Lecture 3

Question 1

What are some general features of drug distribution to take into account?

Answer 1

• Bulk flow (movement through blood, lymphatics, etc.). Occurs through passive diffusion. Diffusion coefficient is inversely proportional to the square root of MW. Size/ MW is only a significant factor when comparing small molecules with proteins.
• transport rates between blood and other compartments vary (once it gets in the blood it needs to get out of the blood).
• mechanisms of movement across cell membranes: passive: diffusion through lipid membranes and movement through aqueous channels. Active: carrier mediated transport and pinocytosis (cell drinking. Cells can take up water and liquids, and in some cases drugs along with them).

Question 2

Which is more readily absorbed, a small molecule drug or a protein based drug?

Answer 2

A small molecule drug is absorbed more readily than a protein based drug. Additionally, a protein based drug is going to be broken down in the stomach. So most protein based drugs have to be given by injection.

Question 3

What is pharmacokinetics?

Answer 3

Absorption
Distribution
Metabolism
Excretion

Process by which a drug enters, is distributed, and eliminated.
Pharmacokinetics. After youve identified Kd and affinity, this is
the next thing you want to look at. Drug can be totally useless if the
drug is excreted too quickly, or not absorbed well. Or maybe it isnt
able to reach its target in the body effectively.

Question 4

What is the rate of drug transfer across a membrane driven by in passive diffusion?

Answer 4

Driven by the concentration gradient across the membrane, and the concentration of drug that dissolves in the membrane.

Question 5

What are some important properties of drugs regarding passive diffusion?

Answer 5

1. Lipid solubility: more lipid soluble drugs can get across the membrane easier.
2. Charge (charged molecules cannot cross membranes by simple passive diffusion).
3. To a limited degree- the size of the molecule (not really much of an influence of size between a MW of 200 and 1000).

Question 6

What’s a way to cross the membrane using an antibody?

Answer 6

if you have a big drug, you can attach it to an antibody, which can bind to a receptor and result
in the endocytosis of the entire receptor with the AB-drug attached. This can be a way to cross
the membrane.

Question 7

How does toxicity relate to lipid solubility?

Answer 7

with passive transport, you need more drug on the outside than inside for it to occur. If you have a drug
that is lipid soluble then the rate of transport is significantly greater. If your drug has a high toxicity, then
this will be more of a problem with the low lipid solubility drugs because you need more of it to be able to
cross the membrane effectively.

Question 8

What is the membrane permeability coefficient dependent upon?

Answer 8

• Partition coefficient: ratio of the solubility of a compound in oil vs solubility in water.
• diffusion coefficient: the mobility of the compound in lipid.

Question 9

What is the therapeutic index?

Answer 9

TI= TD50/ED50

Question 10

What is the correlation between oil water partition coefficient and absorption in the stomach?

Answer 10

Something with a high oil-water partition coefficient can be more readily absorbed in the stomach since it needs to pass through the mucous membrane.

Question 11

What are the two main types of membrane transport?

Answer 11

-passive diffusion:
Simple
Facilitated diffusion requires a carrier protein.

• active transport:
  Requires energy, is saturable, and can work against a gradient.

Question 12

How can you tell the difference between passive and active transport?

Answer 12

• take cells growing in culture and block their energy source (ATPase inhibitors), if the drug is still absorbed then you can infer that it is passive diffusion.
• if you add a lot of drug, active transporters will become saturated.
• if you add drug on one side of the membrane, and are dealing with active transport, the transport should be able to continue working against the gradient.

Question 13

Routes of drug administration

Answer 13

• oral : ideal/ preferred in terms of patient compliance. Aka enteral = administration through the GI tract.
• injection
• sublingual: nitroglycerine under the tongue.
• rectal : drug for vomiting
• nasal
• epithelial
• inhalation
• ophthalmic : eye has restricted communication with the rest of the body due to it’s restricted circulation.
• intrathecal: brain
• perenteral: everything besides oral (IV, subcutaneous, rectal, etc.).

Question 14

What effect would a diet high in fatty foods have on absorption in the stomach?

Answer 14

They delay the emptying of the stomach and can hinder drug absorption.

