Drug Drug Interactions pdf - د. نجلاء

Drug Interactions

(Drug

(Drug--Drug Interactions)

Drug Interactions)

Drug

Drug –– Drug interaction:

Drug interaction:

It is the modification of the effect of one

drug (

the object drug

)

The prior or concomitant administration

of another (

precipitant drug

Drug

Drug –– Drug interaction:

Drug interaction:

It is the modification of the effect of one

drug (

the object drug

)

The prior or concomitant administration

of another (

precipitant drug

Outcomes of drug interactions

Desired (Beneficial

Effects)

undesired (Harmful

Effects)

Risk Factors for Drug Interactions

High Risk Patients

Elderly, young, very sick, multiple disease
Multiple drug therapy, Renal, liver

impairment

High Risk Drugs

Narrow therapeutic index drugs e.g.(digoxin ,

warfarin , theophylline
Recognized enzyme inhibitors or inducers

Risk Factors for Drug Interactions

High Risk Patients

Elderly, young, very sick, multiple disease
Multiple drug therapy, Renal, liver

impairment

High Risk Drugs

Narrow therapeutic index drugs e.g.(digoxin ,

warfarin , theophylline
Recognized enzyme inhibitors or inducers

Site of interaction:



Outside the body.



Inside the body

Site of interaction:



Outside the body.



Inside the body

Outside the body:

Reaction of IV drugs resulting in solutions

after mixing that are not longer safe for the

patient alter stability(change the PH) or

structure leading to:


Loss of drug activity



Formation of precipitates.



Development of toxic product

Outside the body:

Reaction of IV drugs resulting in solutions

after mixing that are not longer safe for the

patient alter stability(change the PH) or

structure leading to:


Loss of drug activity



Formation of precipitates.



Development of toxic product



Penicillin and aminoglycoside should

never be placed in the same infusion

fluid because of formation of inactive

complex.



Protamine zinc insulin + soluble insulin

lead to reduces the immediate effect of

the dose.



With calcium – ceftriaxone precipitates

in the lung and kidneys premature

neonates.



Penicillin and aminoglycoside should

never be placed in the same infusion

fluid because of formation of inactive

complex.



Protamine zinc insulin + soluble insulin

lead to reduces the immediate effect of

the dose.



With calcium – ceftriaxone precipitates

in the lung and kidneys premature

neonates.

Drug Interactions Inside the body



Pharmacokinetics

drug

interactions



Pharmacodynamics

drug

interactions

Drug Interactions Inside the body



Pharmacokinetics

drug

interactions



Pharmacodynamics

drug

interactions

Pharmacokinetics drug interactions

Involve the effect of a drug on another

from the point of view that includes :



Absorption



Distribution



Metabolism



Excretion

Pharmacokinetics drug interactions

Involve the effect of a drug on another

from the point of view that includes :



Absorption



Distribution



Metabolism



Excretion

Interaction at the site of absorption

1. Formation of drug Chelates or

complexes.

2. Altered gut Flora

3. Altered GIT Motility.

4. Altered PH

5. Drug induced Mucosal damage

6. Malabsorption caused by other drugs

7. Interaction other than in the Gut

Interaction at the site of absorption

1. Formation of drug Chelates or

complexes.

2. Altered gut Flora

3. Altered GIT Motility.

4. Altered PH

5. Drug induced Mucosal damage

6. Malabsorption caused by other drugs

7. Interaction other than in the Gut

11. Direct chemical interaction in the gut and

. Direct chemical interaction in the gut and

formation of drug

Chelates

or complex



Calcium (milk), iron, anti acid (Al or Mg

hydroxide) +

Tetracyclin

insoluble

complex



levothyroxine ,digoxine and some acidic

drugs e.g warfarine +

Colestyramine

decrease their absorption

11. Direct chemical interaction in the gut and

. Direct chemical interaction in the gut and

formation of drug

Chelates

or complex



Calcium (milk), iron, anti acid (Al or Mg

hydroxide) +

Tetracyclin

insoluble

complex



levothyroxine ,digoxine and some acidic

drugs e.g warfarine +

Colestyramine

decrease their absorption

22. Altered

. Altered intestinal bacterial flora

intestinal bacterial flora

Antibiotics

kill a large number of the normal

flora of the intestine

Antimicrobials

may potentiates

Oral

Anticoagulant

by reducing bacterial synthesis

of vitamin K

In 10% 0f patients receiving

Digoxin

…..40% or

more

of the administered dose is metabolized by

the intestinal flora

Increase digoxin conc.

