MedChem, Anithistmine, Eiconisoids, and NSIADS

What is histamine?

Naturally developed chemical compound that helps initiate an immune response.

What are some immununologic rxns that histamine can mediate?

1. Inflammation

2. Allergic reactions

3. Gastric Acid Secretion

4.CNS Alertness, Attention

How is histamine created?

Decarboxylation of L-Histidine ( i.e removal of carboxylic acid on the alpha carbon from L-Histidine Compound )

T/F Histamine is rapidly degraded

F; Histamine is not degraded, it is inactivated and stored.

Describe the bonds expressed between histamine and H-receptors.

The nitrogens on the imidazole ring bind to the histamine receptor via Hydrogen Bond

The protonated amine (1*) bind with the histamine receptor via Ionic Bond

Which form(s) of histamine are active?

a. Protonated Amine

b. Protonated amine + imidazole ring

c. Neutral charged compound

A & B

Which form(s) of histamine are the most abundant?

a. Protonated Amine

b. Protonated amine + imidazole ring

c. Neutral charged compound

A only

Which form(s) of histamine are inactive?

a. Protonated Amine

b. Protonated amine + imidazole ring

c. Neutral charged compound

C only

Describe the importance of degranulation, histamine, and allergic reactions.

On the initial contact of an allergen, the B-cells that recognize the the allergen and release IgE antibodies that will initiate mast cells and basophils.

The mast cells and Basophils once recognize the allergen independently will degranulate their content that will release the inflammatory mediator histamine as well as the other contents from the cell.

Where is histamine stored?

Mast Cells, Basophils, Enterochromaffin-like cells /“ECL” ( located in the stomach)

Where do mast cells mediate histamine release?

Mast cells focus on releasing histamine for local tissue injury

Where do basophils mediate histamine release?

Basophils mediate histamine release during systemic allergic reactions or inflammation.

T/F Not all Histamine is an Immune Response

T; (i.e CNS Awakeness and Alertness)

List reasons why histamine is released.

1. Caused by an immunological response from Basophils

2. Exposure to Morphine, Tubocurarine, & certain dyes

3. Mechanical or Chemical Injury from Mast Cells

Describe the pathophysiology of Histamine release in blood/tissues

Seasonal Allergies

Anaphylactic Shock

Describe the pathophysiology of Histamine release in the stomach

Duodenal Ulcers

Zollinger Ellison Syndrome or Gastrinoma

Describe the pathway of GCPR’s ( that are histamine receptors )

G-Protein Couplesdreceptors are a transmembrane protein that regulate phosphorylation. The receptor is attached to an inactive heterotrimeric protien that has an alpha protien which directs the function; this function can be excitatory or inhibitory. Once a ligan binds the alpha protein triggers activation of a second messenger that will either trigger or hinder phosphorylation via adenyl cyclase and the PKA dimer or trigger phosphorylation via PLC-IP3-Ca2+ pathway.

Degranulation is involved in ____ allergic reactions. List some examples.

Type I hypersensitivity / Immediate

Examples: Food, Drugs, and Venoms

List and Describe Clinical Symptoms associated with MILD Histamine release.

1. Erythema - Reddening (of patches ) of the skin

2. Urticaria- Red, Itchy raised patches or wheals on the skin

List and Describe Clinical Symptoms associated with MILD to MODERATE Histamine release.

1. Skin Reactions

2. Tachycardia - fast heart rate

3. Dysrhythmias - abnormal rhythm

4. Moderate hyPOtension

5. Mild respiratory distress

   “ This can be categorized as asthma attack”

List and Describe Clinical Symptoms associated with SEVERE Histamine release.

1. Severe HyPOtension- dramatic fall of BP

2. Ventricular Fibrillations- rapid, irregular heartbeats that can cause the heart to abruptly stop pumping blood into the body an lead into a a heart attack

3. Cardiac Arrest: Electrical issue; the heart stops beating effectively limiting blood flow to organs and brain

4. Bronchospasm: the muscle around the airways tighten making it harder to breath

5. Respiratory arrest: Can’t breath, loss of consciousness can result

6. Anaphylaxis - life-threatening allergic reaction causing multiple system involvement.

Clinical Presentation: Anaphylactic Shock and Asthma Attack

Where are H1 receptors distributed?

Smooth Muscle, Brain , & Endothelium

Where are H2 receptors distributed?

Gastric Mucosa, Cardiac Muscle, Mast Cells, and Brain

Where are H3 receptors distributed?

Presynaptic Auto-receptors and Heteroreceptors in the:

1. Brain

2. Myenteric Plexus

3. Other Neurons

Where are H4 receptors distributed?

Hematopoetic Cells via Bone Marrow and Blood Cells

Which downstream mechanism do H1 receptors go through?

Gq (activate maybe)

Increasing phosphylation (IP3) and DAG

Which downstream mechanism do H2 receptors go through?

Gs (activate adenylate cyclase), increasing cAMP levels.

Which downstream mechanism do H3 receptors go through?

Gi (inhibits adenylate cyclase), decreasing cAMP levels.

Which downstream mechanism do H4 receptors go through?

Gai (inhibits adenylate cyclase), decreasing cAMP levels.

List some Inverse Agonist( s) that are partially selective to H1 receptors

Cetirizine

Mepryamine

Triprolidine

List some Agonist(s) that are partially selective to H1 receptors

Histaprodifen

List some Inverse Agonist(s) that are partially selective to H2 receptors

Ranitidine
Famotidine

Tiotidine

List some Agonist(s) that are partially selective to H2 receptors

Amthamine

T/F all Histamine receptors are GPCR

T

What physiologies occur when H1 receptors are activated, describe the clinical presentation.

