Drug interactions

Lecture by
1 Dr Saira
2
AGENDA

 Types of interactions
 Drugs involved likely to be in interactions
 Pharmaceutical interactions
 Pharmacokinetic interactions
 Pharmacodynamic interactions
3 DRUG INTERACTIONS
An interaction between a drug and another substance that prevents
the drug from performing as expected
drug-drug interactions
Drug-food interactions
Drug- disease interactions
Drug-lab test interactions
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DRUGS LIKELY TO BE INVOLVED IN
INTERACTIONS
Drugs likely to precipitate drug interactions:
 Highly protein bound drugs i.e. Aspirin, sulfonamides
 Alteration of metabolism of other drugs i.e. phenytoin,
carbamezapine, allopurinol, cimetidine
 Renal function & clearance alteration i.e. diuretics
Drugs likely to be the objects of drug interactions:
 Steep dose response curve
 Low toxic: therapeutic ratio
 E.g. aminoglycosides, anticoagulants, anti
hypertensives, anti convulsants
5 PHARMACEUTICAL INTERACTIONS
Physico-chemical interactions e.g. drug in i.v. solution, 2 drugs in
same solution
Can be avoided following certain instructions
6 PHARMACOKINETIC INTERACTIONS
a. Absorption interactions:
↓ GI motility by morphine-like drugs & anticholinergic drugs
(TCAs) ↓ absorption
↓ absorption due to chelation of tetracyclines
↓ absorption due to binding of warfarin & digoxin by
cholestyramine
Extent of absorption not affected
Beneficial absorption interactions; Metoclopramide
↑gastric emptying rate which ↑ absorption of analgesics in migraine
attack
 CONTD..
7
b. Protein binding displacement interactions:
 Increased effect of displaced drug
 Highly bound drug with low apparent volume of distribution are
important
 E.g. warfarin, phenytoin, tolbutamide
 Most common: sulfonamides, salicylates, valproate
 These drugs when displaced, have increase in clearance rate
proportionate to degree of displacement
Case of phenytoin is important
c. Cellular distribution interactions:
 Rifampicin reduces effects of warfarin by inhibiting its uptake by
hepatocytes; also induces warfarin metabolism &
↓ it’s effects
8 CONTD..
d. Metabolism interactions:
 Alteration in metabolism; oxidation
 Transformations include: hydroxylation (phenytoin), deamination
(amphetamine), dealkylation (morphine), sulfoxidation
(chlorpromazine), desulfuration (thiopentone), dehalogenation (DDT)
dichloro-diphenyl-trichloroethane)
 CYP450 has various isozymes & interaction is among those
drugs that are metabolized by same isozyme i.e. erythromycin inhibits
metabolism of both carbamezapine & ciclosporin
9 CONTD..
(i) Induction of drug metabolism:
  Due to induction of metabolism of object drug by
precipitant drug, plasma conc. of object drug is ↓ thereby ↓ its effects i.e.
epileptic fits despite phenytoin therapy.
 With increased dose of object drug & subsequent
withdrawal of precipitant drug, there will be enhanced effect of object
drug i.e. barbiturate withdrawal & bleeding despite of warfarin use
10
CONTD
..
(ii) Inhibition of drug metabolism:
Two types:
1. Precipitant drug is inhibitor of mixed function oxidase reactions i.e. warfarin
inhibition by cimetidine, chloramphenicol, metronidazole, quinolones; phenytoin
inhibition by isoniazid; theophylline inhibition by quinolone & macrolides
2. Involvement of other specific metabolic pathways i.e. interaction of allopurinol
with azathioprine & 6-mercaptopurine; xanthine oxidase activity is inhibited by
which the 2 drugs are metabolized
• INTERACTION OF NON SELECTIVE IRREVERSIBLE MAO (A) INHIBITORS
(MOCLOBEMIDE) WITH DIETARY TYRAMINE RESULTS IN SEVERE & MAY BE FATAL
HYPERTENSION; INHIBITION OF MAO →INCREASE IN NONADRENALINE OF
SYMPATHETIC NERVE ENDINGS, WHEN TYRAMINE IS INGESTED → PASSES VIA
GUT WALL & LIVER TO REACH SYSTEMIC CIRCULATION → RELEASES
NORADRENALINE FROM ITS INCREASED STORES IN NERVE ENDINGS →
HYPERTENSIVE CRISIS
11 CONTD..
e. Excretion interactions:
 Occur in kidneys mostly
 Competition for renal tubular secretion is important
mechanism
 Examples:
1. Diuretics inhibit lithium → lithium toxicity
2. Probencid inhibits tubular penicillin secretion
3. Quinidine inhibits tubular digoxin secretions
4. Loop diuretics inhibit gentamicin → nephrotoxicity
5. Phenylbutazone inhibit chlorpropamide → hypoglycemia
6. Salicylates inhibit methotrexate → methotrexate toxicity
12 PHARMACODYNAMIC INTERACTIONS
Direct: antagonism at same site, synergism at same site,
summation or synergism of effects at different sites
Indirect: coagulation, fluid & electrolyte balance
13 DIRECT:
 Antagonism at same site:
i.e. Reversal of effects of opiates with naloxone & reversal of warfarin
by Vit K
 Synergism at same site:
i.e. warfarin effects can be increased or decreased by changes in affinity of
warfarin for Vit K epoxide reductase, alteration synthesis rate of clotting
factors (anabolic steroids like testosterone), changes in activity of clotting
factor (tetracyclines), reduced Vit K availability secondary to reduced plasma
lipid concentrations
 Summation or synergism of effects at different sites:
i.e. any drug with depressant action on CNS will potentiate effect of another such
drug, whether or not the 2 drugs have effects on same receptors e.g.
combinations of antibiotics in some infections like TB
14 INDIRECT:
 Coagulation:
i.e. warfarin & other anticoagulants can be involved interactions in 3
ways: decrease in platelet aggregation (with salicylates, mefenamic acid,
NSAIDs), GI ulceration (with aspirin, NSAIDs, indomethacin),
fibrinolysis (with biguanides)
 Fluid & electrolyte balance:
Increased effects of cardiac glycosides by K depletion, increased risk
of arrhythmias with hypokalemia (with purgatives, diuretics,
corticosteroids) despite of use of anti arrhythmic drugs
(procainamide, quinidine), effects of diuretics attenuated by fluid
retaining drugs like NSAIDs, carbamazepine, phenylbutazone
15 ROLE OF PHARMACIST IN EVALUATION DRUG INTERACTIONS & ITS
MANAGEMENT

The pharmacist, along with the prescriber has a duty to ensure that
patients are aware of the risk of side effects and a suitable course
of action should they occur
Pharmacists have the ability to relate unexpected symptoms
experienced by patients to possible adverse effects of their drug
therapy.
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MANAGEMENT OPTIONS OF DRUG INTERACTION INCLUDE:

•AVOIDING THE COMBINATION ENTIRELY

•ADJUSTING THE DOSE OF THE OBJECT DRUG
•SPACING DOSING TIMES TO AVOID THE INTERACTION
•MONITORING FOR EARLY DETECTION
• PROVIDE INFORMATION ON PATIENT RISK FACTORS THAT INCREASES THE CHANCE OF AN ADVERSE
OUTCOME
•IMPROVED COMPUTERIZED SCREENING SYSTEMS
•DRUG CLASS DIFFERENCES NOT HANDLED CORRECTLY
17 THANKS

ANY QUESTIONS??

Chapter 10; pages 105-117

Clinical pharmacology & drug therapy, 3rd edition
D.G. Grahame Smith and J. K. Aronson