Drug Incompatibilities and Interactions

Rational and irrational combinations

Combining drugs is justified if it enhances the therapeutic effect or prevents adverse reactions. For example, adding vitamin B₆ to isoniazid prevents neurotoxicity, while combining antibiotics with levorin reduces the risk of candidiasis. Using potassium chloride along with diuretics (saluretics) helps prevent hypokalemia.

However, irrational combination leads to incompatibility — the therapeutic effect is weakened, completely lost, or pronounced adverse reactions appear. Such interactions are divided into two broad groups: pharmaceutical and pharmacological.

Pharmaceutical interaction

Occurs outside the body (ex vivo) — during manufacturing, storage, or immediately prior to administration (e.g., when mixing in an infusion bag or syringe).

Based on physicochemical reactions:

• Formation of inactive or toxic compounds.
• Reduced solubility, precipitation, colloid coagulation.
• Phase separation of emulsions, deliquescence of powders.
• Adsorption of one substance onto another.

This is usually visually apparent: the color, smell, or consistency of the mixture changes. Pharmacists monitor such prescriptions and make pharmaceutical adjustments to the composition to prevent the use of incompatible mixtures.

Pharmacokinetic interaction

Develops inside the body (in vivo). One drug alters the concentration of the active form of another by interfering with its ADME (absorption, distribution, metabolism, excretion) processes.

1. At the absorption stage (in the GI tract): Depends on pH changes (antacids alkalinize the medium and impair the absorption of weak acids, such as acetylsalicylic acid), formation of large complexes (activated charcoal binds other molecules), or motility changes (cholinomimetics accelerate motility, shortening absorption time).
2. At the distribution stage: Competition occurs for binding to plasma proteins. For example, sulfonamides displace tolbutamide from protein complexes, increasing its free fraction, which can lead to dangerous hypoglycemia.
3. At the metabolism stage: Drugs can accelerate the activity of microsomal liver enzymes (inducers, such as phenobarbital), which weakens the effect of other drugs. Conversely, inhibitors (verapamil) slow down the breakdown of substances, causing their accumulation and the risk of toxicity.
4. At the excretion stage: The kidneys excrete ionized forms of substances faster. Acidic urine accelerates the excretion of weakly alkaline compounds (morphine), while alkaline urine accelerates weak acids (barbiturates). This principle is used in forced diuresis.

Pharmacodynamic interaction

Occurs at the level of the mechanism of action rather than drug concentration. Includes two opposite phenomena:

• Synergism: Unidirectional action of drugs leading to an enhanced net effect.
• Antagonism: Reduction of the effect. Can be receptor-mediated (competition between agonists and blockers, e.g., at adrenoceptors), at the mediator level (effect on norepinephrine release), or functional (simultaneous administration of hypnotics and psychostimulants).

Class and exam questions

What else to study on this topic

• Clinical examples of side effect correction using combinations
• Physicochemical signs of pharmaceutical incompatibility (ex vivo)
• Microsomal liver enzyme inducers and inhibitors
• Displacement from plasma protein binding: risks for hypoglycemic agents
• Types of pharmacodynamic antagonism (receptor, functional, mediator)

Other topics in "General Pharmacology"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.