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.