Question 15

Absorption in the stomach

Answer 15

After given orally, first site of absorption is the stomach. Factors that affect absorption include:

• the particle size and rate of dissolution of the drug (bioavailability).
• concentration of soluble drug.
• rate of transit through the stomach.
• rate of clearance (removal from absorption site by the blood flow). More effective blood flow = faster transport of blood.
• stomach contents (full or empty stomach).

Question 16

Are drugs absorbed more efficiently on a full or empty stomach? How can a drug be protected from degradation in the stomach?

Answer 16

It depends on the drug. Some are better absorbed when the stomach is empty (less competition). Sometimes you need a full stomach to increase blood flow to the stomach to increase absorption. Sometimes there can be a protective coating or matrix that the drug is present in to protect degradation.

Question 17

What is bioavailability?

Answer 17

Bioavailibility is comparing the amount of drug that would end up
in a sample of blood plasma when you inject it directly into a vein
or artery, versus the amount that you get from giving some
other way. Low bioavailibility: the drug would be significantly
less present in blood plasma when given through the route
compared to the amount present in blood plasma through injection.

Question 18

What is digoxin?

Answer 18

Cardiac glycoside. Increases the strength and efficiency of heart contractions.

Question 19

What are the phases of the drug plasma level on the graph shown for digoxin?

Answer 19

Initial climb is the absorption (initial slope). Then there is a plateau, followed by a decline as the drug is metabolized.

Question 20

What is the first pass effect?

Answer 20

A drug absorbed in the stomach goes to the liver and passed trough the liver before it reaches the general circulation.

If the drug is metabolized in the liver or excreted in the bile, much of the drug may be metabolized or diverted before it reaches the general circulation.

Question 21

Where are most orally administered drugs absorbed? why?

Answer 21

The intestines. The inner surface of the stomach is lined with mucous which tends to retard the absorption of many drugs. Intestinal absorption is favored in the intestine because of it’s very large surface area with many folds and microvilli; the stomach has a relatively lower surface area.

Question 22

Absorption of weak acids and bases

Answer 22

Affected by the relative proportion of charged vs uncharged neutral drug molecules. Only neutral molecules can cross plasma membranes in the absence of a specific membrane bound transporter protein. The proportion of drug that is charged vs neutral depends on the pka of the drug and the pH of the compartment.

Question 23

What are the pH values of the covered body fluids?

Answer 23

Stomach gastric juice: 1-3
Small intestines (duodenum): 5-6
(Ileum): ~8
Large intestine: ~8 
Blood plasma: 7.4 (invariant) 
Urine: 4-8 

PH of the stomach and intestines is fairly constant, unless you’re taking something like a proton pump inhibitor to decrease stomach irritation. This could alter absorption.

Question 24

What equation can be used to determine the relative proportions of the charged and uncharged forms of weak acids/ bases?

Answer 24

Henderson-Hasselbalch equation:

pKa= pH+log(Acid/Base)

For acid: it’s (AH/A-)
For base: it’s (BH+/B)

Question 25

Where are weak acids and weak bases effectively absorbed? How are charged molecules absorbed?

Answer 25

Weak bases are more effectively absorbed in the intestines where the pH is higher. Weak acids are more effectively absorbed in the stomach where the pH is lower. Charged molecules can be transported using active transport.

Question 26

What are some compounds that inhibt transport across membranes?

Answer 26

- Cytochalasins A and B: inhibit sugar uptake aminoglycoside antibiotics (e.g. Gentamycin and cardiac glycosides (digoxin)). - Hemicoliniun: Blocks choline transport (required for the synthesis of acetylcholine) resulting in muscle paralysis. Creates a problem for endogenous ACh, so generally only used as a research compound.

Question 27

What is the relationship between Kd and time needed to reach equilibrium?

Answer 27

Smaller Kd indicates higher affinity. High affinity compounds need a longer time period to reach equilibrium compared to lower affinity compounds. So a drug with a smaller Kd will take longer to reach equilibrium than a drug with a higher Kd. Had to do with the individual rate constants.

Question 28

What are some drug distribution binding depots?

