Drug Absorption and Factors Affecting Drug Distribution

Question 1

What does absorption mean?

Answer 1

Delivering drug to the blood

Question 2

True or False: The rate of elimination is dependent on the drug concentration.

Answer 2

True. High drug concentration equates to high rate of elimination. Low drug concentration equates to low rate of elimination.

Question 3

What does K stand for?

Answer 3

Partition coefficient. The tendency for the drug to want to be in fatty or oily material versus water.

Question 4

What does C/P stand for?

Answer 4

Drug concentration. Can be denoted as C or P depending on which area you are talking about. P= Plasma concentration and C is used when we are talking about ? distribution.

Question 5

What does Vd stand for?

Answer 5

Volume of distribution

Question 6

What does Ke stand for?

Answer 6

Kinetics of elimination. When you combine Cl and Vd you get Ke.

Question 7

What does Cl stand for?

Answer 7

Clearance

Question 8

What does Q stand for?

Answer 8

Quantity or total drug in the body

Question 9

After drug is administered IV, where can it go?

Answer 9

I will go into the plasma where it will equalibriate with plasma binding proteins. Some proteins will bind to drug. The drug will also go out to the tissue and it will also go to receptors where it can cause therapeutic and toxic effects.

Question 10

True or False: IV administration is 100%?

Answer 10

True. Other methods are not.

Question 11

Rank methods of administering drugs from fastest to slowest

Answer 11

Drugs by iv fastest, then drugs via GI, then skin, then lungs, last is drugs via muscle or fat.

Rate of absorption depends on the site of administration:
intravenous > oral > intramuscular > subcutaneous

Question 12

What are some multiple routes of drug administration?

Answer 12

Intravascular (i.v.)
- Intravenous (i.v.) injection is the common route for rapid, direct introduction of drug into blood

Intramuscular (i.m.)
- This route is useful for drugs that are destroyed by the acidity of the stomach

Subcutaneous (s.c.)
- Absorption from s.c. site slower than from the i.m. site due to less blood flow/g-tissue

Sublingual
- A useful route (75% absorption) for a drug like nitroglycerin, which is extensively destroyed by first-pass metabolism

Rectal
- Useful for patients who are vomiting or when the drug causes nausea

Dermal
- Transdermal patches are useful in smoking cessation, managing motion sickness and angina

Pulmonary (bronchial)
- Inhalation anesthetics, aerosols for asthma

Mucous membranes
- Nasal sprays

Intrathecal
- Dangerous because of the risk of infection, but used in spinal anesthesia

Cornea
- Ophthalmologic agents

Oral (p.o.)
- Most common route of administration; drugs given p.o. subject to “first-pass metabolism”

Question 13

Describe the first pass effect

Answer 13

Drugs are effected by metabolism and sometimes active form is only produced once it is broken down. If you administer drug orally it goes through the GI tract and there are many routes of blood flow. The stomach and the intestines have venous return through the portal vein to the liver, liver to the hepatic vein, hepatic vein to the vena cava. If you want the drug to be metabolized you give it orally. This is the first pass effect (ie the first pass through the liver greatly reduces the bioavailability (how much drug reaches circulation) of the drug)

Out of the mouth and the rectum is venous return that goes straight to the vena cava.

Question 14

What affects the rate of absorption?

Answer 14

Rate of blow flow
More blood flow more absorption

Surface area

Charge/Hydrophobicity
Gentamicin C1a, one of many aminoglycoside antibiotics impractical for oral administration due to polarity and charge; readily absorbed by thecapillary wall pathway after i.m. injection.

Size/Molecular Weight
Polypeptide, MW ≤ 5,000, absorbed primarily by the capillary wall pathway after i.m. or s.c. administration

Polypeptide, MW 5,000-20,000, absorbed by capillary wall and lymphatic pathways after i.m. or s.c. administration

Polypeptide, MW ≥ 20,000, absorbed primarily by the lymphaticpathway after i.m. or s.c. administration

Question 15

What are some miscellaneous factors affecting absorption?

Answer 15

1. Excipient (CaSO4 vs. lactose)- The thing you put the drug in when you make pill
2. Vehicles (aqu. sol’n vs. aqu. suspension vs.
   suspension in oil). Best ab for fungal infections is very soluble.
3. Salt form (absorption pen G Na+&raquo_space; pen benzanthine). pH has big effect this will effect hydrophobicity
4. Gastric contents:
   a. pen G destroyed by acidity of stomach
   b. food delays absorption (gastric emptying)
   c. antacids, milk, laxatives decrease drug absorption
5. Intestinal flora
6. First- pass effect

Question 16

What does F stand for?

