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84. Drug interactions

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We can categorize drug interactions based on the magnitude of the combined effect. When two drugs interact, the result can be:

  • Additive – the combined effect is higher that either of the individual effects but not higher than the sum of the two individual effects
  • Potentiated/synergic – the combined effect is higher than the sum of the two individual effects
  • Antagonized – the combined effect is smaller than that of one of the individual effects

We can also categorize drug interactions based on the mechanism

  • Pharmacokinetic interactions
    • Interaction at the level of absorption
    • Interaction at the level of distribution
    • Interaction at the level of biotransformation
    • Interaction at the level of excretion
  • Pharmacodynamic interactions
  • Pharmaceutical interactions

Clinical significance of undesired interactions

The actual clinical significance of a drug interaction depends on two things and whether the interaction increases or decreases the drug effect.

For interactions which lead to an increased effect of one of the drugs the clinical significance depends on the margin of safety/therapeutic window of the drug in question. If a drug has a small margin of safety and its effect is increased by an interaction the drug effects might become toxic. If a drug has a large margin of safety and its effect is increased, there may be little to no clinical significance.

Drugs which have small margins of safety include:

  • Anticoagulants
  • Antiarrhythmic drugs
  • Cytotoxic drugs
  • Antiepileptic drugs
  • Antidiabetic drugs
  • Cardiac glycosides
  • Cyclosporine

For example, if a person who takes a cardiac glycoside like digitoxin starts taking another drug which increases the effect of digitoxin, he or she may experience severe arrhythmias, because even a small increase in the effect of digitoxin can cause toxic effects. However, if a person who takes an antibiotic starts taking another drug which increases the effect of the antibiotic, there will probably be no clinical symptoms, as an increase in antibiotic effect rarely causes toxic effects.

For drug interactions which lead to a decreased effect, the clinical significance depends on the condition which is being treated. If the condition is question is sensitive to undertreatment a drug interaction which decreases the effect of the drug which treats the condition can be fatal.

Conditions which are “sensitive” to undertreatment include:

  • Arrhythmias
  • Epilepsy
  • Serious infections

If a person who is being treated pharmacologically for rheumatoid arthritis experiences a drug interaction which decreases the effect of the antirheumatic drug, there will be few or no acute clinical consequences. Of course, over time the patient’s condition may worsen. But this is a less dangerous scenario than if a person who takes antiepileptics experiences a drug interaction which decreases the antiepileptics’ effect.

Pharmacokinetic interactions

The pharmacokinetic interactions are those where the concentration of one drug in the body is changed by the body. For example, if one drug increases the excretion of another drug, the second drug will have decreased concentration and possibly decreased clinical effect.

Pharmacokinetic interactions can occur at the level of absorption, distribution, biotransformation or excretion.

Interactions at the level of absorption

Drug 1 Drug 2 Combined effect
Two or trivalent cations (Ca2+, Mg2+, Al3+, Bi3+) Tetracyclines, fluoroquinolones The cations and the antibiotics form chelates, decreasing the absorption of the latter
Cholestyramine Warfarin, digitalis Cholestyramine can bind warfarin and digitalis in the gut and decrease their absorption
Drugs modifying gastric pH (antacids, H2 antagonists, PPIs) Drugs which are weak bases or weak acids, like ketoconazole The increased gastric pH alters the charge on weak bases or acids, decreasing their absorption
Drugs slowing gastric emptying (muscarinic antagonists, opioids) Drugs which are orally absorbed The decreased gastric emptying decreases the absorption of drugs
Drugs accelerating gastric emptying (cholinergic agents, prokinetic drugs) Drugs which are orally absorbed Increased absorption of orally absorbed drugs, faster onset of effect, increased peak plasma concentration
Drugs enhancing intestinal peristalsis (laxatives) Drugs which are absorbed in the intestines Decreased absorption of orally absorbed drugs
Drugs decreasing intestinal peristalsis (opioids) Drugs which are absorbed in the intestines Increased absorption of orally absorbed drugs

Interactions at the level of distribution

Many drugs are bound to plasma proteins to some extent. These drugs exist in two fractions in the plasma, the plasma protein-bound fraction and the free (unbound) fraction. Only the free fraction is biologically active, meaning that changes in the plasma protein-bound fraction of the drug will not change the effect of the drug.