and increase its toxicity

22. Altered

. Altered intestinal bacterial flora

intestinal bacterial flora

Antibiotics

kill a large number of the normal

flora of the intestine

Antimicrobials

may potentiates

Oral

Anticoagulant

by reducing bacterial synthesis

of vitamin K

In 10% 0f patients receiving

Digoxin

…..40% or

more

of the administered dose is metabolized by

the intestinal flora

Increase digoxin conc.

and increase its toxicity

Antibiotics and Oral Contraceptives

Antibiotics kill bacteria in gut

Oestrogen conjugates not hydrolysed

Conjugates not re-absorbed

Less oestrogen - loss of contraceptive effect

(No effect on progestogen component.)

Antibiotics and Oral Contraceptives

Antibiotics kill bacteria in gut

Oestrogen conjugates not hydrolysed

Conjugates not re-absorbed

Less oestrogen - loss of contraceptive effect

(No effect on progestogen component.)

33. Altered gut motility

. Altered gut motility

Slowing

of gastric emptying such as

antimuscarinic drugs and opiate analgesics

anticholinergics

anticholinergics + acetaminophen

+ acetaminophen

Impact: delay in absorption of

acetaminophen

Accelerated

by drugs e.g metclopromide

which hasten gastric emptying

33. Altered gut motility

. Altered gut motility

Slowing

of gastric emptying such as

antimuscarinic drugs and opiate analgesics

anticholinergics

anticholinergics + acetaminophen

+ acetaminophen

Impact: delay in absorption of

acetaminophen

Accelerated

by drugs e.g metclopromide

which hasten gastric emptying

44. Altered PH.

. Altered PH.

The

non-ionized

form of a drug is more

lipid soluble and more readily absorbed

from GIT than the

ionized

form does.

HH--22 blockers , anti acid +

blockers , anti acid + ketoconazole

ketoconazole

Decrease gastric acid

,, dissolution of

dissolution of

ketoconazole

ketoconazole is decreased, resulting in

is decreased, resulting in

reduced absorption

Therefore

, These drugs must be separated

by at least 2h

in the time of administration.

HH--22 blockers , anti acid +

blockers , anti acid + ketoconazole

ketoconazole

Decrease gastric acid

,, dissolution of

dissolution of

ketoconazole

ketoconazole is decreased, resulting in

is decreased, resulting in

reduced absorption

Therefore

, These drugs must be separated

by at least 2h

in the time of administration.

55. Drug

. Drug--induced

induced mucosal

mucosal damage:

damage:

Colchicine (which cause local Mucosal

damage)

Can

decrease absorption

of poorly absorbed

drugs e.g. (digoxin, phenytoin)

55. Drug

. Drug--induced

induced mucosal

mucosal damage:

damage:

Colchicine (which cause local Mucosal

damage)

Can

decrease absorption

of poorly absorbed

drugs e.g. (digoxin, phenytoin)

-Malabsorption

caused by other

drugs

Orlistat

(Xenical)

Inhibits pancreatic

lipases ,preventing hydrolysis of ingested fat)

Orlistat

(Xenical) +

fat soluble

vitamins (A,D,E,K)

-Malabsorption

caused by other

drugs

Orlistat

(Xenical)

Inhibits pancreatic

lipases ,preventing hydrolysis of ingested fat)

Orlistat

(Xenical) +

fat soluble

vitamins (A,D,E,K)

malabsorption of Fat-soluble vitamins

77. Interaction

. Interaction

other than the gut

Addition of vasoconstrictors e.g

adrenalin to local anesthetics delay

absorption and prolong local anesthesia

Effect of drug distribution

Displacement from plasma protein binding

It depends on the affinity of the drug to

plasma protein.

The most likely bound drugs is capable to

displace others.

The free drug is increased.

Sodium valproates displaces phyentoin from

its binding site on plassma albumin in

addition to inhibit its metabolism

Effect of drug distribution

Displacement from plasma protein binding

It depends on the affinity of the drug to

plasma protein.

The most likely bound drugs is capable to

displace others.

The free drug is increased.

