Medical Pharmacology Topics   

Pharmacodynamics: Absorption/Distribution

After a drug is absorbed, it will either bind to plasma proteins, remain as free drug in plasma or be distributed proportionally between bound and free. Even after a drug is excreted in the bile, re-absorption may occur in the small intestine, a process known as enterohepatic recirculation, prolonging the length of time that a drug is in the body. As it reaches other tissues, the drug may bind to and accumulate in proteins and/or lipids.

Absorption

Absorption occurs through one or more membranes by passive diffusion, facilitated diffusion or active transport. Simple diffusion requires no energy and is concentration dependent. It involves either the hydrophobic bonding of lipid-soluble drugs with membrane lipids or the diffusion of water-soluble drugs through aqueous channels.

Facilitated diffusion uses carrier molecules to transport the drug down its concentration gradient, and is selective, saturable and requires no energy. Active transport requires energy to move drugs against their concentration gradient, it is selective, and saturable.

Drug absorption depends on lipid/water solubility, dissolution rate, concentration at the absorption site, blood circulation at absorption site, and area of absorbing surface. The pH gradient across a membrane will determine the absorption rate of week acids and bases. Non-ionized drugs are much more lipid soluble than ionized drugs, therefore will cross membranes more readily. How much is in the non-ionized state is described by the Henderson-Hasselbach equation for a weak acid HA or base B:

Example Problems - Absorption of Weak Acids/Bases

Many drugs are so lipophilic that would not be transported in the blood without the plasma proteins like albumin and a1-glycoprotein. Binding to plasma proteins facilitates absorption from the administration site by removal of drug by the plasma proteins in the circulation.

Endothelial cells of capillaries have spaces between them (fenestrations and "loose" intercellular junctions) that allow the passive diffusion of drugs. But capillaries in barrier areas (blood/brain barrier, placental barrier) do not have fenestrations and have tight intracellular junctions, thus drugs must diffuse through two or more membranes.

Bioavailability (F) refers to the extent by which an oral dose reaches the systemic circulation. Drugs with the lowest bioavailability are those more susceptible to the first-pass effect. The bioavailability of a drug is normally determined by comparing time-course curves for oral and intravenous administration, determining the area under each curve (AUC) and calculating the ratio:

F  =  AUCpo / AUCiv

It is assumed that no first-pass metabolism occurs after intravenous administration and that essentially all drug equilibrates in the blood. The oral dose needed to attain a desired plasma concentration must be increased by F to compensate for the fraction lost.

Distribution

Drug distribution may be described by a one compartment model in which drug distributes throughout the body immediately after administration. The volume of distribution (Vd) may be calculated from the IV dose and steady-state plasma concentration (Pss):

Vd  =  dose / Pss  =  mg/(mg/L)  =  L

or for an oral dose:

Vd =  F dose / Pss

The one compartment model is not very realistic for most drugs. A two compartment model describes how the drug is distributed first to rapidly-equilibrating tissues, for example the vasculature (central compartment), and later to slowly equilibrating tissues (peripheral compartment).

Using the two-compartment model, the volume of distribution becomes an apparent volume of distribution, usually larger than total plasma volume (~ 3 L per 70 kg male) or total body fluids (~ 42 L per 70 kg male). This is due to the accumulation of drug in tissue other than plasma, while still using Pss to assess volume.

Drugs that have a large apparent Vd will have a low plasma concentration relative to total dose administered, i.e. the drug distributes preferentially to tissues other than plasma. Drugs that bind to tissue will reach a saturation point beyond which additional dosage remains as free drug in the plasma, but drugs are seldom given beyond their saturation points.

Example Problems - Volume of Distribution

Tissues like fat, bone and plasma proteins act as reservoirs for some drugs. Fat will store highly hydrophobic drugs. Divalent metal ions are stored in bone. Binding of amphipatic drugs to plasma proteins is non-covalent and saturable.

Diseases of protein depletion alter the total binding ability of plasma proteins. For example, liver function in infants is not fully developed, so bilirubin accumulates in plasma proteins; decreasing the binding capacity of plasma proteins will result in toxicity.

Continue to "Excretion" or take a quiz: [Q1] [Q2].

Advance Topics: Passive Transport (Cellular and Molecular BIology)
                         ATP Pumps (Cellular and Molecular BIology)
                         Physiological Models (Intro to Pharm & Tox)

Need more practice? Answer the review questions below (after sponsor).

1- List 3 ways a drug can distribute in plasma after absorption.

2- What is enterohepatic recirculation?

3- List 3 ways drugs are absorbed through membranes.

4- What are the characteristics of simple diffusion?

5- What are the characteristics of facilitated diffusion?

6- What are the characteristics of active transport?

7- What is the importance of fenestrations and barrier areas to drug absorption?

8- List 6 things that affect drug absorption.

9- How do the pH gradient across a membrane affect absorption?

10- What is the role of plasma proteins in drug absorption?

11- What features of capillaries allow passive diffusion of drugs?

