When drugs are swallowed, they pass through the stomach and are absorbed in the __________.

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Administration of Enteral Tube Feeding

Patients with conditions outlined inTable 70.2 may have a functional gastrointestinal tract and yet be unable to consume adequate diet orally due to medical or surgical conditions (e.g., mechanical ventilation, pancreatitis, dementia, dysphagia, trauma, or burns). Although PN is commonly administered in these settings, this practice is not evidence based; academic guidelines strongly suggest that oral nutritional supplements or enteral tube feedings should be used if specialized nutrition support is indicated in patients with a functional gastrointestinal tract (“if the gut works, use it”). EN is more physiologic, associated with less severe infectious, mechanical, and metabolic complications, and is less costly than PN. Although not evidence based, common contraindications to EN include paralytic ileus, bowel ischemia, and hemodynamic instability requiring mid- to high-dose vasopressors, inability to gain access to the gastrointestinal (GI) tract, intestinal obstruction, intractable vomiting, severe diarrhea, and peritonitis.

E-Table 70.4

E-TABLE 70.4. Complete Enteral Nutrient Formulas and Clinical Indications

ARDS, Acute respiratory distress syndrome;EPA, eicosapentanoic acid;MCT, medium-chain triglycerides.

Enteral Administration

Enteral administration involves absorption of the drug via the GI tract and includes oral, gastric or duodenal (e.g., feeding tube), and rectal administration

Oral (PO) administration is the most frequently used route of administration because of its simplicity and convenience, which improve patient compliance. Bioavailability of drugs administered orally varies greatly. This route is effective for drugs with moderate to high oral bioavailability and for drugs of varying pKa because gut pH varies considerably along the length of the GI tract. Administration via this route is less desirable for drugs that are irritating to the GI tract or when the patient is vomiting or unable to swallow. Drugs given orally must be acid stable or protected from gastric acid (e.g., by enteric coatings). Additional factors influencing absorption of orally administered drugs include the following:

Gastric emptying time. For most drugs the greatest absorption occurs in the small intestine owing to its large surface. More rapid gastric emptying facilitates their absorption because the drug is delivered to the small intestine more quickly. Conversely, factors that slow gastric emptying (e.g., food, anticholinergic drugs) generally slow absorption.

Intestinal motility. Increases in intestinal motility (e.g., diarrhea) may move drugs through the intestine too rapidly to permit effective absorption.

Food. In addition to affecting gastric emptying time, food may reduce the absorption of some drugs (e.g., tetracycline) owing to physical interactions with the drug (e.g., chelation). Alternatively, absorption of some drugs (e.g., clarithromycin) is improved by administration with food.

Intestinal metabolism and transport. The intestinal wall has extensive metabolic processes and transport mechanisms (e.g., P-glycoprotein) that affect absorption of drugs given via the oral route.

Hepatic metabolism. Orally administered drugs are absorbed into the portal circulation and carried directly to the liver. The liver has extensive metabolic processes that can affect drug bioavailability.

Rectal administration via suppositories to produce a systemic effect is useful in situations in which the patient is unable to take medication orally (e.g., is unconscious, vomiting, convulsing). Drugs are absorbed through the rectal mucosa. Because of the anatomy of the venous drainage of the rectum, approximately 50% of the dose bypasses the portal circulation, which is an advantage if the drug has low oral bioavailability. On the other hand, drug absorption via this route is incomplete and erratic, in part because of variability in drug dissociation from the suppository. Rectal administration is also used for local topical effects (e.g., antiinflammatory drugs in the treatment of colitis).

Sublingual (under the tongue) or buccal (between gum and cheek) administration is advantageous for drugs that have low oral availability because venous drainage from the mouth bypasses the liver. Drugs must be lipophilic and are absorbed rapidly. Buccal formulations can provide extended-release options to provide long-lasting effects.

Enteral administration

These routes involve administration via the gastrointestinal tract:

Oral. This is the most common route of administration because it is simple, convenient and readily used by patients to self-administer their medicines. Absorption after an oral dose is a complex process that depends on the drug being swallowed, surviving exposure to gastric acid, avoiding unacceptable food binding, being absorbed across the small bowel mucosa into the portal venous system, and surviving metabolism by gut wall or liver enzymes (‘first-pass metabolism’). As a consequence, absorption is frequently incomplete following oral administration. The term ‘bioavailability’ describes the proportion of the dose that reaches the systemic circulation intact.

