new principles of drug interactions (2)

By

Prof. Dr. Nehal Afifi Head of Pharmacology Dept.

Cairo university

Drug Interactions

Principles and Examples

Drug Interactions

Drug interactions occur when the pharmacological actions

of a drug is modified by the presence of other drugs.

A drug-drug interactions defined as the phenomenon that

occur when the pharmacological action or pharmacokinetic

of a drug are altered by Prior administration or Coadmin.

(concurrent) administration of a second drug.

Drug interactions can have desired, or unwanted effects.

Drug–drug interactions have contributed significantly to

adverse drug reactions.

Drug interactions may be dangerous or even cause deaths

in both man & animals (Adverse interactions).

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Drug–drug interactions (DDIs)

The probability of interactions increases with the number of drugs taken.

Evaluating drug–drug interactions is very important during drug development.

Drug interactions occur on pharmacodynamic and pharmacokinetic levels.

Drug–drug interactions (DDIs) can be classified into:

Pharmacodynamic interactions (ie, additive, synergistic, or antagonistic effects that occur despite unaltered plasma levels of the drugs),

pharmacokinetic interactions (ie, alterations in drug absorption, volume of distribution, metabolism, or excretion),

Pharmaceutical incompatibility (eg, combinations of acids and bases),


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Drug

interactions

Drug

interactions

in vivo

Pharmacodynamic

interactions

Pharmacokinetics interactions

Interactions

In - vitro

In- vitro incompatibilities

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Interactions in vitro (incompatibilities)

Incompatibilities include interactions by mixing of Two drugs

before admin., or the addition of a drug to iv infusion fluids.

This reduce therapeutic potency of the drugs.

Chemical alteration to the active ingredients has

occurred due to chemical reactions .

Change in color and/ or turbidity occurred when

physically incompatible compounds are mixed.

Example: Mixing thiopentone+ suxamethonium PPT


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Incompatibility of drugs with i.v. fluids

Normal saline with pH around 4, must used as a diluents.


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Drugs

Incompatible i.v. fluids

Ampicillin sodium Dextrose sol. & dextran

Adrenaline

Sodium bicarbonate

Benzyl penicillin

Dextrose solution

Oxytetracycline Sol. contain Ca² or Mg²

Heparin sodium Dextrose sol.

Drug-drug interactions(DDI) in vivo

DDI is Classified according to the mechanism of

interactactions into:

1. Pharmacodynamic interactions

One drug induce a change in drug effect without altered its

plasma conc. E.g.; concurrent use of two drugs with the

same , similar or opposing pharmacological actions.

2. Pharmacokinetic interactions

One drug may alter absorption, distribution, metabolism or

excretion of a second drug.


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Pharmacodynamic interactions

This term refers to interactions in which drugs influence each

other’s effects directly.

Pharmacodynamic interaction is actually desired (Benficial), if

potentiating effects in the same direction (synergistic effects).

The desired interactions can improve the therapeutic effect.

for example, sedatives can potentiate each other.

When the effect of one drug is impeded by another, the effects of

these drugs are antagonistic → undesired ( Adverse) Effects.

Interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) are

demonstrated as an example of pharmacodynamic interactions.


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Pharmacokinetic interactions

Pharmacokinetic interactions occur at the levels of

absorption , elimination, transport and metabolism.

pharmacokinetic interactions at the drug metabolism level,

chiefly of cytochrome P450 enzymes.

The systematic knowledge of Pharmacokinetic interactions

help to prevent adverse effects.


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Drug interactions

Adverse

Drug interactions

Beneficial

Drug interactions

Beneficial (desired) drug interactions

Drugs combined to achieve a synergistic effect or to

limit the occurrence of side- effects (Beneficial interac)

Pharmacodynamic interactions may be clinically useful.

Examples:

Combination of Sulpha drugs & Trimethoprim .

Atropine treat the organophosphorus comp. toxicity .

Co administration of Probenecid & Penicillin enhances

effectiveness of penicillin.

Sedatives can potentiate each other.


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Clinical Importance of Beneficial Interactions

Potentiate and enhance drug effects.

Broader the spectrum of activity.

Reduce the recommended dose of each drug.

Minimize the side effects.

Decrease drugs residues.


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Adverse Drug interactions

If fluoroquinolones combined with macrolides; erythromycin,

this result in QT prolongation( cardiac arrythmia).

The combination of ACE inhibitors with potassium-sparing

diuretics as spironalactone can increase potassium retention

→ hyperkalemia

Co administration of Cardiac glycosides & potassium-

wasting diuretics → increase digoxin toxicity.

Adverse drug interaction with NSAIDs is Pharmacodynamic

The concurrent administration of NSAIDs with anticoagulant

warfarin increase the risk of bleeding.

If Antidepressant drugs as selective serotonin reuptake

inhibitors (SSRIs) co administer with NSAIDs →result in

increased GI bleeding .

NSAIDs reduced antihypertensive effects of ACE Inhibitors.

