CLASS: FUNDAMENTALS 2 11:00-12:00Scribe: LAUREN MORRIS

DATE: 11-22-2010Proof: ERIC LARSON

PROFESSOR: BARNESPRINCIPLES OF PHARMACOLOGY 2Page1 of 7

EFFICACY/POTENCY AND FACTORS DETERMINING THE UPTAKE OF DRUGS [S1]
We will be discussing the efficacy and potency of drugs and how does the drug get to its target – what are the factors involved?
SYNOPSIS [S2]
We’ll talk about Routes of Administration. You already have got the concept that sometimes you have to inject, sometimes you prefer to have it orally, but there are other methods like inhalation, intramuscular (injection), intrathecal (into the spinal cord), skin medication, and rectal administration
We’ll talk about absorption. This is how to get a drug to its target.
The GI tract is full of acid. How can you get your materials through the tract, and then what are the consequences of changing pH?
We’ll go through some definitions of some pharmacological terms, potency, efficacy and pharmacokinetics.
We’ll talk about designing a drug and end up with Omics and personalized medicine.
ROUTE OF ADMINISTRATION [S3]
An engineer’s view of the GI tract
If you’re taking drugs orally it’s an obstacle you have to overcome.
It starts off with the chopper at the top
Goes down into the esophagus
Then into the blender, the acid sterilizer, and reservoir (stomach)
Then pancreas adds enzymes and liver adds detergents to break things down
Then there is an absorptive surface
Then it ends with a residue combuster, dessicator, and pelleter
Then you have a very important emission control device.
Drugs have to come through the acid stomach. The acidity of the stomach can be as high as 1 normal HCl (normality of HCl).
FACTORS AFFECTING ORAL DELIVERY [S4]
For a drug to be given orally, the drug must be acid stable, although you can put a compound in a capsule, and then have the capsule either be broken or dissolve at a later time
Penicillin had to be given intramuscularly until the oral penicillins came along.
It wasn’t metabolized and excreted in the urine. When it came out in the urine it was still penicillin.
It was possible to recover the penicillin from the urine and REUSE IT (gross… Ladies when you hit menopause you will have an extract of horse urine as the drug that you will take to offset a lot of the peri-menopausal symptoms like bone loss, hot flashes. )
Most drugs that are taken in the mouth must get through the gut wall.
The gut wall has powerful enzyme systems that are inactivating the drugs and the other zenobiotics that are there. They don’t know the difference between a drug and an antibiotic
Often what might work in a lab animal might not work in the human, b/c the human has a different pattern of metabolizing enzymes
The gut wall is very important to our health.
LIPINSKI RULE OF FIVE [S5]
There is a so called Rule of Five. Lipinski in 1997, having looked at a lot of compounds, said that there was a rule of five.
He said if a compound has more than 5 Hydrogen bond donors (these are N or O atoms combined with a H atom- NH2, OH), then this would not be effective if there was more than 5
If there are more than 10 H bond acceptors, this was also not good. (10= 2 x 5)
If the molecular weight was under 500 daltons, then the material has a chance of getting through the plasma membrane.
If it has an octanol (very hydrophobic, fat-loving), if the partition coefficient log P is less than 5 then the compound probably won’t be taken up very well.
So the Rule of Five refers to each one of these steps.
Things have to be not too complex, not to have too many H bonds, not too water-soluble
If you take something by mouth and it’s gotta get to the membrane, then it must be capable of dissolving in water to an extent, but its got to be capable of being taken up in the lipid nature of the cells that line the GI tract. The compound has to have this dual nature
If it’s too hydrophobic, it won’t go into solution, and you’ll never get it to be taken up
If it’s too water soluble, it won’t get taken up passively, but it could have a transporter
Obviously AA are compounds that are very water-soluble, but they get taken up because they have specific transporters in the membrane that enable them to be taken up.
Glucose, sugar, is very hydrophilic, but it has a specific transporter that enables it to be taken up into cells. If it didn’t we’d be in trouble cause we wouldn’t have a source of energy
WHY ARE LIPINSKI’S RULES RELEVANT? [S6]
This is a cartoon of the GI tract.
Bottom: Gut lumen, water side of the lining cells
On the basolateral side you have the backside of the cells. They allow materials to go into the serosal side (i.e. into the blood)
A compound could be taken up by a specific transporter, on the other hand it could be pumped out by an efflux transporter (like the p-glycoprotein or the multidrug-resistance gene protein)
The cells are held very tightly together. It’s very difficult for things to go through these tight junctions.
Nanomedicine/nanoparticles: people are making these tiny nanometer sized particles into which they put a drug. These materials seem to be able to go through these spaces. So it bypasses this entire system. This could be good or very dangerous. Now there’s excessive uptake other than what you might expect.
