Exploring psychotherapeutic issues and agents in clinical practice
Many drugs are manufactured in different formulations that can be administered orally, nasally, rectally, transdermally, intramuscularly (IM), intravenously (IV), or by inhalation. The route of administration depends on a variety of clinical and practical factors, but oral administration is most common and preferred. Just as the ways in which patients take medications by mouth can be diverse and idiosyncratic (Rowe, 2004), what happens to a pill taken by mouth also varies from one patient to another for physiological reasons. These physiological processes have clinical implications that nurses must understand.
The dissolution of most drugs begins in the stomach, but few drugs are absorbed in the stomach, as most drugs are mainly absorbed in the small intestine. The small intestine is composed of the duodenum, jejunum, and ileum. Most chemical digestion takes place in the duodenum. The primary function of the jejunum is absorption. Much of what is absorbed from the jejunum (including most drugs) passes into the liver via the hepatic portal vein before entering the systemic circulation. First-pass hepatic metabolism refers to the process by which an orally administered drug is absorbed, transported to the liver, and partially metabolized before ever entering the systemic circulation. As a result, only a proportion of a parent drug, together with any metabolites, reaches target organs throughout the body. Some drugs undergo extensive first-pass metabolism, whereas others undergo minimal or no first-pass effects. The absorption of bile salts, vitamin B12, and other substances not absorbed by the jejunum mainly occurs in the ileum. Bile salts, which are synthesized in the liver, are important for the digestion and absorption of dietary fats and play a role in the excretion of some drugs and their metabolites from the liver.
The oral bioavailability of some drugs is influenced by food (Winstanley & Orme, 1989). For example, the bio-availability of ziprasidone (Geodon®) is increased with food. For most drugs, however, the rate of drug absorption can be slowed by food, although the extent of absorption is relatively unaffected. Reductions in gastric acid secretion (especially in older adults or with the use of antacid or proton pump inhibitor drugs) can affect the solubility of weakly acidic or basic drugs, affecting their absorption; however, these reductions and their effect have not been well documented for psychotropic drugs (Ogawa & Echizen, 2010, 2011). Malabsorption syndromes (e.g., Crohn’s disease, celiac disease), previous gastrointestinal (GI) surgery (e.g., gastric bypass, removal of the small intestine), or conditions associated with decreased GI blood flow may impair or delay the absorption of orally administered drugs.
In certain gastric bypass procedures, a smaller stomach pouch is created, and the stomach is attached to a distal portion of the small intestine such that the duodenum or the duodenum and jejunum are bypassed. Decreased drug absorption can occur when the stomach or proximal small intestine is an important site of absorption (Miller & Smith, 2006), such as with lamotrigine (Lamictal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), and zolpidem (Ambien®). Similarly, the absorption of drugs administered through feeding tubes in the small intestine (typically the jejunum) can affect drug absorption because the stomach and proximal small intestine are effectively bypassed (Williams, 2008). Ordinarily, drugs undergoing extensive first-pass hepatic metabolism (e.g., opioid analgesics, antidepressant agents) can have increased serum concentrations and greater systemic effects when administered directly into the jejunum. Initial drug doses and dose titration should be lower and slower, respectively, when these drugs are administered to the jejunum. Extended-release drug formulations (i.e., delayed-release, controlled-release, sustained-released, or extended-release) typically depend on intestinal exposure over a longer period of time, and their absorption is decreased in patients with small intestine disorders, or who have had gastric bypass procedures or jejunum tube administration. Therefore, immediate release drug formulations should be used in these patients.
Antacids might decrease the bio-availability of other drugs taken at the same time (via chelation or altered gastric pH). Antacid interactions with psychotropic drugs have not been well studied, and no clinically relevant interactions have been described (Ogawa & Echizen, 2011). Interaction studies between antacids and other drugs have reported variable results. Because sufficient findings exist across drug classes, it is generally prudent to avoid taking antacids together with other drugs, including psychotropic medication. Patients should be advised to take prescribed medications 1 to 2 hours before or after taking an antacid.
Oral formulations include tablets, capsules, or liquids. Chewable or dissolvable tablets can be used when swallowing is not possible. Liquid formulations and crushed tablets can be given through nasogastric tubes (into the stomach) or enteric tubes (into the duodenum or jejunum). Suppository formulations exist for many drugs, but oral tablet or capsule formulations of most drugs can be administered rectally. Transdermal drug formulations are available (e.g., nicotine, fentanyl, buprenorphine, selegiline, methylphenidate, rivastigmine, scopolamine, clonidine, estrogen, and testosterone). Short-acting IM and IV antipsychotic and benzodiazepine drug formulations are available. Transdermal, sublingual, rectal, and injectable routes of drug administration ordinarily bypass first-pass hepatic metabolism, thus leading to greater bioavailability and higher serum concentrations compared to oral administration of the same dose. Lower non-oral doses should be used to avoid increased side effects or toxicity. Patients switching between oral and non-oral drug administration should have their doses adjusted accordingly and side effects monitored closely. Bypassing first-pass hepatic metabolism is why drugs of abuse are typically injected (or sometimes “sniffed” or “huffed”) and are potentially more toxic.
