Histamine Major mediator of inflammation, anaphylaxis and gastric acid secretion Blocked by antihistamines H1 classical antihistamines

2nd gen nonsedating 3rd gen-newly developed

H2 inhibit gastric

secretion H3 mediate feedback inhibition of release and synthesis of histamine

 Histamine present in many

venoms, bacteria and plants CSF contain high amounts Mast cells-predominant site Also high in tissues containing large # of mast cells
Skin Bronchial mucosa Intestinal mucosa

 Formed from decarboxylation

of histidine
Stored in mast cells and

basophil in the blood H1 receptors: smooth M, endothelial cells, CNS Agonist:2-CH3-histamine Antagonist: Chlorpheniramine H2 receptors: gastric parietal cells, cardiac M, mast cells, CNS Agonist: Amthamine Antagonist: Ranitidine

 H3 CNS, presynaptic

Agonist: - CH3 histamine

Antagonist: Tiprolisant H4 - cells of hematopoietic origin Agonist: 4-CH3-histamine Antagonist: JNJ777120

 Release and Functions of Endogenous

Histamine
Ag + IgE (mast cell surface)

histamine release Immediate hypersensitivity and allergic responses Principal target cells mast cells and basophils Also activates phospholipase A2 production of PAF, leukotrienes C4 and D4
Contract smooth muscles of bronchial tree

 Some compounds-stimulate release of

histamine from mast cells directly w/o prior sensitization

IV injection of amides, amidines, quaternary

ammonium compounds, piperidines, alkaloids, Tubocurarine, succinylcholine, morphine, some antibiotics, radiocontrast media w/in seconds-burning, itching sensation (most marked in palms of hand and face, scalp and ears)intense warmthBP falls, HR

 Pharmacological Effects
H1 and H2 receptors
Causes itching and stimulates secretion from

nasal mucosa Contracts many smooth muscles(bronchi and gut) Potent stimulus of gastric acid secretion H3 and H4 receptors H3 receptors-CNS (basal ganglia, hippocampus and cortex Inhibit histamine release and modulate release of other neurotransmitters Agonists-promote sleep

 H4 receptors-eosinophils, dendritic cells, mast

cells, monocytes, basophils and T cells

Activation causes induction of cellular shape

change, chemotaxis, secretion of cytokines Antagonists-useful inhibitors of allergic and inflammatory responses

Effects on Histamine Release

H2 receptor stimulationfeedback inhibition of

histamine release from mast cells and basophils Histamine-toxin in food poisoning from spoiled scombroid fish (tuna)
Severe N & V, headache, flushing and sweating

Red wine consumption Histamine toxicity-headache

 CVS
Vasodilation most impt vascular effect in humans
Activation of H1 and H2 receptors

Ca2+ dependent activation of eNOS(endothelial cells) cyclic GMP relaxation rapid and short-lived vasodilation H2 receptors stim. CAMP-PKA pathway slow but more sustained dilatation

capillary permeability
Small vessels

Efflux of plasma protein and fluid into EC spaces

and

lymph flow edema

Triple Response of Lewis (ID injection) Localized red spot extending a few mm around site of injection Appears w/in few secs, max in 1 min Results from direct vasodilating effect of histamine Brighter red flush (flare) extending 1 cm beyond orig. red spot
Due to histamine-induced stim. Of axon reflexes

indirect vasodilation
Wheal in 1-2 min
Occupies same area as original red spot capillary permeability

 Heart

force of contraction and HR Directly slows AV conduction

Histamine shock
Profound and progressive fall in BP

Extravascular Smooth M
Contraction H1 receptors Relaxation H2 receptors

Peripheral N
Epidermis-itch Dermis-pain, itching

Clin. Uses: DIAGNOSTIC AGENT ONLY

 H1 receptor antagonists
1st generation
Tricyclic dibenzoxepins Doxepin HCl Ethanolamines Carbinoxamine maleate Clemastine fumarate Diphenhydramine HCl Dimenhydrinate Ethylenediamines Pyrillamine maleate Tripelennamine HCl

Alkylamines Chlorpheniramine maleate Brompheniramine maleate

 Piperazines Hydroxyzine HCl Cyclizine HCl Meclizine HCl Phenothiazines Promethazine HCl Piperidines Cyproheptadine HCl Phenindamine tartrate

2nd generation
Tricyclic Dibenzoxepins Olopatadine HCl Alkylamines Acrivastine Piperazines Cetirizine HCl, Levocetirizine HCl

 Pthalazinones

Azelastine HCl
Piperidines Levocabastine HCl Ketotifen fumarate Loratidine Desloratadine Ebastine Mizolastine Fexofenadine HCl

 Effects on Physiologic Systems

Smooth M
Inhibit both vasoconstrictor effects of histamine Vasodilator effects mediated by activation of H1

receptors on endothelial cells

Capillary permeability Strongly block the inc. capillary permeability and formation of edema and wheal caused by histamine

Immediate Hypersensitivity Reactions:

Anaphylaxis and Allergy

Edema and itch-suppressed

 CNS

1st gen-stimulate and depress the CNS

Stimulation-restless, nervous, unable to

sleep Central excitation-overdose

Convulsions, esp in infants Central depression-older H1 antagonists
Diminished alertness Slow reaction times

Somnolence
Ethanolamines-> prone

 Anticholinergic effects Promethazine Strongest muscarinic-blocking activity Most effective H1 antagonist for motion sickness Local anesthetic effect Promethazine

