DRUG INTERACTION

General Considerations of Drug

Interactions

 What is a drug interaction?

A drug interaction : interaction between one
drug and another drug, herbal medicine,
food, drink or some environmental chemical
agents that cause a change in its effects.
General Considerations of Drug
Interactions

Outcomes of a drug interaction :

a. Harmful/undesirable : an interaction causes an increase in
the toxicity of the drug.
Ex. : - MAOIs may cause an acute and potentially
life-threatening hypertensive crisis if they are taken
together with tyramine-rich foods such as cheese.
- Rifampicin given together with warfarin reduced
markedly the anticoagulant effect of warfarin.

b. Beneficial/valuable : an interaction causes an increase in the

effectiveness
Ex. : Antihypertensive drugs given together with diuretics can
achieve antihypertensive effects effectively.
General Considerations of Drug
Interactions

 Mechanisms of drug interactions

Drug interactions can occur during the
pharmacokinetic or pharmacodynamic process.

1. Pharmacokinetic interactions : interactions that

can affect the process of absorption, distribution,
metabolism, and excretion of drugs (ADME
interactions)
2. Pharmacodynamic interactions : interactions that
cause the effects of one drug are changed by the
presence of another drug at its site of action.
General Considerations of Drug
Interactions

1. Pharmacokinetic interactions

Drug absorption interactions

Drug distribution interactions

Pharmacokinetic
interactions Drug metabolism interactions

Drug excretion interactions

General Considerations of Drug
Interactions

1.1 Drug absorption interactions

- Most drugs are given orally for absorption through the
mucous membranes of the GI tract, and the majority of
interactions within the gut result in reduced absorption.
(the rate of absorption or the total amount of drug absorbed).

- For drugs given chronically on a multiple dose regimen (e.g.

anticoagulants), the total amount of drug absorbed is very
important.
- For drugs given as single doses (e.g. hypnotics/analgesics),
where a rapidly achieved high conc. is needed, the rate of
absorption is very important to achieve an adequate effect.
General Considerations of Drug
Interactions

Drug absorption interactions can be due to :

a. Effects of changes in GI pH
- Absorption is governed by the pKa of the drug, its lipid-
solubility, the pH of the contents of the gut, and other
parameters relating to the pharmaceutical formulation of
the drug.

Some drugs that cause a change in GI pH affect the

absorption of other drugs.
Ex. PPIs, H2-blockers, & antacids cause rises in pH of the
stomach can markedly reduce the absorption of certain
drugs.
General Considerations of Drug
Interactions

b. Adsorption of drugs
- Some drugs that have adsorbing properties can affect the
absorption of other drugs.
- Examples :
* Activated charcol that acts as anadsorbing agent within
the gut can affect the absorption of drugs given in
therapeutic doses.
* Antacids can also adsorb a large number of drugs
General Considerations of Drug
Interactions

c. Chelation & other complexing mechanisms

- Some agents can make chelates or complexes with other
drugs leading to inhibition of absorption of the other drugs.
- Examples :
* Antacids containing Ca2+, Al3+, & Mg3+ can chelate with
tetracycline to form complexes that are both poorly
absorbed and have reduced antibacterial effects of
tetracycline.
* Colestyramine, an anionic exchange resin intended to
bind bile acids and cholesterol metabolites in the gut,
binds to a number of drugs (e.g. digoxin, warfarin, l
evothyroxine), thereby reducing their adsorption.
General Considerations of Drug
Interactions

c. Changes in GI motility
- Drugs that alter the rate of stomach emptying can affect
absorption.
- Examples :
* Propantheline delays gastric emptying and reduces
paracetamol absorption
* Metoclopramide accelarates gastric emptying and
inceases paracetamol absorption.
General Considerations of Drug
Interactions

d. Induction or inhibition of drug transport proteins

- The oral bioavailability of some drugs is limited by the
action of drug transporter proteins, which eject drugs that
have diffused across the gut lining back into the gut.
- Examples :
* Rifampicin that induces drug transporter proteins (P-
glycoprotein) may reduce the bioavailability of ‘digoxin’.
General Considerations of Drug
Interactions

1.2 Drug distribution interactions

a. Protein-binding interacions
- The binding of drugs to the plasma proteins is reversible
an equilibrium between bound and unbound
molecules.
- Unbound molecules remain free and pharmacologically
active, while bound molecules form a circulating but
pharmacologically inactive reservoir which is temporarily
protected from metabolism and excretion.
General Considerations of Drug
Interactions

- As the free molecules become metabolised, some of the

bound molecules become unbound and pass into solution
to exert their normal pharmacological actions.

