study about the drug interaction will help to reduce the risk associated with the therapy .

1. DRUG INTERACTION
ALBIN T THOTTANKARA
M.PHARM SECOND SEM
DEPT .OF PHARMACEUTICS

2. Drug interactions are said to occur when the pharmacological activity
of a drug is altered by the concomitant use of another drug or by the
presence of some other substance
The drug whose activity is affected by such an interaction is called as
the object drug and the agent which precipitates such an interaction is
referred to as the precipitant

3. Drug interactions include-
i)Drug-drug interactions.
ii)Food-drug interactions
( for example, inhibition of metabolism of several drugs by grape fruit
juice)
iii)Chemical-drug interactions
(for example, interaction of a drug with alcohol, tobacco or
environmental chemicals)
iv)Drug-laboratory test interaction
(for example, alteration of diagnostic laboratory test results by the
presence of drug)

4. The net effect of a drug interaction is-
i)Generally quantitative i.e. increased or decreased effect.
ii)Seldom qualitative i.e. rapid or slower effect
.
iii)Precipitation of newer or increased adverse effects.
Most interactions are specific types of adverse reactions with altered efficacy of
drug
For example an enhanced pharmacological activity (e.g. haemorrhagic tendency
of warfarin when Phenyl butazone is given subsequently) or a decrease in the
therapeutic activity resulting in loss of efficacy like that of tetracycline when
concomitantly administered with food, antacids or mineral supplements containing
heavy metal ions.

5. Drug interactions are
Mostly undesirable
Rarely desirable (beneficial):
(for e.g., enhancement of activity of penicillins when administered with
probenecids)
Factors contributing to drug interactions:
1.Multiple drug therapy.
2.Multiple prescribers.
3.Multiple pharmacological effects of drug.
4.Multiple diseases/predisposing illness.
5.Poor patient compliance.
6.Advancing age of patient.
7.Drug-related factors.

7. • Pharmacodynamic interactions
• Direct pharmacodynamic interactions(Antagonism, Addition or
summation, Synergism or potentiation.
• Indirect pharmacodynamic interactions

8. The effect of tissue-binding interactions
The tissue-drug binding is much more significant because the body tissues
comprise 40% of the body weight which is 100 times that of HSA.
A tissue can act as the storage site for drugs
Factors that influence localization of drug in tissues are lipophilicity
& structural features of the drug, perfusion rate, pH differences etc.
The order of binding of drug to extravascular tissue is Liver › Kidney › Lung ›
Muscles
Several example of extravascular tissue-drug binding are: Liver, Lungs,
Kidneys, skin, eyes, hairs, etc
It also seen in hairs, bones, fats & nucleic acids etc

11. Effect on volume of distribution:
Drugs having tissue binding has large volume of distribution.
The simplest expression which relates volume of distribution to tissue binding is given
by
Vpl = plasma volume
V tiss= volume of the other body tissue water
ff=free (unbound) fractions in plasma and tissue respectively
The general form the equation shows that distribution of drug across the physiological
compartments(VD (TOT) ) varying from 5 to more than 10000 in an adult person is
resultant of plasma and tissue binding.
As volume distribution increase , tissue

12. Effect on clearance
Clearance as irrreversible removal of drug is not influenced by tissue binding
Effect on elimination
Elimination half life is a function of both clearance and volume of
distribution and hence can be influenced by tissue binding
Tissue binding results in localization of drug at a specific site in the
body with a subsequent increase in biological half life Effect on diagnosis
Effect on diagnosis
Radio labelled iodine can be used for examining thyroid gland,
thyroid gland has great affinity for iodine containing compounds

13. Cytochrome p450- based drug interactions:
Consists of a superfamily of haemoproteins that catalyse the oxidative
metabolism of a wide variety of exogenous chemicals including drugs carcinogens,
toxins and endogenous compounds such as steroids , fatty acids and prostaglandins
CYP enzymes play important role in phase 1 metabolism of many drugs
Generally drug interactions are result of induction and inhibition of CYP
enzymes
ENZYME INHIBITION
Drug may inhibit the CYP iso enzyme whether or not it is a substrate for that
isoenzyme.
Eg: Cimetidine, amiodarone and stiripentol are non-specific inhibitors of CYP450
enzyme system.

14. If the two drugs are substrate for the same CYP isoenzyme then metabolism of
one or both the drugs may be delayed.
Eg: Erythromycin and midazolam both are substrates for 3A4 isoenzyme so,
there is competition for enzyme sites and metabolism of midazolam is inhibited.
Fluoroquinolones antimicrobials and azole antifungals not metabolized by
CYP3A4 isoenzyme , cause rapid reversible inhibition of CYP3A4 isoenzyme
Macrolide antimicrobials, fluoxetine , lidocaine cause slowly reversible
inhibition of CYP isoenzymes
Cimetidine and macrolide microbials antimicrobial form complex with heme
moeity of CYP isoenzymes

15. ENZYME INDUCTION:
Exposure to environmental pollutants & a large number of lipophilic
drugs results in induction of CYP enzymes.
Mechanism include:
Transcriptional activation: Leading to increased synthesis of more CYP enzyme
proteins.
Autoinduction: Drug induces its own metabolism.
Foreign induction: Induction is by other compounds.
Metabolism of the affected drug is increased leading to decreased intensity and
duration of drug effects.
If the drug is a prodrug or it is metabolized to an active or toxic metabolite then
the effect or toxicity is increased

17. Drug interactions linked to transporters:
Drug transpoters are membrane protein involved in uptake or efflux of drugs by
several tissue such as intestine , liver, kidney and brain
They can have significant impact on pharmacokinetics of endogenous and
exogenous componds
Carrier-mediated inflx (uptake) and efflux of drugs into organs by transporters is
the mechanism responsible for many drug–drug interactions.
In the proximal tubule cells of the kidney, members of another organic anion
transporter family (OAT) cause influx from blood, while other transporters
(including P-glycoprotein, as well as members of the multidrug resistance-
associated protein [MRP] family) cause transfer of drug into the lumen, with sub-
sequent excretion.

19. In the small intestine, P-glycoprotein is an important transporter that pumps
drug which has entered the enterocyte back into the lumen, thus decreasing
drug absorption.
P-glycoprotein is a crucial efflux transporter in the brain, preventing many
drugs from crossing the blood–brain barrier
The membrane transfer of drugs that are substrates for a particular
transporter will change when that transporter is subject to another
drug that induces or inhibits its activity. For example, quinidine, verapamil,
erythromycin, clarithromycin
Inhibition of this trans- porter can interfere with its ability to keep
loperamide out of the brain, resulting in opioid effects in the central nervous
system.
Similarly, inhibition of P-glycoprotein can cause a decrease in urinary and
biliary excretion of digoxin, while at the same time increasing its
bioavailability perhaps to dangerous levels.

20. Rifampin will have the opposite effect on P-glycoprotein, causing a
decrease in plasma concentrations of digoxin
It can also induce the metabolism of drugs that are substrates for
CYP3A4
The OAT family of transporters can be inhibited by probenecid. If a
substrate of this family of transporters, such as penicillin, is administered
concomitantly with probenecid, the drug can have decreased renal
secretion, with a resulting increase in the plasma penicillin concentration
.
Cimetidine is an inhibitor of members of the OAT, organic cation
transporter (OCT) and OATP families of transporters This inhibition has
been shown to result in a decrease in the renal excretion of substrates such
as procainamide and levofloxacin, resulting in increased plasma
concentrations of these drugs.

21. THANK YOU