Which route of medication administration is easiest and most desirable

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

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.

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).

First-Pass Clearance

A special situation occurs for some drugs in which dramatic differences in concentrations and effects occur between enteral and parenteral administration due to first-pass effect or presystemic drug clearance. During absorption after enteral dosing, drug passes through the intestinal wall, enters the portal venous circulation, and passes through the liver before reaching the systemic circulation (Figure 19-3). For some drugs, nearly complete metabolism of a dose may occur in the intestinal wall or the liver (especially for drugs metabolized by cytochrome P450 3A4). When this occurs, the amount of parent drug reaching the systemic circulation is only a small fraction of the dose administered.8,9 The fraction (F) of the oral dose that reaches the systemic circulation is that which remains after hepatic or intestinal metabolism expressed as the extraction ratio (ER) in the following equation:

[19-17]F=1−ER

The ER is determined from the ratio of the AUC after oral administration versus that after intravenous administration. After an intravenous dose of medication infused peripherally, drug enters either the inferior or superior vena caval circulation, returns to the heart, and enters the systemic circulation before perfusing the liver, which receives 25% of the cardiac output. 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 are midazolam,10 morphine,11 and propranolol.12

Route, Dose, and Frequency

Ibuprofen can be given orally or intravenously. Although the peak levels are reached earlier with intravenous delivery, the elimination is slower after enteral administration and thus no adjustment in dose has been suggested for route of administration. The usual dose is 10 mg/kg on day 1, followed by two doses of 5 mg/kg 24 hours apart. However, suggestions for variable dosing based on advancing postnatal age (14-7-7 mg/kg for postnatal ages of 4 to 7 days and 20-10-10 mg/kg for postnatal ages >7 days)43 due to increased clearance of ibuprofen after birth have been made. A reduced rate of failure to close the ductus arteriosus has been observed with high doses of ibuprofen compared with low doses (RR 0.27; 95% CI 0.11 to 0.64).44 In a study of 60 preterm neonates with hsPDA, Pourarian et al.45 reported a 70% ductal closure rate in infants treated with an oral high-dose ibuprofen regimen (20-10-10 mg/kg) compared with a 37% closure rate with standard dosing (10-5-5 mg/kg) with no difference in adverse renal or gastrointestinal side effects. Adaptive dosing in the form of continued doses of ibuprofen (up to six doses if PDA was not closed) was associated with an 88% closure rate (similar to indomethacin).46 Doubling of the doses during the second course was associated with 60% closure rates compared with 10% in infants receiving the same dose when a consecutive treatment protocol was used, underscoring the need for further studies on ibuprofen dosing, pharmacokinetics, and pharmacodynamics.47

Several trials have also compared the efficacy of routes of administration. A systematic review of oral versus intravenous ibuprofen indicated a lower risk of failure to close a PDA with oral ibuprofen use (RR 0.41, 95% CI 0.27 to 0.64).44 However, it should be noted that oral ibuprofen is associated with higher rates of gastrointestinal hemorrhage. Furthermore, higher rates of sustained closure have been observed after continuous infusion compared with bolus infusion (closure after one or two courses 86% in continuous infusion group versus 68% after one or two courses in the intermittent infusion group; P = .02).48

Ibuprofen is available in two preparations, ibuprofen lysine and ibuprofen-tris-hydroxymethyl-aminomethane (THAM). The association of ibuprofen use with pulmonary hypertension was initially thought to be specific to the ibuprofen-THAM preparation; however, in a cohort of 144 neonates who received ibuprofen treatment for PDA, 10 cases developed pulmonary arterial hypertension, of which 7 occurred in the intravenous ibuprofen-THAM group (n = 100), 2 in the oral ibuprofen group (n = 40), and 1 who received intravenous ibuprofen lysine preparation (n = 4). Risk factors for the development of pulmonary arterial hypertension were small for gestational age, maternal hypertension, and oligohydramnios.49 In one retrospective study from Italy, it was identified that ibuprofen lysine was more effective than ibuprofen THAM in PDA ligation (73% vs. 51%, P = .002) when used prophylactically in neonates of ≤28 weeks’ gestation.50

