Drug interactions: when they're beneficial and when they're harmful (Proceedings)

Veterinary pharmacology is increasing in complexity with advances in analgesia. A veterinarian's knowledge of drug interactions is critical to prevention of a potentially harmful event. Drug interactions are considered undesired increases OR decreases in drugs co-administered. Some drugs, in some patients, must be used with caution; knowledge of which drugs interact negatively will prevent future problems. In today's lecture we will discuss drug families and adverse consequences.

Interactions between analgesic and psychopharmacologic drugs

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors, such as fluoxetine (Prozac), are used to treat a variety of canine and feline behavioral problems. By preventing reuptake of serotonin, they enhance serotonergic activity. These drugs in and of themselves are relatively safe, even if an accidental overdose occurs (which cannot be said of tricyclic antidepressants). Fluoxetine is highly protein bound and a potent inhibitor of cytochrome p-450 enzymes (see physiology and drug interactions), which can impact other drugs administered concurrently, especially those dependent on the liver for metabolism. Because most drugs are dependent on the liver for metabolism, and many analgesic drugs are protein bound, patients receiving these drugs can have dangerously high plasma levels of any drugs that are co-administered, if dosage regimens are not adjusted. In addition, other drugs that could increase serotonin levels (selegiline [a monoamine oxidase inhibitor], tricyclic anti-depressants) should not be concurrently administered, as serotonin syndrome may result. Tramadol also works as a serotonin re-uptake inhibitor, and therefore, if co-administered to a patient on fluoxetine, could potentiate serotonin syndrome.

Serotonin syndrome is a potentially fatal syndrome characterized by symptoms ranging from mild agitation and shivering to severe hyperthermia of greater than 104 F, myoclonus, tachycardia and hypertension. This occurs secondary to too much serotonin, by inhibition of its break down. This syndrome is manifested in the neurologic, somatic and autonomic systems. The cognitive effects include agitation, confusion and hallucinations. Somatic effects can manifest as myoclonus, which may result in hyperthermia. Hyperthermia is also secondary to the autonomic system effects, amongst other autonomic effects such as gastrointestinal effects, hypertension and tachycardia. In severe cases, this syndrome is fatal. There is no "silver bullet" therapeutic for this syndrome; care is mainly supportive. This syndrome has not been well documented in animals (presumably because of the relatively paucity of cases prescribed anti-depressants as compared to the human medical field), but with the popularity of tramadol as an analgesic, it is something that warrants care when prescribing analgesics to a patient on medications for behavioral disorder.

Monoamine oxidase inhibitors (MAO inhibitors)

The most well known monoamine oxidase inhibitor in veterinary medicine is selegiline. Selegiline is commonly prescribed to treat canine cognitive dysfunction, and possibly Cushing's disease. Selegiline irreversibly inhibits the monoamine oxidase responsible for the breakdown of dopamine, thus increasing the amount of dopamine available to work at neurologic receptor sites, which may improve signs of cognitive dysfunction. When combined with other drugs that could increase serotonin levels (SSRIs, tricyclic anti-depressants, tramadol), there is the potential for serotonin syndrome to develop (see previous page).

Tricyclic anti-depressants

Unlike SSRIs, these drugs for the most part have a narrow therapeutic window and thus a narrow safety margin. Amitriptyline is used in veterinary medicine to treat behavioral problems, pruritis and possibly feline lower urinary tract disease. While these drugs are infrequently used in veterinary medicine, there is renewed interest in their use in the human medical field for chronic pain syndromes, with success at lower doses compared to the drug's antidepressant dosages. The mechanism of action for these drugs includes blocking reuptake of serotonin, and thus, these drugs are dangerous in combination with SSRIs and MAO inhibitors. Additionally, these drugs have anticholinergic properties. This can lead to cardiovascular side effects, such as hypertension and increased heart rate. Neurologic side effects are also possible, mainly manifested as sedation, although tricyclics can lower the seizure threshold in epileptic patients.

While there are many possible drug interactions for patients receiving tricyclic antidepressants, especially drugs commonly used during anesthesia, opioids are the most common drug for analgesia that could be co-administered resulting in side effects. These side effects are manifested by increased ventilatory depressant effects of opioids and profound sedation. It is highly advisable to reduce drug dosages in patients on both tricyclic anti-depressants and opioids. Tramadol is also contraindicated in these patients because of the potential for serotonin syndrome.

Interactions between analgesic drugs and herbal drugs

Herbal supplements are increasing in popularity in the United States, with an estimated 4.6 billion dollars spent on these supplements in 2006. Herbal supplements currently do not have to receive approval from the Food and Drug Administration, which is why they are so easy for lay people to obtain and dispense. While it is uncommon for veterinarians to prescribe some of the herbal supplements we've discussed, holistic veterinary medicine is on the rise and many owners will medicate their pets with herbs they feel they benefit from. This underscores the importance of asking for a thorough list of medications a patient is receiving, including those medications that may not be prescribed, before beginning any new medications for a patient. By far the most serious herbal supplement is ma huang (ephedra), with the active component being ephedrine. Ephedrine is structurally similar to amphetamines, and can cause serious cardiac problems (dysrhythmias, even death). The adverse effects of ma huang are not secondary to interaction with analgesic drugs (they manifest from use of the drug alone), but are severe enough to warrant mentioning. Drugs known to contain ephedra were banned in 2004.

