The rate of gastric emptying affects all drugs, even those which are well absorbed in the stomach. This is because of the fact that the small intestine has a significantly larger surface area and contributes the most to drug absorption. Ergo, gastric motility is a major determinant of oral drug absorption.
In summary, drug absorption in the stomach is usually a minor player in the total absorption of a drug dose. This is because the stomach has a smaller surface area, and the drug usually does not spend very long in there (see the section on gastric motility ). Moreover some drugs are ionised by gastric pH...
Drug absorption in the GI tract should be investigated thoroughly in the presence of disease. The incidence of disease is higher in the elderly although this factor is rarely considered as the primary cause of variability in drug absorption as drug bioavailability may further be perturbed due to advanced age or a combination of both.
The decrease in intestinal transit time can significantly affect the absorption of drugs exhibiting an absorption window or pre-systemic metabolism as observed with tacrolimus and cyclosporine. Tacrolimus is rapidly absorbed in the duodenum and jejunum.
In most instances, increasing the rate of gastric emptying and gastro-intestinal motility increases the rate of absorption of a drug but, for digoxin and riboflavin, increased gastrointestinal motility is associated with a decrease in the rate of absorption.
Drugs may affect gastrointestinal motility and, therefore, absorption of other concomitantly administered drugs. Gastrointestinal prokinetic agents increase the rate of gastric emptying and also upper intestinal motility.
The rate of gastric emptying affects all drugs, even those which are well absorbed in the stomach. This is because of the fact that the small intestine has a significantly larger surface area and contributes the most to drug absorption. Ergo, gastric motility is a major determinant of oral drug absorption.
A change in the rate of gastric emptying alters the rate of drug delivery from the stomach to the duodenum and upper small intestine. This may profoundly alter the plasma concentration/time curve that follows oral administration of many drugs.
Gastrointestinal (GI) motility refers to the movement of food from the mouth through the pharynx (throat), esophagus, stomach, small and large intestines and out of the body. The GI system is responsible for digestion. The moment you even look at food, your body starts this complicated process.
Drugs used in the management of intestinal motility disorders include cholinergic agonists, prokinetic agents, opioid antagonists, antidiarrheals, and antibiotics.
Lack of or reduced secretion of gastric acid in the stomach, a condition commonly known as achlorhydria or hypochlorhydria, has been shown to significantly impair absorption of weakly basic drugs which show low solubility at high pH.
It is well known that the gastric emptying rate is an important factor affecting the plasma concentration profile of orally administered drugs, and the intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site.
Factors affecting Absorption of DrugsLipid water solubility. Lipid water solubility coefficient is the ratio of dissolution of drug in lipid as compared to water. ... Molecular size. ... Particle size. ... Degree of Ionization. ... Physical Forms. ... Chemical Nature. ... Dosage Forms. ... Formulation.More items...•
small intestineThe small intestine has the largest surface area for drug absorption in the GI tract, and its membranes are more permeable than those in the stomach.
Absorption from the intestine is dependent on: (1) the physiochemical state of the substance, (2) the nonabsorptive physiologic functions and state of the intestine, (3) the metabolic activity and functions of the absorbing cell, and (4) the structure of the absorbing surface.
Drug Absorptionformulation factors.ionization degree.size of drug.concentration of drug.water solubility at site of absorption.lipid solubility.chemical stability.binding of drug to other drugs, foods or particles.
The focus is usually not on gastric motility. However, gastric motility is one of the most important influences on drug absorption and oral bioavailability. Because it is affected by critical illness and shoick, it would also play a role in determining how critical illness in general affects pharmacokinetics ...
Even drugs which are undissociated in gastric acid and fully dissociated in the small bowel are still predominantly absorbed in the small bowel because of its comparatively massive surface area. In brief summary, gastric emptying can be affected by: Food in the stomach (especially fat) Viscosity of the stomach content.
Thus, gastric emptying rate is one of the main determinants of oral drug bioavailability and gastrointestinal drug absorption. If the stomach does not empty, practically nothing is going to get absorbed. Even drugs which are undissociated in gastric acid and fully dissociated in the small bowel are still predominantly absorbed in the small bowel because of its comparatively massive surface area.
