloodstream are often bound to
plasma proteins; only unbound drugs can
leave the blood and affect target organs
 Low serum albumin can increase availability
of drugs and potentiate their effects

24. Effect of drug distribution
 Displacement from plasma protein binding 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.
 Phenytoin is a highly bound to plasma protein (90%),
Tolbutamide (96%), and warfarin (99%)
Drugs that displace these agents are Aspirin
Sulfonamides
phenylbutazone

25. Metabolism
(biotransformation)
 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.
 Primarily in the liver; cytochrome P-450 enzyme system facilitates drug
metabolism; metabolism generally changes fat soluble compounds to
water soluble compounds that can be excreted
 Foods or dietary supplements that increase or inhibit these enzyme
systems can change the rate or extent of drug metabolism

26.  Therefore, the effect of drugs on the rate of metabolism
of others can involve the following
 Examples-
EX1., Enzyme induction-
 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.
 Phenytoin increases hepatic metabolism of Oral Contraceptives Leading to
decreased level Reduced action and Unplanned Pregnancy
 Phenobarbital + warfarin increase metabolism of warfarin (danger of
thrombosis).

27.  EX2. Enzyme inhibition-
 It is the decrease of the rate of metabolism of a drug by another one.
 This will lead to the increase of the concentration of the target drug and
leading to the increase of its toxicity.
 Inhibition of the enzyme may be due to the competition on its binding sites.
 example -
Cimetidine + Theophylline cimetidine reduces the clearance of
theophylline causing an increase in adverse effects.
 Quinolones (Ciprofloxacin)+Theophylline Inhibit oxidative metabolism
of theophylline.
 Inducer (carbamazepine) +Inhibitor (verapamil) The effect of the Inhibitor will
be predominant.

28.  Erythromycin inhibit metabolism of astemazole and terfenadine, Increase the serum
conc. of the antihistaminic leading to increasing the life threatening cardio toxicity.
 Omeprazole
Inhibits oxidative
metabolism
of diazepam

29. Excretion
• Drug interactions that involve
excretion can affect the amount of
drug that is either secreted or
reabsorbed.
• Some strong acids/bases are actively
secreted/reabsorbed by renal tubules.
• Digoxin excretion may be reduced by verapamil
and quinidine.Some drugs sensitive to changes in
urinary pH or sodium balance.

30. Active tubular secretion-
 It occurs in the proximal tubules (a portion of renal tubules).
The drug combines with a specific protein to pass through the proximal
tubules.
When a drug has a competitive reactivity to the protein and in this way one
of the drug can block or reduce the active secrtion of other drug.This will reduce
such a drug excretion increasing its con. and hence its toxicity.
 e.g. probenecid + penicillin Decreases tubular secretion of Pecicillin.
Passive tubular Reabsorption-
Acidification of urine increases reabsorption and decreases excretion of weak
acids, and, in contrast, decreases reabsorption of weak bases.
Alkalinization of urine has the opposite effect.
 In some cases of overdose, these principles are used to enhance the
excretion of weak bases or acids
e.g. sodium bicarbonate + salicylates(weak acid) decrease reabsorption and
Increase excretion of salicylates

31. Pharmacodynamic
mechanisms
 Two drugs acting upon the same (or similar) mechanism in the same
‘direction’ (i.e. two agonists).(Synergism)
 Two drugs acting upon the same (or similar) mechanism in opposite
‘directions’ (i.e. agonist plus antagonist).
 Pharmacodynamics are related to the pharmacological activity of the
interacting drugs .
 Both drugs act on the target site of clinical effect.
i. Synergism – (i) Summation or Additive
ii. Antagonism
(ii) Potentiation.

32.  Synergism: When the therapeutic or toxic effects of two
drugs are greater than the effect of individual drug, it is synergism.
Drug synergism is of two types- additive effect or potentiation.
 Additive effect: When the net effect of two drugs used together is equal to
the sum of the individual drug effects, the drugs are said to have an additive
effect. For example the combination of a thiazide diuretic and a beta
adrenergic blocking drug is used for the treatment of hypertension.
 Potentiation: When the net effect of two drugs used together is greater
than the sum of the individual drug effects, the drugs are said to have
potentiation effect. For example the combination of sulfamethoxazole and
trimethoprim is used as antimicrobial agents.
 Antagonism: The effects of one drug can be reduced or abolished by the
presence of another drug and this effect is termed drug antagonism. Drug
antagonism is of three types- chemical, physiological and pharmacological.
Physiological and pharmacological antagonisms involve an interaction of an
agonist and an antagonist.

