Flashcards in Autacoids and Autacoid Antagonists: Histamine Agonist and Antagonist Deck (36)
Autacoids have a diverse physiological and pharmacological activities. They usually have a....
brief lifetime and act near their sites of synthesis
The first drug we are going to look at in this section is histamine, what is it formed by?
Formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed by histidine decarboxylase
Most tissue histamine exists in bound form in what?
granules in mast cells or basophils
Mast cells can be triggered by many stimuli and are rich at sites of potential tissue injury:
internal body surfaces
particularly at pressure points and bifurcations
Non-mast cell histamine is found in several tissues, including?
Including the brain , where it functions as a neurotransmitter
An important non-neuronal site of histamine storage and release is what?
enterochromaffin- like cell of the fundus of the stomach
--these cells release histamine, one of the primary acid secretagogues, to activate the acid producing parietal cells of the mucosa
Explain the immunologic release of histamine
1. Mast cells and basophils, if sensitized by IgE antibodies attached to their surface membranes, degranulate when exposed to the appropriate antigen
2. This type of release requires energy and Ca2+
3. Degranulation leads to the simultaneous release of histamine, ATP, and other mediators stored together in secretory granules
4. Histamine released by this mechanism is a mediator in immediate (type I) allergic reactions.
Explain the chemical/mechanical release of histamine
1. Drugs like morphine and tubocurarine, can displace histamine from the heparin-protein complex within cells
2. This type of release doesn't require energy and is not associated with mast cell injury or degranulation
3. Chemical and mechanical mast cell injury causes degranulation and histamine release
There are four cell surface receptors H1,H2,H3,H4 that are all G protein linked. All four receptors have what kind of activity?
--so previously considered to be antagonists but are actually inverse agonists.
On a side note, there are various mechanisms of drug antagonism, briefly go through the types of receptor antagonism
Receptor Antagonism: binds to the same receptor to which the agonist is bound.
---Competitive Antagonism: bind to the agonist binding site on the receptor
A. Reversible Competitive Antagonism: in the presence of a fixed concentration of agonist, increasing concentrations of a reversible competitive antagonist progressively inhibit the agonist response. Curve shifts to the right
B. Irreversible Competitive Antagonism: occurs when the antagonist dissociates very slowly or not at all from the receptor, with the result that no change in the antagonist occupancy takes places when agonist is applied. A receptor that is bound by this antagonist can not longer respond to the binding of an agonist.
--Noncompetitive Antagonism: allosteric antagonism, binds to the receptor at a different site from the agonist. Antagonist binding reduces or prevents action of the agonist with or without any effect on the binding of the agonist.
What are the non receptor antagonism?
Non-receptor Antagonism: does not bind to the receptor to which the agonist binds, but it inhibits the respond to the agonist.
A: Indirect Antagonism: antagonist does not bind to the receptor but to an intermediate macromolecule in the pathway that links the receptor to the physiological effect.
B: Physiological Antagonism: one agonist opposes another agonist, but through different receptors. For example: epi and histamine
---Chemical Antagonism: a drug that reacts chemically with an agonist to form a product that cannot activate a receptor is a chemical antagonist.
Finally what is an inverse agonist?
Reverse the constitutive activity of a receptor
--in systems that are not constitutively active, inverse agonist will behave like competitive antagonists
--many drugs that were previously classified as antagonists are now known to be inverse agonists.
Back to histamine, H1 /H2 receptors are located where?
H1 receptors are present on what?
Endothelium, smooth muscle cells and nerve endings
--H1 are couples to PLC; their activation leads to formation of IP3 and DAG
--H1 receptors reside on endothelial cells and their stimulation leads to the formation of NO.
H2 receptors are present on what?
Gastric mucosa, cardiac muscle cells and some immune cells
--H2 receptors are linked to the stimulation of adenylyl cyclase and thus activation of c-AMP dependent protein kinase
--H2 receptors are also located on vascular smooth muscle
Histamine causes vasodilation in the cardiovascular system, explain the mechanism
Vasodilation: involves both H1 and H2 receptors
--H1 has higher affinity for histamine, mediate a faster dilator response and is rapid and short lived
--H2 causes vasodilation that develops slowly and is more sustained
What effects does histamine have on the heart?
