Autacoids and Autacoid Antagonists: Histamine Agonist and Antagonist

Question 1

Autacoids have a diverse physiological and pharmacological activities. They usually have a….

Answer 1

brief lifetime and act near their sites of synthesis

Question 2

The first drug we are going to look at in this section is histamine, what is it formed by?

Answer 2

Formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed by histidine decarboxylase

Question 3

Most tissue histamine exists in bound form in what?

Answer 3

granules in mast cells or basophils

Question 4

Mast cells can be triggered by many stimuli and are rich at sites of potential tissue injury:

Answer 4

nose 
mouth 
feet 
internal body surfaces 
blood vessels
particularly at pressure points and bifurcations

Question 5

Non-mast cell histamine is found in several tissues, including?

Answer 5

Including the brain , where it functions as a neurotransmitter

Question 6

An important non-neuronal site of histamine storage and release is what?

Answer 6

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

Question 7

Explain the immunologic release of histamine

Answer 7

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.

Question 8

Explain the chemical/mechanical release of histamine

Answer 8

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

Question 9

There are four cell surface receptors H1,H2,H3,H4 that are all G protein linked. All four receptors have what kind of activity?

Answer 9

Constitutive activity

–so previously considered to be antagonists but are actually inverse agonists.

Question 10

On a side note, there are various mechanisms of drug antagonism, briefly go through the types of receptor antagonism

Answer 10

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.

Question 11

What are the non receptor antagonism?

Answer 11

Non-receptor Antagonism: does not bind to the receptor to which the agonist binds, but it inhibits the respond to the agonist.
—Functional Antagonism
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.

Question 12

Finally what is an inverse agonist?

Answer 12

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.

Question 13

Back to histamine, H1 /H2 receptors are located where?

Answer 13

Postsynaptic membranes

Question 14

H1 receptors are present on what?

Answer 14

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.

Question 15

H2 receptors are present on what?

Answer 15

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

Question 16

Histamine causes vasodilation in the cardiovascular system, explain the mechanism

Answer 16

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

Question 17

What effects does histamine have on the heart?

Answer 17

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

Question 18

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?

Answer 18

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

Question 19

Intradermal injection of histamine causes the triple response. This consists of what?

Answer 19

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)

Question 20

Histamine affects the extravascular smooth muscle, explain the effect on the GI tract, Bronchiolar smooth muscle

Answer 20

H1: intestinal smooth muscle contraction
H1: bronchoconstriction

Question 21

What is the effect of histamine on the nervous system?

Answer 21

H1: powerful stimulant of sensory nerve endings, esp those mediating pain and itching

Question 22

What is the effect of histamine in the secretory tissue?

Answer 22

H2 receptors: gastric acid secretion and gastric pepsin and intrinsic factor production
-also stimulates secretion in the large and small intestine

Question 23

Systemic mass cell degranulation can cause life threatening condition know as anaphylaxis. what is this treated with?

Answer 23

Epinephrine

Question 24

What are the adverse effects of histamine?

Answer 24

Dose related
–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

Question 25

These next set of cards are going to discuss histamine antagonists. What are the physiological antagonists of histamine?

Answer 25

-Epi: have smooth muscle actions opposite to that of histamine
they act at different receptors
Important to give this is anaphylaxis

Question 26

Release inhibitors: reduce the degranulation of mast cells that results from immunologic triggering antigen-IgE interaction. What are antagonist that have this effect?

Answer 26

Cromolyn and Nedocromil : used to treat asthma

–also B2 agonist are capable of reducing histamine release

Question 27

There are H1 and H2 receptor antagonists, what are the H1 antagonists?

Answer 27

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

Question 28

What are the actions of H1 and H2 receptors antagonists?

Answer 28

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

Question 29

The first use of an H1 receptor antagonist is for allergic conditions. What is the action?

Answer 29

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

Question 30

H1 receptor antagonist can also be used to treat motion sickness/nausea, what is the mechanism of action?

Answer 30

Diphenhydramine, Dimenhydrinate and Promethazine

• -prevent symptoms of motion sickness
• -prevent vomiting through the chemoreceptors and vestibular pathways

Question 31

Finally the last use of an H1 receptor antagonist is somnifacients, what is the action?

Answer 31

Diphenhydramine

–have strong sedative properties and are used to treat insomnia

Question 32

What are adverse effects of H1 receptor antagonists?

Answer 32

Sedation: less common with second generation

Dry mouth: due to anticholinergic agents

Question 33

What are the drug interactions with H1 receptor antagonists?

Answer 33

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

Question 34

Grapefruit juice also inhibits CYP3A4 and has been show to increase what?

Answer 34

Terfenadines blood levels

Question 35

The active metabolite of terfenadine is currently marketed as what?

Answer 35

Fexofenadine

–lacks the cardiac toxicity

Question 36

Acute poisoning, of H1 antihistamines is common among children, what are the effects?

Answer 36

CNS

–including hallucinations, excitement, ataxia, and convulsions