Drug Interactions

Review
 Definitions.
 Types.
 Mechanisms.
 Highrisk patients.
 How to handle an interaction?!
 Resources.
 Definition

 An interaction is said to occur when the

effects of one drug are changed by the
presence of other drug, herb, food, drink.
 An interaction occurs when
pharmacokinetics or pharmacodynamics of
drug are changed.
Type
s Drug - drug interactions.
 Herbal - drug interactions.
 Food - drug interactions.
 Drink - drug interactions.
 Pharmacogenetic interactions.
Mechanisms
Pharmacokinetics :
 Absorption interactions
 Distribution interactions
 Metabolism interactions
 Excretion interactions
Pharmacodynamics :
 Synergistic interactions
 Antagonistic interactions
Absorption interactions
Two important items we should consider:
( rate of absorption and absorbed amount )
- Rate of adsorption is not clinically important
in multiple doses e.g. anticoagulants.
- But in single doses we should reach
therapeutic level rapidly e.g. hypnotics and
analgesics.
Absorption interactions
Mechanisms :
 Altered PH.
 Altered bacterial flora.
 Formation of insoluble complexes.
 Altered GIT motility.
1- altered PH
 Some drugs are absorbed from
stomach (acidic media), so when this
media become neutral or alkaline, this
will affect the absorption of drug.
 Ex :
- antacid and ciprofloxacin
2- Altered bacterial flora
 Bacterial flora has a marked role in
metabolization of some drugs.
 Long term antibiotics may kill normal
flora and affect drug absorption.
 Ex :
erythromycin and digoxin
3-Formation of insoluble
complexes
Ex :
Tetracycline and quinolones with
divalent and trivalent e.g. Ca , Al …
etc
4- Altered GIT motility
 Some drugs increase peristalsis and
decrease time of absorption and
absorbed amount.
 Ex :
Prokinetic
Distribution interactions
Distribution interactions
 There is an important factor :
Vd
 Protein binding interactions :
-unbound molecules remain free and
pharmacological active.
- bound molecules are
pharmacological
inactive.
 Some drugs may compete others for
binding to protein depending on affinity
and concentration.
Distribution interactions cont.
Only drugs with low Vd will be affected.
Ex :
Warfarin (99% bound) and Phenytoin
(90% bound)
Metabolism (biotransformation)
 Most drugs are chemically altered
within Liver to less toxic and less lipid-
soluble metabolites.
 Hepatic metabolism has two pathways
:
◦ Phase 1 (modification)
◦ Phase 11 (conjugation)
Pathways of drug metabolism
CYP450
Metabolism cont.
 CYP450 most important isoenzymes
responsible for liver metabolism.
◦ CYP 3A4
◦ CYP 2D6
◦ CYP 2C8
Metabolism cont.
 Types of drug metabolism interaction :
◦ Enzyme induction
◦ Enzyme inhibition
Enzyme Induction
St john's wort increase metabolism
of ciclosporin by inducing CYP 3A4.
 Rifampicin increase metabolism
of
Ciclosporin by inducing CYP 3A4
Enzyme Induction
 Notes:
◦ Onset of enzyme induction is slow (days
– 2weeks).
◦ Also slow to solve.
◦ We can overcome this problem by
increase the dose
Enzyme Inhibition
 Most common than enzyme
induction.
 This interaction decrease drug
metabolism and so increase its
concentration in serum.
 It takes 2-3 days
 EX :
Ritonavir inhibit metabolism of
sildenafil by inhibiting CYP 3A4
Notes :
◦ If serum levels within therapeutic
ranges so it is not clinically important.
◦ Some drugs can be metabolized by more
than one of CYP450 isoenzymes, so the
reaction may be not clinically important.
Excretion
 Most drug are excreted in Urine or
Bile.
 Some drugs are reabsorbed from
renal tubules or enterohepatic
recirculation.
 Some drugs are excreted in acidic
urine, so changing urine PH will affect
there serum level.
 These interaction is rare.
Excretion
 Mechanisms :
◦ Altered urine PH
◦ Change in active tubular secretion.
 Some drugs may compete for excretion.
 E.g. probenecid and penicillin.
◦ Enterohepatic recirculation.
 E.g. penicillins and oral contraceptives.
Pharmacodynamics
interactions
Pharmacodynamics interactions
 they occur when the effects of a drug
are changed due to presence of
another drug at its site of action either
directly (on the same receptor) or
indirectly (on different receptor).
 Two types :
◦ Synergistic interactions.
◦ Antagonist interactions.
Synergistic interactions
 When two drugs have the same effect
are given together, so the total effect
will increase.
 It may be desired :
◦ e.g. sulfonamides and trimethoprim.
 May be not desired :
◦ e.g. K-sparing drugs (ACEIs , K-sparing
diuretics) and K-supplement >> cause
hyperkalemia.
Antagonistic Interactions
 When the effects of two drugs are
opposite.
 EX :
Warfarin
and
vitamin K
Herbal - drug interactions
St john’s wort and
Ciclosporin

Explained
Food - drug interactions
Liquorice

 Liquorice contain glycyrrhizin

(glycyrrhizinic or glycyrrhizic acid)
 Glycyrrhizinic acid is hydrolyzed in the intestine to
pharmacologically active compound glycyrrhetic
acid which inhibit 11 betahydroxysteroid
dehydrogenase.
 This increase cortisol in kidney and act as
aldosterone (fluid retention, hypokalemia,
hypertension)
 Ex:
◦ Liqourice and antihypertensive
Patients in high risk of drug
interactions
 Polypharmacy people (elder)
 Hepatic disorders
 Renal disorders
 Genetic factors
How to handle an
interaction?!
Is the the Using the Using
interaction dose space alternative will
clinically will solve solve the
important?! the interaction?!
interaction?!
No Ye Ye
s s
Ye No No
s
If the previous solutions don’t work ?!!!
Adjust drug dosage with monitoring of drug
level and physiological functions
Resources
Stockley’s Drug
Interactions
Tables of Drugs
Online Drug Interaction
Checker
http://reference.medscape
.com/drug- interactionchecker
,,,,,,,
https://online.epocrates.com/u/1300/M
ultiCheck?ICID=search-DDI
,,,,,,
http://www.drugs
.com/drug_interactions
.html
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References
 Stockley’s Drug Interactions 9th E
Book.
 Color Atlas of Pharmacology 3rd E
book.
 Material of Dr. Mohamed Emam.
 Notebook of drug interaction of
pharmacology department-Benisuef
pharmacy faculty.