A/Prof. Ken Rodgers School of Life Sciences

Learning Objectives

  • Recognise health care costs associated with Adverse Drug Reactions (ADRs)
  • Outline the contribution of the following to the overall burden of preventable ADRs
    • Age
    • Pharmacogenetics
    • Diseases
    • Idiosyncratic reactions
    • Drug interactions
  • Identify mechanisms for specific clinically relevant drug interactions
  • Identify issues of polypharmacy in the elderly
  • Provide approaches to minimise ADRs

References

  • Rang and Dales Pharmacology (8th ed)
    • Chapters 11 and 57. Individual Variation and Drug Interactions. Harmful effects of drugs
  • World Health Organisation
  • The Food and Drug Administration (FDA) Center for Drug Evaluation and Research
  • Therapeutic Goods Administration (TGA)

Intro to Drug Interactions

Drug Interactions

  • A drug interaction is said to occur when the effects of one drug are changed by the presence of another drug, food, drink or by some environmental chemical
  • Drug-Drug Interaction
    • Occurs when effects of one drug are increased or decreased by previous or concurrent administration of another drug

Drug Interactions: Introduction

  • Contribution of Drug Interactions to the Overall Burden of Preventable ADRs
    • Drug interactions represent 3–5% of preventable in-hospital ADRs
    • Drug interactions are an important contributor to number of ER visits and hospital admissions

Drug Interactions: Introduction

  • The administration of one drug (A) can alter the action of another (B) by:
    • Modification of the pharmacological effect of B without altering its conc (pharmacodynamic interaction)
    • Alteration of the conc of B that reaches its site of action (pharmacokinetic interaction)
    • >6 medications = >80% chance of interaction
    • Consequence: alter dose / change medication

Drug Interactions: Introduction

  • For pharmacokinetic interactions to be clinically important, it is also necessary that the dose-response curve is steep
    • A small reduction in plasma conc will lead to a substantial change in effect
  • For most drugs these conditions are not met since therapeutic margin is usually large (eg penicillin >100)
therapeutic margin

Repeated doses 2

Repeated doses concentration verse days

Drug Interactions: Introduction

  • Several drugs have a steep dose-response relationships and a narrow therapeutic margin
  • Drug interactions can cause major problems with these drugs
    • Antithrombotic drugs
    • Antiarrhythmic drugs
    • Antiepileptic drugs
    • Lithium
    • Several antineoplastic drugs
    • Several immunosuppressant drugs

Drug Interactions: Pharmacodynamic

Pharmacodynamic

  • Often predictable from the actions of the interacting drugs
  • Additive
    • Nephrotoxicity – cyclosporin and aminoglycosides
    • Sedation – H1 receptor antagonists and alcohol
  • Synergistic (different mechanisms of action)
    • Bleeding risk – aspirin and warfarin
    • Rx of Pneumocystis carinii – sulfonamides and trimethoprim
  • Antagonistic
    • Reduction of antihypertensive action – NSAIDsand diuretics
    • Bronchoconstriction – β-blockers and salbutamol
    • Block of coagulation – warfarin and vitamin K-containing foods
      • Beta2-adrenoceptor antagonist + agonist

Drug Interactions: Pharmacokinetic

  • 2. Pharmacokinetic
    • Absorption of the drug into systemic circulation
    • Distribution of the drug to the site of action and into tissues
    • Metabolism of the drug to polar intermediates
    • Elimination of the drug from the body

Absorption

Drug Interactions: Absorption

Absorption in the GI Tract

Absorption in the GI Tract

Drug Interactions: Absorption

  • Absorption (non-GIT)
    • Prevented by complex formation with others substances
      • Phenytoin precipitates in dextrose solutions (e.g. D5W)
      • Amphotericin precipitates in saline
    • Prevented by complex formation with others drugs
      • Thiopentone and suxamethonium shouldn’t be mixed in same syringe
      • Gentamicin complexes with beta-lactams and certain plastics – loss of antibiotic effect
    • Slowed by drugs that cause vasoconstriction at injection site
      • Adrenaline and local anaesthetics

Distribution

Drug Interactions: Distribution

  • Distribution
    • Displacement of plasma protein bound drug is seldom clinically important
    • Only transient increase in free [drug] due to increase in elimination
    • Problem where displacement and a reduction in elimination occur simultaneously
      • Phenylbutazone displaces warfarin from albumin and inhibits metabolism of warfarin to increase bleeding
      • Salicylates displace methotrexate from albumin and reduce its secretion into the nephron by competing for the anion secretory carrier
      • Antiarrhythmics (quinidine, verapamil, amiodarone) displace digoxin from tissue-binding sites and reduce its renal excretion to cause severe arrhythmias through digoxin toxicity

Metabolism

Drug Interactions: Metabolism

  • Drugs can either inhibit or induce drug-metabolising enzymes
  • Enzyme induction
    • Over 200 drugs can cause enzyme induction
    • Eg rifampicin given for 3 days reduces effectiveness of warfarin as an anticoagulant
prothrombin time
plasma warfarin concentration over time

