Drug Absorption Flashcards
Define drug absorption.
Absorption is the movement of a drug from its site of administration into the central compartment.
What are the characteristics of a drug that predict its movement and availability at sites of action?
(1) its molecular size and structural features
(2) degree of ionization
(3) relative lipid solubility
(4) its binding to serum and tissue proteins
How does the ionization affect diffusion of a drug through the cell membrane.
Non-ionized molecules are more lipid soluble and can diffuse readily across the cell membrane.
Ionized molecules are less able to penetrate the lipid membrane because of their low lipid solubility.
Define facilitated diffusion.
This is a type of passive transport where molecules move across a biological membrane from an area of higher concentration to an area of lower concentration with the help of specific transport proteins.
Give one example of an efflux pump that carries out facilitated diffusion.
P-glycoprotein
Explain how efflux pumps like P-gp can significantly affect the oral absorption of drugs.
After a drug is absorbed into the cells lining the GI tract, P-gp can pump it back into the intestinal lumen, reducing the amount of drug that enters the bloodstream.
Describe Ion Pair Transport and give an example.
Ion pair transport is a mechanism that allows highly ionized compounds, which typically have low lipid solubility, to penetrate the lipid membrane layers of the gastrointestinal tract.
Examples include sulfonic acids and quarternary ammonium compounds. These compounds are lipophobic, making it difficult for them to pass through the lipid-rich cell membranes. These highly ionized, lipophobic drugs can reversibly combine with endogenous compounds in the GIT, such as mucin. This combination forms a neutral ion pair complex that can now penetrate the lipid membrane by passive diffusion.
List six ways in which drugs can move across cellular barriers.
➤ Simple diffusion
➤ Facilitated diffusion
➤ Filtration and bulk flow
➤ Endocytosis
➤ Ion-pair
➤ Active transport
What is plasma protein binding?
Plasma protein binding refers to the degree to which drugs attach to proteins within the blood plasma.
Which plasma protein do acidic drugs typically bind to?
Acidic drugs typically bind to plasma albumin.
Which plasma protein do basic drugs usually bind to?
Basic drugs usually bind to alpha-1 acid glycoprotein (a1-glycoprotein).
What happens when the concentration of a drug increases in relation to plasma protein binding?
Increasing concentration of a drug can progressively saturate the binding sites on plasma proteins.
Plasma protein binding
Why is the unbound fraction of a drug important?
Only the unbound fraction of a drug is pharmacologically active, can cross cell membranes, and is available for metabolism and excretion.
What is the effect of drugs with high physicochemical affinity for plasma proteins?
They can displace other drugs or endogenous compounds with lower affinity, increasing the free concentration of the displaced substance.
Why do drugs with high protein binding tend to be long-acting?
Because the bound fraction is not available for metabolism, only the free drug is metabolized and cleared, prolonging the drug’s action.
Further notes:
As the free drug is metabolized and cleared from the body, the bound drug gradually dissociates from the plasma proteins to maintain equilibrium. This slow release of the bound drug into the bloodstream prolongs the drug’s presence and action in the body.
What happens to drug binding in hypoalbuminemia?
Binding is reduced, leading to a higher concentration of free drug in the bloodstream, which can increase the risk of toxicity.
What is the Volume of Distribution of a drug?
It is defined as the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration observed in blood plasma. A higher Vd indicates that the drug is extensively distributed into body tissues, while a lower Vd suggests that the drug remains largely within the plasma.
How is Vd calculated?
Vd = Amount of drug in the body / Plasma drug concentration
What is the bioavailability of a drug?
Bioavailability is the fraction of unchanged drug reaching the system circulation following administration by any route.
How is bioavailability measured?
It is calculated by finding the area under the curve of a concentration vs time graph.
What is extraction ratio?
This refers to the effect of first-pass hepatic elimination on bioavailability.
Further notes:
The systemic bioavailability of a drug (F) can be predicted from the extent of absorption (f) and the extraction ration (ER):
F = f x (1 - ER)
Example:
Morphine is almost completely absorbed (f = 1). Its extraction ratio is 0.67, so (1 - ER) is 0.33. The bioavailability of morphine is thus about 33%.
Drugs with high extraction ratios have marked variations in bioavailability between subjects because of differences in hepatic function and blood flow. Shunting of blood past hepatic sites of elimination will result in substantial increases in drug availability.
For drugs that are poorly extracted by the liver (difference between entering and exiting drug concentration is small), shunting of blood past the liver will cause little change in availability.
What are some alternative routes of drug administration aimed at avoiding the first pass effect?
use of sublingual tablets, transdermal preparations, rectal suppositories
Further notes:
➤ Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead into the liver predominate, thus only about 50% of a rectal dose can be assumed to bypass the liver.
➤ Drugs administered by inhalation bypass the hepatic first-pass effect. However, the lung may also serve as a site of first pass loss by excretion and possible metabolism.
