FUN2: 11:00-12:00Scribe: Brittney Wise

Monday, December 8, 2008Proof: Joan-Marie Manolakis

Dr. PillionAntihistaminesPage1 of 6

Note: in a couple of the drawings he referred to things in the audio but did not say the name of what he was referring to so I could not identify what he was pointing out in the drawings

Introduction on Antihistamines [S1]: All of you are familiar with the use of anti-histamines just from over the counter treatment of runny nose, rhinitis, and so on and so we will talk about how those drugs and we will recognize different classes of those drugs and then after that we will talk about the Leukotriene inhibitors which are cousins of anti-histamines and are used in a lot of the same situations
Mast Cell Mediators [S2] –
Mast cells are little bags of mediators and their job is sit around in the body and wait to be activated, upon which they will release things that have short, long, and intermediate actions; most of those actions are protective for us and they serve a good purpose; when they are triggered in a way that’s excessive or they are triggered by a stimulus that creates problems for us we can sometimes use drugs to block the actions of the mediators that are released from mast cells; the number one component released from mast cells is histamine
Histamine goes out into your blood stream and finds histamine receptors (H1 and H2 are the most common)
we have drugs that are specific for one type of histamine receptor and some that bind to several different histamine receptors
Enzymes like tryptase, chymase, proteases are also released from mast cells
Lipid-derived mediators: (also released from mast cells)
Prostaglandins (ex// PGD2)
Leukotrienes (LTC4) – we will focus on these today
Platelet activating factor
Cytokines – proteins that are released from mast cells and they interact with other cells particularly in the blood stream to activate them to get further involved in the inflammatory process; so, you get a cascade of events
One of the cardinal signs of mast cell action is that the initial trigger causes these cells to release their mediators which then go out into the rest of the system and multiply; when we think of an antihistamine effect we tend to think of anaphylaxis
The reason that one has an anaphylactic response as opposed to a runny nose is due to the amount of histamine that’s released and the rate at which it’s released
Our body has ways of getting rid of histamine
A small amount of histamine released from mast cells in our nose will cause a runny nose; if we have a large amount of histamine released (like if you are allergic to a bee sting) we get mass amounts of histamine released and our body can’t remove all of it all at once so then we have effects all over the rest of our body and we end up with anaphylactic shock and a tremendous loss of blood pressure
We usually deal with the effect of histamine locally with antihistamines drugs; it’s all about how much and how fast histamine is released
Picture of [S3] –a mast cell is shown here with the little bags or storage vesicles that are full of mediators; they are at rest; your lungs have a lot of these cells along with your blood stream; they are waiting to be primed and release these chemicals
Mast Cell Activation[S4] –what triggers a response: a number of different things
IgE-mediated (“allergic”) response – these are primary mediators of it
Pollen; if you have ragweed or hay fever you get inhaled pollen that will trigger a response; some people are allergic to food, drugs, or insects etc.; all these different stimuli can stimulate the release of histamine and other mediators
Anaphylatoxins (C5a)
Direct release by certain drugs (like opiates in old people)
Physical stimuli (heat, cold, trauma)
If you are hit in the nose it will swell up and turn red because you have mast cells lining your nose; this is meant to be a beneficial thing to bring other cells to the site of injury to help repair the area; so again, mast cells and histamines are mediators that we sometimes think of as bad guys but in reality they are a part of a normal natural defense mechanisms; when they are overstimulated or inappropriately stimulated (like with ragweed or hay fever) this is when they are bad
Some people can have an autoimmune response (chronic urticaria) – people will get a rash caused by, among other things, histamine
Histamine [S5] – it’s a chemical that’s a 1stcousin of histidine (one of our normal amino acids); if you decarboxylate histidine you will get histamine; inside your cells you do this all the time and in most cells the histamine doesn’t stick around it gets broken down but in mast cells and in basophils there is storage of histamine inside these vesicles where it’s not broken down so that it can accumulate in these cells
High concentrations are found in skin tissue, mucosa of the bronchial tree and the intestinal tract
Has no clinical use for histamine; we don’t give histamine in anybody to treat anything; if we did give it intravenously, it would have a very short 1/2 life
Released after interaction of Ag with IgE Abs; and again, these same things, pollen, foods, drugs insect bites, etc. … he didn’t finish his thought but I think he was referring to these things acting like Ags and our Abs binding to them
2 different histamine receptors: H1 and H2 (we are going to ignore anything outside of these 2)
Most storage occurs in basophils and mast cells
The immediate pharmacological effects are itching, increased permeability, vasodilatation that is causing redness, smooth muscle contraction, and gastric acid secretion
