Drug Interactions

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.
altered PH -1
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
Altered bacterial flora -2
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
Formation of insoluble complexes-3
Ex :
Tetracycline and quinolones with divalent
and trivalent e.g. Ca , Al …etc
Altered GIT motility -4
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
 Classification of Drug-Drug Interaction
Drug-Drug Interaction

In vitro drug interaction In vivo drug interaction

Physical Chemical Pharmacokinetic Pharmacodynamic

interaction interaction interaction interaction
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

 EX. Drug-Food interaction
Sr. Drug affected Food item Effect of interaction
.No
.1 Anti-coagulant Food rich in vit.k (eg. Decreased anticoagulant effect
Green leafy vegetables, due to enhanced synthesis of
egg yolk, citrus fruits) clotting factors
.2 Griseofulvin Food with high fat Increased absorption rate
content
.3 MAOIs Food rich in tyramine Hypertensive crisis
(eg. Banana, cheese,)
4 Paracetamol Carbohydrates Slow drug absorption and
therapeutic effect
5 Quinidine Milk, nut, most Decreased renal clearance
vegetables
6 Tetracycline Milk products contains Decreased GIT absorption
+Ca
7 Erythromycin Acid fruit juices Decomposition of the drug and
reduced therapeutic effect
8 Antihypertensive Liquorice Causes hyerkalemia, sodium
.retension increase in BP
Patients in high risk of drug
interactions
Polypharmacy people (elder)
Hepatic disorders
Renal disorders
Genetic factors
Tables of Drugs