Drugs entering the systemic circulation can reversibly bind to plasma proteins (e.g., albumin) synthesized in the liver. Most psychotropic drugs (exceptions include lithium, gabapentin [Neurontin®], and pregabalin [Lyrica®]) are highly protein bound. The higher bound fraction (i.e., amount of drug binding to the protein) exists in a reversible state of equilibrium with the smaller unbound “free fraction.” Only the free fraction of a drug exerts its therapeutic and adverse effects and undergoes hepatic metabolism or renal clearance. Plasma proteins are decreased in older adults experiencing liver or renal failure and in debilitated or undernourished patients. Renal failure is also characterized by an accumulation of endogenous binding inhibitors (i.e., organic acids, uremic toxins). Binding inhibitors compete with drugs for their carrier protein-binding site, resulting in diminished protein binding and an increased free fraction. A greater proportion of protein-bound drugs will exist as a free fraction in patients with decreased binding proteins or increased binding inhibitors, and these patients have an increased risk of adverse effects unless drug doses are decreased accordingly. Clinical monitoring for adverse effects in such patients is important.
Protein binding is relevant to interpreting measures of total drug concentrations (i.e., bound fraction plus free fraction). When the free fraction of a drug is high because of decreased binding proteins, the measured total concentration will not reflect the amount of drug that is pharmacologically active, unless the laboratory report specifically describes total and free drug concentrations. A seemingly “therapeutic” drug level might be associated with adverse or toxic effects in patients with decreased binding proteins or increased binding inhibitors, as the drug level does not represent the relative ratio of unbound-to-bound drug.
With a few exceptions, most psychotropic drugs are metabolized in the liver. The two main hepatic metabolic pathways involve phase I and phase II reactions (Liston, Markowitz, & DeVane, 2001). Phase I reactions include oxidative, reductive, and hydrolytic processes, but oxidation mediated by the cytochrome P-450 (CYP450) system is most important. Phase II reactions are conjugations mediated by transferase enzymes, and they include glucuronide, sulfate, glycine, and glutathione conjugation; acetylation; and methylation. Glucuronide conjugation is the most important phase II process. The CYP450 and glucuronidation enzyme systems are both genetically determined, and genetic polymorphisms have been identified. Transferase enzymes are also found in the kidneys, intestines, and lungs, where they play a smaller role in drug metabolism. Many drug metabolites undergo phase II conjugation after their parent drug undergoes initial phase I metabolism, but some parent drugs are largely metabolized via glucuronide conjugation. Examples include lorazepam (Ativan®), oxazepam (Serax®), temazepam (Restoril®), lamotrigine, valproic acid (Depakote®), haloperidol (Haldol®), and olanzapine.
Glucuronide conjugation is greater in men than women; increased in overweight patients and cigarette smokers; and decreased with alcohol use, in underweight or malnourished patients, and in certain disease states (e.g., hepatitis, cirrhosis, hypothyroidism, HIV infection). These factors affect the glucuronidation of some drugs. Glucuronide conjugation also facilitates biliary excretion. Some drugs and metabolites are excreted in bile. The biliary system contributes to excretion only to the extent that drugs are not reabsorbed from the GI tract via the enterohepatic cycle (in which a drug secreted in bile is reabsorbed into circulation from the intestine). Gastric bypass surgery and jejunum tube drug administration would potentially affect this process.
Medical conditions associated with impaired enterohepatic circulation or hepatic function (i.e., acute or chronic liver failure) can affect drug metabolism. Metabolic enzyme activity is generally reduced with increasing liver disease severity, but the relationship is not straightforward (Verbeeck, 2008). Chronic liver diseases are associated with variable and nonuniform reductions in the activity of various CYP450 enzymes. Conjugation reactions, such as glucuronidation, may be affected to a lesser extent than CYP450-mediated reactions, but they can be substantially impaired with advanced liver disease. Age-related decreases in hepatic blood flow and the activity of some metabolic enzymes may also result in decreased drug metabolism in older patients. Conjugation reactions are relatively unaffected by aging; the effect of aging on CYP450 enzyme activity is not uniform across all enzymes. Therefore, age-related changes in drug metabolism depend on the particular enzymes involved.
No accepted way exists to quantify declines in liver function for determining drug metabolizing capacity. Liver function tests do not correlate with hepatic metabolism. Low drug doses and slower dose titration should be used in cases of severe liver disease, but usual dosing strategies can be safely followed for mild to moderate liver disease. Because pre-existing liver disease is associated with an increased risk of hepatotoxicity, avoiding valproic acid is recommended. Other anticonvulsant drugs, such as carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), topiramate (Topamax®), and lamotrigine, should be used and dosed cautiously in these patients. Medications metabolized primarily through conjugation are preferred for use in older patients and in patients with severe liver disease. Among the benzodiazepine drugs, lorazepam, oxazepam, and temazepam are preferred for use in patients with liver disease because they are metabolized by glucuronidation and have no active metabolites. In all patients with known liver disease, careful clinical monitoring is warranted.
The absorption and metabolism of drugs can be influenced by age, sex, pharmacogenetic variability, medical comorbidity, concurrent drug use, drug formulation, and the route of administration. Nurses should understand these factors and how they are relevant for clinical monitoring in particular patient populations, as well as with changes in drug formulation or route of administration. The product package insert and many standard online references have useful information about the absorption, metabolism, protein-binding, and clearance of prescription medications and their various formulations.
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- Winstanley, P.A. & Orme, M.L. (1989). The effects of food on drug bioavailability. British Journal of Clinical Pharmacology, 28, 621–628.