Notice that in the above list all but gastric acid secretion, are all receptors; H2 receptors are associated with gastric acid secretion; these 2 are distinct so our use of anti-histamines are distinct; we use one class of drugs to treat the effects of H1 receptors and we use another class of drugs to treat the effects of the H2 receptors
Histamine [S6] – Test Question: will always be distinguishing between the H1 effect and a H2 effect;
H1 is alwayseverywhere else
H2 is always the one in the stomach
Systemic Effects[S7] and [S8] – what do they do systemically? Their effect is to vasodilate small blood vessels. So, again for example, the blood vessels in your nose dilate, you get edema, you get congestion as a result of that; it can lead to a lowering of systemic blood pressure; this can occur most with H1 and H2 receptors but H1 is primarily the one we think of increasing capillary permeability and then the nasal congestion being the cardinal sign
The one that we intervene with a lot with our anti-histamine drugs are the H1’s
Conventionally when people are using a broad term anti-histamine they usually are talking about an H1 blocker; usually when we talk about H2 blockers you specifically say it’s an H2 blocker; because H1 and H2 both are found in your body you shouldn’t just use that term, but if someone just says anti-histamines, they often times are inappropriately talking just about anti H1’s
In your lungs, bronchiolar smooth muscle are constricted by H1 so if you have a person who is having an allergic reaction or who is having an overly aggressive response to a pollen, what’s the effect on their lungs?
They would constrict their lungs so breathing will become difficult; so when you have an allergic reaction to a bee sting, one of the ways you would die would be the inability to breathe you would get really severe bronchial constriction
How would you intervene to try to overcome this? You could give a person like that a bronchodilator or you could give an anti-histamine, but usually for an emergency you give epinephrine which binds to beta-2 adrenergic receptors in the lungs to make them dilate
Histamine has an opposing effect through a different receptor; so you can use epi to try and counter-effect the effect of histamine there
Histamine causes contraction of smooth muscle in the gut and causes a gastric acid secretion in the stomach; you can think of this as a normal part of our digestive system; if we have overstimulation of this and too much histamine secretion you could have cramping and diarrhea, vomiting, GI distress and the overproduction of gastric acid would lead to acid reflux (many people are troubled at night by overproduction of gastric acids as a result of histamine stimulation and they wake up with burning in their esophagus); this is where we can intervene with an anti-H2 drug
We stimulate nerve endings with itching and pain; if you have hay fever, or pollen problems the itchy nose, redness, and watery eyes are irritating and so an anti-histamine can help these symptoms
Allergic Diseases [S9] –All of these processes below have histamine playing a role in them, and histamine is not the only character in this response but it’s one of the big ones
Allergic rhinitis (hay fever)
Atopic dermatitis (eczema)
Urticaria
Asthma
Anaphylaxis
Picture of a little guy sneezing his brain out [S10]
Allergic Rhinitis: Epidemiology [S11] –
A lot of Americans have it; often it improves with age; you can have dust, pets, family history, all of these things can contribute to it; it’s not a life threatening condition but it’s one that we do seek a lot relief for
Picture of a girl wiping her nose with her hand [S12] – she developed a little crinkle in her nose because she is constantly wiping her nose; so the doctor is likely to think the patient has allergies if they have a crinkle in their nose
Antihistamines in Allergic Rhinitis [S13] –
The symptoms are sneezing, puritis, rhinorrhea, congestion, late-phase reactions; we can use anti-histamines to block these first 3; they may have some effect on congestion
Late phase reactions are probably caused by interleukins and similar things released from mast cells and basophils and going to other cells recruiting them to the site
So, antihistamines don’t prevent the late phase reactions, they prevent the effects of histamine which are the earlier effects
This is kind of a temporal sequence of events; histamine gets released and it causes sneezing, red eyes, runny nose, etc and then the interleukins are released to other cells like white blood cells that will come to the site of injury or irritation; so these later effects will not be treated effectively by anti-histamines
Reduction of histamine effects [S14] –
Epi can be used if you have an anaphylaxtic response; it has the opposite effect of histamine
Mast cell stabilizers – these are the cromalins (word was inaudible) and we will talk about these with the treatment of asthma; they stabilize mast cells so they don’t release histamines; these are a different class of drugs
runners will often use this because when they go running in the cold; they will have an allergic of asthmatic type response, but if they use the mast cell stabilizers before they go run it will stabilize the mast cells so they never release histamine (note the different mechanism of action)
There are 1st and 2nd generation histamine receptor antagonists
