Dr.

Hesham Aly Salem

2008
Cairo University
Faculty of Pharmacy
Dept. of Pharmacology & Toxicology
 when

Drug + • Another drug Changed

• Herbal medicine Effect

• Food
OR
• Drink
• Environmental
chemical agent.
 Outcome of drug
interaction may be
HARMFUL or BENEFICIAL
 Harmful Interaction

↑ the effect ↓ the effect

of the drug of the drug.

Toxicity Combined No therapeutic

Toxicity effect
 Harmful Interaction

Combined
Toxicity

1 The use of more than one drug, each of which has

toxic effects on the same organ Æ ↑ Organ
damage even though the therapeutic dose of either
drug alone may be insufficient to produce toxicity
 Harmful Interaction

Combined
Toxicity

2 The use of two drugs, one of them has toxic effects

on certain organ, while the other has no intrinsic
toxic effect on this organ Æ ↑ Organ damage even
though the therapeutic dose of the toxic drug alone
may be insufficient to produce toxicity
 Harmful Interaction

e.g.:

TOXICITY
MAOIs + Tyramine-rich foods

Acute & potential life-threatening

hypertensive crisis
 Harmful Interaction

e.g.:

TOXICITY
Two or more CNS depressants

Additive CNS depression

Reduction of Therapeutic Effect

Harmful Interaction

e.g.:
Tetracyclines or Quinolones
+
Antacids or Milky foods

↓ or even abolish effects

of these antibacterials
 Beneficial Interaction
e.g.:
Antihypertensive + Diuretics

Additive therapeutic effect

(Antihypertensive effects possibly not
obtainable with either drug alone)
 Patient Variability
• You can predict the mechanism of
drug interaction ………….BUT

• In practice, it is very difficult to

predict what will happen when an
individual patient is given two
potentially interacting drugs
 Patient Variability

• Many drugs may interact in some

patients and may not in others.

• Some patients apparently can

tolerate the adverse outcome of
interactions, while others cannot
tolerate.
Also, do not uncritically extrapolate
the interactions seen with one drug to all
members of the same group:
e.g.:
Erythromycin + Lovastatin

↑ levels of lovastatin
(erythromycin inhibits lovastatin metabolism
but not affect pravastatin)
 SOOOOO
Choose a non-interacting alternative

If this is not available

You can give interacting drugs together but

with appropriate precautions
Pharmacokinetic Pharmacodynamic
Interaction Interaction

Results in Results in
change of the change of the
delivery of the response of the
drug to its site drug at its site of
of action action
BOTH
 Mechanisms
Through Affecting

1. ABSORPTION
2. DISTRIBUTION
3. METABOLISM
(BIOTRANSFORMATION)
4. EXCRETION
 Drug absorption interactions
The interaction may affect:
• The EXTENT of absorption
(total amount absorbed)
•The RATE of absorption
Affecting the EXTENT of drug absorption

1. Changes in GIT pH
2. Changes in drug free from
3. Changes in drug transport proteins
 Affecting the EXTENT of drug absorption
1. Changes in GIT pH

May affect the extent to which the drug exist in

the non-ionized lipid-soluble (absorbable form)

Affect the passage of drugs through mucous

membranes by simple PASSIVE diffusion
Affecting the EXTENT of drug absorption

1. Changes in GIT pH

PPI, H2RA, antacids Æ × pH ÆØ the

absorption drugs that require acid medium
for absorption (e.g. ketoconazole)
Affecting the EXTENT of drug absorption

2. Changes in drug free form

Adsorption - Chelation - Complexation

Reduce the EXTENT of drug absorption

Affecting the EXTENT of drug absorption

2. Changes in drug free form

• Activated charcoal
• Antacids

Æ ADSORB a large number of drugs given

Æ Reduce the amount absorbed of drugs.
 Affecting the EXTENT of drug absorption

2. Changes in drug free form

• Metallic ions
(found in antacids & diary products) Æ
CHELATE with certain drugs.