Medications

In order to extend medication stockpiles in mass critical care, rules should be formulated ahead of time regarding appropriate substitutions, dose and frequency reductions, converting parenteral to enteral administration, restrictive indications, and shelf-life extension.3 Experience in recent PHEs indicates that very large quantities of analgesics and sedatives are essential.6,35 Weight-based dosing may be simplified to improve efficiency by specifying a limited number of weight range categories. When time constraints make it difficult to weigh patients, length-based estimates of weight may suffice.36

Enteral Nutrition

When fluid and electrolyte status has been stabilized with the parenteral regimen, enteral feeding can be considered and should begin as soon as possible. In infants, elemental diets are delivered via continuous enteral infusion. Elemental formulas are well tolerated and avoid the risk of allergy to proteins in more complex feedings. Enteral feeding is typically started very slowly with a dilute concentration (5 cal/ounce), which is slowly increased to 20 cal/ounce for patients less than 1 year of age and 30 cal/ounce for older patients. When final concentration is reached, the volume is slowly advanced. The technique of reaching final concentration prior to increasing volume avoids fluid overloading for the patient also receiving parenteral nutrition.

The continuous and aggressive use of enteral nutrition should be encouraged unless significant dehydrating diarrhea ensues, in which case the infusion should be adjusted so that overall fluid balance improves. Continuous enteral infusion is inconvenient and is thought to decrease the normal developmental processes of eating. However, this can be managed later. Newer, small enteral infusion pumps along with backpack devices have been developed to allow the patient greater mobility. When long-term enteral nutrition is anticipated, i.e., greater than 3 months, gastrostomy tube placement facilitates continuous enteral feeding. The presence of a gastrostomy or nasogastric tube does not contraindicate feeding. However, continuous feeding does alter hunger mechanisms, and rejection of oral feeds is common. Use of continuous enteral feeding does decrease the likelihood of gastroesophageal reflux.

As the child advances in age, a more complex formula, such as a protein hydrolysate, is usually well tolerated. For patients older than 1–2 years of age, whole protein formulas stimulate further adaptation by increasing the workload of the surface epithelium. Carbohydrates in enteral formulas are present in the form of one or more sources, including extensively hydrolyzed starch and disaccharidases such as sucrose. Medium-chain fats, although well absorbed, are not as beneficial as long-chain fats in enhancing adaptation. Therefore, a mixture of both types of fat in the formula is most beneficial. Carbohydrate type is probably the least important type of required nutrient for patients with short bowel syndrome. However, lactose may be more slowly hydrolyzed than glucose polymers. Table IV lists some commonly used formulas for infants and children with short bowel syndrome. Theoretically, a formula with enhanced proportions of fat, even to 50% of the total daily energy intake, may be beneficial not only for delivering more calories in less volume, but also because high-fat formulas may slow gastrointestinal motility to enhance absorption.

TABLE IV. Commonly Used Formulas

Tolerance of continuous enteral infusion is based in part on stool losses; losses of greater than 40–50 ml/kg/day, especially if accompanied by the presence of positive reducing substances, suggest that enteral feedings should be reduced or halted. Infants should be given small volumes of nipple feedings to facilitate developmentally normal stages of eating. At the appropriate ages, introduction of solid foods should also be attempted. Caution should be given to types of solids initially utilized. Avoidance of foods containing high carbohydrate levels reduces osmotic losses. Meats are often well tolerated. Nutrient delivery by the oral route may not be significant due to malabsorption but is key in later stages of therapy. In older infants and toddlers, when the colon is intact, complex diets may be beneficial in enhancing colonic salvage of short-chain fatty acids.

23. When should hypokalemia be corrected by oral supplementation?

Even though widely variable, in the absence of transcellular potassium shifts, the average serum potassium decreases by 0.3 mEq/L for each 100 mEq reduction in total body potassium stores. Oral or enteral administration is preferred when GI function is intact; the patient has mild (K+ > 3 mEq/L) to moderate (K+ 2.5 to 3 mEq/L) asymptomatic hypokalemia with normal kidney function. Oral KCl can be given at 10 to 20 mEq PO thrice daily for mild and 40 to 60 mEq PO thrice daily for moderate hypokalemia. If ongoing losses are present, these doses can be scheduled. The serum K+ should be checked frequently and supplementation stopped or adjusted.