Buccal, intranasal and sublingual (SL). These routes have the advantage of enabling rapid absorption into the systemic circulation without the uncertainties associated with oral administration (e.g. organic nitrates for angina pectoris, triptans for migraine, opioid analgesics).

Rectal (PR). The rectal mucosa is occasionally used as a site of drug administration when the oral route is compromised because of nausea and vomiting or unconsciousness (e.g. diazepam in status epilepticus).

Enteral

Enteral administration delivers the compound into the body through the gastrointestinal (GI) tract. Both ends of the GI tract can be utilized – the mouth and the anus. Administering medications and other compounds by ingesting them orally is, by far, the most common route of administration for medications and supplements. Usually, a pill is swallowed, thus ingesting the substance into the stomach. Prescribers commonly refer to this method of administration as ‘by mouth’ or PO (from Latin ‘per os’). Usually, oral administration is most convenient because it is least invasive.

Substances prepared for oral administration may be available in a variety of pills, including tablets, capsules, and caplets. Tablets are commonly round, and are sometimes coated so that they do not easily dissolve in the mouth. Capsules are oblong and may contain granules of the active compound that release as the outer coating is dissolved in the stomach. Caplets are a cross between the two, and usually are oblong tablets that are softer than traditional round tablets and may dissolve more easily (for example, geltabs). Either way, the substance is introduced into the body when the outer coating dissolves in the stomach and the contents become available for absorption.

Although they offer a convenient way to ingest a substance, pills are problematic for some populations. Children and the elderly may have difficulties swallowing pills, and may resist taking them. It is especially common for children to dislike taking pills. Very young children may have their mouth and throat incompletely formed, limiting the ability to swallow a solid pill. Similarly, children with significant developmental delays may not have formed adequate muscle tone and nerve control to allow sufficient ability to swallow a pill. Generally speaking, those children who have difficulties speaking, and/or cannot swallow a moderate mouthful of water without it dripping out of their mouth, may exhibit immature muscle and nerve development and may not have adequately formed the swallowing reflex to swallow pills.

Some children also dislike pills for psychological reasons. They may be afraid that the pill will be hard to swallow, may hurt while passing through the throat, or may choke them. They may also associate pills with unpleasant medical experiences, like invasive examinations or giving a blood sample. Some children and adolescents may also fear that the compound will change their personality or cause unpleasant side effects. For many teenagers, taking the substance may be a part of a larger power struggle, where accepting the pill may symbolically be seen as succumbing to the parents' wishes and giving up control. The pill may communicate to the teens that something is presumably wrong with them and they are given this compound to get ‘fixed.’ In these instances teens may refuse to swallow the substance.

Instead of pills, using other means of oral administration may sometimes be preferred. Some capsules may be opened, ‘sprinkled,’ and mixed into food. Generally, a strong-tasting, acidic food provides a convenient base. For example, it is common for parents to sprinkle some medications into a spoonful of apple sauce, mix it in, and have the child swallow this mixture. In addition, some medications are available in liquid form (as oral solution or syrup) that can be swallowed directly and/or mixed into other liquids if needed.

Herbal and nutritional supplements are primarily available in a variety of pill forms. Most are capsules that contain the active compound, but traditional tablets sometimes are also produced. When a child or adolescent has difficulties swallowing the pill, some capsules can be opened, allowing the contents to be mixed into a food base. However, many of the supplements have a strong taste, and therefore the base may not sufficiently hide the flavor, thus resulting in a horribly tasting concoction. Trial and error will be needed in those cases.

Some supplements can also be brewed into a tincture. This method, however, requires careful control of the strength, and if preparation is inconsistent, doses of various strengths will result and the compound will be administered unpredictably. This is likely to adversely affect efficacy. Thus, whenever possible, parents are advised to administer supplements in pill form, and if tincture preparation is needed, directions must carefully be followed each and every time it is prepared.