However, plasma proteins have a limited number of sites which drugs can bind to. If a person takes one drug which occupies almost all of these binding sites (a drug with high plasma protein binding), and then begins taking another drug which is also extensively plasma protein bound, the second drug can displace the first drug from the plasma proteins. This decreases the plasma protein-bound fraction of the first drug and increases its free fraction, which increases its biological effect. This is the background for interactions at the level of distribution.

This interaction can be significant. If 99% of the plasma concentration of the drug is plasma protein bound and 1% is free, and a drug interaction occurs which decreases the plasma protein bound fraction from 99% to 95%, the free fraction increases from 1% to 5%. That’s a five-fold increase in biologically active concentration!

Most drug follow first-order kinetics, which means that their elimination is not saturable. Only a few drugs follow zero-order kinetics, where the elimination is saturated in pharmacological concentrations of the drug.

If a drug following first-order kinetics experiences displacement from plasma protein binding, and the free fraction increases in size, the elimination will increase proportionally to compensate. As a result, the increased drug effect will be transient and self-limiting. However, the transiently increased drug effect can be enough to cause clinically significant scenarios.

If a drug following zero-order kinetics experiences displacement, the elimination cannot increase, because it is already saturated. As a result, the increased drug effect will be lasting and can cause severe clinical effects.

Let’s say we have two drugs, drug A and drug B, both of which are highly plasma protein bound. If a person is taking drug A and is starting to take drug B, which properties, except from being highly plasma protein bound, must drug B have for it to displace drug A?

If drug B is very potent, we give it in low concentrations. If drug B is introduced in low concentration to the plasma of the patient taking drug A, the low concentration of drug B only allows drug B to occupy a few of the plasma protein binding sites, only mildly displacing drug A.

If drug B is not potent, we must give it in high concentrations. When we introduce drug B in high concentration to the plasma of the patient taking drug A, the high concentration of drug B allows drug B to occupy many of the plasma protein binding sites, severely displacing drug A.

To summarize:

  • Drugs which are highly plasma protein bound but very potent cannot effectively displace other drugs, but they can themselves be displaced
  • Drugs which are highly plasma protein bound but not very potent can effectively displace other drugs (and they can themselves be displaced)

Here are some examples of drugs often involved in plasma protein binding-displacing interactions:

  • Drugs which can displace other drugs
    • Aspirin
    • Sulphonamides
    • Valproate
  • Drugs which can be displaced by other drugs
    • Coumarins (warfarin)
    • Phenytoin
    • Most NSAIDs

Not only drugs but endogenous compounds like bilirubin and other compounds which accumulate in liver or kidney failure can displace plasma protein bound drugs.

Interactions with transport proteins

P-glycoprotein (Pgp) is a transport protein which pumps drugs out from organs which require extra protection against foreign substances, like the brain, placenta and testicles. It’s also found in kidney tubules, the GI tract and in bile ducts, where it contributes to drug excretion.

Many drugs are substrates for Pgp, like colchicine, cyclosporine, dabigatran, digoxin, fexofenadine and morphine. Other drugs can inhibit or induce Pgp, thereby altering the excretion of the aforementioned drugs.

  • Pgp inducers
    • Rifampin
    • Carbamazepine
    • St. John’s wort
  • Pgp inhibitors
    • Amiodarone
    • Macrolides
    • Cyclosporine
    • Ketoconazole
    • Ritonavir
    • Quinidine
    • Verapamil
  • Pgp substrates
    • Cyclosporine
    • Digoxin
    • Fexofenadine
    • Morphine
    • Tacrolimus

Interactions at the level of biotransformation

Drugs can induce or inhibit the different enzymes involved in biotransformation. If the enzyme whose activity is altered is involved in the elimination of another drug, the concentration of the second drug will be altered. The clinical effect of this depends on whether the first drug induces or inhibits the enzyme and on whether the second drug is a pro-drug or not.

Enzyme induction leads to a slowly developing increase in metabolizing capacity. This decreases the effect of drugs which are converted to inactive metabolites but increases the effect of drugs which are prodrugs.

Enzyme inhibition leads to an immediate decrease in metabolizing capacity. This increases the effect of drugs that are converted to inactive metabolites but decreases the effects of prodrugs.