Increased contractility and increased pacemaker rate
--mediated mainly by H2
In human atrial muscle histamine actually decreases contractility
--mediated mainly by H1
If histamine is given IV its direct cardiac effects are not prominent and are overshadowed by baroreflexes elicited by the reduced blood pressure
Histamine induced edema results from the action of histamine on H1 receptors in the vessels of the microcirculation, especially in the postcapillary vessels. This effect is associated with what?
Separation of the endothelial cells which permits the transudation of fluid and molecules as large as small proteins into the perivascular tissues.
--this effect is responsible for hives
Intradermal injection of histamine causes the triple response. This consists of what?
1. Localized red spot: extending a few mm around the site of injection (vasodilation)
2. Brighter red flush or flare: Extending about 1cm beyond the red spot and developing more slowly (histamine induced stimulation of axon reflexes)
3. A wheal: discernible in 1-2 minutes, which occupies the same area as the original red spot. (edema)
Histamine affects the extravascular smooth muscle, explain the effect on the GI tract, Bronchiolar smooth muscle
H1: intestinal smooth muscle contraction
What is the effect of histamine on the nervous system?
H1: powerful stimulant of sensory nerve endings, esp those mediating pain and itching
What is the effect of histamine in the secretory tissue?
H2 receptors: gastric acid secretion and gastric pepsin and intrinsic factor production
-also stimulates secretion in the large and small intestine
Systemic mass cell degranulation can cause life threatening condition know as anaphylaxis. what is this treated with?
What are the adverse effects of histamine?
--flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction and GI upset
Histamine should not be given to asthmatics or patients with active ulcer disease or GI bleeding
These next set of cards are going to discuss histamine antagonists. What are the physiological antagonists of histamine?
-Epi: have smooth muscle actions opposite to that of histamine
they act at different receptors
Important to give this is anaphylaxis
Release inhibitors: reduce the degranulation of mast cells that results from immunologic triggering antigen-IgE interaction. What are antagonist that have this effect?
Cromolyn and Nedocromil : used to treat asthma
--also B2 agonist are capable of reducing histamine release
There are H1 and H2 receptor antagonists, what are the H1 antagonists?
First generation: have sedative effects and more likely to block autonomic receptors
---Chlorpheniramine, cyclizine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine, and promethazine
Second generation: less sedating due to less distribution to the CNS (substrates of P-glycoprotein transporter)
---Fexofenadine, loratadine, cetirizine, astemizole and terfenadine
What are the actions of H1 and H2 receptors antagonists?
H1 antihistamines were considered to be H1 receptor antagonists
--however they are inverse agonists
Bronchiolar and GI muscle contraction can be blocked
H1 antagonists bind to cholinergeric, alpha adrenergic, serotonin and local anesthetic receptor sites
The first use of an H1 receptor antagonist is for allergic conditions. What is the action?
1. Treating allergies caused by antigens acting on IgE antibody sensitized mast cells
2. Ineffective is treating bronchial asthma
3. Epi is the drug of choice in treating anaphylaxis or any other condition resulting in massive release of histamine
H1 receptor antagonist can also be used to treat motion sickness/nausea, what is the mechanism of action?
Diphenhydramine, Dimenhydrinate and Promethazine
--prevent symptoms of motion sickness
--prevent vomiting through the chemoreceptors and vestibular pathways
Finally the last use of an H1 receptor antagonist is somnifacients, what is the action?
--have strong sedative properties and are used to treat insomnia
What are adverse effects of H1 receptor antagonists?
Sedation: less common with second generation
Dry mouth: due to anticholinergic agents
What are the drug interactions with H1 receptor antagonists?
1. Significant cardiac toxicity including lethal ventricular arrhythmias when taking second generation agents (terfenadine or astemizole) with ketoconazole, itraconazole or macrolide antibiotics such as erythromycin
--these drugs inhibit the metabolism of many drugs via CYP3A4 and cause significant increase in antihistamines
--blockade of the HERG K channels in the heart that are responsible for repolarization of the action potential
-this results in prolongation of the action potential leading to arrhythmias
BOTH DRUGS REMOVED FROM MARKET
Grapefruit juice also inhibits CYP3A4 and has been show to increase what?
Terfenadines blood levels
The active metabolite of terfenadine is currently marketed as what?
--lacks the cardiac toxicity