Drug Interactions: Metabolism

Drug Interactions

Drug Interactions: Metabolism

Prodrugs

prodrugs

Drug Interactions: Metabolism

Toxic metabolites

Toxic metabolites

Drug Interactions: Metabolism

  • Nearly always due to interaction at Phase I enzymes, rather than Phase II
  • Phase I commonly due to interaction at cytochrome P450 enzymes – some of which are genetically absent

Drug Interactions: Metabolism

Phase I Drug Oxidation

a microsomal mixed function oxidation system

Drug Interactions: Metabolism

  • Cytochrome P450 Nomenclature
    • 12 families of enzymes of which 3 are involved in drug metabolism (CYP1, CYP2, CYP3)
    • Each family has ~5 subfamilies (A, B, C, D, E)
    • Individual isoenzymes are identified by a number (eg. CYP3A4, CYP2D6)
    • Individual isoenzymes are responsible for specific metabolic steps for particular drugs
      • codeine to morphine CYP2D6
      • tamoxifen to desmethyltamoxifen CYP3A4
      • tamoxifen to 4-hydroxytamoxifen CYP2D6

Drug Interactions: Metabolism

  • CYP2Cs
    • Major substrates include some nonsteroidal anti-inflammatory drugs, warfarin, phenytoin, PPIs
    • Dramatic interracial polymorphism e.g. CYP2C19
      • CYP2C19 activity is genetically determined, and its genetic polymorphism shows marked interracial difference.
      • The incidence of the poor metaboliser phenotype is markedly higher in Asian populations (13–23%) than in white populations (2–5%) (de Morais et al., 1994)

Drug Interactions: Metabolism

  • See http://medicine.iupui.edu/flockhart/
  • Many, constantly changing
  • Need to be aware of inhibitors, inducers and substrates and how to interpret a situation of multiple drugs
  • Drug interactions (at least metabolic interactions) can be predicted based on knowledge of the characteristics of the particular drugs involved

CYP3A

Drug Interactions: CYP3A

  • Responsible for metabolism of greatest number of drugs:
    • Not polymorphic but activity can vary > 50 fold
    • Most calcium channel blockers
    • Most benzodiazepines
    • Most HIV protease inhibitors
    • Most HMG-CoA-reductase inhibitors
    • Most non-sedating antihistamines eg terfenadine
    • Antiarrhythmics eg quinidine
    • Immune modulators eg. Cyclosporine
  • Present in GI tract and liver

Drug Interactions: CYP3A

CYP3A Inhibitors

CYP3A Inhibitors

Common inducers include:

  • Broccoli
  • Brussels sprouts
  • Char-grilled meat
  • Chronic alcohol use
  • Cigarette smoke

Drug Interactions: CYP3A

CYP3A Inducers

CYP3A Inducers

Drug Interactions: Grapefruit Juice

  • Grapefruit juice inhibits CYP3A4
    • Present in the GUT wall  leads to drug metabolism during absorption (it will normally reduce the levels of drug that reach the systemic circulation)
    • Leads to an increase in plasma concentration (Cp) of susceptible drugs
    • Those affected
      • Mainly metabolised by CYP3A4
    • Examples
      • Calcium channel blockers and statins

Drug Interactions: Grapefruit Juice

Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics

Effects of grapefruit juice

CYP2D6

Drug Interactions: CYP2D6

  • Absent in 7% of Caucasians,1–2% non-Caucasians
  • Hyperactive in up to 30% of East Africans
  • Catalyzes primary metabolism of:
    • Codeine
    • Many β-blockers
    • Many tricyclic antidepressants
  • Inhibited by:
    • Fluoxetine
    • Haloperidol
    • Paroxetine
    • Quinidine
drugs metabolized by known P450's 2000

www.drug-interactions.com

Abrupt smoking cessation can affect the metabolism of drugs

  • Smoking induces the activity of human CYP1A2 and CYP2B6.
  • These enzymes metabolise clozapine, olanzapine and methadone.
  • Decreased CYP1A2 activity after smoking cessation increases the risk of adverse drug reactions, with reports of increased toxicity from clozapine and olanzapine.
  • Replacement therapy does not influence CYP1A2 activity (chemicals in smoke involved).

CYP1A2 activity is significantly higher in heavy smokers (more than 20 cigarettes/day) than in non- smokers. This is likely to be clinically relevant for some drugs which have a narrow therapeutic index and are metabolised by CYP1A2 (Australian prescriber June 2013)

Excretion

Drug Interactions: Excretion

  • One drug can affect the renal excretion of another by:
  • Inhibition of tubular secretion
  • Altered protein binding and filtration
  • Altering urine flow or urine pH

Drug Interactions: Excretion

  • Renal Excretion
    • Clearance of some drugs is directly related to GFR
      • digoxin, methotrexate, gentamicin
    • Inhibiting tubular secretion
      • See table

Drug excretion 1

Drug excretion via urine

Drug Interactions: Excretion

  • Diuretics and drug excretion:
  • Diuretics tend to increase the excretion of other drugs
  • Lithium is an exception since it gets treated like Na+. Initially Na+ is lost when diuretics are given but within a few days there is a compensatory Na+ (and Lithium) retention in proximal tubule.

Drug Interactions: Stepwise Approach

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