Pharmacokinetics 1

Question 1

What influences drugs affects on the body?

Answer 1

• the drugs effects on proteins, receptors, enzymes, ion channels
• also physiochemcial properties - like affinity, efficacy and potency.

Question 2

What to consider when choosing drug concentration?

Answer 2

• Its absorption
• distribution
• Metabolism
• Excretion

Question 3

Why do we use pharmacokinetics to decide upon drug concentrations?

Answer 3

• this is because some drugs concentrations can’t be made to be optimal.

Question 4

What controls drug absorption and distribution through the body?

Answer 4

• remember the body is made of interconnected compartments! (These are different to each other)
• the concentration of drug which may be found in different compartments may differ. E.g. the concentration in the plasma of blood may differ to the concentration of cerebrospinal fluid

The DISTRIBUTION of different drugs is affected by how the drugs pass through different compartments. For instance, if they pass through the lipid barrier of a membrane

Question 5

How does the lipid solubility of drugs affect its distribution?

Answer 5

• A drug may diffuse through the lipid barrier of a membrane depending on the nature of the drug + how hydrophobic it is (affecting if it enters through diffusion or not.)

In the CNS, the more hydrophobic the drug is, the better it diffuses through the blood brain barrier

In terms of diffusion across the membrane, this is in proportion to the size of the drug and the diffusion coefficient.

Question 6

The diffusion coefficient is proportional to 1/the square root of the molecular weight. What does this mean in reference to the size of a drug molecule and the diffusion coefficient?

Answer 6

The bigger the drug molecule, the slower the diffusion coefficient is.

So note, the diffusion coeffiecent is how quickly a drug can move through a barrier

The bigger the molecular weight of the drug is, the smaller the diffusion coefficient will be smaller. As 1 divided by the square root of 2 is bigger than 1/5 (square root)
Thus a bigger weight = a smaller coefficient = slower diffusion rate

HENCE small molecule drugs are preferred as they diffuse better!

Question 7

Why are small molecular drugs preferred to larger ones

Answer 7

Small molecule drugs are preferred as they diffuse better through membrane. They have a bigger diffusion coefficient and diffuse faster.

Question 8

What is pinocytosis?

Answer 8

This is when a drug is engulfed by extracellular solution through the formation of endocytic vesicles - this brings the solution inside

Question 9

What two coefficients does drug absorption and distribution relate to?

Answer 9

The partition coefficient - how lipid soluble a drug is and how well it dissolves.
- The higher this is, the more soluble the drug is

The diffusion coefficent: how well a drug diffuses
- the higher this number is (So the smaller the molecular weight of a drug) the faster the diffusion rate is.
(Remember this is proportional to 1/ sqaure root of molecular weight

Question 10

Non polar drugs?

Answer 10

These drugs dissolve more freely into lipids and penetrate the cells more freely
- they penetrate into the brain and gut more easily.

However they also enter the kidneys more easily so are quickly eliminated.

Question 11

The route of drug administration and the different barriers drugs encounter in the body affect drug absorption. Drugs are further carried in the blood plasma in bulk.

What are the different methods of consuming drugs?

Answer 11

The intravenous route - blood goes straight into the plasma and is distributed around the body. This is the quickest way of distribution.

The ORAL or RECTAL route:

• swallow tablet this is not as invasive
• or insert into retum - this goes straight to the gut

Percutaneous methods:
- putting patches on the skin. This causes the drug to seep into the skin. These drugs are usually very hydrophillic in order to enter. Oestrogen is an example

Intramuscular route:

• this method is good for ensuring drug isnt metabolised
• the drug is injected under the skin straight to the muscle

Intrathecal route:
- drug is directly injected into cerebrospinal fluid. This is very controlled. This goes straight to the brain

Inhalation =
- this is very specific for the lungs.

Question 12

Key note about drugs moving in and out of the body?

Answer 12

• they can move in and out by the same methods

Question 13

Where are most molecular drugs metabolised?

Answer 13

• in the liver, as the drug is delivered to the liver

- thats why alot of the time we get a loss of the drug before it can enter the plasma.

Question 14

What is the bioavailability of drugs?

Answer 14

The free concentration of drug present in the plasma (of blood) one the drug is taken, in comparison to the amount of drug injected in the first place.
Drugs ideally should have a big bioavailability.

Question 15

What affects the bioavailability of a drug?

Answer 15

• the gut and the liver

- inserting the drug through the rectum increases the bioavailability of the drug as it bypasses the gut

Question 16

In what form are drugs ingested orally?

Answer 16

Most are in the form of tablets or salts
They are either WEAK acids or bases
(These WEAK acids and bases have a salt form AND a dissociated form)

Question 17

For a drug to be ingested orally, should it be in the salt or dissociated form of its acid / base?

