Lec 21_Allergies and Histamine

Describe the IgE-mediated allergic response

1. Initial contact with allergen

2. released IgE antibodies from the plasma cell

3. antibodies bind to the mast cell

4. pollen allergen then binds to the IgE on the mast cell

5. This binding triggers the mast cell to release histamine and other inflammatory mediators, leading to allergy symptoms.

What are the 2 main storage sites of histamine?

• mast cells in tissues

• basophils in the blood

Where is the receptor H1 located and its actions?

Smooth muscle

• pain and itching of skin

• bronchoconstriction

• vasodilation (histamine causes NO release)

• local edema

Where is the receptor H2 located and its actions?

Stomach, heart, mast cells

• gastic acid secretion from parietal cells

• cardiac stimulant effect

• (-) feedback to reduce histamine release

Where is the receptor H3 located and its actions?

Nerve endings, CNS

• decrease transmitter release from histaminergic and other neurons

Where is the receptor H4 located and its actions?

Leukocytes

• chemotactic effects on eosinophils and mast cells

What is the Triple response (Intradermal Lewis reaction)?

Histamine effects

1. Flush/red spot - vasodilation of local caps

2. Flare - vasodilation of arterioles = wider reddened area

3. Wheal - localized edema results from increased cap permeability

What effects does histamine have on the nervous system?

• powerful stimulant of pain and itching (bug bites)

• HA - dilate brain arterioles

What effects does histamine have on the skin?

vasodilation leads to reddening of the skin

What effects does histamine have on the CV system?

Decrease BP

• balance between vasodilation effect (NO), baroreceptor reflex, and histamine induced catecholamine release (H1 and H2 effect)

Increase HR

• direct histamine stimulation of the heart - positive inotropic and chronotropic

• reflex tachycardia

Edema

• stimulation causes a separation of the endothelial cells allowing fluid to leak

Overall which receptors do we note lie in the heart?

a. B1, M1, H1

b. B1, M3, H1

c. B2, M2, H2

d. B1, M2, H2

d. B1, M2, H2

Vasodilation effects of histamine stem from _____ receptors on peripheral vasculature

H1

List some of the body’s responses to histamine

• increase HR

• blood clots

• gastric acid secretion

• blood vessel dilation

• bronchoconstriction

• increase permeability of caps

• adrenaline release

• runny nose

• swelling and inflammation

• teary eyes

In allergic rhinitis, what can be expected from

1. Exposure to antigen

2. Subsequent exposure to antigen

1. Exposure to antigen

   • stimulates IgE production

   • sensitization of mast cells

2. Subsequent exposure to antigen

   • produces an allergic reaction

   • “explosive” release of histamine

What is the stepwise management of allergic rhinitis?

Step 1: oral H1 antihistamine PRN and/or intranasal saline

Step 2: add intranasal corticosteroids (fluticasone furoate, fluticasone propionate, mometasone furoate)

Step 3: Intranasal saline + INCS + intranasal antihistamine

Step 4: step 3+ consider additional adjuncts (oral corticosteroids, nasal/oral decongestant)

Step 5: refer to specialist, ENT surgery and/or allergy specialist for allergen immunotherapy

T/F: prevention of sx is more effective than after sx appear

true

What is the primary pharmacotherapy?

oral antihistamines

What is the difference between first generation H1R antagonists vs Second generation H1R antagonists?

First gen

• sedating

• passes BBB

Second gen

• non-sedating

• poor passing into BBB

• longer duration of action

List the 1st generation H1R antihistamines

• diphenydramine (Benadryl)

• chlorpheniramine (Chlor-Trimeton)

• doxylamine (Unisom)

• meclizine (Antivert, Bonine, Dramamine)

• hydroxyzine (Atarax, Vistaril)

• promethazine (Phenergan)

• olapatadine (Patanol, Pataday)

Which of the first gen H1R are used for N/V?

• meclizine (Antivert, Bonine, Dramamine)

• promethazine (Phenergan)

What are the 2nd gen H1R antagonists?

• Fexofenadine (allegra)

• Loratadine (Claritin, Alavert)

• Desloratadine (Clarinex)

• Cetirizine (Zyretec)

• Levocetirizine (xyzal)

• Azelastine (Asteline)

Because of their lower potential to induce drowsiness, _____ and _____ may be recommended for individuals working in jobs where wakefuless is critical

Loratadine and fexofendadine

Which anti-histamine generation is recommended for patients 1st line with uncontrollable sneezing and coughing?

2nd generation H1 antagonists

Which generation of antihistamines is ideal for acute care? long term care?

acute care - 1st

long term care - 2nd

What are the options for intranasal antihistamines?