This is because of the fact that the small intestine has a significantly larger surface area and contributes the most to drug absorption.
Few drugs are absorbed in the stomach. Theoretically the low pH of the gastric fluid should render all but the most acidic drugs into a lipid-soluble nonpolar form, which would favour absorption. However, this is usually not the case for two main reasons.
The consequences of this are that the stomach participates minimally in drug absorption, and any situation which involves drugs sitting in the stomach for a long time will result in poor drug bioavailability.
To be well absorbed in the stomach, a drug would need to be: A small molecule. Weakly acidic (pKa higher than the pH of stomach acid) Highly concentrated (i.e. a large dose of drug) Additional caveats in the ICU environment:
Hogben and Adrian (1957) noted that "salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed" and that surprisingly many drugs "may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol". Knowing this list of gastrically absorbed drugs has some relevance for the intensive care community, as our patients are notoriously lazy at emptying their stomachs (being critically ill, affected by shock and ileus and whatnot).
In fact pKa seems to be one of the major determinants of absorption through the stomach wall. To study these phenomena usually animals either have their pylorus ligated, or have an exteriorised patch of gastric mucosa (a "Pavlov pouch").
This rat study and a subsequent human follow-up by Hogben Adrian and Schanker (1957) laid down that main tenet of gastric pharmacokinetics (" passive transfer at a rate determined by the ionisation and lipid solubility of the drug molecules ") as repeated in Rang and Dale.
Hypothetically, if the patient were to swallow a large rubbery blob of highly fatty paracetamol-rich goo, it would sit in their stomach for hours , and the majority of paracetamol in ther bloodstream would come from their stomach.
Empirically, it is possible to demonstrate that there are a few drugs which will still be absorbed to some small extent even when the stomach is uselessly immobile. Mostly, these are the theoretically predicted weakly acidic drugs which are fully un-dissociated in the presence of normal gastric pH. In fact pKa seems to be one of the major determinants of absorption through the stomach wall. To study these phenomena usually animals either have their pylorus ligated, or have an exteriorised patch of gastric mucosa (a "Pavlov pouch"). In the graph presented below, Schanker et al (1957) were able to demonstrate that acidic drugs with pKa over 2.0 were absorbed much better than bases in the artificially acidified stomach of the anaesthetised rat.
In summary, drug absorption in the stomach is usually a minor player in the total absorption of a drug dose. This is because the stomach has a smaller surface area, and the drug usually does not spend very long in there (see the section on gastric motility ). Moreover some drugs are ionised by gastric pH and do not absorb very well (i.e. they are less lipid soluble in that state). Some drugs are actually inactivated (degraded) by gastric pH, which reduces their absorption.
These properties of the stomach can influence drug formulation and behavior. Because most absorption occurs in the small intestine, gastric emptying is often the rate-limiting step.
Intestinal transit time can influence drug absorption, particularly for drugs that are absorbed by active transport (eg, B vitamins), that dissolve slowly (eg, griseofulvin ), or that are polar (ie, with low lipid solubility ; eg, many antibiotics).
Drug absorption is determined by the drug’s physicochemical properties, formulation, and route of administration. Dosage forms (eg, tablets, capsules, solutions), consisting of the drug plus other ingredients, are formulated to be given by various routes (eg, oral, buccal, sublingual, rectal, parenteral, topical, inhalational). Regardless of the route of administration, drugs must be in solution to be absorbed. Thus, solid forms (eg, tablets) must be able to disintegrate and deaggregate.
Cell membranes are biologic barriers that selectively inhibit passage of drug mole cules. The membranes are composed primarily of a bimolecular lipid matrix, which determines membrane permeability characteristics. Drugs may cross cell membranes by
In adolescents and adults, most drugs are given orally as tablets or capsules primarily for convenience, economy, stability, and patient acceptance. Because solid drug forms must dissolve before absorption can occur , dissolution rate determines availability of the drug for absorption. Dissolution, if slower than absorption, becomes the rate-limiting step. Manipulating the formulation (ie, the drug’s form as salt, crystal, or hydrate) can change the dissolution rate and thus control overall absorption.
