Movement of Drugs Through the Bady: Drug Absorption and Distribution

Question 1

What is the definition of Pharmacodynamics?

Answer 1

What the drug does to the body.

Question 2

What is the definition of pharmacokinetics?

Answer 2

What the body does to the drug.

Question 3

What are Absorption, Distribtion, Metabolism and Elimination referred to as collectively?

Answer 3

(ADME)

Question 4

What is Absorption in (ADME)?

Answer 4

Drug is absorbed from the site of administration allows entry into the plasma.

Question 5

What is Distribution in (ADME)?

Answer 5

Drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids.

Question 6

What is Metabolism in (ADME)?

Answer 6

Drug transformation by metabolism by the liver and other tissues.

Question 7

What is Excretion in (ADME)?

Answer 7

Drug and/or drug metabolites excreted in urine, faeces or bile.

Question 8

In what ways do drugs move around the body?

Answer 8

Bulk flow - this would be via the circulatory system (blood stream)
Diffusion of drug molecules over short distances
Solubility is important - lipid soluble drugs are more likely to diffuse across lipid bilayer membranes.
Large drug molecules move more slowly than small ones.

Question 9

How do cell membranes act as barriers?

Answer 9

Cell membranes are barriers between the aqueous compartments of the body.
The plasma membrane separates the extracellular “compartment” from the intracellular “compartment”.

Question 10

What are ways in which molecules can cross cell membranes?

Answer 10

Passive Diffusion
Facilitated Diffusion
Active Transport
Endocytosis (pinocytosis)

Question 11

How does passive diffusion occur?

Answer 11

Passive diffusion directly through the lipid or through aqueous pores formed by aquaporins that transverse the lipid bilayer. Many lipid soluble drugs cross cell membranes in this way.

Question 12

How does facilitated diffusion occur?

Answer 12

Facilitated diffusion via specialised carrier proteins that bind the drug on one side of the bind molecule on one side of the membrane then change conformation and release on the other side. Does not require energy, but doe require a concentration gradient.

Question 13

How does active transport occur?

Answer 13

Active transport via specialised carrier proteins requires energy and can move drug molecules against the concentration gradient.

Question 14

How does Endocytosis (pinocytosis) occur?

Answer 14

Invagination of a part of the membrane. The drug is encased in a small vesicle then “released” inside the cell.

Question 15

When does passive diffusion normally work well?

Answer 15

Simple passive diffusion generally works for lipid soluble drugs

Question 16

What is Facilitated Diffusion?

Answer 16

Water-soluble drugs can enter the cell through specialised carrier proteins.
Does not require energy.
Can chow saturation kinetics.
(Limited/finite number of carrier proteins).

Question 17

What is Active transport?

Answer 17

Water-soluble drugs can enter the cell through specialised carrier proteins.
Requires energy.
Is capable of moving drugs against a concentration gradient.
Can show saturation kinetics for the carrier.

Question 18

Why is carrier-mediated transport?

Answer 18

Carrier-mediated transport is important for some drugs that are chemically related to endogenous substances such as neurotransmitters.

Question 19

Why is carrier-mediated transport important?

Answer 19

Carrier-mediated transport is important for some drugs that are chemically related to endogenous substances such as neurotransmitters.

Question 20

What is Endocytosis?

Answer 20

Transport of large drugs across the cell membrane - e.g., vitamin B12

Question 21

What type of chemicals are many drugs and what forms do they exist in?

Answer 21

Many drugs are weak acids or weak bases.

These drugs will exist in both their ionised and un-ionised forms.

Question 22

What can be used to determine the proportions of ionised and un-ionised drugs in a given pH environment?

Answer 22

The Henderson-Hasselbalch equation can be used to determine proportion of ionised and un-ionised drugs in a given pH environment.
Equations in notebook!!

Question 23

What is an example of pH trapping across a plasma membrane, how does it occur and what is the effect?

Answer 23

Aspirin (acetylsalicylic acid) pKa =3.5.
Negatively charged aspirin diffuses across the membrane of the gastric mucosa and is trapped in the plasma - good absorption.
This causes a permanent different in pH across the Gastric Mucosal Barrier, stomach pH 1.5 and Plasma pH 7.4.

Question 24

Where do weak bases accumulate and where do weak acids accumulate?

Answer 24

Weak bases accumulate in compartments with low pH, weak acids accumulate in compartments with high pH.

Question 25

What are different body compartments that drugs are distributed in and what is an example of what type of drug would be distributed in that area?

