Pharmacokinetics 2

Question 1

Again what affects the distribution of drugs around the body?

Answer 1

• how well the drug travels through the compartments of the body. Remember when referring to compartments, we have the blood plasma, the cytosol of cell, the cerebrospinal fluid ect.

Question 2

Note when drugs are ingested or taken into the body, they dissolve in the water components of the body (note this doesnt necessarily mean they dissociate out of the salt form, just that they dissolve into the water compartments of the body)

What are the 4 water compartments in the body?

Answer 2

The four water components of the body are:
The extracellular fluid 37.5 %
Intracellular fluid = 30 - 40 % of the water
TransCellular fluid = 2.5 % of water (this is found in the cerebrospinal fluid for example)
Fat = 20 water

Question 3

What makes up the extracellular fluid? In %

Answer 3

Plasma = 4.5% of water
Interstitial fluid = 16%
Lymph fluid = 1-2%

Question 4

How does fat affect lipid soluble lipophilic drugs? As opposed to water soluble drugs?

Answer 4

Lipid soluble drugs have a tendency to diffuse into fat

Water soluble drugs dont tend to diffuse here

Question 5

What two forms can a drug be in?

Answer 5

A free form

Or a form bound to proteins

The free form is often best

Question 6

So what does distribution of a drug rely on?

Answer 6

Solubility and permeability. Basically how easily it crosses borders.

Question 7

The blood brain barrier between the CSF and the brain is made of a linin g of cells that are packed together tightly with tight junctions. This lining is impermeable to water soluble molecules

How are drugs which are water permeable transported into the CFS and how does the blood brain barrier affect bioavailability of drugs?

Answer 7

A carrier protein is needed to take the water permeable drugs across into the CSF

This may LIMIT the bioavailability of drugs in individuals who have a funcitonal BBB.

And how fast the drug is taken up. Why? Because it takes time for the drug to all diffuse into the CSF with the limited number of carrier proteins.

Question 8

What is the benefit of the BBB breaking down seen with individuals suffering from meningitis?

Answer 8

• people with meningitis have a weakened BBB
  This causes the BBB to be leaky
• if diagnosed quickly the advantage is that penicillin (a WATER soluble drug) can enter the CSF across the BBB as the lining of the BBB has broken down

Question 9

Side note what it the advantage of the chemereceptor trigger zone (vomiting centre) being outside of the BBB?

Answer 9

Drugs which are water soluble can access these regions easily, like paracetomol.
Remember the BBB is impermeable to water soluble molecules.

Question 10

Patients who have Parkison’s disease have a loss of dopaminergic neurones. How can these patients be treated with drugs?

Answer 10

Patients can be given an agonist for dopamine receptors to increase the release of dopamine in the brain.

(Note these dopamine receptors may not be releasing enough dopamine due to the lack of dopaminergic neurones in the brain needed to stimulate them, thus an agonist increases the amount of dopamine released released)

An agonist may be apomorphine.

Question 11

How can an antagonist (domperidone) to treat sickness which also affects dopamine neurones be used at the same time as an agonist for the dopamine neurones in the brain? Wouldnt they cancel each other out?

Answer 11

Remember From the side note, feeling nausea is associated with the chemoreceptive trigger zone (the vomiting centre) which is found outside of the BBB.

Here in this zone there are dopaminergic receptors, and the antagonist domperidone can bind to the receptors here stopping the feeling of nausea. However it is important to note this is outside the BBB!

Doperidone doesn’t cross the BBB and thus doesn’t interfere with the dopaminergic receptors in the brain nor does it act on the agonist (apomorphine) in the brain.

Thus doperidone and apomorphine can be administered at the same time. As the anatgonist cant affect the agonists function in the brain. Nausea is prevented and dopamine increases.

Question 12

Note drugs can bind to proteins in the bodies fluids. How does a drug binding to a protein affect its absorption?

Answer 12

If a drug is bound to a protein, the rate that the drug is metabolised and eliminated is affected.

Question 13

How does the protein albumin affect drug absorption? (Found in the. Plasma)

Answer 13

There is about 0.6 mmolar of albumin in the plasma = alot

Each protein can take up 2 drug molecules.

Up to 1.2 mM of a drug from a weak acid can bind to albumin - this helps it to be sequestered (taken away) from metabolism and elimination. Thus it stays in the body

Thus the protein helps stop drug elimination

Question 14

What affects the free drug concentration?

When drugs arent bound to proteins

Answer 14

• proteins like albumin - note these bind to drugs which lowers the free concentration of drugs
• to counteract this a increase in the drug concentration allows the albumin to be saturated.

A higher free distribution of a drug is good for drug absorption and use.

Question 15

How does fat affect free distribution?

Answer 15

Again free distribution of a drug helps it to be absorbed:

Drugs which need to work in the CNS and get passed the BBB need to be highly lipophilic as water soluble drugs cant cross the BBB- they dissolve into fat.

However these drugs can accumulate in fat as they are fat soluble thus it makes it hard for them to enter the CNS. Thus the drug is bound to fat and the FREE distribution decreases

For example sedatives which are lipid soluble (in order to cross the BBB) aim to target the CNS. However in obese people the drug dissipates into body fat. This affects how long the drug lasts in the body system

Question 16

What are the two biochemical reactions involved in drug metabolism? And where does this occur?