St. John's wort is one of the most popular herbal supplements used in the western world, being on the list of the top 20 herbal supplements in the United States and Europe. This drug, considered a "natural" antidepressant, inhibits reuptake of serotonin, amongst other neuroactive amines. This can result in sedation, and all the precautions taken with patients prescribed SSRIs apply to this herb—opioids may enhance sedation in patients receiving this supplement, and tramadol could potentiate a serotonergic crisis. See the next page for a discussion on St. John's wort and the impacts on liver metabolism.

Arctostaphylos uva ursi is an herbal supplement used for its antimicrobial properties to treat infections of the kidney and urinary tract. In addition to the antimicrobial properties, it is believed to have anti-inflammatory properties, thus providing analgesia in its own right. This is counterintuitive as some reported adverse events include the possibility of increasing urinary tract inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids should not be used in patients who are receiving Arctostaphylos uva ursi, as this drug may potentiate their effects, leading to secondary side effects such as ulceration of the gastrointestinal tract, renal damage, and platelet dysfunction.

The next section of this lecture will focus on liver metabolism and how alternation of metabolism can impact any drugs dependent on the liver for metabolism, include those used to provide analgesia. However, we'll specifically mention some of the herbal drugs know to induce changes in liver metabolism. For example, St. John's wort can impact liver metabolism and decrease effectiveness of concomitantly administered drugs. There is some evidence that Ginkgo biloba, green tea (Camellia sinensis), and valerian (Valeriana officinalis) amongst others impacts liver metabolism {Mohamed, 2011}.

Physiology and drug interactions

Some drugs are contraindicated in conjunction with analgesic drugs not because of a drug-drug interaction, but rather because of the impacts of these drugs on liver metabolism, which can impact analgesic drugs that rely on the liver for breakdown. Liver metabolism is either enhanced (in which case a drug may never reach therapeutic concentrations) or inhibited (in which case dosages of drugs within normal therapeutic range may result in an over dosage). There are a variety of mechanisms that contribute to this.

Drugs that decrease blood flow to the liver, such as a-2 agonists, will decrease the exposure of the drug to the liver, resulting in a possible prolongation a drugs effect secondary to a decrease in drug metabolism. This is most noticeable under anesthesia, when cardiac output (and therefore liver blood flow) is severely reduced.

When discussing liver metabolism, a brief review of hepatic physiology is helpful to understand why changes in liver metabolism may occur. For the majority of drugs, before excretion of the drug from the body can occur, the drug must be metabolized. While other organs, such as the lungs, may assist with metabolism of drugs, the majority are metabolized by the liver. The liver accomplishes metabolism of drugs through two phases (Phase I and Phase II), with Phase I (functionalization) relying heavily on oxidation of a compound and Phase II (conjugation) relying heavily on glucuronidation. Cytochrome P-450 (CYP450) is key to phase I metabolism, and this particular cytochrome is enzymatically induced secondary to certain stimuli. The list of drugs that effect CYP450 is diverse and extensive but includes drugs such as ketoconazole and rifampin. However, other environmental stimuli—such as drinking grapefruit juice or taking the herb St. John's wort—can result in enzymatic induction. The result of this depends on the drug co-administered. The drug can become more active, less active or may be unchanged. Therefore, it is prudent to review specific information about a patient's drug history to decide if specific analgesics are suitable in certain cases.

Phase II, with glucuronidation playing a major role, is of particular concern with prescribing drugs for the cat. While cats do not completely lack the ability to glucuronidate, they have limited ability to glucuronidate. This varies by cat, leading to variable metabolism of drugs. For example, carprofen can last anywhere from nine hours to over two days. The unique aspects of feline physiology are addressed in another lecture.

Protein binding is important because drugs that are highly protein bound leave very little drug circulating as a free fraction; it is the free fraction of the drug that exerts the "active" effect. Therefore, if a drug is highly protein bound (the level of protein binding varies by drug), and is administered to a patient receiving drugs that are protein bound as well, one or the other drug could become displaced, rendering more free fraction available, and thus essentially mimicking an over dosage of the drug. The classic example of a highly protein bound drug is warafin. It is most concerning when a drug with adverse effects may become displaced, and so it is important to know the margin of safety for any drug administered concomitantly with highly protein bound drugs. In terms of analgesic drugs, NSAIDs tend to be highly protein bound, and have the potential for gastrointestinal, renal and platelet effects should they have too high of a free fraction. Therefore, when administering NSAIDs, it is prudent to review the protein binding of other drugs the patient is currently prescribed.

Finally, underlying disease that alters a patient's normal physiology may induce adverse drug effects. Disease such as a portosystemic shunt or hypoadrenocortisism may reduce the therapeutic index of drugs administered and cause adverse effects even with conservative dosing if poly-pharmacy is present.

In summary, adverse drug effects and drug interactions can have disastrous consequences for patients; reviewing a patient's physiology, knowing the medications a patient currently receives (including any herbal supplements), and knowing some information about additional drugs intended for use in that patient can prevent some of these consequences. With the need for analgesics, especially in older patients with chronic conditions, and the complexity of what is available, performing this review is increasingly important.

References

Mohamed, M. E. & R. F. Frye (2011) Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med, 77, 311-21.