Drug Interactions

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• OUTCOMES -Describe mechanism types, consequences of interactions -Beneficial and detrimental interactions -How ethnicity and gender influence pharmacotherapeutic outcomes -Action and safe use of herbal/dietary supplements

1. Drug to Drug

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   • -Multiple drugs (OTC meds, caffeine, nicotine, alcohol)
   1. Consequences
      1. Indifference

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         • Unaltered therapeutic effects
      2. Potentiative

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         • Intesnification of effects -Increased therapeutic and adverse effects -Ex: 2 bp medications increase therapautic effects, increase potential for adverse effects
      3. Effect reduction

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         • Reduced therapeutic and adverse effects
      4. Unique response

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         • Interaction creates response that was not expected
   2. Chemical Interactions

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      • -Mixing parenteral drugs (in same syringe or IV solution) can lead to incompatibility --> interfere with pharmacologic activity -Incompatibilities- formation of precipitate/change in color  -Most common in IV solution: Precipitate (do not administer!) -Never combine drugs in same container without establishing compatibility
   3. Pharmacokinetic Interactions
      1. Altered Absorption

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         • -Elevated gastric pH -Laxatives -Depress peristalsis -Induce vomiting -Absorbent drugs -Reduce regional blood flow
      2. Altered distribution

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         • -Competition for protein binding -Alteration of extracellular pH
      3. *Altered metabolism

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         • -Most important and complex mechanism of drug interaction 
         1. CYP450

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            • Enzyme in liver that metabolizes drugs
            1. Inducers

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               • Increases metabolism of other drugs --> sub-therapeutic effects
            2. Inhibitors

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               • Inhibits (impairs) metabolism of other drugs --> prolonged effects, increased side effects
      4. Altered renal excretion

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         • Filtration, re-absorption, active secretion
   4. Mechanisms
      1. Pharmacodynamic
         1. Same receptor

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            • Almost always inhibitory (antagonist/agonist) Ex: Beta-blocker (blocks beta receptors) and beta-agonist (stimulates beta receptors): blocker would have more significant effects
            1. Inhibitory

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               • Drugs that act on the same receptor will always act in an inhibitory fashion towards each other 
         2. Different receptor

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            • May be Potentiative or Inhibitory
            1. Inhibitory

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               • Ex: HCTZ (diuretic agent) and spironolactone  -HCTZ wastes K+, spironolcatone saves K+ -Work on the mechanism of Aldosterone
            2. Potentiative

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               • Ex: morphine and diazepam  -Both act on the CNS -Working together, cause a greater depression of the CNS 
      2. Combined toxicity

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         • Drugs with overlapping toxicities (toxic to the same sites/organs) should not be used together
         1. Similar side effects

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            • -Two drugs given concurrently share same side effect --> combined effect will be more toxic  -Ex: Furosemide (lasix) + aminoglycoside --> Ototoxicity -Cause hearing disturbances and balance problems 
   5. Clinical Significance
      1. Low TI

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         • -Interactions are especially important in drugs with low therapeutic index
      2. Impact on outcome

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         • Potential to significantly impact the outcome of theraphy
      3. Altered responses

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         • Responses may be increased on decreased
      4. Risk proportional to number

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         • -Risk for serious drug interaction is directly proportional to the number of drugs a patient is taking
   6. Minimize Interactions

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      • -Assessment: Drug history -Knowledge of drugs and interactions -Awareness of susceptible patients -Limit number of drugs -Alertness to unusual symptoms -Monitor for early signs of toxicity -Adjust drug doses when needed (metabolizing inducers/inhibitors are added/deleted) -Adjust timing of administration to minimize interference with absorption -Vigilant with low therapeutic index
2. Drug and Food
   1. Absorption
      1. Decreased

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         • -Slows down absorption rate --> delayed onset of action -Interfere with extent of absorption (ex: tetracycline and Ca; drugs bind to food (Ca or other minerals) -> reduce absorption -> decreased therapeutic response 
      2. Increased

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         • Drugs may need food to increase extent of absorption 
      3. Recommendations

