01 druginteraction

KFT332 PHARMACOLOGY 2

ISLAND COLLEGE OF TECHNOLOGY

Drug Interaction



LEARNING OBJECTIVES:

Upon completion of this topic, thestudents should be able to:

1. Define drug interaction.

2. Identify drug interaction outside the body

3. Identify pharmacodynamic interaction.

4. Identify pharmacokinetic interaction



INTRODUCTION

An interaction is said to occur when the

effects of one drug are changed by the

presence of another food,drink or by some

environmental chemical agent.



What can drug interaction lead to?

Outcome will be harmful/adverse effect

1. Increase in efficacy or toxicity

Example warfarin with phenylbutazone

2. Reduce in efficacy-leading to drug failure.

Example : MAOI with tiamine



Outcome will be beneficial

synergism can divided into 2 :

A) Summation

Occurs when 2 types of drugs work by altering different physiological or biochemical activities to produce an additive effect.

Summary = 1+1=2

Example 2 drugs, different MOA,produce larger drop in blood pressure.



B) Potentiation

Occurs when two drugs act, again on

different physiological or biochemical

activities,to produce an effect which is more

than additive

Summary : 1+1=3

Example : Bactrim, combination of

trimetrophrim and sulphamethoxazole.



Outcome will be no effect

Leading to no changes.

The majority of drug interactions are not life-

threatening or serious.

Most often, no or only minor effects occur,

and patient usually are unaware they

happened.



The patient who has HIGHER RISK for drug interaction

Below are several reasons why some people

may experience drug interaction more than

others do.

Having multiple disease.

Taking multiple drugs

Being female

Having a previous drug interaction.

Being very young or very old.



Being overweight.

Being dehydrated.

Having poor nutrition.

Having low blood pressure.

Having congestive heart failure.

Having liver and/or kidney damage.



Interaction Outside the Body

Interaction can occur outside the body and inside the

body.( pharmacodynamic and pharmacokinetic )

Outside the body:

Due to storage condition :

Light,oxygen,moisture

Eg. GTN prone to oxidation,shelf-life 3 months.

Due to incompatibility with material of container.

Eg. Paraldehyde liquid dissolves in plastic,need to

use glass.



Mechanisme Of Drug Interaction inside The Body

2 important

Pharmacokinetic interaction

Pharmacodynamic interaction



PHARMACODYNAMIC INTERACTION

Pharmacodynamic interactions are those

where the effects of one drug are changed

by the presence of another at its site of

action.

The changes will be the effect of one of the

two drugs being enhanced or reduced.



Types Of Pharmacodynamic Interaction

1. Additive or Synergistic interaction

2. Antagonistic or opposing interaction

3. Interaction due to changes in drug transport

4. Interaction due to disturbances in fluid and

electrolyte balance



Additive or Synergistic interaction

If two drugs which have the same

pharmacological effect are given together,the

effect can be additive.

Given gentamycin + cephalothin together.

Both are nephrotoxic drugs,

The effect : increase neprotoxicity.



Antagonistic or opposing interaction

In contrast to additive interactions, there are

some pairs of drugs with activities which are

opposed to one another.

Example propanolol(-adrenoreceptor

antagonist) for angina given with salbutamol

(-adrenoreceptor agonist) for asthma.

The effect of salbutamol with reduce, so

patient with angina who suffered asthma

must be careful.



PHARMACOKINETIC INTERACTION

Any drugs that interfere the pharmacokinetic

process , will be altering the effect with other

drugs.

Absorption

Distribution

Metabolisme

Excretion



Drug absorption Interaction

Effects of changes in gastrointestinal pH

Adsorption,chelation and other complexion

Changes in gastrointestinal motility



Effects of changes in gastrointestinal pH

Drug absorption depends on pKa of the drug and git

pH.

pKa drug absorbed better in git pH

Changes in git pH will alter the drug absorption

pKa = -log10Ka (acid dissociation constant)

The lower the pKa value, the stronger the acid.

Antacids: The presence of these in the

gastrointestinal tract causes a change in

environmental pH. They will increase absorption of

basic drugs and decrease absorption of acidic ones.



Changes in gastrointestinal motility

Gut motility: If motility is increased (Hypermotility )

and therefore transit time is reduced, there will be less

time available for absorption of a drug.

Example drug can cause hypermotility- propantheline

Hypomotility may increase the amount of drug

absorbed if contact with the gut epithelium is

prolonged.

Example drug can cause hypomotility-anticholinergic

drug .



Adsorption,chelation and other complexion

Activated charcoal is intended to act as

adsorbing agent in gut for removing toxic

material.

Given charcoal with other drug will reduce

the absorption amount of the particular drug.



Drug Distribution Interaction

Drug displacement (protein-binding)

interaction.



Example - If two drug bind at the same site of protein molecule and they are administered together,

Example warfarin (anti-coagulant) is administered with aspirin.(pain-killer)

Both are bound at the same protein , but aspirin binds more strongly than warfarin from its binding site.

