Fundamentals II: 10:00-10:50 Scribe: Susan Whitt

Fundamentals II: 10:00-10:50 Scribe: Susan Whitt

Monday, December 7, 2009 Proof: Chris Bannon

Dr. Pillion Antihistamine Cases Page 1 of 8

I.  Introduction [S1] Antihistamine Cases:

a.  The niche that these drugs play in pharmacology

b.  We’ll go through small topics.

c.  [audio starts here, the previous is from the notes I took] self-encapsulated.

d.  I would add that in looking at an old national board exam for dental students at least I saw a couple of questions about these molecules so it’s good that we don’t overlook them completely. You might not get them anywhere else in your curriculum, so this is a good time to do it.

e.  To try to put a bubble over the whole lecture, I would suggest that what we’ve talked about in our discussion so far is epinephrine, norepinephrine, and histamine. Today we’re going to throw in serotonin and dopamine.

f.  All of these chemicals are small chemicals. They can all be used as neurotransmitters. So our nervous system is sophisticated enough that we don’t have a single neurotransmitter but we have multiple neurotransmitters. Some of our neuronal synapses involve 3 or 4 or 5 neurons interacting with each other. Some neurons affect above the site of the synaptic cleft and modulate how much the neurotransmitter is released by a nerve cell.

g.  If you think about it conceptually, you might not want to have norepinephrine communicating with one nerve to modulate how much norepinephrine is released. But rather have another transmitter like serotonin or dopamine available to modulate how much norepinephrine is released. And vice versa. Have norepinephrine modulate how much dopamine or serotonin is released.

h.  Additionally, if you remember about histamine. Do we usually think about histamine as a neurotransmitter? We don’t. When we think about histamine in the body, where do we think? Mast cells in the tissue and basophils in the blood stream. That’s also how you can think about serotonin. Serotonin is found in cells in the body and certain cells in the central nervous system. Therefore, there are receptors for serotonin throughout the body.

i.  The nomenclature for the serotonin receptors are that they are called 5-HT receptors. That’s because the other chemical name for serotonin is 5-hydroxytryptamine. That just tells you what the chemical structure is. The name serotonin came a long time ago before we knew what it was and the idea was that this was a drug that affected vascular permeability, so it controlled the tone of some of the veins and arteries in the body. So it’s called serotonin. That was before we knew what it was chemically. So 5-HT is the chemical name.

j.  What’s interesting about the 5-HT system is that there’s multiple receptors. There’s 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4. The list is getting longer and longer. You say, Dr. Pillion, I don’t really care about that. I say, well, if you were vomiting and if you were getting chemotherapy then you would. The 5-HT3 receptor is the one that stimulates the vomiting reflex. Now there are drugs that have been discovered that are 5-HT3 antagonists that block that vomiting complex and therefore give relief to people who are on chemotherapy. We’re beginning to unravel this whole serotonin story. As we do it’s getting more and more complicated, more stuff to remember. Eventually, we’ll talk about a couple of drugs now that their mechanism of action is known to be binding to 1 or 2 5-HT sub-receptors. As you can imagine the drug serotonin binds to all of those receptors. That’s why they’re called 5-HT receptors. Some of the derivatives of serotonin are chemically tweaked so they only bind to a few of the receptors instead of all of them. What do you think the half-life of serotonin would be in the bloodstream? It’d be quick like most other normal peptide derivatives in the body. It would have a very short half-life. So again, some of the chemical derivatives that are used pharmacologically are tweaked to give them a longer half-life. So again, some of the kind of the overarching principles of drug delivery: the route of administration, the half-life of the drug, and the lipophilicity, or hydrophobicity of the drug’s chemistry, all of those come into play here. Hopefully as we go through, this should be a logical progression for you.

k.  The other pathway we’re going to talk about is the prostaglandin pathway. You’ve been exposed to it before, but we’ll review it one more time because it’s kind of central.

l.  In the plasma membrane we have phospholipids that contain arachidonic acid in the 2 position. They get clipped off with phospholipase A. So phospholipase A clips of the arachidonic acid. The arachidonic acid is unusual in the sense that it has 4 double bonds in it and 20 carbons. I never thought about that too much until last night when I was going through the book and looking at a picture of arachidonic acid and the way it folds. Because it’s got 4 different double double bonds it’s actually able to bend over onto itself. The double bonds can associate with each other. Instead of a long string like a piece of spaghetti, it bends over on itself, and you have a molecule that is a derivative then of prostaglandins.

m.  [He draws picture on board of chain and double bonds and folding]. So most 20 carbon fatty acids that didn’t have any double bonds would be just like that: a long string. If you include 1 double bond not too much happens. If you include 2 double bonds, the molecule becomes much more able to flex itself. The two double bonds can each be in either the up or down position. You can imagine if this was in the down position and that was in a down position again and then you put in two more bonds further down the molecule like that, eventually what happens is that the molecule is able to, probably won’t do too good of a job of this, but I just want to make a point that these things can now double back to where the double bonds are lined up with each other and then this end of the molecule becomes the business end (where the bend is) for the formation of prostaglandins. That wouldn’t happen with most fatty acids. It’s kind of unique that this arachidonic acid has four double bonds and is able to fold like that. And we get a bond formed down here. Then we get prostaglandin H and prostaglandin G and prostaglandin F and prostaglandin E. Those prostaglandins have different properties that we’ll talk about. So as we go through, bare in mind that as we talk about the prostaglandin groups that they’re all coming, again, from the arachidonic acid.

n.  The final group of drugs that we’ll talk about are the ergot alkaloids. Ergot alkaloids are actually natural products made by plants that are the result of a fungal infection of a plant. When human beings get fungal infections we usually get them underneath our nails (have you looked at your grandma’s toes): an area of low oxygenation and low circulation. Fungal infections in humans don’t usually cause serious side effects. They are slow onset and localized primarily, but if they developed into an overgrowth they could cause serious problems.