Answer 16

Bioavailability.

Question 17

What is bioavailability?

Answer 17

This tells us how much is lost after administration

• Fraction of dose appearing in blood after absorption from its site of administration

For i.v. admininistration, F = 1.0 (zero is lost after administration)
For other routes, F is less than or equal to 1.0

Question 18

What can bioavailability indicate?

Answer 18

Bioavailability can indicate:

1. extent to which a drug is released from its formulation
2. failure of absorption due to degradation (stomach) or food complexation
3. losses due to first-pass effects

Question 19

How do you determine Foral?

Answer 19

1. Measure AUCi.v
2. Measure AUCoral

Foral = AUCoral/AUCi.v.

Question 20

What is the bioavailability equation for different doses?

Answer 20

Foral = AUCoral/AUCi.v. x Dosei.v./Doseoral

Question 21

What are the three ways drugs make it across membranes?

Answer 21

1) Passive diffusion- drug can move through the membrane on its own. Driving force is a difference in concentration or electrochemical gradient. No E used except thermal motion.
2) Facilitate diffusion- molecule is soluble in water but cant make it through the lipid bilayer. So they need a carrier protein. The carrier protein is saturable. (Limited number of carrier proteins in
membrane; a saturable process) The max rate of movement has a max. The amt of drug that ends up on both side will be equal. No expenditure of energy.
3) Active transport-protein that actively uses E to pump things in. Has ATP-dependent pump to drive solute against its concentration or electrochemical gradient. This is also a saturable process because there are limited number of pumps in the membrane. You may not end up with an equal number drugs on both sides. This process can be poisoned by a metabolic inhibitor.

Question 22

What does lipophilic/hydrophobic mean?

Answer 22

Able to pass through membrane. Remember heads of membrane are charged.

Question 23

What does Korg/aqu mean?

Answer 23

This is the partition coefficient. Tells you how much a drug likes to be in lipid vs water (ie it indicates affinity for fat)

As PC increases then lipophilicty increases

Question 24

What is the equation for partition coefficient?

Answer 24

Korg/aqu = [Drug]org/[Drug]aqu

Where [Drug] = drug concentration, not the absolute amount of the drug

Question 25

What is the distribution law?

Answer 25

A substance will
distribute itself between two immiscible
phases, so that at equilibrium the ratio of
 the concentrations is a constant, i.e.
[X]org/[X]aqu = Korg/aqu

1. Korg/aqu is independent of amount and
   volumes used.
2. Korg/aqu is dependent on temperature and
   solvents used.

Question 26

In passive or facilitated diffusion, at equilibrium [Diffusable drug]Side A = [Diffusable drug]Side B. However, total drug on the two sides of a membrane may be unequal; only the diffusible form of the drug (bound, nonionic etc) is equal when equilibrium is reached.

Name three reasons why total drug may be unequal on either side of the membrane?

Answer 26

Total drug may be unequal on either side of the membrane when drugs:

1. interact with fat
2. bind to different extents to proteins (macromolecules) on the two sides of the membrane
3. are weak acid or bases and ionize to different extents because of a pH gradient between the two sides of a membrane

Question 27

Explain ion-trapping

Answer 27

If a pH gradient exists across a membrane,
1. drugs that are weak acids or weak bases will ionize to different extents on each side of the membrane, and
2. there will be more total drug (ionized + unionized) on that side of the membrane where
ionization occurs to a greater extent. This is known as ion-trapping of drug.

At equilibrium,

1. the same concentration of unionized drug is found on both sides of the membrane, but
2. unequal concentrations of total drug (ionized + unionized) are found on the two sides of the membrane.

Question 28

What happens when you put a weak acid into an environment that is highly acidic?

Answer 28

It is un-ionized and is free to diffuse through the membrane via passive transport.

Question 29

What happens when you put a weak acids into a highly basic environment?

Answer 29

It becomes ionized and cant diffuse through the membrane, its trapped.

Question 30

What happens when you put a weak base into a highly acid environment?

Answer 30

It becomes ionizes and cant diffuse through the membrane, its trapped.

Question 31

What happens to a weak base placed into a highly basic environment?

Answer 31

It is un-ionized and it diffuses freely from one side of the membrane to the other.