Answer 28

- binding to plasma proteins (serum albumin). - binding to skin (keratin-griseofulvin). - binding to nucleic acids especially in liver and muscle (chloroquin: drug for malaria). - accumulation in fat (DDT, other chlorinated insecticides). Drugs that are lipid soluble. - Binding to lung tissue.

Question 29

What happens when a drug binds no specifically to something? E.g. Something in the plasma?

Answer 29

Generally in the bound state the drug is unavailable to carry out it's action. Drugs that are negatively charged at pH of blood plasma will tend to bind to the plasma proteins. Drugs that are positively charged will tend to bind to alpha-1 glycoprotein.

Question 30

What are some common drugs that bind to serum albumin?

Answer 30

``` Warfarin: anticoagulant. Fairly narrow therapeutic range. Aspirin Sulfonamides: antimicrobial Barbituates: thiopental Tetracyclines Penicillins Diazepam Ibuprofen and other NSAIDS Digoxin ``` Drug-drug interactions at the level of albumin can create complications.

Question 31

Can only one drug bind to albumin?

Answer 31

No, multiple drugs can bind simultaneously to different sites so there isn't competition. This is the case with Ibuprofen and Warfarin.

Question 32

What are some consequences of drug binding to albumin?

Answer 32

- reduces serum concentration of the free form of the drug and reduces the rate of distribution/ elimination. - causes drug-drug interactions (warfarin and diazepam). - makes it difficult to control drug doses. - could increase retention in the body- thus less frequent dosing. For example: there is a significant therapeutic benefit with the drug suramin because of it's tight binding to albumin. As a drug is excreted from the body it can unbind from albumin at a rate that is desired, so a single dose can end up lasting longer which is beneficial in some instances. Depends on the Kd of drug binding to albumin.

Question 33

What does the graph of drug binding look like in the presence and absence of albumin?

Answer 33

in the case of drug bound to albumin, the concentration is fairly linear. When its free, the metabolism affects the levels of drug. As you go from low to higher range, there is a range where you get a rapid change in the amount of the free drug which can be a potential problem in regulating the amount of free drug.

Question 34

What is kernicterus?

Answer 34

Can result from drug binding to albumin. Yellow skin results from excess bilirubin. Bilirubin is the breakdown product of hemoglobin. Infants lack P450 enzyme required for bilirubin excretion. Bilirubin toxicity is normally not a problem due to the capacity of albumin to bind to bilirubin. Bilirubin induced brain dysfunction.

Question 35

Give some detail into why infants are often born with jaundice and how certain drugs can lead to a similar condition.

Answer 35

Infants are often born with Jaundice, usually resolves itself but to speed it up they are usually kept in the hospital under UV lights (phototherapy), which help to promote the breakdown of bilerubin. Bilirubin itself is a breakdown product of hemaglobin which occurs naturally. P450 breaks down bilirubin. P450 are genreally oxidative enzymes and can either directily enhance the solubility of something that isnt all that soluble, or they make a substrate for further modification for excretion. Usually the free bile rubin (even in infants) is usually very low because the albumin soaks it up (just like it does for many other things in the blood). However, if you have something binding in excess, Kernicterus can result from too much free bilerubin (not conjugated to albumin). One scenario in which this has been observed to occur is with Sulfa drugs (bind with high affinity to albumin).

Question 36

What are some symptoms of kernicterus and treatment?

Answer 36

Symptoms: excessive lethargy, loss of muscle tone, permanent brain damage, loss if hearing, cognitive loss, symptoms of cerebral palsy. Treatment: photo-therapy, which destroys bilirubin; must commence immediately after birth.

Question 37

How can kernicterus result from use of sulfa drugs to treat post-natal infections?

Answer 37

``` Sulfoxozole= sulfa drug. Start with safe level of bilerubin, which gradually rises over time. Sulfa drug concentrations goes down over time as it is binding to albumin. Ideally, you would then stop giving the drug and give a differetn antibiotic that doesnt bind to albumin. Or maybe you can deal with it using phototherapy if its critical that the patient stay on this class of drugs. ```

Question 38

What are some new methods of drug delivery?

Answer 38

Insulin pumps: remote control to initiate injection. Pulsed microjets and nanoparticles: people don't like needles, so pulsed microjets were created which force solution through the skin (totally painless).