Administering a substance by mouth (PO), either in pill or liquid form, presents additional pharmacologic challenges. When the compound is swallowed, it travels down the esophagus, passes the lower esophageal sphincter, and enters the stomach. No absorption takes place in the stomach. Instead, the main functions of the stomach are to eliminate undesired bacteria that may have been ingested with the foodstuff, break down the food into a semi-liquid mass that allows distribution over a larger surface area for easier digestion, and release contents into the small intestine. The breakdown of the food is attained by various gastric acids that are quite caustic. While many (but not all) nutrients ingested during meals generally survive this environment, some supplements may not. For this reason, some pills are covered with a coating that resists the stomach acids and allows the contents to pass into the small intestine, where absorption begins. However, liquid preparations obviously do not allow for such a mechanism, so any tincture that is ingested must survive the stomach environment in order to be available for absorption in the small intestine.

Ingesting substances by mouth has another major disadvantage. As mentioned above, no absorption takes place in the stomach, and absorption begins when contents of the stomach are released into the duodenum (the first portion of the small intestine). The stomach is preprogrammed to release its contents into the duodenum at a controlled rate, allowing the small intestine sufficient time for chemical digestion and absorption to take place. This means that there is a time delay between the ingestion of a substance (like a pill) and its release into the small intestine. When a compound is taken on an empty stomach, it is passed into the duodenum more quickly. Since it becomes absorbed right after it enters the small intestine, the action of effect may be seen in about 15–20 minutes. This is generally the fastest onset that can be expected with any orally administered compound, and usually the delay is more significant. Factors like the contents of the stomach when the compound is ingested, the solubility of the compound (discussed in the next section), and the metabolic processes (addressed later in the chapter) significantly affect the rate of absorption, and, generally speaking, most substances ingested orally take between 30 and 60 minutes before absorption begins (sometimes much longer). Consequently, oral ingestion is among the slowest routes of administration.

When it is necessary to deliver an active compound into the body as soon as it is possible, and injections are not possible or practical, the substance may be introduced into the body via the rectum. This is commonly used in emergency settings – for example, some seizure medications are available in crèmes or suppositories and can be inserted into the rectal area even when a person is in a midst of a grand convulsion. However, this method of administration also has drawbacks. It is considered more invasive, and (when conscious) individuals may not be comfortable having suppositories or creams inserted into this private area. In addition, since the substance is introduced into the large (rather then small) intestine, different absorption properties apply and the substance must be highly hydrophilic in order to be absorbed, and this presents its own challenges and drawbacks (as discussed in the next section). Generally, the vast majority of supplements are not delivered through rectal administration.

Enteral Administration

The enteral routes of administration are those in which the drug is absorbed from the gastrointestinal tract. These include thesublingual, buccal, oral, andrectal routes.

Insublingual administration, a drug product is placed under the tongue. Inbuccal administration, the drug is placed between the cheek and the gum. Both the sublingual and the buccal routes of administration enable the rapid absorption of certain drugs and are not affected by first-pass drug metabolism in the liver. Drugs for sublingual and buccal administration are given in a relatively low dose and must have good solubility in water and lipid membranes. Larger doses might be irritating to the tissue and would likely be washed away by saliva before the drug could be absorbed. Two examples of drugs available for sublingual administration arenitroglycerin for treating ischemic heart disease andhyoscyamine for treating bowel cramps.Fentanyl, a potent opioid analgesic, is available in an oral transmucosal formulation (Actiq) with a lozenge on a stick (“lollypop”) for rapid absorption from the buccal mucosa in the treatment of breakthrough cancer pain.

In medical orders and prescriptions,oral administration is designated asper os (PO), which means to administer “by mouth.” The medication is swallowed, and the drug is absorbed from the stomach and small intestine. The oral route of administration is convenient, relatively safe, and the most economical. It does have some disadvantages, however. Absorption of orally administered drugs can vary widely because of the interaction of drugs with food and gastric acid and the varying rates of gastric emptying, intestinal transit, and tablet disintegration and dissolution. Moreover, some drugs are inactivated by the liver after their absorption from the gut, calledfirst-pass metabolism (seeChapter 2), and oral administration is not suitable for use by patients who are sedated, comatose, or experiencing nausea and vomiting.

Rectal administration of drugs in suppository form can result in either a localized effect or a systemic effect. Suppositories are useful when patients cannot take medications by mouth, as in the treatment of nausea and vomiting. They can also be administered for localized conditions such as hemorrhoids. Drugs absorbed from the lower rectum undergo relatively little first-pass metabolism in the liver.

