Pharmacokinetics 2 Flashcards
(34 cards)
Again what affects the distribution of drugs around the body?
- 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.
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?
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
What makes up the extracellular fluid? In %
Plasma = 4.5% of water
Interstitial fluid = 16%
Lymph fluid = 1-2%
How does fat affect lipid soluble lipophilic drugs? As opposed to water soluble drugs?
Lipid soluble drugs have a tendency to diffuse into fat
Water soluble drugs dont tend to diffuse here
What two forms can a drug be in?
A free form
Or a form bound to proteins
The free form is often best
So what does distribution of a drug rely on?
Solubility and permeability. Basically how easily it crosses borders.
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?
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.
What is the benefit of the BBB breaking down seen with individuals suffering from meningitis?
- 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
Side note what it the advantage of the chemereceptor trigger zone (vomiting centre) being outside of the BBB?
Drugs which are water soluble can access these regions easily, like paracetomol.
Remember the BBB is impermeable to water soluble molecules.
Patients who have Parkison’s disease have a loss of dopaminergic neurones. How can these patients be treated with drugs?
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.
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?
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.
Note drugs can bind to proteins in the bodies fluids. How does a drug binding to a protein affect its absorption?
If a drug is bound to a protein, the rate that the drug is metabolised and eliminated is affected.
How does the protein albumin affect drug absorption? (Found in the. Plasma)
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
What affects the free drug concentration?
When drugs arent bound to proteins
- 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.
How does fat affect free distribution?
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
What are the two biochemical reactions involved in drug metabolism? And where does this occur?
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.
What enzymes are located in the liver and are responsible for drug metabolism?
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.
How do polar drugs get into the liver?
Via transporters. Remember salt based acid/ base non polar drugs enter more easily than dissociated polar drugs
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)
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.
Problem with some drugs being ingested orally?
They go straight to the liver where they are digested
Some drugs may also bind to bile here reducing their bioavailability
Describe the elimination of aspirin:
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.
How many genes code for the p450 enzymes? And what does the CVP1 and 2 enzymes do?
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
Problems of paracetamol metabolism?
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.
Why can you have neurofen and paracetamol at the same time?
Neurofen is metabolised by another cytochrome enzyme
