drug interactions

2. -Modification or alteration of response of
one drug by another when administered
simultaneously or in quick succession
-Respose Qualitative( )
Quantitative (Abnormal)

3. -Synergistic action of
1.ACE inhibitors + diuretics(HT)
2.Sulfamethoxazole+Trimethoprim (bacterial
infection )
3.Furosemide + Amiloride (prevent
Hypokalaemia)
*These are well-recognized interactions and do
not pose any undue risk to the patient

4.  Poly pharmacy
 Multiple prescribers
 Multiple pharmacies
 Genetic make up
 Specific population like- elderly, obese, criticaly
ill patient
 Specific illness E.g. Hepatic disease,
Renal dysfunction,
 Narrow therapeutic index drugs -
Digoxin, Lithium , Antidepressant, Warfarin

5. 1.Drugs affecting closely regulated body
functions e.g. antihypertensives,
antidiabetics, anticoagulants
2. Highly plasma protein bound drugs like
NSAIDs,oral anticoagulants, sulfonylureas
3.Drugs metabolized by saturation kinetics,
e.g. phenytoin, theophylline

6. 1)Loss of therapeutic effect
2)Toxicity
3)Unexpected increase in pharmacological activity
4)Beneficial effects e.g additive & potentiation
(intended) or antagonism (unintended)
5) Chemical or physical interaction
e.g I.V incompatibility in fluid or syringes mixture

7.  Pharmacokinetic
 Pharmacodynamic

8. -Alter the conc of the drug at its site of
action (and consequently the intensity of
response) by affecting its – ADME by:
 Reduced rate and/or completeness of absorption
 Altered bioavailabilty
 Reduced plasma protein binding
 Altered tissue distribution
 Altered hepatic metabolism
 Altered renal excretion

9.  Potentiation/antagonism at target receptor
 Potentiation at non-target receptor
 Alteration of fluid/electrolyte environment
 Interference with transport mechanisms

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

11. -Formation of insoluble and poorly absorbed
complexes in the gut lumen, as occurs between
tetracyclines and calcium/iron salts, antacids
or sucralfate
-Phenytoin absorption is decreased by sucralfate
due to binding in the g.i. lumen
-Minimized by administering the two drugs
with a gap of 2–3 hrs so that they do not
come in contact with each other in the g.i.t

12. 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.

13. 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
-Ketoconazole absorption is reduced by H2 blockers
and PPIs because they decrease gastric acidity which
promotes dissolution and absorption of ketoconazole

14. H-2 blockers, anta acid + ketoconazole
Decrease gastric acidity, dissolution of ketoconazole is
decreased, resulting in reduced absorption
Therefore, These drugs must be separated by at least
2h in the time of administration

15. 3. Antibiotics like ampicillin, tetracyclines,
cotrimoxazole markedly reduce gut flora that
normally deconjugates OC pills secreted in the
bile as glucuronides and permits their
enterohepatic circulation
*Several instances of contraceptive failure have
been reported with concurrent use of these
antibiotics due to lowering of the contraceptive
blood levels

16. 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)

17. 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

18. -Primarily due to displacement of one drug
from its binding sites on plasma proteins by
another drug
-Esp drugs with small volume of distribution
like oral anticoagulants, sulfonylureas,certain
NSAIDs and antiepileptics
-Displacing drug should bind to the same
sites on the plasma proteins with higher
affinity

19. -Displacement of bound drug will initially raise
the conc of the free and active form of the drug
in plasma that may result in toxicity brief,
because the free form rapidly gets distributed,
metabolized and excreted
-Such interactions are significant only when
displacement extends to tissue binding sites as
well, or is accompanied by inhibition of
metabolism and/or excretion.

20. Effect of drug distribution
Eg:-Sodium valproates displaces
phyentoin from its binding site on
plasma albumin in addition to inhibit
its metabolism.

21. -Binding Quinidine with digoxin and cause
increase concentration of free digoxin in
addition to impair renal excretion
-Quinidine has been shown to reduce the
binding of digoxin to tissue proteins as well
as its renal and biliary clearance by inhibiting
the efflux transporter P-glycoprotein,
resulting in nearly doubling of digoxin blood
levels and toxicity

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

23. They affect:-
- the bioavailability (if the drug
undergoes extensive first pass metabolism in
liver)
- the plasma half-life of the drug (if the
drug is primarily eliminated by metabolism)

24. Eg:-Macrolide antibiotics, azole antifungals,
chloramphenicol, omeprazole, SSRIs, HIV-
protease inhibitors, cimetidine, ciprofloxacin
and metronidazole
-They compete for the same CYP450 isoenzyme
or cofactor and attain clinical significance
mostly for drugs that are metabolized by
saturation kinetics
-They inhibit the metabolizing enzymes and raise
chances of toxicity of the drug

25. -Barbiturates,phenytoin, carbamazepine, rifampin,
cigarette smoking, chronic alcoholism and pollutants
-They induce microsomal drug metabolizing enzymes
and enhance biotransformation of several drugs
(including their own in many cases)
-Involves gene mediated increased synthesis
of certain CYP450 isoenzymes; takes 1–2 weeks
(contrast inhibition of metabolism which develops
quickly) and regresses gradually over 1–3 weeks after
discontinuation of the inducer.

26. 1.Decreased intensity and/or duration of action
of drugs
e.g. failure of contraception with oral
contraceptives
2. Increased intensity of action of drugs that
are activated by metabolism.
Eg:-Acute paracetamol toxicity is due to one of
its metabolites—toxicity occurs at lower doses in
patients receiving enzyme inducers

27. 1. Congenital nonhaemolytic jaundice: It is due
to deficient glucuronidation of bilirubin;
Phenobarbitone hastens clearance of jaundice
2. Cushing’s syndrome: phenytoin may reduce
the manifestations by enhancing degradation
ofadrenal steroids which are produced in
Excess
3. Chronic poisonings: by faster metabolism of
the accumulated poisonous substance
4. Liver disease.