Answer 16

These occur in the liver

Phase 1 reactions = catabolic reactions which CAN produce more reactive compounds from the drug breakdown

Phase 2: synthetic reactions (anabolic) these are involved in conjugation to produce inactive products.

Question 17

What enzymes are located in the liver and are responsible for drug metabolism?

Answer 17

Cytochrome p450 enzymes, alcohol dehydrogenases and mono amine oxidases

These are referred to as microsomal enzymes - they are found in the intracellular fluids of the cell

Alcohol dehydrogenase breaks down alcohol and remember alcohol is a drug
Mono amine oxidase MAO - metabolises amines in the body and some drug in the CNS target MAO.

Question 18

How do polar drugs get into the liver?

Answer 18

Via transporters. Remember salt based acid/ base non polar drugs enter more easily than dissociated polar drugs

Question 19

Remember phase 1 metabolism of drugs happens in the liver. How can we exploit this stage? Remember this stage causes more reactive drugs to be made once the original drug is broken down in the liver)

Answer 19

So in this case we can administer durgs we know will be metabolised only when they reach the liver. Once here these drugs can be broken down into drug which make more reactive drugs which can help you. This is the smooth induction drug effect. You get a slow build up of useful drugs in the body.

Question 20

Problem with some drugs being ingested orally?

Answer 20

They go straight to the liver where they are digested

Some drugs may also bind to bile here reducing their bioavailability

Question 21

Describe the elimination of aspirin:

Answer 21

In the liver
There is phase 1 metabolisation in which the apirin is hydrolysed so it has an OH group
This is done by cytochrome p450 enzymr
The derivative is very reactive - the OH group on the apririn is quickly conjugated to a glucuronan molecules - this forms glucuronide.
The size of the molecule has now increased and so has its molecular weight . This affects the diffusion coefficent, thus the aspirin molecule diffuses less easily into the body. This molecule is then pumped out of the liver, it enters the plasma and then is collected in the kidneys. It doesnt move out of the plasma as the molecular weight has increased (diffusion coefficient has decreased) thus it is eliminated easily.

Question 22

How many genes code for the p450 enzymes? And what does the CVP1 and 2 enzymes do?

Answer 22

There are 57 genes which code for the p450 enzymes.

• the CVP1 and 2 drugs are involved in drug and steroid metabolism
• caffeine is every metabolised by one of these enzymes

Question 23

Problems of paracetamol metabolism?

Answer 23

Paracetomol is metabolised in the liver forming NAPQI. This is toxic but is normally rapidly metabolised in phase 2 or metabolism

Note paracetamol in high levels can be dangerous. Metabolic capacity of cytochrome enzymes can be overwhelmed. The toxic intermediate forms in accumulation.

Question 24

Why can you have neurofen and paracetamol at the same time?

Answer 24

Neurofen is metabolised by another cytochrome enzyme

Question 25

How are foods and cytochrome enzymes related?

Answer 25

The expression of cytochrome enzymes may be altered foods

E.g. grapefruit juice can affect drug metabolise

If p450 enzymes are affected it may cause drug transcription to be up Regulated

Sprouts can cause p450 enzymes to be induced and metabolism is accelerated, such seen with caffeine.

Smoking tabacco also induces cytochrome p450 enzymes.

Question 26

How are drugs eliminated?

Answer 26

Through the urine

Question 27

Why does it take a long time for lipophilic drugs to be eliminated

Answer 27

Because of their lipid soluble nature they dont enter the kidneys as easily as acid base water soluble drugs.

These drugs have to be metabolised to become polar before they were excreted.

Question 28

Three ways drugs are excreted?

Answer 28

Renal excretion:
- 20% of drugs move out via glomerular filtration - this is good for small molecules of 20kDa

Active tubular secretion:
- metabolised drugs actively transported across membrane for elimination

Passive diffusion
- if drug is non polar it may passively diffuse out through the kidneys membranes. This only really happens for lipophilic drugs but again these are usually stuck in fat

Question 29

Two transporters involved in active tubular secretion of drugs for elimination?

Answer 29

Organic cation transporters = work on WEAK bases

Organic anion transporters work on WEAK acids.

Question 30

Antibiotics and metabolism? Where does it remain? How easily is it excreted? What doesnt it corss? Why do they have to be take often?

Answer 30

Antibiotics dont cross the BBB
They remain in body fluids
They are metabolised easily. Excretion is efficient
They have to be taken in regular doses and times so the correct concentration remains otherwise they will be excreted rapidly. Like penicillin

Question 31

How quick is diazepam excreted from the body?

Answer 31

Very slowly. Takes 48 hours.

Question 32

What is GI excretion??

Answer 32

Is associated with drugs inhaled or drugs bound to bile

They are cleared through the lungs / faeces

Question 33

What should you ensure about the rate of drug administration, metabolism and excretion?

Answer 33

You should ensure the rate you administer a drug never exceed the max rate you metabolise and excrete a drug

Question 34

Why is a free distribution of drugs good?

Answer 34

Easier to be absorbed.

Remember when bound to albumin however this can stop the drug from being eliminated and keep it in the body. (May be why your blood is checked for drug tests as you retain the drug for some time)