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Drug InteractionsBy: Ahmed Omar
Review
Definitions.
Types.
Mechanisms.
High risk 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.
Types
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?!
If the previous solutions don’t work ?!!!
Adjust drug dosage with monitoring of drug
level and physiological functions
Is the theinteraction clinically
important?!
No
Yes
Using the dose spacewill solve the interaction?!
Yes
No
Using alternative will
solve the interaction?!
Yes
No
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
Apps
https://play.google.com/store/apps/details?id=com.medscape.android&hl=en
………………….
https://play.google.com/store/apps/details?id=com.epocrates&hl=en
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.