In order for most drugs to be taken up, they have to go through bypassive diffusion. This is the apical side, and it’s very hydrophobic. Compounds get into these cells and move across a concentration gradient usually.
While it’s in the cell it can be attacked by Phase I or Phase II Enzymes.
If a compound is able to get through all of these places that are holding it back, it will enter the mesentery drainage and then will be distributed around the body – this is a big barrier.
FACTORS GOVERNING TRANSPORT [S7]
How do things get through? There are different types of transport.
Facilitated/Active Transport
Active: ATP will be consumed to drive the process. The concentration in the blood can be higher than in the gut, b/c ATP is driving the material uphill.
Facilitated: usually there is a binding protein that facilitates but it doesn’t drive a concentration gradient across. You are more rapidly moving material across the membrane, but much more so than you would expect from passive diffusion. Example: glucose is going to have a facilitated diffusion, and it’s very hydrophilic – you wouldn’t expect it to diffuse so fast. It’s using a receptor that is able to take it through.
Within these categories are AA transporters, p-glycoprotein (takes things in the reverse direction)
Passive Diffusion
Depends on the relative concentrations on either side of the gut wall
The speed at which things go across is determined by the hydrophobicity. A more hydrophobic compound, providing it’s water soluble, will be available to be moved across the membrane. If it’s too hydrophilic, then it may not achieve a high enough water concentration to drive an effective, rapid transport.
Paracellular
Between cells
The actual size of a compound may also depend on its state of hydration. Its ability to move through the space is the hydrated compound’s size and not the compound itself. You have to take that into account.
CHOLERA [S8]
A lot of news about cholera recently – the Haitians are in a bad state. Most people don’t have a memory of Cholera, so they don’t know how to avoid the rampages of Cholera in the scenarios that they currently are in.
It’s a failure to reabsorb water that are secreted in the intestines. There is a tremendous recycling of water in the GI tract. If that recycling gets blocked, you dehydrate very quickly
What these people are dying from is dehydration. You can treat them in various ways, but you could put water and electrolytes in if you can get to a doctor in time.
There’s an infection that is blocking the transport of sodium across the GI tract. So, just giving people water wasn’t sufficient- you had to give them water with electrolytes and glucose. These were required in order to transport the water.
It’s profound if we don’t transport electrolytes across membranes.
FACTORS AFFECTING DRUG PRESENTATION [S9]
Other things that affect how well a drug will be absorbed is the form in which the material comes.
Hard pellet or a highly dispersed form in a material that can be easily digested – we think of this in terms of isoflavonoids that come from soy, people make tablets out of them, or you can actually take some real food in which the compound is dispersed.
In order to get this to work, the manufacturers will put sodium bicarbonate into the pellet, and the idea is when it hits the acid in the stomach, the acid reacts, like an alkaseltzer, and causes lots of gas, and breaks the particle up into smaller particles. This increases the surface area and therefore helps in the resorptive process.
Formulation is important. If you had something that could be digested by enzymes, then it would fall apart and you’d have a very high surface area for the same amount of material. This material will probably be absorbed much faster than that material, but it would depend on whether the enzymes would hydrolyze it are released.
FACTORS AFFECTING DRUG PRESENTATION [S10]
We mentioned earlier you can take acid sensitive compounds and put them in capsules so these contain the drug and prevent pre-mature absorption, smooth transit through the esophagus.
Prevents the destruction in the stomach and frequently is made of gelatin.
The gelatin will be dissolved by proteases that are released from the upper small intestine (pepsin is present in wall of stomach and does initial digestion, and then the proteases from the pancreas complete the task)
Protease-deficient disease (alcohol problems, cystic fibrosis): very low pancreatic output, don’t digest their food, might not digest gelatin tablet
FACTORS AFFECTING DRUG PRESENTATION [S11]
There are different factors that affect how a drug will be presented to the gut wall. Some are purely physicochemical.
Hydrophobicity: a compound that is otherwise hydrophobic could have charge on it, and now the compound has dual capabilities. It is both hydrophobic and hydrophilic, and so this may affect the way it is absorbed from the gut.
If you had something that had amino groups on it, a physician might tell you “don’t take this on an empty meal.” The stomach is most acid when you have nothing in it. People with ulcer disease wake up at 3:00 am with a burning feeling in their stomach because their food has been digested and there’s nothing to buffer the acid that is being produced (painful).
If you had something which was turned into a very charged form under strong acid conditions, it wouldn’t be absorbed very well.
HENDERSON-HASSELBALCH EQUATION [S12]
We consider this from an academic standpoint with the Henderson-Hasselbalch equation
For a drug that is going to form a negatively charged anion: The pH (how acid is) equals the pKa plus the log of the ratio of the anion to the protonated species of the anion.
