Post on 02-Jan-2016
description
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: ®-α – 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 de pointes when their metabolism is impaired
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 Meniere’s 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 Alzheimer’s dse
Thioperamide-1st specific H3 antagonist
available experimentally
Other imidazole derivatives developed as H3
antagonists
Clobenpropit, Ciproxifan, Proxyfan
Imidazole group can bind to/inhibit CYPs, reduce
bioavailability and penetration into CNS-non-
selective
Tiprolisant-phase II clinical trials
For epilepsy, narcolepsy, sleep D/O, cognitive
impairment, Alzheimer’s 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 ½ (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 If not effectiveDiphenhydramine in pregnant
women only
H2 antihistamines 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, Alzheimer’s dse
H4: Tx allergic rhinitis, asthma, RA, pruritus, neuropathic pain