Histamine

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Week 1, Block 2 - Pharm High Yield

Histamine is synthesized from ___.

L-histidine

Rate limiting enzyme for Histamine synthesis.

histidine decarboxylase - inducible

Histamine synthesis cofactor.

Pyridoxal - 5 - phosphate

Enzyme that inhibits histidine decarboxylase.

methyl-histidine

In mast cells: Storage of histamine in _______ granules as a complex with ______________________ and ATP.

secretory granules / heparin sulfate

In basophils: Storage of histamine in ______ granules as a complex with _________.

secretory granules / chondroitin

If histamine is not stored in a mast cell, it is being stored in a non-mast cell. Name the 5 types.

Epidermal cells
Gastric mucosa cells
Neurons
Tumor cells
Any cell that regenerates

The release of histamine depends on what 2nd messenger.

Ca2+

The release of histamine causes ____ within seconds. But ____ within minutes.

Within seconds: burning, itching, BP drop, HR increase, headaches.
Within minutes: BP recovers / hives appear

Describe the Antigen-Antibody reaction.

Steps:
1. Free drug binds carrier.
2. IgE mediated allergy induced.
3. Prednisone can inhibit IgE proliferation.
4. Differentiation.
5. Fixation of IgE antibodies to mast cells/basophils. This is the first exposure.

6. Upon the second exposure, the binding induces mediator release.
7. Ca2+ dependent degranulation and mediator release takes place.
8. Antihistamines can block the the histamines binding to the receptors on the smooth muscle cells and other organs at this point.

Note: This reaction requires prior exposure.

What other things can promote the release of histamine from mast cells besides the Ag-Ab reaction?

Drugs, peptides, and venoms.
1. Drugs: Vancomycin...et al.
2. Peptides: substance P and Complement (C3a/C5a).
3. Venoms: wasp

Explain Red Man Syndrome

Vancomycin induced inflammatory response.

Gram + bacteria infects patient. We provide rapid IV infusion of Vancomycin, the "last resort" antibiotic. The patient gets rash in the face, neck and upper torso. The mediator is mast cell degranulation caused by Vancomycin's increase of intracellular calcium.

2 drugs that inhibit the release of histamine.

Cromolyn Sodium

Omalizumab

Can you use cromolyn sodium to treat an asthma attack? Explain your answer.

No. Cromolyn sodium's mechanism of action is to stabilize mast cell membranes and prevent the release of histamine upon inhalation. Therefore, it is not effective for treating attacks. It is inhaled.

What is the mechanism of action (MOA) of omalizumab and what is the major SE?

It is a monocolonal antibody. It is an anti-antibody. It is an IgG antibody made against the IgE antibody. It binds tightly to free IgE in the circulation to form Omalizumab-igE complexes that prevent the binding of the IgE antibody to the mast cell thereby preventing the immune response.

It is given subcutaneously. The major side effect is: life threatening anaphylaxis / bleeding related adverse effects.

It is used to treat moderate to severe asthma. Allergic asthma.

Admin of Omalizumab

It is given subcutaneously.

Major use of Omalizumab vs Cromolyn Sodium.

Omalizumab = emergent asthma

Cromolyn Sodium = asthma prophylaxis

H1 receptor couples with ______G protein____ to _____increase/decrease______ this second messenger molecule _________.

H1: Gq / Ca2+ increase

H2 receptor couples with ______G protein____ to _____increase/decrease______ this second messenger molecule _________.

H2: Gs / cAMP increase

Where does H1/H2 vasodilation occur?

H1: endothelial cells (contractile cells)
H2: vascular smooth muscle cells

How does H1 stimulate vasodilation?

1. Increase Ca2+
2. Increase NOS
3. Increase NO
4. Increase cGMP

NO is a potent dilators.

How does H2 stimulate vasodilation?

1. Increase cAMP which is a dilator effect.

What happens if H1 receptors are located on vascular smooth muscle?

Vasoconstriction due to increase in Ca2+ which will increase contraction response.

Complete the sentence: In general, histamine ______ resistance vessels, ________ capillary permeability, and causes an overall _________ in BP. In some vascular beds, histamine constricts veins, contributing to ______ formation.

In general histamine DILATES resistance vessels.

INCREASES capillary permeability.

Causes and overall DROP in blood pressure.

In some vascular beds, histamine constricts veins, contributing to EDEMA formation.

How does the H1 receptor cause an increase in vascular permeability?

H1 receptors are located on post capillary venule endothelial cells. An increase in calcium causes the endothelial cells to contract and expose the basement membrane. This makes it freely permeable to plasma

Which histamine receptor acts on the heart? What are the effects?

H2 receptors are located on cardiac myocytes. Histamine binding causes an increase in contractility and electrical conduction.

What are the effects of the H1 and H2 receptors on bronchiole smooth muscle?

H1 = contraction
H2 = dilation / relaxation

Identify: Histamine receptor for intestinal smooth muscle and its effect.

H1 - contraction

Identify: Histamine receptor for gastric GI secretions and its effect.

H2 - gastric acid secretion

Identify: Histamine receptor for peripheral nerve endings and its effects.

H1: pain and itching

Identify: Histamine receptor for CNS and its effects.

H1 - arousal / wakefulness

Explain the Triple Response of Lewis.