When these two species (anion and cation) are in equal amounts, it becomes the log of 1 which is 0.
So the pKa is the pH in which the drug is half charged.
If we know what that is, then we can look at the pH of the gut and understand is this drug likely to be absorbed or not?
IMPACT OF DRUGS ALTERING THE ACIDITY OF THE STOMACH [S13]
If you have an ulcerative form of disease, you may have excess acid production. You may be sensitized to the acid.
Normally you have 1 normal hydrochloric acid in our stomach. If I was to take a glass of 1 N HCl and asked you to put your hand it in, would you? No, it would be painful. But normally, we don’t feel this in our gut. Most of the time we’re protected.
That protection can be broken b/c of the ulcer, b/c you now have the underlying tissue directly exposed, or the intestine could become inflamed. There is a microorganism that lives in the acid of the stomach called H. pylori.
If you try to quell the acid to make it hurt less, then you change the pH of the gut. So other things that you were eating or taking might be absorbed in a different way because you’ve changed the pH. It’s very important to understand a particular subject you might be dealing with, whether or not the drug you’re going to give them is going to work, if they have a background of some other ulcerative disease that they are treating.
There are also some diseases that are tumors that produce excess hormones that cause lots of acid to be produced. That’s for another day.
It’s the proton pump that we’re gonna talk about on another day.
FACTORS AFFECTING DRUG PRESENTATION [S14]
The other issue is that of phase separation.
We talked about the optimal water partition, but if you take somebody’s intestinal contents out just after a meal, depending on what they eat there could be a very significant fat phase.
A drug you were taking might partition into that fat phase and in doing so not be available to be taken up into the body. You might not want to take a drug prone to this with a fatty meal b/c the fatty meal might cause it to be held back from being absorbed.
Some people are given paraffins as a way to overcome store passage. If you’ve had GI surgery and you’re told not to strain for a few days, in order for the store to be more easily passed they might give you a paraffin. Very hydrophobic drugs might partition into the paraffin which is not gonna be absorbed. You need to know what the pt is taking. Fat soluble vitamins is another area that would be sensitive to this.
FACTORS AFFECTING DRUG PRESENTATION [S15]
We have natural detergents that help us to overcome this. They are called the bile acids
They come from cholesterol. It has a carboxylic acid group and that’s usually conjugated to glycine or to teurine.
Extremely water-soluble, but they aggregate with fatty acid and cholesterol to form these micelles and keep cholesterol in solution. Cholesterol solubility in water is about 1nM. The cholesterol content of bile is about a million times higher than that due to the combined action of the bile acid and the phospholipids.
If you have a low bile acid ouput, then this might affect how well a drug gets dispersed or taken up. These might be people will different types of liver disease or cystic fibrosis.
The way in which materials are taken up by the GI tract, and also how they’re metabolized, can be seriously affected by someone with liver disease. They might be very sensitive to the drug because they can’t get rid of it, or they may be sensitive because they can’t absorb it.
ONCE IN, WHERE DO DRUGS GO? [S16]
Where do drugs go once they’re into the body? In an ideal world they’d go where we tell them to go to (but this is like telling your kids to go to the right place in a department store).
We try to be intelligent, but drugs go where they want to.
The drugs that go into the bloodstream go throughout the body and are capable of being absorbed by any of the tissues.
The endothelial cell layer within the bloodstream is very much like the small intestine, so there may be transporters that enable the drug to be transported back and forth across that layer. There may also be efflux issues that prevent the drug being effective in a particular patient.
Getting drugs to get into the brain is really tough. A really good example is when the brain itself becomes infected, how do you get an antibiotic into the brain? Most Ab are kept out of the brain. Finding material that will cross the blood brain barrier is a challenge. Sometimes we can take advantage of that.
BLOOD BRAIN BARRIER [S17]
The blood brain barrier separates materials that are circulating in the blood from entering the brain. You don’t want things that will alter brain function getting through.
The tight junctions are much tighter. It’s hard to get into the brain.
There are two barriers.
There are transporters for sugars and AA, so these are important in the function of the brain.
40% of all glucose that we metabolize is metabolized by the brain.
Fortunately it’s also difficult for microorganisms to get through the blood brain barrier.
DRUGS AND THE BLOOD-BRAIN BARRIER [S18]
Codeine is a pharmaceutical that is restricted. It used to be widely available for controlling diarrhea. Unfortunately it gets into the brain and has bioactivity in the brain and will cause dependence.
Another drug is an over the counter drug for treating diarrhea. It doesn’t go through the blood brain barrier, so we can use this material to help us control the way in which the intestinal motion is going on which is what is going on. Since it doesn’t cross the blood brain barrier, it’s available over the counter.
ELIMINATING DRUGS [S19]
Anything that comes in we have to get rid of.