Functions of Histamine in vivo

• allergy--rhinitis, conjunctivitis
• anaphylaxis-urticaria, shock, asthma
• gastric secretion
• cell proliferation & differentiation, wound healing
• hematopoeisis
• embryonic development
• sleep-wake cycle regulation
• feeding and obesity
• cognition and memory

Histamine Formation, Storage, and  Metabolism

     Histidine---------------------->Histamine

histidine decarboxylase

Storage: 1. In granules bound to heparin in mast cells and basophils in skin & mucous membranes of GI and respiratory tracts

2. In histaminergic nerve terminals in brain & gastric mucosa

Breakdown by N-Methylation + Oxidation in brain & periphery vs. Oxidatitve Deamination outside brain only

Histamine release in Allergy and Anaphylaxis

IgE mediated Immediate Hypersensitivity Rxn:

allergen-specific IgE made by plasma cells, bound to FcER1s on mast cells, cross-linked by allergen-->histamine granule release

along with serotonin, bradykinin, PGs, LTs, Proteases, Eosinophil and Neutrophil chemotactic factors

Physiological effects and symptoms of allergy and anaphylaxis

• bronchial smooth muscle constriction-->asthma, wheezing
• vasodilation
• increased vascular permeability
• mucous secretion
• platelet aggregation
• complement activation
• eosinophillia & neutrophillia
• hay fever
• rash
• anaphylaxis

Non-allergic causes of Histamine release

Frank Tissue Damage of any sort

Organic bases like the opiates, especially morphine (large IV doses)

NMJ blocker D-Tubocurarine (large IV doses)

Anti-histamines-->contact dermatitis if applied topically, so they are not recommended for topical use in urticaria

Triple Response of Lewis

3 part skin reaction to histamine injection, insect bite/sting, scratch, blunt injury, etc. 

H1 mediated

1. Localized red spot (few mm), immediate local vasodilation (1st)

2. Red flush or Flare (1-5 cm), local axon reflex from stim. of nearby sensory nerves, more extensive vasodilation (2nd)

3. Wheal, localized edema, increased venule permeability (3rd)

H1 Histamine Receptor Signal Transduction

Ach-like action:

GPCR linked to Gq/11 stimulates Phospholipase C-->increased IP3/DAG formation-->increased calcium intracellularly which activates calmodulin protein-->myosin light chain kinase activation-->phosphorylated myosin light chain-->enhanced and accelerated cross bridge formation & contraction in smooth muscle (bronchial tree) & venule endothelial cells (increased permeability results)

Gq/11 can also activate a NO synthase in certain cells (arteriole and venule endothelial cells-->vasodilation)

H1 Histamine Receptor Physiological Actions

• bronchoconstriction (MLCK-->smooth muscle contraction)
• arterioles and venules dilate (NO production)-->decrease in BP, flush/flare rxn.
• large veins constrict (MLCK)
• venule endothelial cells contract (MLCK)-->increased protein and fluid leakage, edema=wheal rxn.
• bronchial, nasal and lachrymal secretions increase (ACh-like)

Neurological Effects of Histamine

PNS stimulation: itch (involved in urticaria), pain on deep injection, axon reflex involved in flare response

CNS and PNS together: histamine acts as a neurotransmitter or neuromodulator in wakefulness, arousal, cognition and memory systems

presynaptic H3 receptors often coupled to Gi/o proteins-->decreased cAMP

affects GABA, Ach, Serotonin, dopamine, NE, etc.

under investigation

H2 Histamine Receptor Signal Transduction

Isoproterenol-like action

B adrenergic-like effects: vasodilation, increased HR

Gs coupled protein-->increase cAMP intacellularly

H2 Histamine Receptor Physilogical Effects

• arteriolar vasodilation (like a B2 adrenergic agonist)-->decreased BP
• gastric secretagogue, increases HCl, pepsin, and intrinsic factor output from stomach
• + ionotropic and chronotropic effects on the heart (like a B1 adrenergic agonist)--> increased HR and contractility
• may contribute to bronchocontriction (though mostly due to H1 and LTs)

H4 Histamine receptors

poorly understood,  under research

found in bone marrow, peripheral hematopoietic cells, mast cells, basophils, eosinophils, dendritic cells, monocytes and T-cells

coupled to Gi/o-->decreased cAMP

appeart to be involved in hematopoeisis and inflammation

Gatric Fxn. Tests

administer a gastric secretagogue to induce stomach acid production, measure secretory output of stomach

used to use histamine but it often causes a dangerous drop in BP

so now they use Pentagastrin w/less frequent side effects (nausea, dizziness, pain, urge to defecate, & rarely: flushing, fainting, numb extremities)

Common Mechanism of Action of Antihistamine Drugs

Inverse Antagonism

antihistamines activate receptor signalling cascades which counteract the signalling cascades initiated by histamine binding

antihistamines may counter H1 effects, H2 effects, or both

First Generation oral Antihistamines

Anti-H1 action

1.Dimenhydrinate, 2.Diphenhydramine, 3.Chlorpheniramine, 4.Promethazine

Used to treat/prevent allergic sneezing, rhinorrhea, nasal iching, and ocular symptoms. Purely palliative, best prophylactically. Nasal congestion refractory. 1&4 prevent motion sickness. 2&4 given as sedatives and anaesthesia adjuncts b/c local anesthetic action.

