03: Autocoids

Self-remedy

What does autocoids basically mean?

autacoids

All cells secretes certain substances called ____________that affect our body one way or another.

endogenous

Autocoids are varied groups of ____________ substances occurring in minute amounts, with brief duration, act near the site of synthesis, possessing distinct chemical structure and biologic / pharmacologic activity

• Biological active amines

• Ergot alkaloids

• Eicosanoids

• Vasoactive peptides

Specific autacoids consist of:

Inflammation

This defense mechanism may be good or bad for the body and is used primarily as a reaction of our body to fight off certain things that destroy us, most notably in infections and certain injuries

Allergies

These are certain conditions where inflammation can go out of control, causing an increase in inflammatory markers and causing problems such as allergies.

Anaphylaxis

This is a severe form of allergic reaction that can cause difficulty in breathing and severe hypotension that can lead to death.

Autacoids

___________are produced by many cells and released in response to specific reactions or stimuli, acting locally.

Hormones

___________are produced by specific cells and transported through the blood to act on distant target tissues.

Histamine

What is released in defense for pathogenic microorganism?

IgE or non IgE-mediated reactions

Histamine is triggered by __________________ which results in allergy conditions and bronchial asthma

Endogenous molecules

What causes local vasodilation and leakage of plasma-containing mediators of acute inflammation and antibodies

histidine decarboxylase

What transforms histidine to histamine?

Diamine oxidase (DAO) and histamine-N-methyltransferase

What metabolizes histamine?

basophils, hypothalamus, GI tract and mast cells

Where is histamine stored?

degranulate

Once there is cross-linking, mast cells will ______________and release histamines and other substances such as tryptase which can now have its effect in the body

Lower DAO activity

This is a potential indicator of intestinal mucosa damage in inflammatory response and neoplastic diseases, and in persons undergoing chemotherapy

Histamine-N-methyltransferase (HNMT)

What degrades histamine the most often?

bronchial epithelium

Histamine-N-methyltransferase (HNMT) is a key enzyme in histamine degradation especially in the ___________________

HNMT

Between DAO and HNMT which has higher affinity?

Attachment of an allergen to IgE antibody leads to degranulation of mast cells and basophils, releasing preformed mediators such as histamine.

How is histamine released, starting from an allergen?>

hay fever or allergic rhinitis, urticaria

What are examples of type 1 Hypersensitivity reactions?

Negative Feedback Control Mechanism

What is the ability of histamine to modulate its own release that is common in mast cells of the skin and basophils?

H2 receptors

Negative Feedback Control Mechanism of histamine is mediated by what receptor?

Antigen Presenting Cells (eg. Dendritic cells)

Antigens (eg. dust mites, seafoods) are processed by _____________

T lymphocytes (Th2 lymphocytes)

APCs will present the captured antigen to ______________________within secondary lymphoid organs

naive T lymphocytes

APCs will train the _______________ that there is a presence of foreign substance

plasma cell

T helper cells will be stimulated and activate B-lymphocytes to become ___________

IgE antibodies

Plasma cells will produce________________ that are very specific for the particular antigen

explosive degranulation

IgE that is specific to the antigen attaches to the mast cells, and basophils resulting in _______________

calcium and energy

Explosive degranulation of basophils requires what?

sensitization

In IgE-mediated allergy, there must be a prior exposure to the allergen before developing an allergic reaction. This is a period known as __________________

cross-linking degranulative release

Upon re-exposure to the antigen, sensitized cells (basophils, mast cells) will trigger _____________________ of preformed mediators (histamine, prostaglandins, kinins)

H1, H2, H3, and H4 receptors.

Autacoids exert their biological effects by binding to specific cell membrane receptors, such as ________________

• cAMP signal pathway

• Phosphatidylinositol Signal and DAG pathway (IP3, DA

All four autacoid receptor types belong to the large superfamily of G protein-coupled receptors (GPCRs) and activate two signal transduction pathways which are:"

Smooth muscles, Endothelium & Brain

Where is the distribution of H1 receptors?

Gq → ↑ IP3, DAG

What transduction pathway is used by H1 receptors?

• Flushing, headache

• Bronchoconstriction

• Vagal afferent nerve and cough receptor activation

What are the functions of H1 receptors?

• ↑ CR;

• ↑ pruritus, pain

• ↑ vascular permeability

• And: Histidine uptake , PG synthesis, Release of histamines, LTs and other mediators, Eosinophils and other inflammatory cell recruitment

What is increased when H1 receptors are used?

AV conduction time & Blood pressure (Hypotensio)

What is decreased when H1 receptors are used?

Gastric mucosa, Cardiac muscle, Mast cells, Brain

Where is the distribution of H2 receptors?

GS ↑ cAMP

What transduction pathway is used by H2 receptors?

• Bronchial smooth muscle relaxation

• Flushing, headache

• Esophageal relaxation

What are the functions of H2 receptors?

• Chronotropic and inotropic actions

• Gastric acid secretion

• Vascular permeability

• Mucus production

• Glycoprotein secretion

• Ts, Tc, NK, PMN, and basophil chemotaxis and enzyme release

What is increased when H2 receptors are used?

Blood pressure (Hypotension)

What is decreased when H2 receptors are used?

• CNS: Presynaptic autoreceptors & Heteroreceptors Brain

• Myenteric plexus

• Other neurons

Where is the distribution of H3 receptors?

Gi ↓ cAMP

What transduction pathway is used by H3 receptors?

• Pre-synaptic heteroreceptor on both histamine and non-histamine containing nerves in CNS and PNS

• Prevents excessive bronchoconstriction

• Gastric acid secretion

What are the functions of H3 receptors?