Here are some examples:

  • Enzyme induction
    • Drugs that have their effect increased by enzyme induction (prodrugs)
      • Tramadol
      • Codeine
      • Tamoxifen
      • Clopidogrel
    • Drugs that have their effect decreased by enzyme induction (not prodrugs)
      • Coumarins
      • Oestrogens
    • Drugs which are enzyme inducers
      • Phenytoin
      • Carbamazepine
      • Phenobarbital
      • Rifampin
  • Enzyme inhibition
    • Drugs that have their effect increased by enzyme inhibition
      • Haloperidol
      • Prednisolone
      • Zopiclone
    • Drugs that have their effect decreased by enzyme inhibition (prodrugs)
      • Tramadol
      • Codeine
    • Drugs which are enzyme inhibitors
      • Ketoconazole
      • Ritonavir
      • Erythromycin
      • Amiodarone
      • Allopurinol
      • Cimetidine
      • Verapamil

Interactions at the level of excretion

Many drugs are actively secreted in the proximal tubules by the same transport proteins. There are three major active transport systems, each of which have substrates which can compete for the transport.

  • Organic anion transporter (OAT)
    • All substrates are organic anions
    • NSAIDs
    • Penicillins
    • Cephalosporins
    • Thiazides
    • Loop diuretics
  • Organic cation transporter (OCT)
    • All substrates are organic cations
    • Metformin
    • Cimetidine
    • Amiloride
  • P-glycoprotein (Pgp)
    • Colchicine
    • Cyclosporine
    • Digoxin
    • Fexofenadine
    • Morphine
    • Tacrolimus

Many drugs are passively reabsorbed in the collecting duct. This passive process depends mainly on the charge of the protein. Changes in the urine pH can alter the charge of drugs which are weak acids or bases, altering their passive reabsorption and thereby their excretion rate.

  • NaHCO3
    • Makes the urine more basic
    • Reduces reabsorption of phenobarbital, salicylate
  • NH4Cl
    • Makes the urine more acidic
    • Reduces reabsorption of quinidine

Some drugs, mainly diuretics, increase the diuresis, thereby increasing the excretion of drugs which are cleared by the kidney.

Drugs which are excreted by bile may compete with each other for the hepatobiliary active transport systems in hepatocytes. Fexofenadine and valsartan are examples of this.

Pharmacodynamic interactions

Pharmacodynamic interactions are those where the biological effect of one drug alters the effect of another drug, without altering the concentration.

Drug 1 Drug 2 Combined effect
Thiazides Cardiac glycosides Thiazide-induced hypokalaemia enhances the effect of glycosides
Non-selective beta blockers Insulin Nonselective beta blockers enhance insulin-induced hypoglycaemia, and mask the signs of it
Ethanol Sedatohypnotic drugs (benzos, Z-drugs, barbiturates) Increased central depression
Non-depolarizing skeletal muscle relaxants Aminoglycosides Aminoglycosides increases the muscle relaxing effect
MAO-A inhibitors Indirect sympathomimetics Increased sympathomimetic effect as the release pool of noradrenaline increases
Drugs which increase serotoninergic transmission (SSRI, MAO inhibitors, …) Drugs which increase serotoninergic transmission (SSRI, MAO inhibitors, …) Increased serotoninergic effect, serotonin syndrome
Anticoagulants Antiplatelets Increased bleeding tendency
PDE inhibitors (like sildenafil) Organic nitrates Increased effect of nitrates, potentially severe hypotensions

Advantageous drug interactions

Some drug interactions are advantageous and exploited clinically. Here are some examples.

Drug 1 Drug 2 Combined effect
Antihypertensive, antineoplastic, antidiabetic, antibiotic, antiviral, etc. Different drug in same class Increased therapeutic efficacy, reduced side effects
Vasoconstrictors Local anaesthetics Prolonged anaesthetic effect, fewer side effects
Vasodilators Beta blockers Beta blockers eliminate the reflex tachycardia caused by vasodilators
Vasodilators Diuretics Diuretics eliminate the fluid retention caused by vasodilators
Carbidopa Levodopa Carbidopa increases the CNS availability of levodopa and decreases peripheral side effects

In vitro drug interactions

Some drug interactions occur outside the body. An example of this is thiopental and succinylcholine, which form complexes if mixed and therefore cannot be given in the same syringe. Heparin is another example. It is highly charged and can inactivate basic drugs if both are given in the same IV line without clearing the line with saline in between.