Drug Interactions

Pharmacokinetic Interactions

Historically, certain foods and drugs have been known to inhibit drug metabolism. Among the more dramatic of such interactions is the inhibition of CYP3A4 by grapefruit juice. CYP3A4 is responsible for nearly one half of all drug metabolism. Ingestion of grapefruit juice has been shown to increase the plasma concentration of drugs metabolized by CYP3A4.^[30] Many drugs also inhibit CYP3A4, including the antifungal drugs ketoconazole and itraconazole; the protease inhibitors ritonavir, indinavir, and saquinavir; the antibiotics troleandomycin, clarithromycin, and erythromycin; and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline. Propofol also inhibits CYP3A4, although it is unclear whether there is any clinical consequence to this. Conversely, several drugs induce CYP3A4, increasing the metabolism of 3A4 substrates. These include rifampin, rifabutin, tamoxifen, glucocorticoids, carbamazepine, barbiturates, and the herb St. Johns Wort.

CYP2D6, responsible for the conversion of codeine to morphine, is also subject to inhibition. Quinidine and the SSRIs fluoxetine and paroxetine produce significant inhibition with standard clinical doses. Codeine, oxycodone, or hydrocodone would be relatively poor analgesic choices for patients on SSRIs.

Anesthetics also interact pharmacokinetically with many drugs by reducing cardiac output and hepatic blood flow. The reduction in cardiac output probably decreases intercompartmental clearance of most drugs, whereas the reduction in hepatic blood flow is expected to decrease metabolic clearance for drugs with high hepatic extraction ratios.

Pharmacodynamic Drug Interactions

Drug-Time Interaction: Desensitization

Desensitization is broadly defined as waning of physiologic responsiveness to a drug over time. For example, acute desensitization (i.e., tachyphylaxis) typically occurs to sodium nitroprusside. It is often necessary to increase the nitroprusside infusion rate over time to maintain the desired amount of vasodilation.

In general, stimulation of receptor pathways results in activation of kinases (e.g., protein kinase A, G protein-coupled receptor kinases, protein kinase C) that phosphorylate specific regions of the receptor, preventing further interaction of the receptor with G proteins or second messengers. Continuous stimulation of a receptor provides a negative-feedback mechanism to receptor stimulation, resulting in desensitization. Although desensitization was initially thought to occur only at the receptor level, it is now recognized that alterations of G proteins and second messengers also occur in response to agonist stimulation. Effectively, desensitization shifts the dose-response curve to the right (see Fig. 3-35, curve B to C ) or decreases maximal drug effect, or both. Efficacy and potency can be diminished by desensitization.

Desensitization of receptor responses is a feature of many diseases in the aging population and is therefore relevant to consider during the perioperative period. Common diseases in which desensitization is important include congestive heart failure, hypertension, and diabetes; a hallmark of each of these diseases is elevation of hormone (agonist) concentrations. In the case of congestive heart failure, poor cardiac output induces compensatory sympathetic nervous system stimulation, often resulting in a doubling of circulating catecholamine concentrations (specifically, the sympathetic neurotransmitter norepinephrine). On a long-term basis, this results in desensitization of the myocardial β-adrenergic-receptor signal transduction pathway; specifically, β₁ -adrenergic-receptor density and function decrease (75%) with relative sparing of β₂ -adrenergic receptors (25%). G_i levels also increase without change in G_s . G protein-coupled receptor kinase concentrations increase, and adenylyl cyclase isoforms are modulated. Physiologic effects of changes important in desensitization of myocardial β-adrenergic receptors have been examined using transgenic and knock-out mice (see Table 3-1 and "Developments in Molecular Pharmacology"). To break the cycle of elevated agonist exposure and resultant desensitization, cardiologists cautiously use long-term, low-dose β-adrenergic-receptor

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Drug-Time Interaction: Increased Receptor Sensitivity

The opposite of desensitization is increased receptor sensitivity. Long-term exposure to a drug often results in compensatory responses by the receptor system. For example, when a receptor antagonist is administered on a long-term basis, receptor number (density) often increases. If the receptor antagonist is suddenly discontinued, exaggerated responsiveness to agonist may occur. This is the rationale for continuing long-term β-adrenergic-receptor antagonists during the perioperative period. Abrupt discontinuation of these drugs leaves the myocardium vulnerable to exaggerated heart rate and inotropic responses to routine procedures such as tracheal intubation, potentially leading to myocardial ischemia and infarction. Careful consideration should be given before discontinuing a long-term medication before surgery.

A much-feared anesthetic example of increased receptor sensitivity is the upregulation of nictonic receptors at the neuromuscular junction in patients with spinal cord injuries (see Chapter 13 ). Such patients are hyperreflexic because small releases of acetylcholine generate exaggerated reflex responses. The potential for such patients to have a life-threatening hyperkalemic response to succinylcholine is classically taught to every anesthesia resident.

Drug-Drug Interactions

There is a huge variety of mechanisms by which drugs can interact pharmacodynamically. The nature of pharmacodynamic drug-drug interactions is so diverse that an anesthesiologist can safely assume there is some interaction between anesthetic drugs and virtually all drugs that have action on the CNS or the cardiovascular system.

Some of these drug interactions, such as that between opioids and hypnotics, are fundamental to the practice of anesthesia and were discussed previously. An example of interactions between anesthetics and nonanesthetics is the influence of nonanesthetic drugs on the MAC of inhaled anesthetics (see Chapter 4 ). Drugs that increase central catecholamines in general increase the MAC. This has been clearly demonstrated for amphetamines (acute exposure), ephedrine, and monoamine oxidase (MAO) inhibitors. Conversely, drugs that decrease central catecholamines decrease the MAC (see Chapter 31 ). This has been shown for methyldopa, reserpine, and α₂ -adrenergic agonists. It has also been demonstrated for chronic amphetamine use.