New principles of drug interactions (2)

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  • 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.

    Drugdrug 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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  • Drugdrug interactions (DDIs)

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

    Evaluating drugdrug interactions is very important during drug development.

    Drug interactions occur on pharmacodynamic and pharmacokinetic levels.

    Drugdrug 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 Ca or Mg

    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

    others 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 drugs 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 (Ca-, Mg-, Al-,

    & Fe-). 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 drugdrug 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 bloodbrain 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.