Sodium valproates displaces phyentoin from

its binding site on plassma albumin in

addition to inhibit its metabolism

Displacement from tissue bindings

Binding Quinidine with digoxin and

cause increase concentration of free

digoxin in addition to impair renal

excretion

Displacement from tissue bindings

Binding Quinidine with digoxin and

cause increase concentration of free

digoxin in addition to impair renal

excretion

Altered drug

Altered drug metabolism

metabolism

The effect of one drug on the metabolism

of the other is well documented.

The liver is the major site of drug

metabolism

CYP450 family

is the major metabolizing

enzyme in phase I (oxidation process).

Altered drug

Altered drug metabolism

metabolism

The effect of one drug on the metabolism

of the other is well documented.

The liver is the major site of drug

metabolism

CYP450 family

is the major metabolizing

enzyme in phase I (oxidation process).

Effect on drug metabolism

Enzyme induction

:the drug called(

inducer

)

A drug may induce the enzyme that is responsible for the

metabolism of another drug or even itself e.g:

Carbamazepine

(antiepileptic drug ) increases its

own

Metabolism

Phenytoin

increases hepatic metabolism of

Oral

Contraceptives

Leading to decreased level

Reduced

action and Unplanned Pregnancy

Phenobarbital

+ warfarin

metabolism of warfarin

(danger of thrombosis)

Effect on drug metabolism

Enzyme induction

:the drug called(

inducer

)

A drug may induce the enzyme that is responsible for the

metabolism of another drug or even itself e.g:

Carbamazepine

(antiepileptic drug ) increases its

own

Metabolism

Phenytoin

increases hepatic metabolism of

Oral

Contraceptives

Leading to decreased level

Reduced

action and Unplanned Pregnancy

Phenobarbital

+ warfarin

metabolism of warfarin

(danger of thrombosis)

Enzyme

Enzyme inhibition

inhibition::

It is the decrease of the rate of metabolism of a

drug by another one.

This will lead to the

Increase

of the

concentration of the target drug and leading to

the increase of its

toxicity

Cimetidine

Cimetidine ++ Theophylline

Theophylline

cimetidine

cimetidine reduces the clearance of

reduces the clearance of theophylline

theophylline

causing an increase in adverse effects

Enzyme

Enzyme inhibition

inhibition::

It is the decrease of the rate of metabolism of a

drug by another one.

This will lead to the

Increase

of the

concentration of the target drug and leading to

the increase of its

toxicity

Cimetidine

Cimetidine ++ Theophylline

Theophylline

cimetidine

cimetidine reduces the clearance of

reduces the clearance of theophylline

theophylline

causing an increase in adverse effects

Inducer

(carbamazepine)

Inhibitor

(verapamil)

The effect of the Inhibitor will be

predominant

Inducer

(carbamazepine)

Inhibitor

(verapamil)

The effect of the Inhibitor will be

predominant

Most important

enzyme Inhibitors

1. Cimetidine.
2. Erythromycine.
3. Quinolones.
4. Sodium valproate.
5. Allopurinol.

Most important

enzyme Inhibitors

1. Cimetidine.
2. Erythromycine.
3. Quinolones.
4. Sodium valproate.
5. Allopurinol.

Alterations in renal clearance

•• Increase in Renal Blood Flow

Increase in Renal Blood Flow

•• Inhibition of Active Tubular Secretion

Inhibition of Active Tubular Secretion

•• Alterations in Tubular

Alterations in Tubular Reabsorption

Reabsorption

Alterations in renal clearance

•• Increase in Renal Blood Flow

Increase in Renal Blood Flow

•• Inhibition of Active Tubular Secretion

Inhibition of Active Tubular Secretion

•• Alterations in Tubular

Alterations in Tubular Reabsorption

Reabsorption

Increase in Renal Blood Flow

hydralazine

hydralazine ++ digoxin

digoxin

hydralazine

hydralazine increases the renal

increases the renal

clearance of

clearance of digoxin

digoxin

Increase in Renal Blood Flow

hydralazine

hydralazine ++ digoxin

digoxin

hydralazine

hydralazine increases the renal

increases the renal

clearance of

clearance of digoxin

digoxin

•• Active

Active tubular secretion:

tubular secretion:

It occurs in the proximal tubules.

The drug combines with a specific protein to pass through

the proximal tubules.

When a drug has a

competitive reactivity

to the protein

that is responsible for active transport of another drug

This will reduce such a drug excretion increasing its conce.

probenecid

probenecid + penicillin

+ penicillin

Decreases tubular secretion of

Pecicillin

•• Active

Active tubular secretion:

tubular secretion:

It occurs in the proximal tubules.