Warfarin will therapeutically active only when in free state,and when take together with aspirin there will be more than the usual amount free in the plasma

This will effectively like giving an increased dose of warfarin.So, overdose happened i.e haemorrage/bleeding



Drug Metabolisme Interaction

Enzyme induction

Enzyme inhibition

Changes in blood flow through the liver



Enzyme induction

Enzyme is important for metabolisme

process in liver

Example : Cytochrome P450 a group of

enzyme.

Example : drug which induce CP450

rifampicin.

Taking rifampicin with ketoconazole,will

decrease the serum level of ketoconazole.



Enzyme inhibition

Opposite effect of enzyme induction.

The normal pace of metabolisme is slackened so that the metabolisme of other drugs given concurrently is also reduced and they begin to accumulate wihin the body.

The effect is just like overdose.

Example : drug inhibit enzyme : metronidazole

Metronidazole give anticoagulant- anticoagulant effects increase, bleeding is possible.



Changes in blood flow through the liver

Liver is the site of metabolisme

Cimetidine reduce blood flow

Prodrug (labetolol) need to metabolise to

become active.

Given cimetidine with labetolol will slow the

onset of labetolol.



Drug Excretion Interaction

Interactions due to changes in excretion

1. Changes in urinary pH

2. Changes in active kidney tubule excretion

3. Changes in kidney blood flow

4. Biliary excretion and the enterohepatic

shunt.



Anatomy Of Nephron



Interactions due to changes in excretion

Most of drug excreted in bile or urine ( except inhalation anesthetic ).

Excretion- drug interactions may result from

1. An alteration in urine pH,

2. urine volume

3. Changes in tubular transport mechanisms.

4. Changes in kidney blood flow



An alteration in urine pH

Elimination of weak acids or bases is

affected by urine pH.

Alkalinization of the urine by administration of

acetazolamide or NaHCO3 increases the

elimination of weak acids,

While acidification of the urine by

administration of ascorbic acid or NH4Cl

increases the elimination of weak bases.



Changes in Urine Volume

Diuretics, which increase urine volume, often

increase the elimination of other drugs. For

elimination by the urine, drugs enter the renal

tubules by filtration by the :

glomerular apparatus or by active secretion

by the tubular transport system.



Changes in tubular transport mechanisms.

Drug which use the same active transport

mechanisme in the kidney tubules can

compete with one another for excretion.

Example probenecid reduces the excretion

of penicillin by sucessfully competing for

excetory mechanisme, so the loser (

penicillin ) is retain in blood.



Changes in kidney blood flow

The blood flow through kidney is controlled

by prostaglandin ( renal, vasodilator).

If indomethacin (inhibit prostaglandin) is

given with lithium (lithium excretion is

reduce)



Biliary excretion and the enterohepatic shunt.

Physiology of bile excretion need gut flora to

metabolise the parent drug.

Drug which metabolise through bile will stay longer

in body because of recycling-need gut flora.

Penicillin will decimate gut flora.( function of bile

metabolisme is disturb,recycling disturbed)

Oral contraceptive mainly excrete by bile.

Taking oral contraceptive(oc) with penicilin will make

failure of oc.



Important Points

Drug interaction can occur before the actual delivery

to the patient,for example by mixing two drugs in a

syringe.

Drugs can be affected by food intake.

Drugs taken together have the potential to lead to

many adverse effects.

Drug-drug interaction can be related to all

pharmacokinetic parameters.

Most drug-drug interactions are probably related to

enzyme inhibition or potentiation.



Example Of Drug-Food Interaction

Milk- can bind up some drugs in gut,example

tetracycline

Grapefruit juice-can slow down the rate at which

other drugs are removed from the body, example

Nifedepine.

Vitamins and mineral Vitamin K and warfarin,

vitamin K will promote formation of substances that

thicken the blood, which is opposite effect of

warfarin.

High-fat meals can increase absorption of some

drugs and decrease the absorption of others.



When Are Interactions Most Likely To Occur?

Drug interactions are most likely when an interacting drug is being introduced, or when it is stopped.

The time course of an interaction can vary depending on the dosage, ROA , importance of active metabolites, and half-life of the drugs involved.

Enzyme inducers one/three weeks

Enzyme inhibitors within 24 hours.



Which Interactions Are Important?

1)Drugs with a narrow therapeutic margin

Example warfarin, digoxin, antiepileptics, theophylline

2)Drugs which require careful dosage control

Example antihypertensive, antidiabetic

3)Enzyme inducers

Example rifampicin, phenytoin, carbamezepine, barbiturates

4)Enzyme inhibitors

Example cimetedine, ketoconazole, ciprofloxacin, erythromycin.



What Action Should Be Taken?

Avoid the combination

Choose an alternative drug.

Adjust the dose.

Maybe needed when starting or stopping an interacting drug

Monitor the patient

If relevant and practical.

Continue medication as before.

If interacting drugs are the optimal theraphy for a condition or if the interaction is not clinically significant.

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01 druginteraction