• Olopatadine (Patanase)

• Azelastine (Astelin)

• Azelastine (Astepro)

• Azelastine/fluticasone (Dymista)

• Olopatadine/Mometasone (Ryaltris)

Which of the intranasal antihistamines is OTC only?

• Azelastine (Astepro)

What are the side effects typically experienced with intranasal antihistamines?

• bitter taste

• epitaxis

• somnolence (drowsy,sleepy)

• HA

What is the mechanism of nasal steroids?

1. reduce inflammation by reducing mediator release

2. suppress neutrophil chemotaxis

3. reduce intracellular edema

4. mild vasoconstriction (help with nasal stuffiness)

Do nasal steroids undergo first pass effect?

no

List the OTC and Rx intranasal steroids

• Fluticasone (flonase)

• Mometasone (Nasonex)

• Triamcinolone (Nasacot)

• Budesonide (Rhinocort)

• Beclomethasone (Qnasl) - Rx

What are the ADE of intranasal steroids?

Minor

• sneezing, stinging, HA, epitaxis, taste

• very little systemic absorption

What are the therapeutic receptor antagonists (LTRA) options?

montelukast (singulair)

Zafirlukast (Accolate)

What are common and serious ADE for LTRAs

Common

• HA

• flu-like syndrome

• elevated liver enzymes

• N/V/D

• neuropsychiatric events - agitation, aggression, anxious, irritability, restlessness, insomnia, tremors, dream abnormalities, hallucinations, depression and suicidality including suidice

Serious

• hypersensitivity - Churg-strauss syndrome

• Hepatitis (zafirlukast)

allergic granulomatosis, asthma, fever, eosinophilia and other signs of vasculitis

Churg-strauss syndrome

Besides allergies, what other condition includes recs for use of LTRAs?

asthma

What are the mechanism of mast cell stabilizers?

Indication of use?

MOA: inhibit mediator (histamine) release from mast cells

Use: prophylaxis (for prevention, not tx because onset takes 2 weeks)

What are the therapeutic options for mast cell stabilizers?

Cromolyn

Nedocromil

What are the PK of mast cell stabilizers?

• inhalation of eye drop delivery

• poor absorption because of low solubility (local effect)

• long onset of action (weeks)

How do decongestants work?

alpha stimulation vasoconstricts the nasal mucosa vessels, shrink swollen mucosa and improve breathing

T/F: decongestants are only found as nasal sprays

false - oral tablets too

What are the routes and meds of decongestants?

Nasal spray

• phenylephrine (neo-synephrine)

• oxymetazoline (afrin)

Oral

• pseudoephedrine (sudafed)

• phenylephrine (sudafed PE)

What are the common and serious side effects of decongestants?

Common

• hypertension and cardiac acceleration (vasoconstriction)

• asthma exacerbation

Serious

• hypertension and cardiac acceleration (vasoconstriction)

• dryness of nasal mucosa

define rhinits medicanentosa

nasal congestion that occurs after 5 days of topical use (rebound)

• from over use of nasal spray

Which decongestant is considered the safest systemic decongestant?

Pseudoephedrine

Describe Pseudoephedrine

• safest systemic decongestant

• oral delivery

• slow onset with long duration of action

• minimal effects on BP and HR - pt with HTN should be controlled before use

What is the general contraindication of pseudophedrine?

It is a MOI (monoamine oxidase inhibitor) and may result in extreme hypertension

Are decongestants alpha agonists or antagonists?

Decongestants are primarily alpha agonists that stimulate alpha-adrenergic receptors to cause vasoconstriction and reduce nasal congestion.

What are the therapeutic options for cough suppressants?

Benzonatate (Tessalon)

Opiates

Guaifenesin

local anesthetic on stretch receptors that trigger cough in respiratory passages

is known as cough reflex suppressants and can help alleviate coughing by numbing these receptors - Benzonate (Tessalon)

• prevents muscle contraction > > cough reflex is stopped

Describe opiates used as cough suppressants

• Codeine

• Dextromethorphan (Delsym)

  • OTC

  • crosses BBB and activates opioid receptors

Which cough suppressant works as an expectorant  where mucus is loosened ONLY 

Guaifenesin (mucinex)

What is the goal of immunotherapy for allergies?

desensitization

• slow and gradual process

• increasing doses of specific antigen

What is the MOA of immunotherapy?

• diminished IgE production

• Increased IgG production

• reduced inflammatory mediator release

• reduced tissue response

Who is immunotherapy for allergies NOT recommended for?

• pre-existing immunological conditions (immunocompromised)

• history of non-compliance 

Besides allergies, what are alternate uses for H1R antagonists?

Motion sickness (1st gen)

• meclizine (antivert)

• promethazine (phenergran)

Sleep aids (1st gen)

• diphenhydramine (benadryl)

• Doxylamine (unisom)