 Absorption, Distribution and Elimination

Well absorbed, effects last 4-6 hours
1st gen-distributed widely throughout the body,

including CNS 2nd gen

Terfenadine, Astemizole Induce a potentially fatal arrhythmia-torsades

pointes when their metabolism is impaired

de

 Therapeutic Uses
Allergic diseases
H1 antagonists-most useful in acute types of

allergy presenting w/ symptoms of rhinitis, urticaria, conjunctivitis Effect is confined to symptoms due to histamine release Asthma-limited efficacy Systemic anaphylaxis epinephrine, autocoids other than histamine are impt Seasonal rhinitis, conjunctivitis(hay fever, pollinosis)
Relieve sneezing, rhinorrhea, itching of

the eyes, nose and throat Acute urticaria

 Common cold
Little/no value

Motion sickness, Vertigo, Sedation

Scopolamine most effective drug for prophylaxis

and Tx of motion sickness Dimenhydrinate, Piperazines Vestibular D/O like Menieres dse Promethazine-more potent and more effective Given 1 hour before anticipated motion Diphenhydramine Present in OTC remedies for insomnia

 Adverse Effects
1st generation
Sedation Additive effect w/ alcohol or other CNS

depressants
Also dizziness, tinnitus, lassitude,

incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia and tremors GI: loss of appetite, N, V, epigastric distress, constipation or diarrhea Dryness of mouth and respiratory passages, urinary retention, frequency, dysuria

 Drug allergy: p.o., > common after topical

application Caution during pregnancy Azelastine, Hydroxyzine, Fexofenadine Excreted in small amounts in breastmilk-may cause irritability, drowsiness, respiratory depression in infant Acute poisoning: hallucinations, excitement, ataxia, incoordination, athetosis, convulsions
Fixed, dilated pupils, flushed face, sinus

tachycardia, urinary retention, dry mouth, fever

Deepening coma w/ CV collapse, death (2-18 H)

 Pediatric and Geriatric Indications and

Problems
2nd generation-for elderly patients (>65 yo) 1st gen-not for use in children
Sedative effects can impair learning and school

performance 2nd gen drugs loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, azelastine Approved for use in children in lower dose preps OTC cough and cold medicines-assoc. w/ serious side effects and death in young children 2008-FDA recommended not to be used in children < 2 y.o.

 Available H1 antagonists
Dibenzoxepin Tricyclics (Doxepin)
Marketed as tricyclic antidepressant Causes drowsiness Associated w/ anticholinergic effects

Ethanolamines (Prototype: Diphenhydramine) Possess significant antimuscarinic activity Pronounced sedation Low incidence of GI side effects Ethylenediamines (Pyrilamine) Somnolence Common GI side effects

 Alkylamines(Chlorpheniramine)
Most potent Less prone to drowsiness > common CNS stimulation

1st generation Piperazines Hydroxyzine-long-acting; for skin allergies CNS depressant activity-reason for its prominent anti-pruritic action Cyclizine and Meclizine-motion sickness
2nd gen Piperazines
Cetirizine Assoc. w/ higher incidence of drowsiness than

other 2nd gen H1 antagonists

 Phenothiazines (Promethazine)
Antiemetic

1st gen Piperidines(Cyproheptadine,

Phenindamine)
Antihistamine and antiserotonin activity

2nd gen Piperidines (Terfenadine) Loratadine, Desloratadine, Fexofenadine Highly selective for H1 receptors Lack significant antichol. Actions Penetrate poorly into CNS

 H3 receptor and its antagonists

Decrease histaminergic transmission brain

Inhibit gastrin-induced release of histamine

HCl secretion enterochromaffin-like cells of stomach H3 antagonists

Promote wakefulness, improve cognitive function

(ebhance memory, learning and attention), reduce food intake For possible Tx of sleeping D/O, ADHD, epilepsy, cognitive impairment, schizophrenia, obesity, neuropathic pain and Alzheimers dse

 Thioperamide-1st specific H3 antagonist

available experimentally
antagonists

Other imidazole derivatives developed as H3

Clobenpropit, Ciproxifan, Proxyfan Imidazole group can bind to/inhibit CYPs, reduce

bioavailability and penetration into CNS-nonselective Tiprolisant-phase II clinical trials For epilepsy, narcolepsy, sleep D/O, cognitive impairment, Alzheimers dse, Schizophrenia, ADHD

 H4 Receptor and its Antagonist

H4 receptor-expressed on cells w/ inflammatory

or immune functions

Mediate histamine-induced chemotaxis Induction of cell shape change Secretion of cytokines and upregulation of

adhesion molecules
JNJ7777120 1st selective H4 antagonist Acceptable oral bioavailability Short t (0.8 hour)

 CLINICAL SUMMARY
H1 Antihistamines
Most effective in relieving the sx of seasonal

rhinitis and conjunctivitis (sneezing, rhinorrhea, itching of the eyes, nose, throat) No use in bronchial asthma Useful adjuncts to epinephrine Tx of systemic anaphylaxis or severe angioedema Relieves itch in atopic/contact dermatitis, no effect on rash Side effects: most prominent w// 1st gen H1 antihistamines (sedation) Some have anticholinergic effects 2nd gen antihistamines do not penetrate CNS, no antimuscarinic properties DOC for Tx of allergic D/O

 Caution for pregnant/lactating women

Esp. 1st gen drugs-possible teratogenicity or

symptomatic effects on infants Cetirizine and Loratadine preferred if necessary

women only
H2 antihistamines

If not effectiveDiphenhydramine in pregnant

Inhibit gastric acid secretion

H3 and H4 antihistamines

Not approved for clinical use H3: Potential for Tx of sleeping D/O, ADHD, epilepsy,

cognitive impairment, schizophrenia, obesity, neuropathic pain, Alzheimers dse H4: Tx allergic rhinitis, asthma, RA, pruritus, neuropathic pain