To be absorbed, a drug given orally must survive encounters with low pH and numerous gastrointestinal (GI) secretions, including potentially degrading enzymes. Peptide drugs (eg, insulin) are particularly susceptible to degradation and are not given orally. Absorption of oral drugs involves transport across membranes of the epithelial cells in the GI tract. Absorption is affected by
Controlled-release forms are designed to reduce dosing frequency for drugs with a short elimination half-life and duration of effect. These forms also limit fluctuation in plasma drug concentration, providing a more uniform therapeutic effect while minimizing adverse effects. Absorption rate is slowed by coating drug particles with wax or other water-insoluble material, by embedding the drug in a matrix that releases it slowly during transit through the gastrointestinal tract, or by complexing the drug with ion-exchange resins. Most absorption of these forms occurs in the large intestine. Crushing or otherwise disturbing a controlled-release tablet or capsule can often be dangerous.
They are not absorbed to any extent from the stomach but may be absorbed very rapidly from the small intestine. Thus factors influencing the rate of gastric emptying may alter the rate of absorption of most if not all orally administered drugs. Food, hormones, posture, peritoneal irritation, severe pain, gastric ulcer, ...
Delayed drug absorption due to altered gastric emptying usually results in therapeutic failure, especially if the drug has a short biological half-life. At present it is not possible to predict accurately the magnitude and clinical relevance of all drug absorption interactions.
In most instances, increasing the rate of gastric emptying and gastro-intestinal motility increases the rate of absorption of a drug but, for digoxin and riboflavin, increased gastrointestinal motility is associated with a decrease in the rate of absorption.
The impact of the intestinal microbiota system on oral drug absorption is particularly critical for low solubility and/or low permeability compounds, as well as for extended release formulations, which are subject to long residence time in the gut and may therefore interact with the intestinal microbiome.
However, the morphology and physiology of the gastrointestinal (GI) tract is influenced by multiple factors such as age, sex, ethnicity, genome, or the disease state of the treated patient .
The effect of pregnancy on drug absorption has been studied using clinical pharmacological tools (i.e., by studying the PK of drugs that are metabolized or transported by a specific enzyme or transporter, and can therefore serve as probe substrates to reflect the activities of the involved enzyme/transporter), as well as via physiological measurements of relevant mechanistic determinants of the absorption process. In terms of gastric acid secretion, several previous reviews report increased gastric pH during pregnancy ( Costantine, 2014; Pariente et al., 2016 ). However, looking back to several original studies, which addressed heartburn during pregnancy, learns that there are also reports of no major changes in gastric pH taking place between the different trimesters of pregnancy and the non-pregnant situation. In these studies also no significant effect of pregnancy on basal and peak acid outputs could be found, suggesting that changes in gastric acidity may not be that prominent ( O'Sullivan and Bullingham, 1984; Van Thiel et al., 1977 ). In terms of gastric emptying, it has been demonstrated using ultrasound studies that gastric emptying time for fluids does not appear to be affected by pregnancy ( Chiloiro et al., 2001 ). In line with this, it was found that the absorption of acetaminophen (maximum plasma concentration (C max ), time to C max (T max )), was not altered by pregnancy over the trimesters and compared to non-pregnant women ( Whitehead et al., 1993 ). The authors reasoned that due to the very rapid absorption of this drug from the small intestine, gastric emptying will be absorption-limiting. Hence, the fact that no differences occur in absorption profile also led them to conclude that gastric emptying times are not very different between trimesters. Nevertheless, overall GI transit time was found to be longer in the third trimester, indicative of an overall lower intestinal motility ( Chiloiro et al., 2001 ). Consequently, intestinal absorption may be delayed during pregnancy possibly resulting in slower T max and lower C max values for drugs in which the intestinal transit time is the rate-limiting step.
Although oral drug administration is generally not the preferred route especially for life-saving drugs, there are nevertheless several reasons for selecting oral medications, i.e., absence of intravenous access, higher occurrence of side-effects with intravenous administration, absence of appropriate intravenous formulations (especially for the paediatric population).