The drug combines with a specific protein to pass through

the proximal tubules.

When a drug has a

competitive reactivity

to the protein

that is responsible for active transport of another drug

This will reduce such a drug excretion increasing its conce.

probenecid

probenecid + penicillin

+ penicillin

Decreases tubular secretion of

Pecicillin

••

Passive tubular

Passive tubular Reabsorption

Reabsorption

Acidification

of urine increases reabsorption and

decreases excretion of weak acids, and, in contrast,
decreases reabsorption of weak bases.

Alkalinization

of urine has the opposite effect.

In some cases of overdose, these principles are used

to enhance the excretion of weak bases or acids

••

Passive tubular

Passive tubular Reabsorption

Reabsorption

Acidification

of urine increases reabsorption and

decreases excretion of weak acids, and, in contrast,
decreases reabsorption of weak bases.

Alkalinization

of urine has the opposite effect.

In some cases of overdose, these principles are used

to enhance the excretion of weak bases or acids

e.g. sodium bicarbonate

salicylates(weak acid)

decrease

reabsorption and Increase excretion of salicylates

Pharmacodynamics

Interaction

Pharmacodynamics

are related to the

pharmacological activity of the interacting

drugs .

Both drugs act on the target site of clinical

effect.

Synergism



Summation or Additive



Potentiation

Antagonism

Pharmacodynamics

Interaction

Pharmacodynamics

are related to the

pharmacological activity of the interacting

drugs .

Both drugs act on the target site of clinical

effect.

Synergism



Summation or Additive



Potentiation

Antagonism

Results of drug interactions:

Synergism:

occures when the effects of 2 drugs

having the same action or increase the action of

another drugs
1-Summation(Additive):
Ex. β-adrenoceptor blocker + thiazide

additive

anti hypertension effect
1 + 1 = 2
2-Potentiation:

When one drug

Increase

the action of another

1 + 1 = more than 2
Ex. Trimethprim + sulfamethaxazole

Results of drug interactions:

Synergism:

occures when the effects of 2 drugs

having the same action or increase the action of

another drugs
1-Summation(Additive):
Ex. β-adrenoceptor blocker + thiazide

additive

anti hypertension effect
1 + 1 = 2
2-Potentiation:

When one drug

Increase

the action of another

1 + 1 = more than 2
Ex. Trimethprim + sulfamethaxazole

Antagonism

When the action of one drug

opposes

the

action of another.
1 + 1 = 0 (or 0.5)
Ex.

Histamine

and

Adrenaline

Bronchi(physiological

antagonism)

Flumazenil

and

diazepam

they compete

reversibly for the same drug

receptor(

competitive antagonism

)

Antagonism

When the action of one drug

opposes

the

action of another.
1 + 1 = 0 (or 0.5)
Ex.

Histamine

and

Adrenaline

Bronchi(physiological

antagonism)

Flumazenil

and

diazepam

they compete

reversibly for the same drug

receptor(

competitive antagonism

)

Interactions directly on Receptor or

body system

Actions on receptors



Beneficial interaction
Naloxone for morphin over dose(opiod

receptor)



Unwanted interaction
Atenolol +cold remedies containing

ephedrine or Phenylephrine loss of

antihypertensive effect

Interactions directly on Receptor or

body system

Actions on receptors



Beneficial interaction
Naloxone for morphin over dose(opiod

receptor)



Unwanted interaction
Atenolol +cold remedies containing

ephedrine or Phenylephrine loss of

antihypertensive effect

Action on body system

NSAIDs especially

indomethacin

+ α

adrenoicepter blocker lead to loss some

antihypertensive efficacy

By inhibition of production of vasodilator

prostpglandins by the kidney leading to

sodium retention

Action on body system

NSAIDs especially

indomethacin

+ α

adrenoicepter blocker lead to loss some

antihypertensive efficacy

By inhibition of production of vasodilator

prostpglandins by the kidney leading to

sodium retention

Onset of drug

Onset of drug interaction

interaction

•

It may be seconds up to weeks

•

For example in case of enzyme induction,

it needs weeks for protein synthesis

•

while enzyme inhibition occurs rapidly.

Onset of drug

Onset of drug interaction

interaction

•

It may be seconds up to weeks

•

For example in case of enzyme induction,

it needs weeks for protein synthesis

•

while enzyme inhibition occurs rapidly.