e.g.: Tetracycline can chelate with Ca, Al, Bi, Fe Æ

complexes Æ poorly absorbed Æ Reduce the
amount absorbed of drugs Æ Reduced antibacterial
effects.
 Affecting the EXTENT of drug absorption

2. Changes in drug free form

• Cholestyramine
(Resin intended to bind bile acids and
cholesterol metabolites in the gut) Æ BINDS
to several drugs (e.g. digoxin, warfarin, l-
thyroxine), Æ reduce the amount absorbed of
drugs.
Affecting the EXTENT of drug absorption

2. Changes in drug free form

Separating the administration of the

interacting drugs by 2 to 3 hours may
reduce the effects of this type of
interaction.
Affecting the EXTENT of drug absorption

3. Changes in drug transport proteins

Drugs & endogenous substances
cross biological membranes by:

1. Passive diffusion
2. Carrier (transporter)-mediated process
The most well known is P-glycoprotein.
glycoprotein
 P-glycoprotein
Efflux pump found in the membranes
of certain cells Æ Push drugs &
metabolites out of these cells
Was
Was first
first identified
identified in
in some
some cancer
cancer cells , where
cells, where itit actively
actively
transported
transported multiple
multiple chemotherapeutic
chemotherapeutic drugsdrugs outout of
of cancer
cancer
cells,
cells,thereby
therebyrendering
renderingthemthemresistant
resistantto
todrug
drugaction.
action.
The
The development
development of of specific
specific PP-glycoprotein
-glycoprotein inhibitors
inhibitors
valspodar) Æ
((valspodar) Æ improve
improve the the penetration
penetration of of cytotoxic
cytotoxic drugs
drugs
into
intothe
thecancer
cancercells.
cells.
 P-glycoprotein

Have an impact on:

1. The extent of drug absorption (via
intestine)
2. The drug distribution (to brain, testis,
placenta)
3. The drug elimination (in urine, bile).
 P-glycoprotein
Affecting the EXTENT of drug absorption

P-glycoprotein in cells of the gut lining

Ejects some already-absorbed drug

molecules back into the intestine

Ø total amount of drug absorbed

 P-glycoprotein
Effect
Effect on
on the
the drug
drug distribution
distribution
P-glycoprotein in endothelial cells of BBB

Ejects certain drugs from the brain

& Limiting CNS penetration & effects

 P-glycoprotein
Effect
Effect on
on the
the drug
drug elimination
elimination
P-glycoprotein in tubular cells of kidney

Ejects certain drugs into the urine

(Active tubular excretion)

Elimination of these drugs

 P-glycoprotein
The actions of P-glycoprotein can be:

induced or inhibited
by some drugs Æ Affect the pharmaco-
kinetic of drugs that depend on this
protein on their absorption,
distribution & elimination.
 P-glycoprotein
Inducers of P-glycoprotein: Rifampin
Inhibitors of P-glycoprotein: Verapamil – Ketoconazole
Example:
Digoxin affected by P-glycoprotein
Rifampin Æ ↓ plasma digoxin levels ??
Verapamil Æ ↑ plasma digoxin levels.
Example:
Ritonavir affected by P-glycoprotein
Ketoconazole Æ ↑ CSF levels of ritonavir
Affecting the RATE of drug absorption

Changing the GIT motility & gastric

emptying are the main factors
affecting the rate of drug absorption
 Affecting the RATE of drug absorption

Changes in GIT motility

Decrease the rate of Increase the rate of

stomach emptying stomach emptying
Delay the drug delivery to Hasten the drug delivery
the site of absorption to the site of absorption

Ø Rate of absorption × Rate of absorption

For drugs that absorbed in ileum (Most of drugs)

 Affecting the RATE of drug absorption

However,...
The changing in the RATE of drug
absorption is seldom clinically important
BUT
in certain cases it may be important ...When?
 Affecting the RATE of drug absorption
1. If the drug is administered as single dose
regimen and intended to give rapid effect
(e.g. hypnotics, analgesics)
Reduction in the rate of absorption may lead to
failure to achieve the adequate effect “providing that
no change in the total amount of drug absorbed”.