the 1st generation anti-histamines were things like Benadryl (diphenhydramineand diphenhydrinate), and these drugs were taken orally for the relief of runny noses
the biggest thing about these is that they did penetrate the CNS and so they would get into the brain and bind to other receptors in addition to the histamine receptor like the serotonin receptor or the adrenergic or cholinergic receptor; and so they had side effects like drowsiness
1st thing that you think of when kids take diphenhydramineand diphenhydrinateis drowsiness; if you take a motion sickness drug it will get into the brain and interact with other receptors and dry out your nose but it will also make you drowsy; a few people had the opposite effect and they got wired from taking these drugs
These are all reversible competitive antagonist of H1 receptors; because they are reversible they have a relatively predictable ½ life anywhere from 1 hour to 8 hours and the ones that last longer you take less frequently during the day; most of the more commonly used ones you have to take more than once a day
In summary, we call this 1st generation because of the side effects that were produced; with the 2nd generation, these didn’t cross the CNS so they didn’t have the side effects
Histamine H1Receptor [S15] – **he said we did not have to know numbers of weights and stuff**
Be able to know and recognize the fact that the H1 receptor mechanism is to increase phospholipase C which means you are going to affect Ca++ movement into a cell; it’s got one mechanism of action
These are found in the smooth muscle, intestine, blood vessels, bladder, trachea, heart, adrenal gland, vascular endothelium, CNS (all over the place)
it is thought that histamine plays a normal role and a lot of different functions in a lot of places all over our body including digestion, and blood pressure control, and so on
This H1 receptor (he used the example of the one in your nose) involves Ca++ entering causing smooth muscle cells to constrict or relax depending on what part of the body they are in and so it’s effect is mostly at the level of smooth muscle cells
It should make sense to you that we have 2 different receptor classes so it should not be surprising that we can get a drug that binds to the H2 receptor that doesn’t bind to the H1; or vice versa; we are talking about apples and oranges
Histamine H2 Receptor [S16] –
This is a whole different protein compared to H1;
This activates adenyl cyclase which raises the levels of cAMP; cAMP phosphorylates the proton pump and pushes acid out
This one is more localized and the big player is the stomach but it can also be found some in the heart, uterus, and the CNS
You might wonder why these 2 have completely different receptor classes (H1 and H2) …
H1 Receptor Antagonists [S17] –
This is not in your power point; there is a list of 19 drugs for this category in your text; a few of them are used a lot and most of the others, you just need to know that they exist; for test purposes he would only pick the prototypical H1 antagonists for us to recognize and to know that they are H1 as opposed to H2; there are only 3 2nd generation H1’s and those you should recognize as being 2nd generation; don’t memorize the long list in your book, but be able to recognize the 2nd generation ones because you could see this on your test; he repeated that we should for sure memorize the 2nd generation ones
They commonly cause sedation, blurry vision, nervousness, dryness of the mouth, urinary retention, and some of these effects are because they bind to other receptors like cholinergic receptors
There are paradoxal effects in some children where they become awake and they become very awake instead of sleepy; they can be used to prevent motion sickness and nausea and vomiting; again, it’s because these enter the CNS, it’s because they bind to other receptors it’s why they have these effects; they are built as H1 receptor antagonists but actually they’re some of them are more effective for treating motion sickness or nausea because they bind to other receptors in the brain
2nd generation H1 receptor antagonists won’t affect motion sickness anymore because they don’t get into the CNS
This is the good news and bad news about drugs entering the brain; sometimes it does what we desire and sometimes it goes off and does things we don’t desire
2nd Generation Antihistamines [S18] –
They are rapidly absorbed
Long duration of action; either once a day or twice a day
Poor distribution to the CNS
Little to no sedation
They are not metabolized by Cytochrome P450 so you avoid all that drug/drug interaction that some of the other drugs cause
Can be combined with pseudoephedrine in some products; you have a double whammy in terms of affect on a runny nose
2nd Generation Antihistamine Type 1 blocking drug [S19] – you should be able to recognize these 3 drugs for the exam; these don’t cause sedation, drowsiness, they are not effective for motion sickness or nausea
Cetirizine (Zyrtec) – can get by with 1 a day and be effective; came along later so it was approved for ages 6 and up; age 6 and up are FDA approved
Loratadine (Claritin) – can get by with 1 a day and be effective; came along later so it was approved for ages 6 and up; age 6 and up are FDA approved
Fexofenadine (Allegra) – not seen as often; is less potent, but can be just as efficacious and that’s a big point; you have to take it twice a day, 60mg 2 times a day so 120mg a day; this was only originally approved for age 12 and up
Remember from earlier that we are not