Hematopoietic cells (eosinophils, neutrophils, CD4 T cells)

Where is the distribution of H4 receptors?

Gi ↓ cAMP

What transduction pathway is used by H4 receptors?

IL-6 and TNF-α

Transcriptional activity of H4 receptors is stimulated by?

IL-10 and IL-13

Transcriptional activity of H4 receptors is inhibited by?

H1 and H3 receptors

Histamine acts on the nervous system mainly through _______________ in the brain.

appetite and satiety

H1 and H3 receptors help regulate ____________________, with histamine contributing to appetite suppression.

wakefulness and alertness.

Histamine also promotes ______________________

acetylcholine, amine, and peptide neurotransmitters.

Activation of H3 receptors can reduce the release of ___________________________________

urticarial response.

Histamine stimulates sensory nerve endings, causing pain and itching, and can produce a ______________

depolarize efferent nerve endings,

Histamine can also ______________, contributing to the sensations associated with allergic reactions.

vasodilation of arterioles and precapillary sphincters.

Histamine affects the cardiovascular system primarily by causing ____________________________

vasodilation of arterioles

This _____________can cause flushing, a sense of warmth, headache, and decreased blood pressure.

stimulatory

Histamine also has a _____________ effect on the heart, which can lead to an increased heart rate.

reflex tachycardia.

The resulting drop in blood pressure caused by histamine may additionally cause ______________

nitric oxide (NO) release.

At low doses, histamine causes vasodilation mainly through _________________

H2 receptors

At high doses, histamine activates _________________, increasing cAMP and producing further vasodilation.

H1 receptor activation.

Histamine causes vascular edema primarily through _________________

postcapillary vessels

Histamine acts on __________________, causing increased vascular permeability, which results from vascular leakage as endothelial cells separate from one another.

edema

The increased spaces between endothelial cells allow fluid to transudate into the surrounding tissues, producing ____________.

limit the spread

This vascular response contributes to the inflammatory process but also helps _________________ of inflammation.

H1 receptor activation

Histamine causes through ________________ in the airway smooth muscle.

wheezing on physical examination.

H1-mediated bronchoconstriction can produce a hyperactive neural response and result in _______________

asthma

Patients with ________are especially sensitive to histamine and may develop marked bronchoconstriction.

asthma and cystic fibrosis.

Small doses of inhaled histamine can be used to assess bronchial hyperreactivity, which may help in the diagnosis of suspected ________ & ___________

H2 and H1 receptors.

Histamine affects the gastrointestinal system through both ______________

H2

___________ receptor activation stimulates gastric acid secretion, while ____________ blockers can therefore be used to treat GERD and peptic ulcer disease (PUD).

H1

____________ receptor activation causes contraction of gastrointestinal smooth muscle.

diarrhea

Large amounts of histamine may cause ___________, particularly following massive degranulation of mast cells and other cells, due to histamine interacting with H1 receptors and causing smooth muscle contraction.

contraction of other smooth muscles,

Histamine can cause ____________________, including the uterus in pregnant women

NF-κB

Histamine can contribute to the inflammatory response by activating ___________.

pro-inflammatory cytokines and adhesion molecules

NF-κB promotes the synthesis of_______________________ which help initiate and maintain allergic inflammation

Cytokines

_____________are cell-signaling molecules that help start and regulate the inflammatory response.

triple response

The _____________ occurs after intradermal injection of histamine and consists of a red spot, edema, and a flare response due to the involvement smooth muscle and capillary or venular endothelium.

F. Histamine has no current routine clinical application, but it may be used as a provocative test for bronchial hyperreactivity.

(T/F) Histamine has many current routine clinical applications

Scombroid fish poisoning

___________________ occurs after eating spoiled deep-sea fish containing high levels of histamine and can produce anaphylactic-like reactions.

TRE

(T/F) Unlike a true fish allergy, which tends to recur whenever the same fish is eaten, scombroid poisoning is caused by spoiled fish and may occur only once.

histidine-derived histamine

Spoiled fish accumulates________________, and ingestion of large amounts can produce these allergy-like manifestations.

Anaphylaxis

_____________is a severe type of allergic reaction in which massive histamine release from degranulating cells occurs after exposure to a trigger.

difficulty breathing, loss of consciousness, and abdominal pain.

Anaphylaxis can cause ______________, _______________and __________

Epinephrine

__________is the drug of choice for immediate treatment of anaphylaxis, not antihistamines or steroids.

β2-receptor agonist

Epinephrine acts as a ______________ producing bronchodilation to improve breathing.

α1-receptor agonist

Epinephrine acts as an _________________, causing vasoconstriction and helping increase blood pressure.

β2-receptor agonist &

α1-receptor agonist

Through these actions, epinephrine counters the effects of histamine at H1 receptors.

0.1 mg/kg

Epinephrine dose is ___________using a 1:1000 solution.

0.15–0.30 mL.

Epinephrine dose for children under 30kg?

0.3–0.5 mL.

Epinephrine dose for adults?

tachycardia and cardiac arrhythmias.

Epinephrine is preferably administered intramuscularly, while IV administration can cause __________________

Ammi visnaga.

Cromolyn (disodium cromoglycate) and nedocromil are chromones derived from _______________

mast cell stabilizers

Chromones are _______________used mainly for the treatment of allergic asthma.

inhibit

Chromones ________mast cell degranulation triggered by antigen-IgE interaction.

very low drug interactions

Chromones have _____________ and are relatively safe and can be administered orally or by inhalation.