N.B.: The rate of absorption is usually not important

for chronically-given multiple dose drug regimen
 Affecting the RATE of drug absorption

2. If the change in the RATE of absorption results in

change in the EXTENT of absorption.

FOR
1. Poorly absorbed drugs
2. Drugs subjected to intestinal mucosal metabolism
 Affecting the RATE of drug absorption

1. For poorly absorbed drugs

Changes in gut motility Æ Affect the time

available for drug dissolution & absorption

Affect the total AMOUNT absorbed

 Affecting the RATE of drug absorption

Changes in GIT motility

Decrease the gut motility Increase the gut motility

(e.g.: Anticholinergic drugs) (e.g.: Prokinetic drugs)

× time available for drug Ø time available for drug

dissolution & absorption dissolution & absorption

× amount absorbed Ø amount absorbed

 Affecting the RATE of drug absorption

2. For drugs subjected to intestinal mucosal

metabolism

Changes in gut motility Æ Affect the contact time

between the drug & the intestinal mucosa Æ Affect
the amount metabolized before absorption

Affect the total AMOUNT absorbed

 Affecting the RATE of drug absorption

Changes in GIT motility

Decrease the gut motility Increase the gut motility

( e.g.: Anticholinergic drugs) (e.g.: Prokinetic drugs)

× time available for drug Ø time available for drug

metabolism by mucosa metabolism by mucosa

Ø amount absorbed × amount absorbed

 Affecting the RATE of drug absorption

Changes in GIT motility

e.g.: Anticholinergic drugs /Levodopa

Anticholinergic effects Æ may reduce the amount

absorbed of levodopa, possibly because the
exposure time to intestinal mucosal metabolism is
increased.
 Drug absorption interactions
Malabsorption caused by certain drugs

Neomycin
Malabsorption syndrome
↓ absorption of certain drugs
(digoxin & methotrexate)
 Drug distribution interactions
HOW
HOW

1. Changes in drug transport proteins

2. Changes in drug-plasma protein

binding
 Drug distribution interactions
1. Changes in drug transport proteins

Inhibitors of P-glycoprotein
Æ ↑ uptake of drug into the brain
Æ ↑ CNS effects OR adverse effects
(may be beneficial or harmful).
 Drug distribution interactions
2. Changes in drug-plasma protein binding

Many drugs are transported with some

proportion of their molecules in
solution (free, unbound) and the rest
bound to plasma proteins (particularly
albumin).
 Drug distribution interactions
2. Changes in drug-plasma protein binding
Drug + PP ↔ Drug-PP
Free Bound

Free ¾ Pharmacologically active

¾ Subjected to metabolism & excretion.

Bound ¾ Pharmacologically inactive

¾ Reservoir which is temporarily protected from
metabolism & excretion.
 Drug distribution interactions
2. Changes in drug-plasma protein binding
Drug + PP ↔ Drug-PP
Free Bound

As the free molecules become metabolized,

some of the bound molecules become unbound
and pass into solution to exert their normal
pharmacological action.
 Drug distribution interactions
2. Changes in drug-plasma protein binding

¾ One drug may compete with another on PP Æ

Displacing it (Depending on their concentrations
and relative affinities for PP) Æ ↑ number of free
and active molecules
¾ Such increase in the free concentration (and thus
the effect) of the displaced drug in plasma will be
transient owing to Compensatory increase in drug
disposition
 Drug distribution interactions
2. Changes in drug-plasma protein binding
SO…Clinically, such interactions are unlikely to
result in adverse effects …UNLESS…??????.
For:
• Drugs given IV Or having very low Vd and have
• Narrow therapeutic index Æ Toxicity OR
• High extraction ratio - Short t1/2 Æ Reduced effect
 Drug distribution interactions
2. Changes in drug-plasma protein binding
This interaction is important in therapeutic drug
monitoring.
As the drug is displaced from PP Æ ↑free drug Æ Quickly
eliminated by metabolism and excretion Æ The amount of free
active drug returns to normal. However, the total amount of
drug would now be reduced.

Therefore
if the total drug was monitored Æ ???
if the free drug was monitored Æ ???☻