Chapter 7 | Therapeutic Incompatibilities (Drug-Drug Interactions)

DRUG INTERACTIONS

• Assessing interactions is a clinical skill.
• May be accessed through Micromedex and generative AI, but pharmacists add clinical judgment.
• Drugs may be incompatible or interact in the body.

INCOMPATIBILITY

• Problems when 2+ drugs are combined during compounding, dispensing, or administration.
• Leads to changes in chemical, physical, or therapeutic properties.

INCOMPATIBILITY VS. INTERACTION

• Physicochemical incompatibility: Outside the body (e.g., precipitation, vaporization, sorption).
• Drug interaction: Occurs inside the body.

DEFINITION OF DRUG INTERACTIONS

• Also known as Therapeutic Incompatibilities.
• Effects of one drug are changed by another drug, herbal medicine, food/drink, or environmental chemical agent.

INCIDENCE OF DRUG INTERACTIONS

• More drugs = more interactions.
• Polypharmacy is more common in elderly and people with multiple conditions.
• Weigh benefits and risks of polypharmacy.

EFFECT OF DRUG INTERACTIONS

HARMFUL OR BENEFICIAL?

• Lithium + caffeine → loss of Lithium efficacy (harmful).
• "Anti-hypertensives" + Diuretics → Increased antihypertensive effect (beneficial).
• Quetiapine + Metformin → Decreased hyperglycemic effect (harmful if for diabetes, beneficial if for antipsychotic-induced weight gain prevention).
• Goal: Maximize benefits and minimize risks.

TYPES OF DRUG INTERACTIONS

• Drug - food
• Drug - laboratory test
• Drug - drug
• Drug - herb
• Drug - patient
• Drug - procedure
• Drug - environment

DRUG-DRUG INTERACTIONS

• Effects or pharmacokinetics of a drug are altered by prior administration or co-administration of a second drug.

IMPORTANT CONCEPTS

• Receptor: binds/interacts with an active molecule (drug or hormone).
• Affinity: Ability to bind with receptors.
• Intrinsic Activity / Efficacy: Drug + Receptor → Drug-receptor complex → Response.
• Potency: Amount or concentration of drug to elicit pharmacologic response.
• Agonist: Drug which can combine with the receptor to elicit a pharmacologic response; ↑ affinity and ↑ intrinsic activity.
• Antagonist: Drugs that combine with the receptor but do not produce pharmacological response; ↑ affinity and ↓intrinsic activity/ efficacy.

2 KEY PLAYERS

• Object: Drug whose activity is altered.
• Precipitant: Drug causing the change.

PHARMACODYNAMIC INTERACTIONS

• Drug induces a change in the patient’s response to a drug without altering the pharmacokinetics.
• Change in drug action without altered plasma concentration.
• Includes Pharmacological interactions: Concurrent use of 2 or more drugs with similar or opposing pharmacological actions

ADDITION

• Response equal to combined individual responses
  • Aspirin + Warfarin
  • Alcohol + CNS depressants

THE REAL EQUATION

• Combination Index (CI) – one example of a way to model drug interactions
  • CI=1 additive
  • CI<<<1 synergistic
  • CI>>>1 antagonistic

SYNERGISM

• Response > additive sum
  • Different MOAs w/ crosstalk
  • Confirmed examples (preclinical, clinical)
    • LABA + LAMA + ICS (COPD)
    • Cephalosporins + protein synthesis inhibitors + topoisomerase inhibitors (E. coli)
    • Pyrazinamide + Ethambutol (TB)

ANTAGONISM

• 4 Types:
  • Chemical (Chelation, Neutralization)
  • Functional
  • Competitive/ Reversible
  • Noncompetitive/ Irreversible

FUNCTIONAL ANTAGONISM

• 2 Agonist drugs that act independently of each other but has opposite effects that cancels out each other’s effects

COMPETITIVE/ REVERSIBLE ANTAGONIST

• Antagonist combines with receptor but has no intrinsic activity
• Displacement Effect

POTENTIATION

• One drug has none of the desired effect but will enhance another drugs activity when used in combination
  • Amoxicillin + Clavulanic acid (Co-amoxiclav)

