Gut Absorption Pharmacology Flashcards
What is responsible for transporting blood from most of the gastrointestinal tract to the liver for metabolic processing before the blood returns to the heart?
The hepatic portal system
The portal system drains venous blood from the distal end of the esophagus, stomach, small and large intestines, proximal portion of the rectum, pancreas, and spleen
The liver receives nutrient-rich deoxygenated blood and oxygenated blood from where? What function does each type of blood have in the liver?
deoxygenated- portal vein (provide blood for metabolism and detoxification)
oxygenated- hepatic arteries (provide oxygen for hepatocytes).
What is the role of hepatocytes in the liver?
detoxify the blood, metabolize fats, carbohydrates, and drugs, and produce bile
Blood entering the liver is delivered to what structures?
tiny vascular channels known as sinusoids
Blood exiting sinusoids goes where?
Blood exits the sinusoids into a central vein, which empties into the hepatic veins and ultimately into the inferior vena cava, which passes through the diaphragm before entering the right atrium of the heart.
What is the first-pass effect?
Oral drugs travel throughout the gastrointestinal tract, where they are absorbed by the small intestine. These drugs then travel to the liver via the hepatic portal system, where they are metabolized before entering the systemic circulation. Because of hepatic metabolism, the concentration of oral drugs is reduced before entering the systemic circulation. This is known as the first-pass effect.
What is the main impact of the first-pass effect in terms of drug administrations?
Some drugs (i.e. nitroglycerin) can be inactivated by the liver and must be delivered through a mechanism other than oral administration
FYI: nitroglycerin is administered sublingually (absorption under the tongue) to avoid inactivation
Which portion of the rectum drains via the superior rectal vein, which drains into the inferior mesenteric vein of the hepatic portal system?
The proximal portion of the rectum. Thus, the first-pass effect is seen here
What is the significance of the fact that the remainder (more distal portion) of the rectum not drained by the hepatic portal system?
first-pass effects are not seen
What is the most common, safest, most convenient, and most economical method of drug administration?
oral administration
What are some disadvantages of oral administration?
possible limited absorption of some drugs because of their physical characteristics (e.g., low water solubility or poor membrane permeability), emesis as a result of irritation to the GI mucosa, destruction of some drugs by digestive enzymes or low gastric pH, irregularities in absorption or propulsion in the presence of food or other drugs, and the need for cooperation on the part of the patient
In addition, oral drugs may be metabolized by enzymes found in the intestinal flora, mucosa, or liver before they gain access to the general circulation.
What is enteral drug administration?
Enteral administration involves the esophagus, stomach, and small and large intestines (i.e., the gastrointestinal tract). Methods of administration include oral, sublingual (dissolving the drug under the tongue), and rectal.
What is parenteral drug administration?
Parenteral dosage forms are intended for administration as an injection or infusion. Common injection types are intravenous (into a vein), subcutaneous (under the skin), and intramuscular (into muscle). Infusions typically are given by intravenous route. Parenteral dosage forms may be solutions, suspensions, or emulsions, but they must be sterile
What is bioavailability?
defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route
Why are oral dosages typically higher than parenteral dosages?
parenteral dosages have significantly higher bioavailability (assumed to be close to 100%) due to two main reasons—incomplete extent of absorption across the gut wall and first-pass elimination by the liver
Blood concentration-time curves are good for showing what?
how changes in the rate of absorption and extent of bioavailability can influence both the duration of action and the effectiveness of the same total dose of a drug
What happens to drugs that are too hydrophilic?
If too hydrophilic, the drug cannot cross the lipid cell membrane (e.g., atenolol), limiting absorption efficiency
What happens to drugs that are too hydrophobic/lipophilic?
if too lipophilic, the drug is not soluble enough to cross the water layer adjacent to the cell (e.g., acyclovir)
What is the role of P-glycoprotein and what effect does it have on drug administration?
Drugs may not be absorbed because of a reverse transporter associated with P-glycoprotein (aka P-gp, multidrug resistance protein 1 (MDR1), ABCB1, or cluster of differentiation (CD243))
This process actively pumps drug out of gut wall cells back into the gut lumen.
What can inhibit P-glycoprotein and gut wall metabolism and what is the main effect?
grapefruit juice.
May be associated with substantially increased drug absorption (more later on this topic).
Notes on first-pass effect
Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall (e.g., by the CYP3A4 enzyme system) or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination.
