Gut Absorption Pharmocology

Question 1

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?

Answer 1

The hepatic portal systemThe 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

Question 2

The liver receives nutrient-rich deoxygenated blood and oxygenated blood from where? What function does each type of blood have in the liver?

Answer 2

deoxygenated- portal vein (provide blood for metabolism and detoxification)

oxygenated- hepatic arteries (provide oxygen for hepatocytes).

Question 3

What is the role of hepatocytes in the liver?

Answer 3

detoxify the blood, metabolize fats, carbohydrates, and drugs, and produce bile

Question 4

Blood entering the liver is delivered to what structures?

Answer 4

tiny vascular channels known as sinusoids

Question 5

Blood exiting sinusoids goes where?

Answer 5

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.

Question 6

What is the first-pass effect?

Answer 6

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.

Question 7

What is the main impact of the first-pass effect in terms of drug administrations?

Answer 7

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

Question 8

Which portion of the rectum drains via the superior rectal vein, which drains into the inferior mesenteric vein of the hepatic portal system?

Answer 8

The proximal portion of the rectum. Thus, the first-pass effect is seen here

Question 9

What is the significance of the fact that the remainder (more distal portion) of the rectum not drained by the hepatic portal system?

Answer 9

first-pass effects are not seen

Question 10

What is the most common, safest, most convenient, and most economical method of drug administration?

Answer 10

oral administration

Question 11

What are some disadvantages of oral administration?

Answer 11

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.

Question 12

What is enteral drug administration?

Answer 12

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.

Question 13

What is parenteral drug administration?

Answer 13

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

Question 14

What is bioavailability?

Answer 14

defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route

Question 15

Why are oral dosages typically higher than parenteral dosages?

Answer 15

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 in oral dosages

Question 16

Blood concentration-time curves are good for showing what?

Answer 16

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

Question 17

What happens to drugs that are too hydrophilic?

Answer 17

If too hydrophilic, the drug cannot cross the lipid cell membrane (e.g., atenolol), limiting absorption efficiency

Question 18

What happens to drugs that are too hydrophobic/lipophilic?

Answer 18

if too lipophilic, the drug is not soluble enough to cross the water layer adjacent to the cell (e.g., acyclovir)

Question 19

What is the role of P-glycoprotein and what effect does it have on drug administration?

Answer 19

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.

Question 20

What can inhibit P-glycoprotein and gut wall metabolism and what is the main effect?

Answer 20

grapefruit juice.May be associated with substantially increased drug absorption (more later on this topic).

Question 21

Notes on first-pass effect

Answer 21

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.

Question 22

What are pharmaceutical equivalents?

Answer 22

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

Question 23

When are two pharmaceutically equivalent drug products considered to be bioequivalent?

Answer 23

when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions

Question 24

Why does rectal administration have higher bioavailability than oral administration?

Answer 24

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

Question 25

What variables impact the rate and extent of drug absorption from the GI tract?

Answer 25

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).

Question 26

T or F. There are large differences between the underlying gastrointestinal mechanisms present in men and women

Answer 26

T. For example, studies have shown that gastro-intestinal transit tends to be slower in women, and is subject to hormonal influences. Gastricacid output also differs by gender, leading to significantdifferences 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.

Question 27

For a drug to be absorbed—to enter the bloodstream—the drug must cross biologic barriers. For orally administered drugs, what are these barriers?

Answer 27

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

Question 28

T or F. Most drugs cross biologic barriers by passive diffusion

Answer 28

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

Question 29

For drugs that are absorbed by passive diffusion, what is a key determinant for predicting how well the drug will be absorbed?

Answer 29

the lipid solubility of the drug

Question 30

What is the major rule for determining the lipid-solubility of a drug?

Answer 30

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.

Question 31

T or F. Absorption is fast for drugs that are large in size or that possess “bulky” or oxygenated side chain groups

Answer 31

F. It is slow. Most drugs are 250-450 Da in size, and can readily cross membranes.

Question 32

What is the degree of ionization of a drug?

Answer 32

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.

Question 33

What is an important effect of drugs that change gastric acidity (like a drug given for heartburn)?

Answer 33

Gastric acidity is an important consideration for drugs that require a low pH for maximal absorption.

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.

Question 34

What effect can diarrhea or constipation have on drug efficiency?

Answer 34

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.

Question 35

What is the most prominent type of drug metabolizer?

Answer 35

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.

Question 36

Where is the highest concentration of cytochrome P450s found in the body?

Answer 36

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.

activity of CYP3A can also be modulated by changes in expression (enzyme induction or down-regulation), genetically determined limitations in function, and by substrate competition

Question 37

Can hormones impact drug effusion in the GI tract?

Answer 37

Yes. The rate and extent of perfusion of the gastrointestinal system can be influenced both by the release or local factors (hormones) in the gastrointestinal wall as well as the application of exogenous agents (drugs) that are administered for other purposes.

For example, the use of vasodilators (drugs increasing the diameter and therefore flow rate of arteries and veins) can increase the rate of drug absorption, whereas vasoconstrictors used to maintain blood pressure, can result in tissue ischemia and damage as a consequence of gastrointestinal hypo-perfusion.

Question 38

Notes on Intestinal Drug Pumps

Answer 38

in certain anatomical locations in the body active (energy dependent) trans- porter proteins (pumps) also play a crucial regulatory role, often working against the concentration gradient

Many of the pumps act to carry
materials into the enterocyte, for example, the
organic anion transporter protein (OATP), but
there are also ABC transporters (coloured
brown or black in the figure) that provide a
barrier function, namely P-glycoprotein (P-
gp), multidrug resistance protein (MRP), and
breast cancer resistance protein (BRCP)

Question 39

Notes on Intestinal Microflora

Answer 39

The human intestinal microbiota can have a major impact on drug metabolism and ultimately on oral bioavailability

the next generation of drugs has a higher probability of being presented to the microbiota in the lower gut, either through poor solubility/permeability properties or formulation development strategies

the total number of bacteria
depends upon location within the length of the GI tract.Therefore metabolic capacity varies by location. Regardless, the microflora have been shown to be capable of conducting a large
number of metabolic reactions. The clinical significance of the microfloral metabolism of drugs with respect to efficacy and toxicity is only now beginning to be investigated.