2024 Lecture 27 Drug Interactions

Drug Interactions

• Definition:

  • Occur when two or more drugs (prescribed or OTC) are taken together, leading to altered effects of one or both drugs.

  • Can result in:

    • Reduced therapeutic effect

    • Increased toxic effect

    • Occasionally beneficial outcomes (e.g., vasoconstrictor enhancing local anaesthetic)

• Drug-Food Interactions:

  • Also part of drug interactions but focus on drug-drug interactions in this context.

Learning Outcomes

• Understand the basic principles of drug interactions:

  • Why they occur

  • General mechanisms of drug interactions

  • Specific examples illustrating mechanisms

Types of Drug Interactions

Drug-Drug Interactions

• Account for ~15% of Adverse Drug Reactions (ADRs)

• Common risks include:

  • Patients requiring prophylactic therapy for chronic diseases

  • Individuals taking multiple medications or having multiple conditions

  • common amongst elderly

Factors Influencing Interactions

• Factors of clinical importance:

  • Dose - determine Magnitude of effect

  • Duration of treatment - determine Magnitude of effect

  • Steepness of dose-response relationship - determine Clinical significance

  • Therapeutic ratio - determine Clinical significance

Dose-Response Relationship

• adding another drug can cause an increase in plasma concentration of the first drug:

  • Increase from 1 to 2 leading to altered responses:

    • Steep dose-response curve = higher toxicity risk

    • Examples of drugs with steep curves: Anti-coagulants, Anti-diabetics, Anti-hypertensives

Therapeutic Ratio

• Calculated as: MTC / MEC

  • MTC = Minimum Toxic Concentration

  • MEC = Minimum Effective Concentration

• A smaller therapeutic ratio indicates:

  • Increased difficulty in using drug safely

  • adding another dru can cause a change in plasma concentration of the 1st drug → below MEC or about MTC

• Plasma concentration effects:

  • Monitoring required for repeated oral dosing to maintain steady states

Mechanisms of Drug Interactions

Pharmaceutical Interactions

• Represent drug incompatibilities:

  • Physical or chemical nature (e.g., organic acids and bases)

• drug interacts with infusion solution or with another drug in the same infusion solution

• occur before the drug enter the body

• Specific examples:

  • Amphotericin unstable in dextrose-saline

  • Mixing penicillins and aminoglycosides (gentamicin) causes insoluble precipitate

  • Chlorhexidine cation negatively interacts with anions in toothpaste forming a insoluble salt, reducing antibacterial activity → space out time between chlorhexidine mouth rinse and tooth brushing by more than 1 hr

Pharmacokinetic Interactions

• Influence absorption, distribution, metabolism, and excretion (ADME)

• One drug Alters concentration of another drug reaching its site of action.

Pharmacodynamic Interactions

• One drug affects the action of another without altering concentration at the action site.

Pharmacokinetic - Drug Absorption Factors

• One drug can either increase or decrease the absorption of another by altering

• Influenced by:

  • Luminal pH

  • Drug solubility

  • Chelation/formation of non-absorbable complexes

  • Absorptive surface area

  • Gastric emptying and intestinal transit

Examples of Drug Absorption Interactions

Inhibit drug absorption

• Benzylpenicillin is unstable in acidic fruit juices

• Tetracyclines and milk or antacid - from insoluble precipitates

• Activated charcoal in poisoning overdose case, charcoal act as competitive inhibitor in lumen, limit rate of absorption

• phenytoin and Cytotoxic anti-cancer agents - damage absorptive surface

• oral mediceine and laxative (speed up intestinal transit - reduce time for absorption

Potentiate drug absorption (increase)

oral medicine and opioid analgesic - antimotilty agents, slow intestinal transit, increase time for absorption

oral MAO inhibitor and tyramine containing food

tyramine is a breakdown product of tyrosine in the gut by MAO

But when the MAO is inhibited, the "first-pass" clearance of tyramine is blocked and circulating tyramine levels increase

Elevated tyramine competes with tyrosine for transport across the blood–brain barrier, enters adrenergic nerve terminals.

Once in the cytoplasmic space, tyramine competes with noradrenaline for uptake into synaptic vesicles, thereby displacing norepinephrine.

More Noradrenaline leak from its vesicular storage space into the extracellular space, precipitate the hypertensive crisis.

Hypertensive crises further lead to stroke or cardiac arrhythmia

Distribution

distribution altered if one drug displace another from protein binding sites in blood

Unbound molecules of the first drug are therefore free to move more readily across membranes into and out of compartments (tissues)

potentially increase concentration of drug molecules as site of action, there is also potential for increased movement into clearance organs such as liver and kidney and therefore removal of drug molecules from the body.

Displacement from Protein Binding Sites

• Interactions can raise the plasma concentration of pharmacologically active unbound drugs:

  • Relevant for highly protein-bound drugs (e.g., warfarin)

• Important drugs involved:

  • NSAIDs displacing methotrexate leading to myelosuppression

Displacement reactions are particularly important for drugs extensively bound to plasma proteins such as warfarin, enabling more warfarin molecules to enter the liver either to inhibit clotting factor synthesis or to be metabolized by liver enzymes. One interaction of particular clinical significance is ability of NSAIDs to displace methotrexate from plasma proteins, this can enable more unbound methotrexate to enter the bone marrow causing myelosuppression

Drug Metabolism in liver

Phase 1 and Phase 2 Reactions

• Phase 1: Oxidation via Cytochrome P450

• Phase 2: Conjugation (glucuronidation, acetylation, sulfation)

• Drug interactions can occur via:

  • Enzyme induction (increased metabolism)

  • Enzyme inhibition (decreased metabolism)

Enzyme Inducers and Inhibitors

• Examples of inducers (PC BRAGS):

  • Phenytoin, Carbamazepine, Rifampicin, Barbituates, Alcohol, Glucocorticoids, St John’s Wort

• Examples of inhibitors:

  • Amiodarone (CYP 2C9) and azole antifungals (CYP3A4)

Inhibition of Metabolism Examples

• Metronidazole inhibits alcohol metabolism - nausea, drowsiness

• Erythromycin inhibits carbamazepine metabolism - nausea drowsiness

• more on ppt

Excretion of Drugs

Renal Clearance

• Rate of renal or biliary clearance affects duration and activity of drug.

• Inhibition and alterations of tubular secretion:

  • Probenicid blocks OAT, useful in penicillin overdose

  • Diuretics increase Li+ reabsorption leading to toxicity.

Pharmacodynamic Interactions

• Modifications in pharmacological effects without change in disposition:

  • Includes receptor and physiological interactions.

Receptor Interactions

• Competition for same receptor can alter responses:

  • Examples include salbutamol/propranolol affecting bronchospasm.

Antagonism and Summation

• Antagonism reduces the response to a drug:

  • Example: Penicillin and tetracycline interactions.

• Summation involves combined pharmacologic effects:

  • Example: Co-trimoxazole (Trimethoprim/Sulfamethoxazole).

Warfarin interactions

• Increased anti-coagulation via enzyme inhibitors (fluconazole, doxycycline, metronidazole, erthryomycin)

• Reduced anti-coagulation via enzyme inducers (phenytoin, carbamazepine, rifampicin)

• Potential risk of displacment from protein binding sites by NSAIDs

• Potential risks from protein binding displacements.

Preventing Drug Interactions

• Awareness of common interactions

• Prescribing only when necessary

• Thorough drug history before prescribing

• Consult BNF before prescribing drugs, especially with narrow therapeutic index.

Conclusion

• Understanding drug interactions is crucial for safe prescribing and patient management.