effect = potency at the site of action × concentration at site of action × inter-individual variance
In other words, the clinical response equals the drug’s potency at the site of action times the drug’s concentration at the site of action times the patient’s underlying biology. Likewise, when we consider variability among patients, the second equation becomes:
effect = pharmacodynamics × pharmacokinetics × inter-individual variance
Table 3
HOW PHARMACOKINETICS MAY CAUSE ADVERSE DRUG-DRUG EVENTS
| Mechanism of interaction of two or more drugs | Two or more drugs interact where … | Examples |
|---|---|---|
| One negatively affects the other’s absorption | Use of tetracycline with substances containing calcium | |
| One negatively affects the other’s distribution | Amiodarone and quinidine, by inhibiting P-glycoprotein, reduce the volume of distribution and/or clearance of digoxin, doubling its serum level | |
| One negatively affects the other’s metabolism | One negatively affects the other’s oxidative metabolism by inducing CYP enzyme activity | Carbamazepine induces CYP 2C9 and CYP 3A4 activity, which stimulates warfarin biotransformation, decreases its half-life, and lowers its serum concentration |
| One negatively affects the other’s oxidative metabolism by inhibiting CYP enzyme activity | Ketoconazole inhibits CYP 3A4 activity, which inhibits terfenadine metabolism, resulting in serum terfenadine levels 32 to 100 times normal | |
| One inhibits hydroxylation of the other’s toxic metabolites, inhibiting their clearance | Combination of carbamazepine and valproate | |
| One negatively affects the other’s elimination | Lithium plus hydrochlorothiazide or an NSAID (both impair lithium excretion) |
This addition to the equation explains how inter-individual variability can shift the dose-response curve to produce a greater or lesser effect than that which would be expected in the “usual” patient taking the prescribed dosage.
Inter-individual variance. The metabolism of dextromethorphan illustrates the effect of inter-individual variance. After a single dose, about 93% of Caucasians develop relatively lower dextromethorphan:dextrophan ratios, and about 7% develop relatively higher ratios. This difference defines patients who are pharmacogenetically CYP 2D6 extensive metabolizers versus those who are not.
Similarly, drugs sometimes cause biological variance, which predisposes to a drug-drug interaction. For example, the literature is replete with case reports and case series reporting that a substantial CYP 2D6 inhibitor—such as fluoxetine—blocks the metabolism of drugs that are principally metabolized by CYP 2D6. If the drug being metabolized has a narrow therapeutic index—such as amitriptyline—the resultant increase in its serum level can cause serious cardio and neurotoxicity, including arrhythmias, delirium, seizures, coma, and death.12
In such cases, a CYP 2D6 inhibitor converts the phenotype from a CYP 2D6 extensive metabolizer into a CYP 2D6 poor metabolizer. Hence, the clinician must consider how a specific patient may differ from the usual patient when selecting and dosing a drug. The difference may be genetic or acquired, as in this example.
Table 4
RISK FACTORS FOR POLYPHARMACY
| Psychiatric disorders | Medications being taken |
| Schizophrenia | Cardiovascular agents |
| Bipolar disorder | Antipsychotics |
| Depression | Mood stabilizers |
| Borderline and other personality disorders | Antidepressants |
| Substance abuse (including tobacco habituation) | Self-medication with aspirin |
| Neurologic disorders | Demographic variables |
| Mental retardation | Age 65 or older |
| Dementia | Ethnicity (Caucasian, African-American) |
| Chronic pain, facial pain | Female gender |
| Headache (including migraine) | Psychosocial variables |
| Insomnia | Lower socioeconomic status |
| Epilepsy | Inner-city residence |
| Medical disorders | Lower level of education |
| Chronic diseases, multiple diseases | Unemployment |
| Obesity | Self-medication |
| Diabetes | Concealed drug use |
| Chronic hypertension | |
| Coronary artery disease |
The following equation explains how dose is related to drug concentration, which takes into account the drug’s pharmacokinetics:
drug concentration = dosing rate (mg/day) ÷ clearance (ml/min)
In other words, the concentration achieved in a specific patient is determined by the dosage relative to the patient’s ability to clear the drug from the body.
Consequences, prevalence of polypharmacy
Polypharmacy increases patients’ risk for many ill effects, including incidence and severity of adverse events, drug-drug interactions, medication errors, hospitalizations, morbidity, mortality, and direct and indirect costs. At least 12 reports and studies have been published showing the association between polypharmacy and death,2,13-23 and in some of these reports the association is present even after controlling for underlying diseases.
The prevalence of polypharmacy varies by country and population. In Denmark, for example, the prevalence of polypharmacy is approximately 1.2%,6 compared with approximately 7% in the United States.24 Nearly one-half (46%) of all elderly persons admitted to U.S. hospitals may be taking seven or more medications.25 Polypharmacy is especially problematic in patients age 65 and older (Box 2),26-31 in whom the top five preventable threats to health are congestive heart failure, breast cancer, hypertension, pneumonia, and adverse drug events.32 Although older persons make up less than 15% of the population, they take the greatest number and quantity of medications, purchase 40% of all nonprescription medications, and use 33% of all retail prescriptions.30
POLYPHARMACY RISKS IN PATIENTS AGE 65 AND OLDER
- 14% of older patients prescribed psychotropics experience a hip fracture, accounting for 32,000 annual hip fractures in the United States.26
- 28% of older patients’ hospitalizations are due to adverse events or non-adherence to drug therapy.27
- 35% of older patients taking three or more prescription medications at hospital discharge are re-hospitalized within 6 months. Problems with medications lead to 6.4% of these re-admissions.28
- Among older drivers, taking a psychoactive drug multiplies the risk of a motor vehicle accident involving injuries by 1.5 to 5.5 times. The greater the dosage, the greater the risk.29
- Hospital admissions related to adverse events from medications in older patients cost $20 billion annually (excluding indirect costs).30
- Morbidity and mortality related to drug therapy in ambulatory patients in the United States costs $76.6 billion annually.31