12- What are blood-tissue barriers? List 2 such barriers.

13- What is a one compartment pharmacokinetic model?

14- What is volume of distribution according to the one compartment pharmacokinetic model?

15- What is a two compartment pharmacokinetic model?

16- What is volume of distribution according to the two compartment pharmacokinetic model?

17- List 3 tissues that may be drug reservoirs, and the types of drug they often store.

18- List 2 plasma protein that may bind drugs.

19- What is the basis of bilirubin toxicity in newborns?

20- What is bioavailability?

21- Which drugs have the lowest bioavailability? How this relates to an oral dose?

22- How is the bioavailability of a drug determined?

Continue scrolling to answers below (after sponsor).

Hey! DON'T PEEK!!! Finish the questions fist!

1- List 3 ways a drug can distribute in plasma after absorption.
binds to plasma proteins
remain as free drug in plasma
is distributed proportionally between plasma bound and free

2- What is enterohepatic recirculation?
Even after a drug is excreted in the bile, re-absorption may occur in the small intestine, a process known as enterohepatic recirculation, prolonging the length of time that a drug is in the body

3- List 3 ways drugs are absorbed through membranes,
simple diffusion
facilitated diffusion
active transport

4- What are the characteristics of simple diffusion?
Requires no energy, is concentration dependent, and involves either the hydrophobic bonding of lipid-soluble drugs with membrane lipids or the diffusion of water-soluble drugs through aqueous channels.

5- What are the characteristics of facilitated diffusion?
Uses carrier molecules to transport the drug down its concentration gradient, is selective, saturable and requires no energy.

6- What are the characteristics of active transport?
Requires energy to move drugs against their concentration gradient, is selective and saturable.

7- What is the importance of fenestrations and barrier areas to drug absorption?
Fenestrations are thin membrane spaces between the endothelial cells of capillaries that allow the passive diffusion of drugs. But capillaries in barrier areas (blood/brain barrier, placental barrier) do not have fenestration, therefore drugs must diffuse through two membranes.

8- List 6 things that affect drug absorption.
lipid/water solubility of the chemical
pH gradient across absorbing membrane
dissolution rate
concentration at absorption site
blood circulation at absorption site
area of absorbing surface

9- How do the pH gradient across a membrane affect absorption?
Non-ionized drugs are much more lipid soluble than ionized drugs and will cross the membrane more readily. How much is in the non-ionized state is described by the Henderson-Hasselbach equation:

10- What is the role of plasma proteins in drug absorption?
Many drugs are so lipophilic that would not me transported in the blood without the plasma proteins like albumin and a1-glycoprotein. Binding to plasma proteins facilitates absorption from the administration site by removal of drug by the plasma proteins in the circulation.

11- What features of capillaries allow passive diffusion of drugs?
Endothelial cells of capillaries have spaces between them (fenestrations and "loose" intercellular junctions) that allow the passive diffusion of drugs.

12- What are blood-tissue barriers? List 2 such barriers.
Capillaries in barrier areas (blood/brain barrier, placental barrier) do not have fenestrations and have tight intracellular junctions, thus drugs must diffuse through two or more membranes.

13- What is a one compartment pharmacokinetic model?
Describes drug distribution throughout the body immediately after administration.

14- What is volume of distribution according to the one compartment pharmacokinetic model?
Vd = dose / steady-state plasma concentration.

15- What is a two compartment pharmacokinetic model?
Describes how a drug is distributed first to rapidly-equilibrating tissue (central compartment) and later to slowly-equilibrating tissues (peripheral compartment) .

16- What is volume of distribution according to the two compartment pharmacokinetic model?
Becomes an apparent volume of distribution usually larger than total plasma volume due to the accumulation of drug in tissue other than plasma, while still using Vd = dose/Pss to asses volume. Drugs with a large apparent Vd will have low plasma concentration relative to total dose administered.

17- List 3 tissues that may be drug reservoirs, and the types of drug they often store.
fat - hydrophobic drugs
bone - divalent metal ions
plasma proteins - amphipatic drugs

18- List 2 plasma protein that may bind drugs.
albumin
a1-glycoprotein

19- What is the basis of bilirubin toxicity in newborns?
Liver function in infants is not fully developed, so bilirubin accumulates in plasma proteins; decreasing the binding capacity of plasma proteins will result in toxicity.

20- What is bioavailability?
Bioavailability (F) refers to the extent by which an oral dose reaches the systemic circulation.

21- Which drugs have the lowest bioavailability? How this relates to an oral dose?
Drugs with the lowest bioavailability are those more susceptible to the first-pass effect. The oral dose needed to attain a desired plasma concentration must be increased by F to compensate for the fraction lost.

22- How is the bioavailability of a drug determined?
The bioavailability of a drug is normally determined by comparing time-course curves for oral and intravenous administration, determining the area under each curve (AUC) and calculating the ratio: F  =  AUCpo / AUCiv . It is assumed that no first-pass metabolism occurs after intravenous administration and that essentially all drug equilibrates in the blood.