(Remember oral drugs are given as a acid or a base)

Answer 17

Note - the salt form of a drug is better than the dissociated form of a drug because the salt form ISNT CHARGED and thus can diffuse through the membrane

• the charge of the drug depends on the environment. But the drug is only charged when it is dissociated!

Question 18

What is the pk / pka value of a drug?

Answer 18

Its just the charge on the drug. But note this is when the drug is in the dissociated form not the salt form

The pKa of a drug tells you the proportion of a drug in the charged form (dissociated) and un charged form (salt form)

Question 19

The pKa of a drug tells you the proportion of a drug in the charged form (dissociated) and un charged form (salt form)

What is the equation for this?

Answer 19

PKA = pH + log10 (HA+/A-)

Question 20

An example question of working out how much of aspirin has dissociated?
The pka for aspirin is 3.5
The pH in the stomach is 3
What ratio of the drug is dissociated?

Answer 20

So pka = pH + log[ha+]/[A]

So 3.5 = 3 + log[HA]/[A]
0.5 = log [HA]/[A]

Doing the inverse log gives you the ratio = 3.2

So 3.2 = [HA]/[A]

So note this is telling you that 3.2 of the drug is in the dissociated form. And you know this because HA+ and A_ is when the drug is NOT in the salt form. So the ration has told you the proportion of the drug in the dissociated form.

Question 21

Again remember that salts of acids/ bases are more easily absorbed in comparison to dissociated versions froms.

Aspirin is an acidic salt, is it absorbed fast or slowly in the stomach?

Answer 21

• so note aspirin is an acid. It has an acidic salt. In conditions in the stomach, the environment is acidic.

When an acid salt is in a base environment they dissociate quickly. To compensate for the take of polarised ions.

When an acid salt is in an acidic environment they don’t dissociate quickly. They stay as salts!

Therefore Aspirin is quickly absorbed in the stomach as the condition are acidic. Aspirin does not readily dissociate and stays in the salt form as it doesnt need to compensate for the lack of polar acidic ions. Because apririn is a salt and salts aren’t CHARGED they are readily absorbed across plasma membranes. Especially as aspirin is a small molecule.

Question 22

What would happen if we put an acidic salt drug into an environment that has a pH of 7.4, such seen in the blood?

Answer 22

• then more of the acidic salt drug enters the dissociated form
• this traps A LOT of the drug in the blood plasma as MORE (emphasis) of the acidic salt drug is in the dissociated form and remember dissociated forms of the acidic salt drug are charged and polar.

Remember charged and polar molecules dont pass through the plasma membrane!

As the blood gets filtered it makes its way to the kidneys, remember that blood is carried in long narrow tubes to the kidneys! It does not diffuse there! Don’t get confused! The blood then goes to the kidneys

Here the enviroment in the kidneys is basic in nature. This means the acidic drug (which was originally in the salt form) remains dissociated (to compensate for the lack of acidic ions)
The drug is trapped in the kidneys and accumulates there.

Question 23

Context: a poison may be a weak acid. How can we ensure this weak acid is excreted quickly from the body?

Answer 23

• we aim to make the urine, bladder and kidneys are more basic in nature. As said before this causes an acidic salt poision to remain in the dissociated form as the drug tries to compensate for the lack of acidic ions. If the poison is in the dissociated form it does not diffuse through plasma membrane and is isolated to the blood and the kidneys

We can give patients who have been poisoned with weak acids sodium bicarbonate. This causes the conditions in the blood plasma and urine to remain basic.

Question 24

What affect does ionisation of a drug have on absorption?

Answer 24

Simple:
- if the drug is not in the salt form, it is dissociated and thus ionised
Ions dont diffuse well across plasma membrane
So if the acidic drug is ionised or a basic drug is ionised it won’t pass through the plasma membrane.

Question 25

Not all drugs diffuse through the membrane. So how do they get across?

Answer 25

Through carriers

• main examples are solute carrier transporters. This allow transport both passively or actively
• another example = ATP cassette transporters

Note how well the carrier saturates across the membrane affects the rate that the drug is absorbed in this type of transport.

Question 26

How does metformin get passed the plasma membrane barriers?

Metformin is widely prescribed for type 2 diabetes and act on hepatocytes which are involved in metabolism

Answer 26

• ## these drugs use the transporter OCT 1 to pass into the membrane of the hepatocytes.

Question 27

What happens when an OCT 1 transporter has a polymorphism? (An alteration in one of the amino acids which may alter its function)

Answer 27

The individual transports metformin (remember this used the OCT 1 transporter) less well into the cells which needed them for glucose metabolism. This causes their blood glucose levels to remain high and for diabetes to be less well controlled.