H. pylori infection is known to induce alterations in some physiological functions of the stomach, particularly affecting gastric acid secretion and GI motility. The impact on gastric acidity depends on the severity of the infection and distribution of the affected tissue in the stomach. Inflammation in the antral region is associated with increased production of gastrin, which in turn increases acid secretion in the gastric corpus. However, if the corpus is affected by severe inflammation, the response to gastrin is greatly reduced, resulting in reduced capacity to secrete acid ( El-Omar, 2006 ). Thus, H. pylori positive subjects can exhibit either increased or decreased stomach acidity. Between 25 and 40% of patients also exhibit antral hypomotility and a delayed gastric emptying ( Mearin et al., 1995; Miyaji et al., 1999; Thor et al., 1996 ). Furthermore, there is increasing evidence that H. pylori infection affects the GI functions indirectly by influencing the brain-gut axis ( Budzynski and Klopocka, 2014 ). This may have an impact on the pathophysiology of other organs than the stomach, and generate disturbances in permeability, motility and secretion along the entire GI tract ( Budzynski and Klopocka, 2014; Gerards et al., 2001; Su et al., 2000 ).
The increased stomach emptying time, associated with nausea and vomiting, delays the onset of action of medications and may result in uncontrolled or sub-therapeutic plasma concentrations. The selection of appropriate dosage forms, such as sublingual or orally disintegrating tablets, suppositories, or parenteral formulations is therefore particularly important in the treatment of patients exhibiting nausea or concomitant diseases.
As age advances, the GI tract undergoes a variety of morphological and functional changes that result in a general decline in bodily function. The complex deterioration of normal GI parameters can therefore compromise effective drug absorption in the elderly population, who is often subject to polypharmacy. The impact of advanced age on GI physiological factors including GI transit, pH, expression of metabolising enzymes and membrane transporters, permeability and the microbiome are limited ( Khan and Roberts, 2018 ), but studies have demonstrated minor differences when compared with healthy adults ( Brogna et al., 1999; Carríon, 2017; Fakhoury et al., 2005; Holt, 2018; Russell et al., 1993 ).
In addition to the lipid–water partition coefficient of drugs, local blood flow, and intestinal surface area, other factors may affect absorption from the gastrointestinal tract.
In general, fac-tors that accelerate gastric emptying time, thus permit-ting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption unless the drug is slow to dissolve. A list of physiolog-ical, pathological, and pharmacological factors that in- fluence the rate of gastric emptying is provided in Table 3.1.
However, it has now become apparent that drug-metabolizing enzymes, such as the cytochrome P450 en-zymes, play a major role in determining the extent of drug absorption of some drugs. Significant expression of cytochrome P450 3A4 and 3A5 occurs in the entero-cytes lining the small intestine.
As a substrate for Pgp, a drug will enter the cell, usually via passive diffusion, but then be picked up by the Pgp transporter and carried back to the gut lumen (efflux). As this continually occurs along the intestine, some of the drug molecules are prevented from being absorbed, which decreases overall absorption.
Cytochrome P450 2C9 and 2C19 are also expressed in measurable quantities in the human intestine. With any of these four cytochrome P450 en-zymes, the variation in expression between individuals is substantial, and so their relative contribution to presystemic metabolism of drugs will vary from person to person.
Drugs such as the tetracyclines, which are highly ionized, can complex with Ca++ ions in mem-branes, food, or milk, leading to a reduction in their rate of absorption. For drugs that are ionized in the stomach and un-ionized in the intestine, overall ab-sorption will be delayed by any factor that delays gas-tric emptying. Finally, increased splanchnic blood flow, as occurs during eating, will increase the rate of drug absorption.
Drugs may be inactivated in the gastrointestinal tract before they are absorbed. Until recently, only gut mi-croflora were implicated in the metabolism of drugs in the gastrointestinal system, affecting drug absorption. However, it has now become apparent that drug-metabolizing enzymes, such as the cytochrome P450 en-zymes, ...