What are pharmaceutical equivalents?
Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration
When are two pharmaceutically equivalent drug products considered to be bioequivalent?
when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions
Why does rectal administration have higher bioavailability than oral administration?
the potential for hepatic first-pass metabolism thus is less than that for an oral dose; furthermore, a major drug metabolism enzyme, CYP3A4, is present in the upper intestine but not in the lower intestine
NOTE: Approximately 50% of the drug that is absorbed from the rectum will bypass the liver
What variables impact the rate and extent of drug absorption from the GI tract?
dependent upon the individual drug structure (stability, solubility, membrane permeability and likelihood of being a substrate for metabolism and efflux pumps), the presence of concurrent drugs or food in the GI tract, and the functional status of the digestive system with respect to aspects like GI transit time (constipative/diarrheal influences, level of enzyme expression, etc).
T or F. There are large differences between the underlying gastrointestinal mechanisms present in men and women
T. For example, studies have shown that gastro-
intestinal transit tends to be slower in women, and is subject to hormonal influences. Gastric
acid output also differs by gender, leading to significant
differences in the pH of the stomach with men having more acidic conditions
NOTE: Even within gender there is huge variability: among women, differences (e.g. motility pattern and mucosal enzyme activity) during pre- and post-menopause, with and without hormonal treatments, and during menstrual cycle need to be properly assessed.
For a drug to be absorbed—to enter the bloodstream—the drug must cross biologic barriers. For orally administered drugs, what are these barriers?
the epithelial cells lining the gut and the endothelial cells of the vasculature
Most drugs move down their concentration gradients from an area of high concentration to an area with a lower drug concentration
T or F. Most drugs cross biologic barriers by passive diffusion
T.
On the other hand, a few drugs cross biologic barriers using active transport mechanisms. In this case, the drug may move “uphill” against its concentration gradient—from an area of low concentration to an area with higher concentration. This type of transport requires energy expenditure, typically ATP
For drugs that are absorbed by passive diffusion, what is a key determinant for predicting how well the drug will be absorbed?
the lipid solubility of the drug
What is the major rule for determining the lipid-solubility of a drug?
Drugs that are lipid soluble easily pass through the lipid bilayer of cell walls. As a general rule, the more carbon atoms and the fewer oxygen atoms a drug has, the more lipid-soluble the drug is. However, the problem with lipid solubility is that a drug must be lipid soluble (hydrophobic) enough to pass through cell membranes.
T or F. Absorption is fast for drugs that are large in size or that possess “bulky” or oxygenated side chain groups
F. It is slow
Most drugs are 250-450 Da in size, and can readily cross membranes.
What is the degree of ionization of a drug?
The ratio of ionized versus un-ionized fraction of drug
Ionized drugs are poorly lipid soluble and do not readily cross lipid membranes, but they dissolve well in aqueous media. Un-ionized drugs, on the other hand, are highly lipid soluble and readily cross biologic membranes
The ratio of ionized versus un-ionized fraction of drug depends on the pKa (ionization constant) of the drug and the pH of the surrounding tissues or fluids.
What is an important effect of drugs that change gastric acidity (like a drug given for heartburn)
By making the gastric pH more neutral, these drugs can decrease the solubility of some other medications and reduce the rate and extent of absorption. They can also change to extent of ionization, shifting the balance between the fraction that can and cannot be absorbed based upon its current ionization state.
What effect can diarrhea or constipation have on drug efficiency?
for oral drugs to be maximally absorbed there must be adequate residence time of the drug dose in the appropriate portion of the GI tract. If there is the concurrent presence of a GI condition, such as diarrhea, or constipation, this can alter the time available for absorption.
What is the most prominent type of drug metabolizer?
a family of isozymes known as the cytochromes P450, usually abbreviated to CYPs. The CYPs play a vital role in intermediary metabolism, for example steroidigenesis, and in the context of drugs, they act to facilitate drug excretion by transforming the (drug) substrates into more water-soluble and polar molecules that can be eliminated in the urine and bile.
Where is the highest concentration of cytochrome P450s found in the body?
in the liver, with lesser amounts in other organ systems
In the wall of the small intestine CYP3A4 plays an important and complementary role to the efflux pumps in modulating drug access to the hepatic portal vein and ultimately to the systemic circulation. Thus, CYP3A4 serves to “break down” or inactivate drugs before they can have any pharmacologic effect in the body.