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         • -Usually drugs better absorbed on empty stomach; Ex: give drug 1 hour before meals or 2 hours after meal -With food: irritating to gastric mucosa, cause nausea with empty stomach 
   2. Metabolism

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      • -Ex: Grapefruit (juice, pulp, peel, dietary supplements) can interfere with enzymes that metabolize drugs  -List of drugs that should not be taken with grapefruit -Enzyme that impairs liver's ability to metabolize drug Ex: Tangelo (hybrid grapefruit) and Seville oranges Metabolism inhibited by Grapefruit juice: -Anti-seizure -Antidepressants -Tranquilizers -Anti-hypertensives -Anti-arrhythmics -HIV medications -Cholesterol lowering -Immunosuppresants -Analgesics -Erectile dysfunction medications
   3. Detrimental effects

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      • -May lead to drug toxicity, could be almost lethal  -Ex: MAOIs (depression) and tyramine-containing food (aged, processed) --> hypertensive crisis -Ex: Theophylline and caffein (jitters and heart effects) -Ex: Potassium-sparing diuretics and salt substitutes both increase K+ levels --> profound effects on heart
   4. Counteract

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      • -Coumadin (inhibits vitK), counteracted by green leafy vegetables (high levels of vitK)
3. Drugs and Dietary Supplements
   1. FDA Definition

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      • "Vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites" intended to supplement diet -Exempt from examination of FDA -Can be manufactured without proof of efficacy -FDA can remove dangerous supplements
   2. Regulation of Herbal products

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      • Dietary Supplement and Nonprescription Drug Consumer Protection Act (2007) -Labeling mandates to include contact information for consumers to report adverse effects -Manufacturer must report to FDA serious adverse
4. Drug-Herb

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   • -Conventional drugs can interact with herbal preparations -Interactions with herbal medicines are just as likely as with prescription medicaitons -A lack of reliable information is available on drug-herb interactions -Ex: St. John's wort (used to treat depression) induces drug metabolizing enzymes and reduces levels of many drugs 
   1. Black cohosh

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      • Use: menopause DI: antihypertensives and insulin
   2. St. John's Wort

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      • Use: Depression DI: Many due to induction of P450 enzyemes and P-glycoproteins --> increase drug excretion --> decrease drug effect
   3. Gingko

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      • Use: PVD pain, improve memory? DI: supresses coagulation --> interacts with coagulants --> increases bleading
   4. Garlic

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      • Hyperlipidemia  DI: suppresses coagulation --> interacts with coagulants --> increases bleading  DI: Oral hypoglycemic agents --> increase hypoglycemia 
   5. Special care

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      • -Pts taking drug with low therapeutic index: anticoagulants, antiseizure, antidysrhythmias 
5. Other Influences
   1. Gender variations

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      • -Influences health-seeking behaviors and symptom manifestations
      1. Alcohol

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         • -Metabolized more slowly by women
      2. Opioid analgesics

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         • Certain ones are more effective in women
      3. Adherence

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         • May differ by gender due to side effects 
   2. Ethnicity/Cultural

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      • -Cultural plays role in how individuals respond to drug therapy -Aware of cultural dietary preferences
      1. Incidence of disease

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         • -AA highest rate of hypertension, death rate due to cancer -Compared to caucasians, hispanics 2x more likely to die from diabetes, increased obesity and hypertension
      2. Beliefs

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         • Cultural beliefs can influence compliance and use of alternative therapies
      3. Pharmacogenetic variations

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         • Result in altered differences based on ethnicity --> results in altered pharmacokinetic properties (ex: metabolism)
   3. Socio-economic disparity

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      • Degree to which individuals have the capacity to obtain, process and understand basic health info needed to make appropriate health decisions and services needed to prevent/treat illness
      1. Low health literacy

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         • Prevalent among: -Older adults -minority populations -low socioeconomic status -medical underserved difficulty finding providers, filling out forms, sharing medical history, managing health conditions, understanding medication directions
6. Responding by teaching

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   • -Sensitive to client's need to seek alternative therapy -Discuss options -Complete a health history and check for drug interactions -Instruct to take as directed -Monitor for effectiveness