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