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H2 inhibit gastric
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
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
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
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
change, chemotaxis, secretion of cytokines Antagonists-useful inhibitors of allergic and inflammatory responses
histamine release from mast cells and basophils Histamine-toxin in food poisoning from spoiled scombroid fish (tuna)
Severe N & V, headache, flushing and sweating
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
and
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
Histamine shock
Profound and progressive fall in BP
Extravascular Smooth M
Contraction H1 receptors Relaxation H2 receptors
Peripheral N
Epidermis-itch Dermis-pain, itching
H1 receptor antagonists
1st generation
Tricyclic dibenzoxepins Doxepin HCl Ethanolamines Carbinoxamine maleate Clemastine fumarate Diphenhydramine HCl Dimenhydrinate Ethylenediamines Pyrillamine maleate Tripelennamine HCl
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
CNS
Somnolence
Ethanolamines-> prone
Anticholinergic effects Promethazine Strongest muscarinic-blocking activity Most effective H1 antagonist for motion sickness Local anesthetic effect Promethazine
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
Common cold
Little/no value
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
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
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
Phenothiazines (Promethazine)
Antiemetic
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
(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
available experimentally
antagonists
bioavailability and penetration into CNS-nonselective Tiprolisant-phase II clinical trials For epilepsy, narcolepsy, sleep D/O, cognitive impairment, Alzheimers dse, Schizophrenia, ADHD
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
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