Drug-drug interactions can occur through various mechanisms including pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic interactions involve effects on the absorption, distribution, metabolism, and excretion of drugs when taken concurrently. Common types of pharmacokinetic interactions include enzyme induction or inhibition altering drug metabolism, and displacement from plasma protein binding changing a drug's distribution in the body.

1. Drug-Drug
Interactions
Dr. Archana Dhavalshankh
Professor & Head
Department of Pharmacology
D Y Patil Medical College, Kolhapur

2. DEFINITION
• 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 refered to as the “Precipitant”.

3. Types of Drug Interactions
1.Drug-Drug interactions
2.Drug-food interactions
3.Drug-disease interaction
4.Drug-laboratory test interactions
5.Chemical-drug interactions

4. Drug interactions: some facts
• Mostly undesirable (Harmful)
• Rarely desirable/intentional
(beneficial):
Levodopa + Carbidopa
Adrenaline + Lignocaine
Sulfa-methoxazole + trimethoprim
Penicillin + probenecid.
Anti-biotics
Anti-tuberculosis
Anti-HIV
Anti-leprosy
Anti-Hypertensive
Anti H- pyloric drugs
The Net effect of a Drug Interaction is:
•Generally quantitative i.e. increased
or decreased effect.
•Seldom qualitative
i.e.rapid or slower effect.
Precipitation of newer or increased
adverse effect.

5. Types of Drug – Interactions
• Thiopentone + Succhinylcholine- if combined
then inactivate each other . Let some fluid pass
after one drug administration .
• Carbenicillin + Aminoglycosides – if combined
in same syringe inactivate each other.
• Benzylpenicillin + heparin
• Ciprofloxacin + Frusemide
• (Mechanisms of drug
interactions)
1. Pharmacokinetics drug – drug
Interactions - Pharmacokinetics involve the
effect of a drug on another drug kinetic that
includes absorption ,distribution , metabolism
and excretion.
2. Pharmacodynamics drug- drug
interactions
Pharmacodynamics are related to the
pharmacological activity of the interacting
drugs E.g., synergism , antagonism, altered
cellular transport effect on the receptor site.
In Vitro drug interactions
(Outside the body )
In vivo drug Interactions
(Inside the body)
Quinupristin & Daltopristin + (N.Saline ) – IC / 5 %
Dextrose
Noradrenaline + N. Saline & Sod. Bioacarbonate
Amp, amox, penicillin G, phenytoin, phenobarbitone,
sulfonamdes , heparin + acidic PH ( % dextrose )

6. Altered PH
• Antacids + Ketoconazole: Antacids Decrease the tablet dissolution of Ketoconazole (acidic) H2
antagonists Therefore, these drugs must be separated by at least 2h in the time of administration of
both
Altered motility
• Metoclopramide + Cyclosporine: Antiemetic Increase the toxicity Increase absorption of
cyclosporine due of cyclosporine to the increase of stomach emptying time
Complexion or
chelation
• Tetracycline + Milk / Iron : Tetracycline interacts with iron preparations or Milk (Ca2+ ) Un-
absorbable complex
• Antacid + Ciprofloxacin : Aluminium or Magnesium hydroxide of antacid decrease absorption of
ciprofloxacin by 85% due to chelation.
Altered
intestinal
bacterial flora
• Digoxin: 40% or more of the administered digoxin dose is metabolised by the intestinal flora.
• Antibiotics kill a large number of the normal flora of the intestine Increase digoxin conc. and
increase its toxicity
Drug-induced
mucosal damage
• Antineoplastic agents + digoxin : Cyclophosphamide vincristine procarbazine Inhibit
absorption of several drugs eg., digoxin
Pharmacokinetic interactions- Absorption- Altered GIT absorption

7. Highly bound to plasma protein
Phenytoin (90%),
Tolbutamide (96%)
warfarin (99%)
Drugs that get displaced are
Aspirin
Sulfonamides
phenylbutazone
Displaced protein binding It depends on the affinity of the drug to
plasma protein. The most likely bound drugs is capable to displace
others.
Pharmacokinetic Interactions- Distribution- Displacement due to plasma protein binding
The free drug is increased by displacement by another drug
with higher affinity.

8. Pharmacokinetic Interactions- Metabolism
Enzyme Induction
• A drug may induce the enzyme that is responsible
for the metabolism of another drug or even itself
• Carbamazepine (antiepileptic drug ) increases its
own Metabolism.
• Phenytoin + Theophylline – Phenytoin increases
hepatic metabolism of theophylline Leading to
decrease its level reduces its action and Vice versa
Enzyme induction involves protein synthesis
Therefore, it needs time up to 3 weeks to reach a
maximal effect
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 , so the onset of action is short may be
within 24h.
• When an enzyme inducer ( e.g. carbamazepine) is
administered with an inhibitor (verapamil) The effect of
the inhibitor will be predominant.
• Erythromycin + Astemazole/ Terfinadine –
Erythromycin inhibit metabolism of astemazole and
terfenadine Increase the serum conc. of the antihistaminic
leading to increasing the life threatening cardiotoxicity
• Omeprazole + diazepam – Omeprazole inhibit
oxidative metabolism of diazepam

9. Pharmacokinetic Interactions- Excretion
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 con. and hence its toxicity.
• Probenecid + Methotrexate …..
Decreases tubular secretion of
methotrexate.
• Probenecid + Penicillin…..Decreases
tubular secretion of penicillin
Passive tubular Reabsorption
• Excretion and reabsorption of drugs occur
in the tubules by passive diffusion which
is regulated by concentration and lipid
solubility.
• Ionized drugs are reabsorbed lower than
non-ionized ones
• Sodium bicarbonate + Lithium – Sod
bicarb Increases lithium clearance and
decreases its action
• Antacids + Salicylates - Increases
salicylates clearance and decreases its
action.

10. Pharmacodynamics Interactions-
It means alteration of the dug action without change in its serum concentration by
pharmacokinetic factors
Additive effect 1 + 1 =2 Aspirin +Pparacetamol
Ibuprofen + Paracetamol
Synergistic effect 1 +1 > 2 Procaine + Adrenaline
Aspirin + Codeine
Potentiation effect 1 + 0 =2 Levodopa + Carbidopa
Amoxyciliin + Clavulinic acid
Antagonism : 1-1 = 0 Next slide

11. Competitive/ Reversible
Antagonism
Acetylcholine + Atropine
Noradrenaline + Prazosin
Non-competitive /
Irreversible Antagonism
Acetylcholine + Decamethonium
Noradrenaline+ Phenoxybenzamine
Pharmacodynamics Interactions- Receptor

12. Examples – PD interactions
• ACEIs & ARBs + NSAIDS (Not Aspirin)- Loss of antihypertensive effect-
inhibit vasodilatation effect of PGs as formation of PGs by the kideny is
inhibited.
• Glyceryl trinitrate (NO donor )+ Sildenafil – severe hypotension- both
vasodilators
• CCBs + B blockers – bradycardia- depress SA node activity
• Aminophylline + Salbutamol – Dysarrhythmia-
• Loop diuretics & ethacrynic acid – Ototoxicity
• Propranolol + insulin – potentiate hypoglycemia

13. Assignment
• Drug –drug interactions at PK level
• Pharmacokinetic drug interactions
• Factors affecting drug drug interactions