1. Drug-Drug
Interactions
Dr. Najlaa Saadi Ismael
Department of Pharmacology
college of Medicine - Mosul
University of Mosul

2. Drug – Drug interaction:
It is the modification of the effect of one
drug (the object drug )
By
The prior or concomitant administration of
another (precipitant drug).

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

4. 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

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

6. Outside the body:
Incompatibilities: reaction of IV 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.

7.  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.
 Pheyntoin with infusion fluids particularly
dextrose so care should be taken to follow
the manufacture's instruction including
the use of an in – line filter.

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

9. Pharmacokinetics drug interactions
Involve the effect of a drug on another
from the point of view that includes:
 Absorption.
 Distribution.
 Metabolism.
 Excretion.

10. 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.

11. 1. Direct chemical interaction in the gut and
formation of drug Chelates or complex
 Calcium (milk), iron, anti acid (Al or Mg
hydroxide) + Tetracyclin insoluble
complex.
 levothyroxine ,digoxine and some acidic
drugs e.g warfarine + Colestyramine
decrease their absorption.

12. 2. Altered intestinal bacterial flora
Antibiotics kill a large number of the normal
flora of the intestine
Antimicrobials may potentiates Oral
Anticoagulant by reducing bacterial synthesis
of vitamin K
In 10% 0f patients receiving Digoxin…..40% or
more
of the administered dose is metabolized by
the intestinal flora Increase digoxin conc.
and increase its toxicity

13. Antibiotics and Oral Contraceptives
Antibiotics kill bacteria in gut
Oestrogen conjugates not hydrolysed
Conjugates not re-absorbed
Less oestrogen - loss of contraceptive effect
(No effect on progestogen component)

14. 3. Altered gut motility
Slowing of gastric emptying such as
antimuscarinic drugs and opiate analgesics
anticholinergics + acetaminophen
Impact: delay in absorption of
acetaminophen
OR
Accelerated by drugs e.g metclopromide
which hasten gastric emptying

15. 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.

16. H-2 blockers, anti acid + 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.

17. 5. Drug-induced mucosal damage:
Colchicine (which cause local Mucosal
damage) can decrease absorption of poorly
absorbed drugs e.g. (phenytoin)

18. 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

19. 7. Interaction other than the gut
Addition of vasoconstrictors e.g adrenalin
to local anesthetics delay absorption and
prolong local anesthesia

20. 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.
Sodium valproates displaces phyentoin
from its binding site on plassma albumin in
addition to inhibit its metabolism.

21. Displacement from tissue bindings
Binding Quinidine with digoxin and cause
increase concentration of free digoxin in
addition to impair renal excretion.

22. Altered drug Metabolism
The effect of one drug on the metabolism of
the other is well documented.
The liver is the major site of drug metabolism
CYP450 family is the major metabolizing
enzyme in phase I (oxidation process).

23. Effect on drug metabolism
Enzyme induction:the drug called(inducer)
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 Oral
Contraceptives Leading to decreased level Reduced
action and Unplanned Pregnancy
Phenobarbital + warfarin increase metabolism of
warfarin (danger of thrombosis)

24. Most important enzyme inducers:
1. Carbamazipine.
2. Phenytoin.
3. Phenobarbital.
4. Rifampicine.

25. 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 .
Cimetidine + Theophylline
cimetidine reduces the clearance of theophylline
causing an increase in adverse effects

26. Quinolones (Ciprofloxacin)
+
Theophylline
Inhibit oxidative metabolism of
theophylline

27. Inducer (carbamazepine)
+
Inhibitor (verapamil)
The effect of the Inhibitor will be
predominant

28. Most important enzyme Inhibitors
1. Cimetidine.
2. Erythromycine.
3. Quinolones.
4. Sodium valproate.

29. Alterations in renal clearance
Increase in Renal Blood Flow.
Inhibition of Active Tubular Secretion.
Alterations in Tubular Reabsorption.

30. Increase in Renal Blood Flow
hydralazine + digoxin
hydralazine increases the renal clearance
of digoxin

31. Active tubular secretion:
It occurs in the proximal tubules.
The drug combines with a specific protein to pass through
the proximal tubules.
When a drug has a competitive reactivity to the protein that
is responsible for active transport of another drug
This will reduce such a drug excretion increasing its conce.
probenecid + penicillin
Decreases tubular secretion of
Pecicillin

32.  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

33. Pharmacodynamics Interaction
Pharmacodynamics are related to the
pharmacological activity of the interacting
drugs .
Both drugs act on the target site of clinical
effect.
Synergism
 Summation or Additive.
 Potentiation.
Antagonism

34. Results of drug interactions:
Synergism:occures when the effects of 2 drugs
having the same action or increase the actionof
another drugs
1. Summation(Additive):
Ex. β-adrenoceptor blocker + thiazide additive
anti hypertensioneffect
1 + 1 = 2
2. Potentiation:
When one drug Increase the action of another
1 + 1 = more than 2
Ex. Trimethprim + sulfamethaxazole

35. Antagonism
When the action of one drug opposes the
action of another.
1 + 1 = 0 (or 0.5)
Ex. Histamine and Adrenaline on
Bronchi(physiological antagonism)
Flumazenil and diazepam they compete
reversibly for the same drug
receptor(competitive antagonism)

36. Interactions directly on Receptor or
body system
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

37. Action on body system
NSAIDs especially indomethacin + α
adrenoicepter blocker lead to loss some
antihypertensive efficacy
By inhibition of production of vasodilator
prostpglandins by the kidney leading to
sodium retention

38. 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.

39. Thank you
For
Attention