some anticholinergic activity--cold relief

short duration of action (4-8 hrs), oral drugs

cross BBB

Adverse Effects of First Generation Antihistamines

sedation, impaired concentration and coordination, excitation, confusion, anxiety, euphoria, tremor, insomnia, neuritis, convulsions (tx with diazepam or barbituates), parasthesias, vertigo/tinnitus/labarynthitis, epigastric distress(take with meals), anorexia, nausea, vomiting, diarrhea, constipation, dry nose/mouth/throat, blurred vision, exacerbated BPH & narrow angle glaucoma, wheezing, thickened respiratory secretion, +/- teratogenic, adverse interaction with alchohol and sedatives

Overdose: severe CNS depression and cardiovascular collapse (adults), severe CNS stimulation and atropine-like symptoms with hypotension (kids)

Second Generation Antihistamines

Anti H1 action

1.Cetirizine 2.Desloratadine 3.Fexofenadine 4.Levocetirizine 5.Loratadine

have largely replaced 1st gen. in treatment of allergic sneezing, nasal itching, and cojuntivitis. nasal congestion refractory unless combined with a decongestant agent

longer duration of action (8-24hr)

oral administration

no anticholinergic activity

fewer side effects

anti-inflammatory effects likely due to mast cell stabilizing activity

Adverse Effects of Second Generation Antihistamines

generally less likely than with first generation antihistamines b/c they do not cross the BBB or have anticholinergic activity

minimal sedation at recommended dose

Cetirizine causes slightly more sedation

GI distress (take with meals)

Overdose: CNS depression or stimulation like first generation drugs

potentiate alcohol and sedatives

fexofenadine absorption inhibited by apple, orange and grapefruit juice

Dimenhydrinate

aka Dramamine

salt of diphenhydramine

1st generation oral antihistamine

high anti-cholinergic activity (nasal drying, may exacerbate BPH and narrow angle glaucoma)

often used to prevent motion sickness

marked sedation

rarely used for allergy now

Diphenhydramine

aka Benadryl

free base form of drug

1st generation oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

atropine-like pronounced anitcholinergic activity (drying, wheezing, urine retention, constipation, BPH flare up)

marked sedation

anti-motion sickness activity

still used for allergy

local anaesthetic activity

also used to induce peri-operative sedation

Chlorpheniramine

aka Chlor-Trimeton

1st generation oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

common component in OTC cold medicines

moderate anticholinergic activity (may cause drying, wheezing, urine retention)

only slight sedation

Phenothiazine derivatives

Promethazine, Phenergan

1st generation antihistamines (used for allergic rhinitis, conjunctivitis and urticaria)

marked antiemetic effects

marked sedation

local anaesthetic action

often used as peri-operative anaesthesia adjuncts (sedation and antinausea side effects put to good use)

also used to prevent motion sickness

major anticholinergic action (drying, wheezing, etc.)

Cetirizine

aka Zyrtec

2nd generation oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

OTC racemic mix

causes more sedation than the other second generation antihistamines but usually less than 1st gen.

Desloratadine

aka Clarinex

2nd generation oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

Rx only

discovered as an active metabolite of Loratadine (Claritin)

less likely to cause CNS sedation vs. 1st gen.

Fexofenadine

aka Allegra

2nd generation oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

discovered as active metabolite of the discontinued original 2nd gen. drug Terfenadine/Seldane (CYP450 conversion to fexofenadine)

minimal sedation (far less than 1st gen. b/c doesn't cross BBB)

absorption impaired by orange, grapefruit, or apple juice ingestion via inhibition of organic anion transporter OATP

Levocetirizine

aka Xyzal

2nd generation oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

Rx only

single enantiomer version of cetirizine

mild sedation

Loratadine

aka Claritin

2nd gen. oral antihistamine (used for allergic rhinitis, conjunctivitis and urticaria)

mild sedation

very popular

some formulations with psuedoephedrine (a sympathomimetic decongestant) available to counteract nasal congestion too

Shortfalls of Using Antihistamines to Treat Allergy

antihistamines have no effect on the numerous other mediators of allergic inflammation such as leukotrienes, kinins, prostaglandins, etc.

nasal congestion is refractory to antihistamine therapy (this is why combination with decongestants is common)

2nd gen. can't touch rhinorrhea b/c they lack anticholinergic activity

post-nasal drip also refractory

not useful in anaphylaxis (epinephrine instead!)

despite all this, antihistamines offer symptomatic relief for many allergy sufferers

Topical Antihistamines

Olopatadine, Azelastine

eyedrops or nasal sprays for allergic conjunctivitis or rhinitis

fast acting

must be used several times each day

highly effective

localized action (CNS or GI effects less likely)

H1 receptor antagonist activity

mast cell stabilizing activity

Adverse: transient stinging, headache, somnolence, bitter/sweet taste perversion, potential teratogens

Olopatadine

aka Patanol (eyedrops) or Patanase (nasal spray)

topical antihistamine (used in allergic conjuctivitis and rhinitis respectively)

eyedrop formulation may cause stinging and  headache

nasal spray may cause headache, somnolence, and taste perversions

both are teratogenic in mice

Azelastine

aka Optivar (eyedrops) or Astepro (nasal spray)

topical antihistamine

drops used in allergic conjunctivitis

spray used in allergic rhinitis and non-allergic vasomotor rhinitis

eyedrops may cause stinging and headache

spray may cause headache, marked somnolence, and taste perversions

both possible teratogens

Review Inhaled Corticosteroid Nasal Sprays

very effective in allergic rhinitis/conjuctivitis and nasal congestion!, also used to control asthma

beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, mometasone furoate, triamcinolone acetonide

metered dose pump administration

adverse: epistaxis (bloody nose), nasal ulceration, dryness, irritation, burning, perforation of nasal septum, localized Candida infection (rare), increased intraocular pressure (rare), cataracts (rare)