Drug Interactions

Classify and describe mechanisms of drug interaction.

Drug interactions occur "when the action of one drug modifies that of another".

Mechanisms of Drug Interaction

Drug interactions are best classified into three categories:

• Physicochemical
• Pharmacokinetic
• Pharmacodynamic

Physicochemical

Physicochemical interactions occur because of an incompatibility between chemical structures.

• e.g. Thiopentone and suxamethonium precipitate out of solution if prepared together or delivered together in the same line

Pharmacokinetic

Pharmacokinetic interactions can be sub-classified into those affecting absorption, distribution, metabolism, or elimination.

Absorption

For oral medications, absorption may be affected by drugs which alter:

• Gastric pH
• Gastric emptying time

Metoclopramide resolves gastric stasis and improves absorption of orally administered drugs

Distribution

Distribution may be affected by:

• Competition for plasma protein binding
  Loss of albumin and α1-acid glycoprotein
• Medications which alter cardiac output
• Displacement from tissue binding sites This typically occurs due to alteration of metabolic capacity of one drug by the other.
• Chelation of drug from tissues
  Chelating agents bind toxic elements and prevent tissue damage

Phenytoin is usually highly (90%) protein bound. A reduction in protein binding to 80% will double the free phenytoin level. For drugs with first-order kinetics, metabolism will increase proportionally however phenytoin rapidly saturates the enzyme system, leading to zero-order kinetics and a high plasma level.

β-blockers reduce cardiac output and will prolong the time to fasciculation of suxamethonium.

Metabolism

Metabolism may be affected by changes to the CYP450 enzymes:

• Enzyme induction
  • Barbiturates
  • Phenytoin
  • Carbamazepine
• Enzyme inhibition
  • Amiodarone
    Amiodarone inhibits metabolism of S-warfarin by CYP2C9, enhancing its effect.
  • Diltiazem
  • Verapamil
  • Ciprofloxacin
  • Macrolides
  • Metronidazole
  • Grapefruit juice

Elimination

Renal elimination can be affected by:

• Changes in urinary pH
• Competition for active tubular transport mechanisms

Sodium bicarbonate increases urinary pH and enhances excretion of weak acids such as aspirin.

Pharmacodynamic

Pharmacodynamic interactions can be direct, due to interaction on the same receptor system; or indirect, when they act on different receptor system. These interactions can be classified as either:

• Additive
  When the effects summate.
  • e.g. Administering midazolam with propofol reduces the amount of propofol required to generate an effect.
• Antagonistic
  When the effects oppose each other.
  • e.g. Neostigmine indirectly antagonises the effect of NDMRs by increasing the level of ACh at the NMJ.
• Synergistic
  When the combined effect is greater than would be expected from summation alone.
  • e.g. Co-administration of remifentanil and propofol has a synergistic effect in maintenance of anaesthesia.

These three interactions can be graphically demonstrated using an isobologram, which draws a line of equal activity versus concentration of two drugs.

References

1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
2. Khan S, Stannard N, Greijn J. Precipitation of thiopental with muscle relaxants: a potential hazard. JRSM Short Reports. 2011;2(7):58.