o.  However, if we consume a plant that has a fungal infection, we can become seriously ill and die from it. That’s because the plant fungus produces these chemicals called ergot alkaloids, which look like 5-HT or dopamine. They’re related to those chemicals. They are small peptides that can go and interact with receptors in our body. The one characteristic that is devastating to us is that they cause severe vasoconstriction. Back in the early times, the Middle Ages, people would eat wheat. They got a fungal infection, and they would come down with St. Elmo’s Fire, which is a disease where you get severe vasoconstriction. The fingers would turn black and eventually fall off. You could imagine that to the medieval man this was not a good thing. It was difficult to understand where this disease was coming from. It was actually coming from the food they ate. When they had a bad year, a wet year, the wheat got infected, the fungus developed. People ate the bread, and they came down with this disease. So it caused very severe vasoconstriction. The ergot alkaloids you would think they wouldn’t be used too much in man. But remember when we talked previously about treating a woman who has a post-partum bleed. One of the chemicals we can use is methylergometrine, which is an ergot alkaloid derivative. What’s cool about it is that it’s a double whammy. Not only is it a vasoconstrictor but also it strongly contracts the uterine muscle right after delivery. There’s something about right after delivery that the hormonal milieu has made the uterus extremely sensitive to methylergometrine whereas in a normal non-pregnant woman the uterus would respond to it but not very strongly.

p.  So as we go through we’re going to talk about the utilization of this.

II.  Case 24 [S2]

a.  Let’s talk about these cases. These cases come from your textbook Toy.

b.  First one is a 24 year old (he meant 8 year old girl, case 24), and she’s got a runny nose, sneezing, and treated with diphenhydramine. What kind of drug is diphenhydramine? Antihistamine. What type of antihistamine is it? First generation. So what are the side effects you associate with it? [can’t hear student response on audio, but see slides 4 and 5]

III.  What is the mechanism of action of antihistamines? [S3]

a.  What is the mechanism of action of the antihistamine? Is a competitive inhibitor, a noncompetitive inhibitor, reversible inhibitor, what receptors? Test question. You’ve got to know it, so what’s the answer? Competitive antagonist.

IV.  Competitive antagonism of histamine at histamine receptors. [S4]

a.  Antihistamine receptors. Does it block H1 of H2? Test question. You’ve got to know this stuff. H1 indeed.

V.  What are the common side effects of antihistamines? [S5]

a.  Drowsiness, that makes sense. What else? Drowsiness is number one. You can get dizziness. That may be as you change the fluid balance inside your inner ear.

VI.  Drowsiness, dizziness, nausea, constipation, diarrhea, and anti-cholinergic effects: dry mouth, dry eyes, blurred vision, urinary retention [S6]

a.  Nausea, constipation, and diarrhea. These are all kind of not found all the time but they are occasionally. The big thing is anti-cholinergic effects, which can be dry mouth, dry eyes, blurred vision, urinary retention. In fact the dryness is why sometimes we use these effectively as decongestants. They have this anti-cholinergic effect.

b.  Some of the drugs are more anti-cholinergic than others. We have a long list of first generation anti-histamine drugs. Some are used as decongestants. Some of them are used as anti-emetics as they block the vomiting center.

c.  As we go through our talk to day we’re going to come back to other drugs that are also used as anti-emetics.

d.  What I want to try to point out to you is that these drugs that look like histamine chemically are not that different from drugs that look like dopamine or that look like serotonin, or 5-HT. These are all cousins to each other. So it’s not too surprising that the effect of 1 might overarch and react with the others. Some look enough like norepinephrine to bind to adrenergic receptors. If it bound to an alpha-1 adrenergic receptor or to a beta-2 adrenergic receptor, what are the effects that you would expect it to have? If you remember the adrenergic lecture then you know what to expect from an agonist that would cross over and react with that receptor as well. Receptor. So if we look at the side effect profile of some of these things, and if they look like they fall outside of the category it may be because they are reacting with other receptors.

VII.  What is the advantage of fexofenadine over diphenhydramine? [S7]

a.  They decided to give this girl fexofenadine. Second generation, doesn’t enter the CNS, doesn’t cause drowsiness as much.

VIII. Less entry into CNS [S8]

a.  So less central nervous system, less drowsiness. Everyone cool with that? That’s just a complete revisit of what we said last time, so you should know all of that.

IX.  Distribution of H1 and H2 Histamine receptors [S9]

a.  Where do we usually think about H1 receptors being located? Everywhere. Yeah, they’re all over the place, including the brain.

b.  How about H2 receptors? Where do we find them? Primarily from a clinical point of view we think the stomach. We think about acid secretion. They are found in some other places, but that’s usually the business end.

X.  H1 receptors: Located in vascular smooth muscle, brain, heart, bronchi, and GI tract, H2 receptors: Located in Gastric parietal cells [S10]

a.  So for H1 receptors we think about vascular smooth muscle, we think about the brain, the heart, the bronchi, and the GI tract. H2 receptors we usually think about the gastric cells, the parietal cells that secrete acid. So that when the parietal cells were exposed to histamine if I asked would H2 receptor increase the level of cAMP, promote the secretion of acid into the stomach.

XI.  Mechanism of action of histamine at H1 and H2 [S11]

a.  What’s the mechanism of action of H1 and H2? Another test question. This one’s a little less obvious or probably easier for you to not think as important but one that we do want you to know.

b. 

XII.  H1 receptors: Increased phospholipase C activity, increased intracellular calcium and increased diacylglycerol [S12]