33. Chemical antagonism: When a drug antagonizes the effect of another drug by
simple chemical reaction without action on the receptor. For example, antacid
neutralizes the gastric acid.
Physiological antagonism: When the physiological effect of a drug is antagonized
by another drug by acting on two different types of receptors. For example,
acetylcholine causes contraction of intestinal smooth muscle by acting on
muscarinic cholinoceptors. Whereas this action of acetylcholine is antagonized
(that is relaxation of the intestinal smooth muscle) by adrenaline
Pharmacological antagonism: When a drug antagonizes the effect of another
drug by acting on the same receptor it is called pharmacological antagonism.
Pharmacological antagonism is of two types- competitive and noncompetitive.

34. Competitive antagonism:
Competitive antagonism is reversible. The inhibitory effect of an antagonist is
overcome by-using large amount of agonist. Here, both, the agonist and
antagonist compete for the same receptor and are able to displace each other
at the receptor site. For example acetylcholine causes contraction of intestinal
smooth muscle. Atropine blocks this effect of acetylcholine.
Noncompetitive antagonism:
The maximum response of an agonist in the presence of antagonist is reduced.
The inhibitory effect of a drug is not overcome by using large amount of agonist
In this case the antagonist acts at some rate-limiting step of the response, distal
to the drug-receptor complex.
 Actions on receptors
 Beneficial interaction -
Naloxone for morphin over dose(opiod receptor)
 Unwanted interaction-
Atenolol +cold remedies containing ephedrine or Phenylephrine loss of
antihypertensive effect

35. Probability of drug interaction
0%
10%
20%
30%
40%
50%
60%
2 5 10 15 20
number of drugs used
riskofdruginteraction
Probability of drug interaction rises with the
number of drugs patient uses

36. More drug = More interactions

37. FOOD / NUTRIENT - DRUG INTERACTIONS
food, beverages (including alcohol), and dietary supplements alter the effects of
drugs the person takes.
Food: The presence of food in the digestive tract may reduce absorption of a
drug. Often, such interactions can be avoided by taking the drug 1 hour before or
2 hours after eating.
Dietary Supplements: Supplements are regulated as foods, not as drugs, so
they are not tested as comprehensively. However, they may interact with
prescription or over-the-counter drugs. People who take dietary supplements
should tell their doctors and pharmacists, so that interactions can be avoided.
Alcohol: Taking alcohol with the antibiotic metronidazole
can cause flushing, headache, palpitations, and nausea
and vomiting.

38. Example: 1
Affected Drug
Terfenadine, cyclosporin
Interacting food
Grapefruit juice
Interaction
Food, even orange juice, coffee, or mineral water, may markedly reduce the absorption and
effectiveness of these drugs.

39. example: 2
Affected Drug Anticoagulants
Interacting Food
Foods high in vitamin K (such as broccoli, brussels sprouts, spinach, and kale)
Interaction
Such foods may reduce the effectiveness of anticoagulants (such as warfarin),
increasing the risk of clotting. Intake of such foods should be limited, and the
amount consumed daily should remain constant.

40. example:3
Affected Drug
Digoxin
Interacting Food
Oat meal
Interaction
The fiber in oatmeal and other cereals, when consumed in large amounts, can
interfere with the absorption of digoxin .

41. example:4
Affected Drug
Tetracycline
Interacting Food
Calcium or foods containing calcium, such as milk and other dairy products
Interaction
These foods can reduce the absorption of tetracycline which should be taken 1
hour before or 2 hours after eating.

42. DRUG-DISEASE INTERACTIONS
Sometimes, drugs that are helpful in one disease are harmful in another disorder.
Drug-disease interactions can occur in any age group but are common among older
people, who tend to have more diseases
For example,
● some beta-blockers taken for heart disease or high blood pressure can worsen
asthma
●Some drugs taken to treat a cold may worsen glaucoma.
People should tell their doctor all of the diseases they have before the doctor
prescribes a new drug.