DRUG INTERACTION

969-978

DR TAREK ABD EL.AZEEM

1- Mohammed Raafat Mostafa 969

Introduction and types of drug

interations

Drug interaction

beneficial

bad

beneficial

duration

efficacy

Side
effect

Drug
toxicity

duration

efficacy

Side effect

Drug toxicity

Types

Additive

Potentiation

Antagonism

Additive

2=1+1

Potentiation

2<=1+1

Receptor

Physiological

Disposition

Antagonism

Inactivation

Chemical

physiological

chemical

Acid

Base

Inactivation

Disposition

Receptor antagonism

Chloramphenicol

Macrolides

Mohammed Ragab 970

Pharmaceutical interaction

* Pharmaceutical interactions occur when

drugs are mixed inintravenoous
infusions ,vial ,syringes etc outside the
body prior to administration.
* Theses interactions occur due to
physicochemicalinteractions between the
drugs ,where precipitations or inactivation
may occur
* It is better not to mix drugs together in
same solution or adding drugs to
blood.single drug in solution is better.

examples

heparin

Loses its activity

Glucose ,antibiotics

thiopental

Succinyl choline

* Another example is the incompatibility of

phenobarbital with chlorpromazine or
opioid analgesics when mixed in the same
syringe.

* IV fluoroquinolones should not be mixed

with cation-containing fluid solutions..

* Admixing tetracyclines with calciumcontaining solutions will result in

precipitation.
* mix salts of hydrochloric acid (HCl) (e.g.,
dobutamine HCl, dopamine HCl, and
epinephrine HCl) with alkaline solutions.

Mohammed Refaat Ahmed

971

Pharmacodynamic
Pharmaco
interaction

Definition of pharmacodynamics
It is the action of the drug on the body and principles of
receptor interaction ,mechanism of therapeutic and toxic
actions and dose response relationship

Definition of pharmacodynamic
interaction
Administration of 2 or more drugs
at the same time

Dugs with opposing

pharmacologic effects
Thiazides elevate blood
sugar
Insulin lower blood
sugar level

Another example on opposing

interaction
-B drug
adrenergic
blockers
diminish the
effectiveness of
bronchodilators
-Such as
salbutamol or
turbutaline in
asthma

Drugs with similar pharmacologic

action
1-Exaggerated CNS
depressant effect
when using
- Antianxiety,
antipsycotic,
antihistamines
- Alcohol
at the same time

rugs with similar pharmacologic

action
2-Excessive
anticholinergic
effect by
-antipsychotic
(chlorpromazine)
-antiparkinsonism
(trihexyphenidyl)
-tricyclic
antidepressant
(amitriptyline)

This interaction cause

Dry mouth
Blurring of vision
Hyperpyrexia

Another example
Patient with
rheumatoid arthritis
uses prescribed
ibuprufen
also take OTC
ibuprufen for pain
not associated with
the arthritis
So increase the risk of
adverse effects

Another example at
receptor
site
Hypertensive crisis
which
-

occur due to using

MAO inhibitors
(phenelizine)
OTC cold ,allergy
(ephedrine)
Or antineoplastic
(procarbazine)
Or anti-infective
(furazplidone)

Mohammed Ramzy

972

Pharmacokinetic interactions at GIT absorption

Pharmacokinetic interactions at GI absorption:

1_PH:
-Drug Ionization.(non
2-complexation,adsorption:
ionized drugs more radily
*Tetracyclines,metal ions
absorped).
non absorbable complex
*antacids,H2Blockers,proton
pump inhibitors.
*Antacids(metalions),fluoroqu
decreasedissolution,absorpti
nolones
absorption.
on of anti fungal drugs.
*
PH
disintegration
of enteric coating in stomch
*oilofparaffin Dissolution of
fat soluble vitamins.

Alteration in motility:

Anticholinergics:Del
ay in absorption from
small intestine.

Metoclopramide:
Reduced absorption
of drugs.

Effect of food

Absorption may be delayed,

but not reduced
Total amount of drug
absorbed may be reduced.
MECHANISM: it could be
because;
- slow gastric emptying
- binding with drugs
- altering dissolution of drugs
- altering pH of GIT

Effect of flora.

Oral contraceptivesantibiotics: Decrease

effectiveness of oral
contraceptives, because
antibiotics (amoxycillin) reduce
bacterial flora, thus reducing
serum estrogen conc.

Anticoagulents- antibiotics:
Enhanced effect of
anticoagulents.