Answer 25

Drug distribution varies with different body compartments:
Total body water - small water-soluble molecules
Extracellular water-larger water-soluble molecules
Blood plasma-highly plasma protein-bound molecules, large molecules, highly charged molecules.
Adipose tissue-highly lipid soluble molecules
Bone teeth-certain ions.

Question 26

Important Pharmacokinetics Concept #1

The apparent Volume of Distribution (Vd (d is subscript)). What is this and what is the equation to calculate it?

Answer 26

The apparent volume of distribution (Vd) describes the extent to which a drug partitions between the plasma and tissue compartments.
Vd = Dose/(Drug)plasma
Analogy:
Think of the body as a well stirred beaker. If 1g of a drug is then dispersed by the beaker, however the volume of solution is unknown. A sample is taken and a drug concentration of 10mg/L is recorded. We can conclude that the volume of solution is 100L. This describes what the apparent volume of distribution is.

Question 27

How do you calculate:
Vd
(Drug)plasma
Volume of Beaker

Answer 27

Vd = Dose/(Drug)plasma
(Drug)plasma = Amount added/Volume of Beaker
Volume of Beaker = Amount added/(Drug)plasma

Question 28

What is Vd (d is subscript), and how does it affect how easily a drug can cross membranes?

Answer 28

Vd is a reproducible and clinically relevant value.
Apparent volume of distribution (Vd) is an extrapolated volume based upon (Drug)plasma.
Not a physical volume - Many drugs will have an apparent volume of distribution greater than the body’s total volume of water (41L), hence “apparent”. “Volume” is used in a metaphorical sense.
Physiochemical properties largely determine a drug’s Vd. It is more difficult for hydrophilic or ionized drugs to cross membranes - Vd is closer to total body volume of water (41L).
Lipophilic drugs cross membranes easily and Vd is generally greater than total body volume.

Question 29

What is the process used to determine the apparent volume of distribution (Vd) from drug blood plasma concentrations.

Answer 29

Administer drug dose.
obtain blood sample.
Separate plasma from RBCs.
Assay for (Drug)plasma.
Calculate Vd

Question 30

What is invagination?

Answer 30

The action or process of being turned inside out or folded back on itself to form a cavity or pouch.

Question 31

What affects the proportion of ionisation of a drug?

Answer 31

The proportion of ionisation of a drug depends upon both the pKa of the drug and the local pH.

Question 32

What does the pKa value mean?

Answer 32

The pKa = pH at which 50% of drug is ionised and 50 % un-ionised.

Question 33

What form of many drugs can permeate the membrane?

Answer 33

For many drugs the non-ionised form can permeate the membrane.

Question 34

What is the ionisation reaction of acids and bases?

Answer 34

Acids
AH = A- + H+ (reversible reaction)
Bases
BH+ = B + H+ (reversible reaction)

Question 35

What does the low pH of the stomach and the higher pH of the intestine facilitate?

Answer 35

The low pH of the stomach facilitates absorption of weak acids (think about ionisation and crossing membranes), whilst the higher pH of the intestine facilitates absorption of weak bases.

Question 36

Where does most oral route drug absorption occur and why?

Answer 36

Note: that most oral route drug absorption occurs in the small intestine due to the large surface area.
The field of pharmaceuticals looks into developing devices for drug delivery and release in the optimal physiological environment to facilitate drug absorption.

Question 37

What is the Vd for a given drug essentially?

Answer 37

Vd for a given drug is essentially the result of the “pull” between blood and tissue.
Initia restriction of drug to highly vascularised parts of the body, hydrophilic or ionized drugs such as aspiri (Vd = 10).
Eventual Free Access of Drug to many Areas of Body following slow equilibration, lipophilic drugs or un-ionised drugs such as amitriptyline (Vd = 1221).
For drugs of equal potency, a drug with a high Vd will require a higher dose than a drug with low Vd.

Question 38

What is the difference between drugs with a low Vd and drugs with a high Vd?

Answer 38

Low (Vd) drugs that are retained in vascular compartments.

High (Vd) in adipose, muscle and other non-vascular compartments.

Question 39

What is the most abundant plasma protein?

Answer 39

Albumin

Question 40

How do many drugs with low affinity bind to albumin?

Answer 40

Many drugs with low affinity bind to albumin via electrostatic and hydrophobic forces?

Question 41

What does plasma protein binding result in?

Answer 41

Plasma protein binding reduces the availability of the drug for diffusion to the drug target organ.
May also reduce the transport of the drug to non-vascular compartments.

Question 42

How does plasma protein binding affect the Vd of a drug?

Answer 42

The lower the (Drug)plasma, the higher the Vd.
Vd = Dose/(drug)Plasma
The higher the plasma protein binding, the lower the Vd.