Intradermal histamine exhibits the following response:

1. Flush caused by H1 vasodilation

2. Flare caused by H1 receptors on sensory nerve endings which cause vasodilation. (the skin patch flares outwards)

3. Wheal caused by H1 receptors increasing vascular permeability on the post capillary venule endothelial cells. (the bump now raises up due to the edema this caused).

What are the first generation anti-histamines? (4)

Ethanolamines: Diphenhydramine & Dimenhydrinate

Alkylamines: Chlorpheniramine

Phenothiazines: Promethazine (also a D2 blocker)

What receptor do the First generation anti-histamines target?

Non-specific, Inverse agonists of H1 receptors because they reduce the constitutive activity of the receptor and compete with histamine. The 2nd generation drugs are MORE specific for H1 than the 1st gen drugs bc the 1st gens can affect other nonrelated receptors.

Do 2nd generation antihistamines affect the CNS?

No. they are non-sedating. they cannot cross the BBB.

What are the major indications for the use of First gen antihistamines and H1 receptor blockers?

Reduce the symptoms associated with acute allergic responses.

Inhibits vascular permeability
Suppresses itching
BP: NO EFFECT
Bronchoconstriction: NO EFFECT

How are the 1st generations administered?

Orally due to rapid absorption.

Some topical and nasal.

What are the effects of the 1st generation antihistamines? (CNS, Peripheral/Central anticholinergic effects, and Local anesthetic effect)

• CNS:
1st Generation: sedation / decreased alertness
1st Generation: Paradoxical excitation = stimulates CNS at HIGH doses and in children.
1st Generation: motion sickness due to anticholinergic effects

• Peripheral / Anticholinergic effects:
1st Generation: Dry mucus membranes, urinary retention
SLUDGE: due to structures causing blockade of muscarinic receptors

• Local anesthetic effects: ONLY AT HIGH DOSES
Promethazine is the only drug known so far.

What are the 2nd generation ant-histamines (4) and why are they better? What receptor do they use?

Fexofenadine (from Terfenadine)

Loratadine to Desloratidine

Cetirizine (active metabolite of hydroxyzine)

They are better because they do not enter the brain and cause less sedation. They are also H1 receptor specific.

Which 2nd generation anti histamine has the most sedative effects.

Cetirizine (rememeber paradoxical excitation)

How does sedation occur because of 1st generation anti-histamines?

Two step process:
1. Inhibition of central H1 receptor
2. Inhibition of central cholinergic receptors (anticholinergic effects)

What are the SE of first generation ant-histamines?

Sedation

Loss of appetite, vomiting, nausea

Rare: Increased appetite / weight gain due to H1 central effect to normally reduce appetite

Dry mouth, dry respiratory passages, urinary retention all due to non-specific MOA of 1st generation anti-histamines.

1st generation with most sedation effect

Diphenhydramine

2nd generation with most sedation effect

Cetirizine

Therapeutic use: Diphenhydramine

Acute allergies

Sleeping tablets (profound sedation)

Motion sickness

Early Parkinson's

Therapeutic use: Dimenhydrinate

Motion sickness (anticholinergic effect) / vestibular disturbances

Therapeutic use: Chlorpheniramine

Acute allergies / Most potent & Less prone to cause sedation

Therapeutic use: Promethazine

Motion sickness (anticholinergic effect)

Therapeutic use is chemotherapy induced nausea and vomiting.

Promethazine

Therapeutic use is Early Parkinson's

Diphenhydramine

Therapeutic use is for vestibular disturbances

Dimenhydrinate

Therapeutic use for this class of drugs is to relieve symptoms of gastric upset / peptic ulcer disease.

Name other uses.

H2 receptor blockers

GERD

Peptic ulcer caused by helicobacter pylori infection

Gastric injury caused by NSAIDS

What are the H2 receptor blocking drugs?

Cimetidine

Ranitidine

Famotidine

Describe the physiology of gastric acid secretion.

Steps:
1. Vagus nerve / gastrin act on enterochromaffin-like cells (ECL) ....or mast cells

2. Histamine is released

3. Histamine acts on H2 receptor on parietal cells which uses Gs protein to increase adenylate cyclase

4. cAMP and Protein Kinases are activated

5. Result is increased H+ (gastric acid) secretion (K+ enters the parietal cell and H+ exits)

Note: Ach and Gastrin also DIRECTLY increase gastric acid secretion.

What are the major SE of cimetidine?

• Inhibits P450 enzymes:
Decreases metabolism of other drugs

Prolongs half-life of these drugs

• Long term use at high doses:
Decreases testosterone binding & inhibits CYP enzyme that hydroxylates estradiol

Men get gynecomastia, reduced sperm count, and impotence.

The 3 motion sickness drugs and their MOA.

Dimenhydrinate
Promethazine
Diphenhydramine

Their anticholinergics effects block the muscarinic cholinergic transmission that takes place between the eyes, inner ear, and GI tract. It also involves the cerebellum which controls balance and the vestibular system (labyrinth) which control equilibrium.

Give two reasons why loratidine is less likely to cause sedation compared to diphenhydramine.

1. less likely to enter CNS and block H1 receptors that mediate arousal.

2. no anticholinergic activity, which mediates CNS sedation.

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