Free drug Liver

Conjugate
Bile

Free drug Bacteria Conjugate

Gut

Mohammed ramadan hassan 973

Pharmacokinetic interactions at Distribution

1-Introduction:

After absorption, Most of drugs distribute widely, some are dissolved

in plasma water, some are bound to plasma proteins, and some are
bound to tissue proteins. Volume of distribution is the amount of
space available in the body in which drugs may be stored .

2-The mechanisms by which drug interactions

alter drug distribution include:
A-competition for plasma protein binding:
**Def.
**Examples:
*Warfarin can be displaced by Salicylates or Indomethacin increasing
its anticoagulant activity.
*Phenylbutazone can displace the oral antidiabetic agents
Tolbutamide or Chlorpropamide leading to severe hypoglycemia.

*Sodium valproate when given to patients taking Phenytoin.

B-Displacement from tisuue binding sites.

C- Alteration in local tissue barriers:

e.g P-glycoprotein inhibition in the blood-brain

barrier.

D-Alteration in blood flow :

e.g Propranolo
specially in large dose
decreases cardiac
output and in turn
decreases hepatic
blood flow and thus
decrease hepatic
clearance of some
drugs like Lidocaine.

3- Importance knowing drug

interactions at distribution:
e.g plasma protein binding.
The clinical importance of protein binding displacement has
been overemphasized; current evidence suggests that
such interactions are unlikely to result in adverse effects.
Displacement from tissue binding sites would tend to
transiently increase the blood concentration of the
displaced drug .
But the concept that plasma protein binding is a common
cause of clinically significant interactions may still widely
taught in some medical schools , often appears in text
books, and is accepted by many in the medical
community and by drug regulators.

*The diagram below shows how it

is important to know the degree of
plasma protein binding of a drug:

Mohammed Ramadan Abd El Rahman 974

Pharmacokinetic interactions at Drug

metabolism

Phamacokinetic interactions of drug

metabolism

1. Enzyme induction

2. Enzyme Inhibition

Enzyme Induction:
Definition:
Increase Hepatic
clearance of some
drugs
Target:
Cytochrome P450 Enz.
Mainly in the Liver.

Ex. Of Inducers:
Warfarin
Phenobarbitone

Phenytoin

Losartan

 Carbamazepine

Tolbutamide

Rifampin

increase
clearance

of losartan,
,phenytoin
, Tolbutamide
S-Warfarin
to the
Double

Enzyme inhibition:
Definition:
Decrease rate of
metabolism, prolong
T1/2 of a drug

Cimetidine:

1.Tolbutamide
Weak Inhibitor
of CYP450
Dose-dependant

(1.6 g)

2. Warfarin
(1 g)

 Fluvastatin

HMG-CoA reductase Inhibitor

Cloramphenicol

Antimicrobial agent

Fluconazole

Antifungal drug
inhibit tolbutamide metabolism

Mohammed Raaoof

976

Pharmacokinetic interactions with excretion

Excretion of drugs is related to the kidneys and

drug interactions with excretion explained in three
mechanisms as follow:
1-By competition for active renal tubular secretion
many drugs share the same tubular active
transport system and can compete with each
other for secretion and those may interfere with
the renal secretion of other drugs causing their
accumulation and toxicity
Example: Digoxin serum concentration is
increased with quinidine

 2-by change in urine pH:

change in urine pH leads to decrease
tubular reabsorption of filterd drugs and so
increase their elimination
urinary alkalinization icrease acidic drugs
elimination*
Example:acetazolamide icrease
elimination of salicylates
*this interaction used in treatment of
toxcicity

 3-by change in fluids and electrolyte balance.

This change alters the effect of drugs that act on
myocardiam and on the kidney.eg.diurtics that cause
hypokalemia,potentiate side effects of cardiac
glycoside.
0One of the most clinically significant drug interactions
involving excretion related to kidneys is interaction with
lithium
Lithium is filterd by kidney and reabsorbed by the
proximal renal tubule in parallel with sodium.A sustained
increase in urinary sodium excretion such as that
produced by thiazide diuretics promotes compensatory
reabsorption of sodium by the proximal renal
tubule.lithium reabsoption is similarlu enhanced.

Mohammed Zakaria 977

Therapeutic importance of drug

interactions

Definition :
-its an interaction between different
drugs results in useful therapeutic use
1-Intended interactions in treatment of toxicity with
atropine in the treatment of OFC.
2-intended interactions may be used to increase
the therapeutic efficiency of drugs e.g.
combinations of antibiotics or combination
therapy in treatment of hypertension.
3-Interactions may be useful to reduce toxicity of
some drugs e.g. potassium salts given with
thiazidediuretics.