Which GPCR is relative to H1 receptors?

Smooth Muscle Contraction ( i.e Ca2+)

Vaso(blood vessels) dilation (i.e endothelial eNO)

Symptoms

• Wakefulness

• Alertness

• Vasodilation

• Separation of the endothelial cells

• Vascular smooth muscles relaxation

GPCR: Gq/11

What physiologies occur when H2 receptors are activated, describe the clinical presentation.

Which GPCR is relative to H2 receptors?

Activation of Adenyl Cyclase - Cyclic AMP -PKA- cAMP

Presentation

• Relaxation of Vascular smooth muscles

• Vasodilation

• Cardiac Stimulant

• Gastric Acid Secretion

GPCR: Gs

What physiologies occur when H3 receptors are activated, describe the clinical presentation.

Which GPCR is relative to H3 receptors?

Inhibition of Adenyl Cyclase - decreased cAMP.

Presentation includes sedation, appetite stimulation, and modulation of neurotransmitter release.

GPCR: Gi/o.

What physiologies occur when H4 receptors are activated, describe the clinical presentation.

Which GPCR is relative to H4 receptors?

Stimulates Chemotaxis of mast cells and leukocytes towards sites of inflammation. ( local)

T/F H3 is a postsynaptic receptor

F

Describe the Feedback Regulation of Histamine Release

Stimulation of H2 receptors increase cyclic AMP and leads to feedback inhibition. Of histamine release from mast cells and basophils in the human skin.

T/F Histamine has no clinical relevance other than diagnostic

T

Where can we find histamine being used as a diagnostic?

Pulmonary Function

Allergy testing for histamine sensitivity

Gastric sensitivity testing

What are these two drugs examples of ? Betazole & impromidine

Histamine Agonist

T/F Vasodilation is the most important effect of histamine in humans and can result from activation of either H1 or H2 receptors

T

Infusion or Injection of histamine causes …

Decrease in Blood Pressure ( both systolic and diastolic)

Increase in Heart Rate

Why does histamine cause blood pressure changes?

The Vasodilation Action in the arterioles and pre capillary sphincters

Where does the histamine vasodilation action of histamine occur?

Arterioles and Pre-capillary Sphincters

Describe the ways histamine effects the heart

Direct : Histamine increases heart rate and contractility, leading to increased cardiac output.

Indirect: Histamine caused vasodilation, which causes reflex tachycardia

Which histamine receptor is the major mediator for increase capillary permeability ?

H1

Describe Histamine effect on capillary permeability

Histamine causes an effluent of plasma protein and fluid in extra cellular spaces, causing am increase in blood flow, and increase in capillary permeability, and eventually edema.

Is this an H2 or H1 activity? Positive Chronotropism

H2

Is this an H2 or H1 activity? Negative Inotropism

H2

Slows AV conduction

H1

Is this an H2 or H1 activity? Increasing Heart automaticity

H1 & H2

Describe the “ Triple Response Phenomenon” and it’s relation to histamine

Is this the same thing Dr. Williams was talking about?

The Triple Response Phenomenon refers to the three-part reaction of the skin to injury, irritation, and Intradermal injections of Histamine

1. Development of a red spot (erythema),

2. Flushing (flare)

3. Swelling of a Wheal

Figure out the effects of histamine of the extravascular smooth muscles

I think just vasodilation,the slide cut off, check the video

List some adverse effects to Histamine ( ~6 listed on the slide)

Flushing ( feeling of warmness)

Hypotension

Tachycardia

Headache

Bronchoconstriction

GI Upset

What is Histamine Shock?

Occurring during a rapid release of histamine or large doses of histamine administered, histamine chock is systemic anaphylaxis causing profound and progressive drop in blood pressure

Name the indication from this antihistamine: Chlorpheniamine

Allergy, ___ Generation

Name the indication from this antihistamine: Chloropheniramine

Allergy (1rst gen)

Name the indication from this antihistamine: Diphenhydramine

Allergy ( 1rst gen), Nausea, Insomnia Cough, Cold, and Pain relief

Name the indication from this antihistamine: Hydroxyzine

Allergy ( 1rst gen ) and Itching

Name the indication from this antihistamine: Cetirizine

Allergy (2nd gen)

Name the indication from this antihistamine: Fexofenadine

Allergy ( 2nd gen)

Name the indication from this antihistamine: Loratadine

Allergy (2nd gen)

Name the indication from this antihistamine: Desloratadine

Allergy ( 2nd Gen)

Name the indication from this antihistamine: Levocetirizine

Allergy (2nd gen)

Name the indication from this antihistamine: Cyproheptadine

Anti-migraine

Name the indication from this antihistamine: Ergotamine + diphenhydramine

Anti-Migraine

Name the indication from this antihistamine: Azelastine

Intranasal antihistamine

Name the indication from this antihistamine: Doxepin

Generalized Itching

Name the indication from this antihistamine: Dimenhydrinate

Nausea and Motion Sickness

Name the indication from this antihistamine: Cyclizine

Nausea and Motion Sickness

Name the indication from this antihistamine: Meclizine

Nausea and Motion Sickness

Name the indication from this antihistamine: Promethazine

Nausea, Motion Sickness, and Insomnia

Name the indication from this antihistamine: Pyrilamine

Insomnia

A 45 year old truck driver complains of seasonal allergies. Which of the following would be indicated?

A. Cyclizine

B. Dozxepin

C. Doxylamine

D. Hydroxyzine

E. Fexofenadine

E

Doxylamine and Promethazine