1. Amino glycoside antibiotics produce skeletal neuromuscular

Relaxant effect. Thus the Combination of Aminoglycoside &

non-depolarizing neuromuscular blockers (curare, gallamine)

leads to excessive skeletal muscle relaxation.

Curare is not recommend in patients TTT with antibiotics.

2. General Volatile anesthetics (Ether, Halothane, Enflurane ,

methoxyflurane) potentiate effect of neuromuscular Relaxants

Reduced does of neuromuscular Relaxants must be used in

patients anaesthetized with General Volatile Agents.


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Pharmacodynamics Interactions at drug-

Receptor-sites

The desirable & undesirable effects of a drug are related

to its conc. at the sites of action, to the dose

administered and to the drug’s absorption, distribution,

metabolism, and/or excretion (ADME).

All these influenced by the concurrent administered drugs.

Observed changes arising from pharmacokinetic drug–

drug interactions such as a decrease or increase in blood

Conc. of a drug, formation of complexes, or inhibition and

induction of metabolizing enzymes.

Pharmacokinetic drug interactions lead to adverse effects.


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Pharmacokinetic interactions

I. Interactions at the Absorption level a. formation of complexes:

Complexes reduce the bioavailability of drugs after oral

administration.

Multivalent cations such as di- or tri valent (Ca²-, Mg²-, Al³-,

& Fe³-). Form Nonabsorbable complex by Chelation with

Tetracyclines or quinolones → reduce drugs absorption.

Concurrent intake of calcium-containing foods, Laxatives

or Antacids containing aluminum or magnesium ions,with

Tetracyclines or quinolones must therefore be avoided.

Multivalent cations reduce absorption of levothyroxine.

The concurrent intake of alendronate(for osteoporosis) with

proton pump inhibitors at the same time resulting in a

reduction of alendronate absorption.

.


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II.Transporter-based drug–drug interactions: Interactions between drugs and transporter are of increasing

interest in clinical development.

P-glycoprotein (P-gp) is the Multidrug efflux transporters

[membrane transport] .

P-glycoprotein is expressed in many tissue barriers such as

intestine, liver, kidney, and blood–brain barrier,

Example of a typical drug interaction at P-gp level is the

much higher absorption of the cardiac glycoside digoxin

when acompanied by oral admin. of the calcium antagonist

verapamil.

Examples of transporter-based interactions include:

the interactions between digoxin and quinidine,

penicillin and probenecid.


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III. Interactions at the Metabolic level

Inhibition of drug metabolism is a frequent cause of DDI.

pharmacokinetic interactions at the drug metabolism level, chiefly

due to competition for the cytochrome P450 enzs.

cytochrome P450 enzyme (CYP), is expressed in the liver and

catalyzes the phase I oxidation of all medical drugs .

Interactions at the cytochrome P450 enzyme level: , when used in

combination with inhibitors or inducers of the same enzyme,

either increased effects and increased occurrence of unwanted

effects,(in case of inhibitors) .

or reduced effects or loss of effect (in case of inducers)


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Interactions with the most important

cytochrome P450 enzymes Inhibitors

1. Anticoagulants—with a narrow therapeutic spectrum,

such as ciclosporin or phenprocoumon and warfarin .

vitamin K antagonists cause life-threatening hemorrhage .

The cause is interactions with macrolide antibiotics as

erythromycin , clarithromycin, which inhibit cytochrome P450

3A4, important in metabolization of warfarin, phenprocoumon.

2. The calcium channel blockers verapamil and azole

Antimycotics can be highly potent CYP3A4 inhibitors.

Ketoconazole, Fluconazole inhibits the cytochrome P450

system so strongly that it is now used as a standard inhibitor .

In this case, the increased bioavailability of verapamil is due

to fluconazole-mediated inhibition of CYP2C9 .


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Antidepressants—Selective serotonin reuptake inhibitors

(SSRIs) are potent inhibitors of CYP2D6 and CYP1A2 .

Interactions between antidepressants and beta-

blockers(metoprolol),→ inhibit metabolism of metoprolol

cause lowering of blood pressure,& bradycardia.

IV- Interactions affecting drug Excretion

a- Reduction in urinary elimination

Altered active transport in the tubules

Probenecid block excretion of penicillin

Aspirin block excretion of methotrexate

b- Change in urine PH :

Influence elimination of weak acids & bases (passive

reabsorption to un-ionized) , e.g. Acetazolamide , sod.

Bicarbonate (urinary alkalinizer) increase acids

excretion.

Urinary alkalinizer increase sulfa excretion prevent

crystal urea.


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Reducing the Risk of drug interactions

Drug interactions can be avoided if adequate precautions

are taken.

Monitoring therapy & make adjustment to the drug dose

regimen.

Avoid multiple-drug therapy & complex therapeutic

regimens & Use individualized therapy.

Hepatic & kidney functions must be tested firstly.

Knowledge on the pharmacology of drugs used in therapy.


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new principles of drug interactions (2)

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