4-interaction may lead to change in the

effect of some drugs e.g. changing the
activity of soluble insulin when mixed with
the same syringe with lente insulin.
5-drug interactions are important when lead
to changes in plasma concentration of
drugs which need accurate control in
plasma concentration.
6-In the eldery where interactions may
increase the susceptibility to adverse
reactions.

7-Interactions are important with drugs given

for long duration e.g. oral contraceptives
or antiepileptic drugs where precise
plasma concentration is required.
8-Drug interactions are important with drug
metabolism inducers or inhibitors which
can alter the drug concentration with
subsequent change in the response.

oncarbidopa with levodopa

(available as
Carbidopa/levodopa).
Metabolic drug interactions Many drug interactions are
due to alterations in drug
metabolism.Further, human
drug-metabolizing enzymes
are typically activated through
engagement of nuclear
receptors.a is used in the
management of Parkinson's
disease e of them.

Mohammed Samy El Sayad

977

Minimizing drug interaction

MNIMIZING DRUG INTERACTION

We can minimize drug

interaction by:

1-PRESCRIBES should know all drug taken

by the patient.
2-Change the sequence of administration.
3-Asking patient a question about diet and
alcohol consumption may be appropriate.

4-The fewest drugs in the lowest dose for the

shortest possible time should be prescribed.
5-Educate the patient.
6-Patients should be monitored for adverse
events; particularly after change in treatment.
7-Drug interaction should be considered as a
possible cause of any unexpected problems.

When unexpected clinical responses occur -8

:prescribes should
A- Determine serum concentration of selected
.drugs being taken
.B- Consult an expert in drug interactions
C- Adjust the dosage until the desired effect is
.obtained
D-If dosage adjustment is ineffective; the
drug should be replaced by one that does
.not interact with other drugs being taken

Changing drug therapy should be-9

.minimal
.Avoid multiple therapy-10
.Keep in mind genetic factor-11
Check for any warning about the drug -12
.interaction
You should take all your medication from one -13
.pharmacy
.You could use online tools-14

Mohammed Saad Mahbob 978

Food drug interaction

MONOAMINE OXIDASE
INHIBITOR AND FOOD
CONTAINING TYRAMINE
INTERACTION
It was found that the combination of an MAOI
and a food containing tyramine resulted in the
hypertensive interaction ("the cheese
reaction"). Because of the risk of intracerebral
hemorrhage and death.

Tyramine (Potent vasoconstrictor)

Is a monoamine compound derived from the amino acid
tyrosine.
Tyramine is formed from the breakdown of protein.
Tyramine appears naturally in a variety of foods,
especially those that are aged and those containing a
large amount of yeast. Ordinarily, tyramine is
deaminated in the liver to an inactive metabolite, but
when the hepatic MAO (primarily MAO-A) is
inhibited, the "first-pass" clearance of tyramine is
blocked.

FOOD CONTAINING
TYRAMINE

MAO-Inhibitors

Un selective
MAOI A&B

Hydrazines

-Non
hydrazines

mebanazine

tranylcypromine

Selective

MAOI-A

moclobemide

Selective
MAOI-B

selegiline

Mode of action
MAOIs act by inhibiting the activity of monoamine oxidase, thus
preventing the breakdown of monoamine neurotransmitters
and thereby increasing their availability.
There are two isoforms of monoamine oxidase, MAO-A and
MAO-B. MAO-A preferentially deaminates serotonin,
melatonin, epinephrine and norepinephrine.
MAO-B preferentially deaminates phenylethylamine and trace
amines.
When tyramine ingested orally, MAOIs inhibit the catabolism of
dietary amines.Sufficient intestinal MAO-A inhibition can lead
to hypertensive crisis, when foods containing tyramine are
consumed (so-called "cheese syndrome"), or
hyperserotonemia if foods containing tryptophan are
consumed

Mechanism
The exact mechanism by which tyramine causes a
hypertensive reaction is not well understood, but it is
assumed that tyramine displaces norepinephrine from
the storage vesicles.
Tyramine is absorbed and displaces nor epinephrine
from sympathetic nerve ending and epinephrine from
the adrenal glands.
This may trigger a cascade in which excessive amounts
of norepinephrine can lead to a hypertensive crisis.
Another theory suggests that proliferation and
accumulation of catecholamines causes hypertensive
crises.

Any questions ???

Thank you