28. -Important mostly in case of drugs actively
secreted by tubular transport
e.g.
a) probenecid inhibits tubular secretion of
penicillins and cephalosporins and prolongs their
plasma t½
Utility:-For the single dose treatment of
gonorrhoea
.

29. b)Aspirin blocks the uricosuric action of probenecid
and decreases tubular secretion of methotrexate
c)Change in the pH of urine can also affect
excretion of weakly acidic or weakly basic drugs.
This has been utilized in the treatment of
poisonings (Q.Explain why)
d)Diuretics and to some extent tetracyclines, ACE
inhibitors and certain NSAIDs have been found to
raise steady-state blood levels of lithium by
promoting its tubular reabsorption

30. This principle is utilized for facilitating elimination of
the drug in poisoning,
i.e. urine is alkalinized in barbiturate and salicylate
poisoning
-Though elimination of weak bases (morphine,
amphetamine) can be enhanced by acidifying
urine, this is not practiced clinically, because
acidosis can induce rhabdomyolysis, cardiotoxicity
and actually worsen outcome
-The effect of changes in urinary pH on drug
excretion is > for those having pKa values between 5 –
8, becoz only in their case pH dependent passive
reabsorption is significant
pka-> ph at which 50% of drug is ionized

31. -These are independent of a change in its
conc
-Derived from modification of the action of
one drug at the target site by another drug
- This may result in an enhanced response
(synergism), an attenuated response
(antagonism) or an abnormal response

32. Drugs Effects
DZP+Antihistaminic+Neu
rolept+opoiod+alcohol
Excessive sedation,
respiratory
depression,motor
incordination
Αlpha1 blocker+ACE
inhibitor+vasodilator?Hig
h ceiling
diuretics/cardiac
depressants
Excessive fall in BP,
fainting
Propranolol+insulin/sulph
onureas in DM
Pronounced+asymptomat
ic hypoglycaemia
Blockade of beta
receptors contributes
to recovery from
hypoglycaemia+ its
sympyoms
Ceftriaxone/cefoperazo
ne+oral anticoagulent
Prolonged prothrombin
time
Aspirin/clopedogril/ticlo
pidine+carbenicillin
Excessive platelet
inhibition+bleeding

33. Drugs Effects
Organic
nitrates+sildenafil
Ppt fall in BP & MI Becoz nitrates cGMP &
sildenafil prevents its
degradation by inhibiting
PDE5
ACEI+K Sparing agents Severe hyperkalemia
Aminogly+furosemide Additive ototoxicity
ACEI/beta
blockers/diuretics+NSAI
Ds
Attenuation of
antihypertensive effect
of
Due to inhibition of renal
PG synthesis
Levodopa+neurolept/meto
clopramide
Anti-DA action
Alcohol+metronidazole/ce
foperazone
Disulfuram like effect Distressing effects

34. -Certain drugs react with each other and get
inactivated if their solutions are mixed before
administration
-In combined oral or parenteral formulations, the
manufacturers take care that such
incompatibilities do not take place
*In vitro interactions occur when injectable
drugs are mixed in the same syinge or infusion
bottle

35. Eg:-
1.Penicillin G or ampicillin mixed with gentamicin or
another aminoglycoside antibiotic
2. Thiopentone sodium when mixed with succinylcholine or
Morphine
3. Heparin when mixed with Penicillin /gentamicin /
Hydrocortisone
4. Noradrenaline when added to sodium bicarbonate solution.
*In general, it is advisable to avoid mixing of any two or more
parenteral drugs before injecting

36.  Grapefruit juice and Terfenadine
 Grapefruit juice and cyclosporin
 Grapefruit juice and felodipine
 Grapefruit contains : furanocoumarin compounds
that can selectively inhibit CYP3A4

37. -Certain varieties of cheese, beer,wines, pickled meat and
fish, yeast extract contain large quantities of tyramine,
dopa, etc
-In MAO inhibited patients these indirectly acting
sympathomimetic amines escape degradation in the
intestinal wall and liver → reaching into systemic
circulation they displace and release large amounts
of NA from transmitter loaded adrenergic nerve endings
→ hypertensive crisis, cerebrovascular accidents
-When such a reaction occurs, it can be treated by i.v.
injection of a rapidly acting α blocker, e.g. phentolamine.
Prazosin or chlorpromazine are alternatives.

38.  Dose related events may be managed by
changing the dose of the affected drug.
 Eg.,when miconazole oral gel causes an increase
in bleeding time of warfarin then reducing the
warfarin dose will bring the bleeding time back
into range and reduce the risk of haemorrhage
 It is important to retitrate the dose of
warfarin when the course of miconazole is
complete.

39.  The potential severity of some interaction require
immediate cessation of the combination
 Eg:combination of erythromycin and terfenadine can
produce high terfenadine level with the risk of developing
Torsades de Pointes
 Dose spacing is appropriate for interaction involving the
inhibition of absorption in the GI tract .
Eg.,avoid the binding of ciprofloxacin by ferrous salts

40.  Interactions are easily forgotten when
prescribing
 Interactions are difficult to remember
 Pharmacodynamic interactions can often
be predicted across drug classes
 Pharmacokinetic interactions can not be
predicted – experiments needed
 Many interactions probably remain
undescribed – so look out for them
 The chances of interaction are 60 times
higher in a patient taking 5 drugs than in
one taking 2.

41. Thank you
For
Attention

42. 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.

43. Alteration of gut motility by atropinic drugs,
TCAs, opioids and prokinetic drugs like
metoclopramide or cisapride can also
affect drug absorption.