Levodopa carbidopa intestinal gel

Continuous 16-hour enteral infusion of levodopa carbidopa intestinal gel (LCIG) is a proven treatment of motor fluctuations in advanced PD (Nutt, 2006; Olanow et al., 2014; Fernandez et al., 2015). Devos (2009) reported that, within a sample of 75 patients, 61% had fewer postural instability, festination, and FOG symptoms following levodopa infusion. More recently, small retrospective and prospective open-label studies have reported that continuous 16-hour (Cossu et al., 2015; Zibetti et al., 2018) or 24-hour (Chang et al., 2015) LCIG can reduce levodopa-unresponsive FOG and associated falls.

Animal cell therapy

Cell therapy consists of the parenteral or enteral administration of cells or parts of cells obtained from animal organs and/or tissues from cattle, sheep, pigs, or rabbits. Three different types of cell preparations are in use: fresh cells, frozen cells (snap-frozen cell suspensions), and lyophilized cells (sicca cells) [145]. Cell therapy can cause local and generalized allergic reactions (fever, nausea, vomiting, urticaria, and anaphylactic shock). Other untoward consequences include fatal and non-fatal encephalomyelitis, polyneuritis, Landry–Guillain–Barré syndrome, fatal serum sickness, perivenous leukoencephalitis, and immune-complex vasculitis [146].

Treatment and outcomes

Therapy is straightforward, i.e., oral or enteral administration of l-serine 200–600 mg/kg/day until normalization of l-serine in blood and ideally in CSF. If seizures persist, glycine should be added up to a maximal dose of 200 mg/kg/day. In cases with low 5-methyltetrahydrofolate (5-MTHF), additional treatment with folinic acid (10 mg/day) should be provided.

Oral l-serine supplementation has proven to be effective in the treatment of seizures in these patients, especially those with 3-PGDH deficiency; also, a remarkable increase of white matter volume on MRI has been noted. The effect of therapy on the patients’ psychomotor development during long-term follow-up was much less. Prenatal treatment of a mother with l-serine has proven effective; 1 case with 3-PGDH deficiency born to a mother who was treated from week 27 onward did not develop any of the neurologic symptoms of the disorder (de Koning et al., 2004).

Probiotics

Some placebo-controlled RCTs have shown that prophylactic enteral administration of probiotics is capable of reducing the incidence of infectious complications in pancreas and liver surgery.15 Two small RCTs from Hungary suggested a beneficial effect of prophylactic use of probiotics in predicted severe pancreatitis. In the large Dutch probiotics trial in patients with predicted severe acute pancreatitis, however, no effect on infectious complications was found, but a more than twofold higher mortality rate (16% vs. 6%) was shown in the patients receiving probiotics. So far, no satisfactory answer to this puzzling finding has been presented, in spite of several follow-up studies, clinically and experimentally. At this stage, prophylactic probiotics are not recommended for patients with predicted severe acute pancreatitis.

FIRST-PASS CLEARANCE

A special situation occurs for some drugs in which dramatic differences in concentrations and effects occur between enteral and parenteral administration as a result of first-pass effect or presystemic drug clearance. During enteral absorption, drug passes through the intestinal wall, enters the portal venous circulation, and passes through the liver before reaching the systemic circulation (see Fig. 20-3). Nearly complete metabolism may occur in the intestinal wall or the liver (especially for drugs metabolized by cytochrome P450 3A4), so the amount of parent drug reaching the systemic circulation is only a small fraction of the dose administered.12,13 The fraction (F) of the oral dose that reaches the systemic circulation is that which remains after hepatic or intestinal metabolism and is expressed as the extraction ratio (ER) in the following equation:

The F is determined from the ratio of the area under the plasma concentration curve after oral administration compared with that after intravenous administration. After an intravenous dose of medication, drug enters either the inferior or superior vena caval circulation, returns to the heart, and enters the systemic circulation before perfusing the liver. Drugs that undergo almost complete hepatic or intestinal metabolism before reaching the systemic circulation are described as having a high hepatic or intestinal intrinsic clearance. Some drugs used in the care of newborns that exhibit moderate to significant first-pass, presystemic clearance in adults and infants include midazolam,14 morphine,15 and propranolol.16