- Depending on the concs. and their affinity for their binding

sites, drug molecules binding to proteins can be displaced
by other drug molecules from their sites of binding,
the concs of the displaced mols rise.
General Considerations of Drug
Interactions

b. Induction or inhibition of drug transport proteins.

- Distribution of drugs into organs such as brain and testes is
limited by the action of drug transporter proteins such as
P-glycoprotein.
- These proteins actively transport drugs out of cells when
they have passively diffused in.
- Drugs that are inhibitors of these transporters could
therefore increase the uptake of drug substrates into the
brain, which could either increase adverse CNS effects, or
be beneficial.
General Considerations of Drug
Interactions

1.3 Drug metabolism interactions

- Some drug metabolism: in the serum, kidneys, skins, &
intestines, but the greatest proportion: in the membranes of
the ER of the liver cells.
- Two phases of metabolisms
a. Phase I reactions (oxidation, reduction, or hydrolysis),
more polar compounds. The enzymes: cyt. P450,
(others : MAO & epoxide hydrolyses)
b. Phase II reactions (conyugation), drugs couple with some
other substances (e.g. glucuronic acid) inactive
compounds. The enzymes: glucuronyltransferase, N-
acetyltransferases
General Considerations of Drug
Interactions

- Drug metabolism interactions occur due to :

a. Changes in blood flow through the liver
b. Enzyme induction
c. Enzyme inhibition
General Considerations of Drug
Interactions

1.4 Drug excretion interactions

- Most drugs are excreted in the urine either by passive or
active transport systems.
- Reabsorption of drugs accurs in the renal tubular cells.
- Drug excretion interactions occur due to :
a. Changes in urinary pH
Passive reabsorption of drugs depends upon the solubility
of the drugs, and in its turn depends on its pKa and the pH
of the urine. The non-ionised mols (lipid soluble) are able
to diffuse back through the lipid membranes of the tubule
cells.
General Considerations of Drug
Interactions

Plasma Tubule Acid tubular Alk tubular Tubule Plasma

wall filtrate filtrate wall

Drug reabs HX H+X X+H HX

by diffusion
Drug lost
in urine
General Considerations of Drug
Interactions

b. Changes in active excretion

- Drugs that use the same active transport systems in
the renal tubules can compete with one another for
excretion.
- Example : Probenecid reduces the excretion of
penicillin and other drugs
c. Changes in renal blood flow
-The flow of blood through the kidneys is partially
controlled by the production of renal vasodilatory
prostaglandins. If the synthesis of these prostaglandins
is inhibited, the renal excretion of some drugs may be
reduced.
General Considerations of Drug
Interactions

Drugs affected Interacting drugs Outcomes of

interactions

Cefalosforins Probenecid Levels of drug

Penicillins affected raised,
Quinolones possibility of
Methotrexate toxicity with some
drugs
General Considerations of Drug
Interactions

2. Pharmacodynamic interactions
Pharmacodinamic interactions : interactions where
the effects of one drug are changed by the presence
of another drug at its site of action.

Sometimes the drugs directly compete for particular

receptors (e.g beta-2 agonists such as salbutamol
and beta-blockers such as propranolol) but often the
reaction is more indirect and involves interference
with physiological mechanisms.
2.1 Additive or synergistic interactions
If two drugs that have the same pharmachological
effect are given together the effects can be additive.

Additive effects can occur with both the main effects

of the drugs as well as their adverse effects.

Additive effects can increase effectivity or cause

toxicity.
2.2 Antagonistic interactions
If two drugs that have the opposite
pharmachological effect are given together the
effects can be decreased.

2.3 Drug or neurotransmitter uptake interactions

Drugs whose actions occur at adrenergic neurones
can be prevented from reaching those sites of
action by the presence of other drugs.
Examples:
Tricyclic AD prevent the re-uptake of
noradrenaline/norepinephrine into pra-synaps of
neurons Patients on tricyclic AD given
parenteral noeadrenaline have a merkedly
increased response (hypertension, tachycardia)