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Drug-Drug

Interactions

Dr. Najlaa Saadi IsmaelDepartment of Pharmacologycollege of Medicine - Mosul

University of Mosul

Drug – Drug interaction:

It is the modification of the effect of one drug (the object drug )

By

The prior or concomitant administration of another (precipitant drug).

Outcomes of drug interactions

Desired (Beneficial Effects)

undesired (Harmful Effects)

Risk Factors for Drug InteractionsHigh 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.

Outside the body:

Incompatibilities: 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.

Pheyntoin with infusion fluids particularly dextrose so care should be taken to follow the manufacture's instruction including the use of an in – line filter.

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.

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.

1. 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 + Colestyraminedecrease their absorption.

2. Altered 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)

3. Altered gut motility

Slowing of gastric emptying such as antimuscarinic drugs and opiate analgesics

anticholinergics + acetaminophen

Impact: delay in absorption of acetaminophen

OR

Accelerated by drugs e.g metclopromidewhich hasten gastric emptying

4. Altered PH.

The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does.

H-2 blockers, anti acid + ketoconazole

Decrease gastric acid, dissolution of ketoconazole is decreased, resulting in

reduced absorption

Therefore, These drugs must be separatedby at least 2h in the time of administration.

5. Drug-induced mucosal damage:

Colchicine (which cause local Mucosal damage) can decrease absorption of poorly absorbed drugs e.g. (phenytoin)

6.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

7. 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 phyentoinfrom 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.

Altered drug 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 increase metabolism of warfarin (danger of thrombosis)

Most important enzyme inducers:

1. Carbamazipine.

2. Phenytoin.

3. Phenobarbital.

4. Rifampicine.

Enzyme 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 + Theophylline

cimetidine reduces the clearance of theophyllinecausing an increase in adverse effects

Quinolones (Ciprofloxacin)

+

Theophylline

Inhibit oxidative metabolism of

theophylline

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.

Alterations in renal clearance

Increase in Renal Blood Flow.

Inhibition of Active Tubular Secretion.

Alterations in Tubular Reabsorption.

Increase in Renal Blood Flow

hydralazine + digoxin

hydralazine increases the renal clearance of digoxin

Active 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 + penicillin

Decreases tubular secretion of

Pecicillin

Passive tubular 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

Results of drug interactions:Synergism:occures when the effects of 2 drugs having the same action or increase the actionofanother drugs

1. Summation(Additive):

Ex. β-adrenoceptor blocker + thiazide additive anti hypertensioneffect

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 on Bronchi(physiological antagonism)

Flumazenil and diazepam they compete reversibly for the same drug receptor(competitive antagonism)

Interactions directly on Receptor or body systemActions on receptors

Beneficial interaction

Naloxone for morphin over dose(opiodreceptor)

Unwanted interaction

Atenolol +cold remedies containing ephedrine or Phenylephrine loss of antihypertensive effect

Action on body system

NSAIDs especially indomethacin + αadrenoicepter blocker lead to loss some antihypertensive efficacy

By inhibition of production of vasodilator prostpglandins by the kidney leading to sodium retention

Onset of drug 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.

Thank youFor

Attention