PHARMACOKINETIC INTERACTIONS

ALTERED ABSORPTION

• Transport of drug from the cell membrane to the systemic circulation
  • Most common remedy is adjusting of administration times.
  • Drug Adsorption
    • Lincomycin + Kaolin
  • Chelation / complex formation
    • Antacids, Iron + Tetracycline* / Fluoroquinolones / INSTI
  • Changes in gastric pH
    • Weak acids → absorbed in low pH
    • Weak bases → absorbed in high pH
  • Changes in GI motility
    • Gastric emptying rate/ Intestinal motility
  • Problems with transport proteins/enzymes
    • P-glycoprotein transports drugs back from blood to GIT
  • Inhibition of enterohepatic circulation
    • Antibiotics + OCP – decreased absorption of OCPs

ALTERED DISTRIBUTION

• Usually result of altered protein-binding
  • Albumin → acidic drugs
  • Glycoprotein → basic drugs

ALTERED METABOLISM

• Metabolism: transformation of foreign compounds in the body
  • Drug is made more polar/hydrophilic to facilitate excretion
  • Cytochrome P450 enzymes (“Mixed function oxidases”)

CYP INDUCERS

• Ethanol (chronic)
• Barbiturate (phenobarbital)
• Phenytoin
• Rifampicin
• Griseofulvin
• Carbamazepine
• St. John’s wort, Smoking

CYP INHIBITORS

• Sodium valproate
• Isoniazid
• Cimetidine
• Ketoconazole
• Fluoxetine, Fluconazole
• Alcohol (acute), Amiodarone
• Chloramphenicol
• Erythromycin
• Sulfonamides. Ciprofloxacin, Omeprazole, Metronidazole
• Grapefruit, Protease inhibitors and paroxetine

ALTERED EXCRETION

• Altered active transport in the tubules
  • Probenecid + Penicillin/Indomethacin
  • NSAIDs + Lithium salts/methotrexate
  • Quinidine + Digoxin – decreased digoxin excretion
• pH effect on passive transport of weak acids and bases
  • +pH: Phenobarbital, salicylates – increased excretion
  • +pH: Memantine, amphetamine – decreased excretion
  • ASA + NaHCO3 – increased excretion of ASA

DYNAMIC + KINETIC

• Carbamazepine + Clozapine
  • Inducer si Carbamazepine so iinduce niya kasi Clozapine is 1A2 substrate
  • Carbamazepine & Clozapine can suppress bone marrow leading to reduction in white blood cells

ASSESSING DRUG INTERACTIONS

• Read CASE REPORT (2nd to the last in the hierarchy of evidence)

WHERE TO CHECK DIs?

• Drugs.com
• Lexicomp
• Medscape.com
• Rxlist.com
• Drug Interaction Facts
• Epocrates

ALWAYS READ THE INTERACTION DETAILS

REQUIRED KNOWLEDGE

• Requires knowledge of:
  • Evidence base
  • Rational use

SIGNIFICANCE OF DRUG INTERACTIONS

• Refers to type and magnitude of effect and the necessity of monitoring or altering the therapy
• Primary factors:
  • Onset
  • Severity
  • Documentation

ONSET

• Determines the urgency with which preventive measures should be instituted to avoid the consequences of the interaction

RAPID

• Less than 24 hours

DELAYED

• More than 24 hours

SEVERITY

• Assessing risk vs. benefit of therapeutic alternatives

MINOR

• Bothersome or unnoticeable

MODERATE

• Deterioration in patient’s clinical status

MAJOR

• Life-threatening or capable of causing permanent damage

DOCUMENTATION

• Determines degree of confidence that an interaction can cause an altered clinical response

ESTABLISHED

• Proven to occur in well-controlled studies

PROBABLE

• Very likely but not proven clinically

SUSPECTED

• May occur; some good data; needs more study

POSSIBLE

• Could occur; data very limited

UNLIKELY

• Doubtful; no good evidence of altered clinical effect

PREVENTING DRUG INTERACTIONS

• Identify the patient’s risk factors
• Take thorough drug history
• Be knowledgeable on the actions of drug being used
• Consider therapeutic alternatives
• Avoid complex therapeutic regimens
• Educate the patient
• Monitor therapy