Most individuals who are prescribed five or more drugs are taking unique drug combinations.8 These heterogeneous regimens represent “an uncontrolled experiment,” with effects that cannot be predicted from studies in the literature.9Tables 1, 2, and 3 describe how contratherapeutic polypharmacy may occur with combinations of any number of drugs, whether five or more by the classic definition or only two. For example, contratherapeutic polypharmacy may occur when a patient is given the mood-stabilizing drugs valproate and carbamazepine (CBZ) at the same time.10 Here is why this combination may be dangerous:
- Carbamazepine is oxidized by arene oxidase to CBZ 10,11-epoxide, which is hydrolyzed by epoxide hydrolase to CBZ 10,11-dihydroxide. The metabolite CBZ 10,11-epoxide has both therapeutic and toxic effects.
- In monotherapy, the ratio of carbamazepine to CBZ 10,11-epoxide is 10:1, with CBZ 10,11-epoxide having a shorter half-life than carbamazepine.
- However, when carbamazepine and valproate are taken as co-pharmacy, valproate blocks the hydrolysis of CBZ 10,11-epoxide by inhibiting epoxide hydrolase, so that the ratio of carbamazepine to CBZ 10,11-epoxide becomes 2:1. Higher concentrations of the epoxide metabolite contribute to neurotoxicity.
Table 1
POLYPHARMACY WITH TWO OR MORE MEDICATIONS
| Description | Example |
|---|---|
| Two or more drugs from the same drug category | Two nonsteroidal anti-inflammatory drugs (NSAIDs), two ACE inhibitors, or two phenothiazines |
| Use of multiple medications across therapeutic classes | Use of multiple CNS medications, as in multiple antidepressants, antipsychotics, or anticonvulsants |
| An inappropriate or unnecessary medication is prescribed to a patient taking other medication | Inappropriate prescription due to relative or absolute contraindications Inappropriate prescription due to weak or no indication |
| Prescription of an exceedingly high dose to a patient taking other medication | The maximum recommended dose may be functionally exceeded to a serious degree if a drug with a narrow therapeutic index (e.g., amitriptyline) is combined with one that blocks its metabolism (e.g., fluoxetine) |
| Two or more drugs sharing similar toxicities | Anticholinergic toxicity due to combining a low-potency phenothiazine antipsychotic and a tertiary amine tricyclic antidepressant |
Other examples of potentially dangerous drug combinations include those associated with torsades de pointes, which may occur with certain combinations of antihistamines, antidepressants, antipsychotics, antivirals, antibacterials, antifungals, antiarrhythmics, and promotility agents.
Drug-drug interactions
In a drug-drug interaction, the presence of one drug alters the nature, magnitude, or duration of the effect of a given dose of another drug; the interaction may be either therapeutic or adverse, depending on the desired effect. A drug-drug interaction may be intended or unintended and is determined by pharmacokinetics and pharmacodynamics rather than by therapeutic class.
Most available drug information describes the effects of individual drugs used alone (monopharmacy). Information on how one drug interacts with another (co-pharmacy) is more difficult to come by. A recent literature search using broad criteria for drug-drug interactions uncovered 4,277 indexed articles. Another search, this time using narrow criteria, produced only 316 articles, suggesting that systematic studies regarding drug-drug interactions are few.
Table 2
HOW PHARMACODYNAMICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism | Examples |
|---|---|
| One drug has a mechanism of action directly opposing the mechanism of action of a co-prescribed drug | Bromocriptine and prochlorperazine in treating a patient with parkinsonism and nausea Levidopa/carbidopa and risperidone in treating a patient with parkinsonism and psychosis Venlafaxine and atenolol in treating a patient with depression and hypertension |
| One drug has an action that increases the potential for an adverse event of a co-prescribed drug | Orthostatic hypotension and syncope when an ACE inhibitor is added to a diuretic Orthostatic hypotension and syncope when risperidone, because of its action as an alpha-1 adrenergic blocker, is added to a diuretic Narcosis and respiratory failure when parenteral fentanyl is added to oral meperidine Neurotoxicity (absence status epilepticus) when valproate is added to clonazepam in children with absence seizures |
However, if you understand the pharmacodynamics and pharmacokinetics that rule co-pharmacy, then you can apply this knowledge to more complex drug-drug interactions involving contratherapeutic polypharmacy.
How drug effects are determined. The nature and magnitude of a drug’s effect are determined by its site of action and its binding affinity, concentration, and action at that site.11 This relationship can be represented by the formula:
effect = potency at the site of action × concentration at the site of action
Potency at the site of action is determined by the binding affinity for the drug and the degree to which the receptor is stimulated or blocked, thus activating or inhibiting transmembrane and intracellular messengers (pharmacodynamics). Concentration at the site of action is determined by absorption, metabolism, distribution, and elimination (pharmacokinetics). Thus, the above model can be represented mathematically by:
effect = pharmacodynamics × pharmacokinetics
These factors determine a drug’s usual effect in the usual patient on the usual dosage, which is the goal of most clinical trials. However, all patients are not “usual,” because of inter-individual differences due to genetics, gender, age, environment, social habits such as smoking, intercurrent diseases affecting organ function, and concomitant drug therapy. Thus, when we take these factors into account, the first mathematical equation becomes: