HISTAMINE & ANTAGONISTS

• Histamine is a major mediator of• Inflammation• Anaphylaxis• Gastric acid secretionAlso plays a role in neurotransmission

• Histamine• 5-HT• Angiotensin, BK, Kallidin• PG, Leukotrienes• Cytokines

• Histamine has no clinical application in the treatment of disease

• The receptor agonists and antagonists

Autacoids

Tissues contain Substances (when released by various stimuli)

Reddening of skin Pain or itching BronchospasmMany of these substances are also present in

nervous tissue and have multiple functionsHistamine and serotonin are biologically active

amines, function as neurotransmitters, present in nonneural tissues and have complex physiologic and pathologic effects, have multiple receptors, released locally→autocoids

It is synthesized in 1907 and later isolated from mammalian tissues.

CHEM & PK• H occurs in plants

and animal tissue, a component of some venoms and stinging secretions

• H is formed by decarboxylation of the aa L-histidine by histidine decarboxylase

• Once formed H is either stored or rapidly inactivated

CHEM & PKAlthough H is found in most tissues, it is very

unevenly distributed Most tissue H is sequestered and bound in

granules in mast cells or basophils. Bound form is inactive, but many stimuli can trigger the release of mast cell H

Mast cells are especially rich at sites of potential tissue injury-nose, mouth, and feet, internal body surfaces and blood vessels

CHEM & PKNon-mast cell H is found in several tissues,

including the brain, where it functions as a neurotransmitter.

It is also found in enterochromaffin-like cell of the fundus of the stomach.

STORAGE AND RELEASE OF HISTAMINE

In human mast cells and basophils, storage granules contain H complexed with heparin (sulfated polysaccharide) or chondroitin sulfate (acidic protein).

A.Immunologic release: If mast cells and basophils are sensitized by IgE antibodies attached to their surface membranes, they degranulate when exposed to the appropriate antigen

ATP, and other mediators are released as well

PATHOPHYSIOLOGY OF THE IgE-MEDIATED HYPERSENSITIVITY

REACTION

Requires energy and calcium

CHEMICAL AND MECHANICAL RELEASE

B. Chemical & mechanical releaseCertain amines, including drugs such as morphine

and tubacurarine, can displace H from the heparin-protein complex within the cells. This type of release does not require energy and is not associated with mast cell injury or degranulation.

CHEMICAL & MECHANICAL RELEASE

Loss of granules from the mast cell will also release H

Chemical 48/80 specifically releases H from tissue mast cells by an exocytotic degranulation process requiring energy and calcium

Very little H is excreted unchanged → conversion to N-methylhistamine, methylimidazoleacetic acid and imidazoleacetic acid

PHARMACODYNAMICSH exerts its biological actions by combining

with specific cellular receptors located on the surface membrane H1, H2, H3 & H4, no subtypes

All 4 type receptors types have been cloned, they are coupled with G proteins

Receptor Distribution Post receptor mechanism

Agonists Antagonists

H1 Smooth muscle, endothelium, brain

Gq,↑IP3, DAG

Histaprodifen Mepyramine

H2 Gastric mucosa, cardiac muscle, mast cells, brain

Gs, ↑cAMP Amthaine Cimetidine, ranitidine, tiotidine

H3 Presynaptic autoreceptors and heteroreceptors; brain myenteric plexus

Gi, ↓cAMP İmetit,R-α-Methylhistamine

thioperamide

H4 Eosinophils, neutrophils, CD4 T cells

Gi, ↓cAMP Thioperamide

TISSUE AND ORGAN SYSTEM EFFECTS OF H

Nervous SystemPowerful stimulant of sensory nerve endings → pain

and itching. H1 mediated effect is an important component of urticarial response and reactions to insect and nettle stings.

H1 and H3 →appetite and satiety antipsychotics block these receptors

Presynaptic H3 modulate release of NT→decrease release Ach, amine, peptide transmitters in brain and peripheral tissues

CV

Injection or infusion of H →

BP changes →Direct vasodilator action on arterioles and precapillary sphinctersHeart→ stimulatory action of H and reflex tachycardia

TRIPLE RESPONSEIntradermal injection of H causes a characteristic

red spot, edema and flare response that was first described 60 years ago

At the site of injection a reddening appears →dilation of small vessels, and precapillary sphincters followed by edematous wheal and a red irregular flare surrounding the wheal (H1). Rubor (redness), calor (heat), dolor (pain), tumor (edema) and loss of function. Flare is caused by an axon reflex

H induced edema → the action of amine on H1 receptors in the vessels of the microcirculation, especially the postcapillary vessels

BRONCHIOLAR SMOOTH MUSCLE

Causes bronchoconstriction via H1 receptors. Provacative tests using increasing doses of inhaled H are of diagnostic value for bronchial hyperreactivity in patients with asthma or cyctic fibrosis

GI TRACTCauses contraction of intestinal smooth muscle.Powerful stimulant of gastric acid secretion and to

a lesser extent of gastric pepsin and intrinsic factor production. H2 receptors on parietal cells and increased adenyl cyclase activity, cAMP and Ca++ concentration.

METABOLIC EFFECTSH might be important metabolic functionsH3-receptor knockout mice ↑ food intake↓ energy expenditure and obesity↑ blood levels of leptin and insulinHumans???

H1 RECEPTOR ANTAGONISTSAvailable without prescription.

2nd generation

PKRapidly absorbed orally, widely distributed,

1st generations readily enter CNS, block autonomic receptors. Onset of action 15-60 min, duration 4-6 h

Several 2nd generation agents are metabolized by the CYP3A4 system!

Meclizine and several 2nd gen duration12-24h less sedating

Pgp

PD• Reversible competitive binding of the H1

receptor some have been shown to be inverse agonists

CLINICAL USES1.H1 antagonists are often the first drugs used to prevent

or treat the symptoms of allergic reactions. Allergic rhinitis and chronic urticaria H1 antag are DOC. In bronchial asthma they are not very effective because other mediators are involved.

2. Numerous allergic dermatoses can be treated3. In systemic anaphylaxis H1 antihistamines have no

primary therapeutic role, cannot control marked hypotension and bronchospasm

4. Little effect on bronchial asthmaSleep aid

5. Chlorpheniramine combined with nasal decongestants and analgesics are used for symptomatic relief of common cold

6.Via CNS action can be used for nausea vomiting, motion sickness

• Promethazine, hydroxyzine and diphenhydramine may be used for sedating agents Antihistamines (e.g. diphenhydramine and promethazine) can be used to induce sleep. They are included in various over-the-counter preparations

• ADVERSE EFFECTS• Drowsiness, diminished alertness, lethargy and

diminished motor coordination• GI disturbances nausea vomiting, epigastric

distress uncommon• Tremors, nervousness, irritability, palpitation,

tachycardia urinary retention dose related

• Overdose of Astemizole terfenadine prolonged QT; interval drug interactions can cause this (No longer available in US)

• Loratadine is free from these effects• Blood dyscrazias• Increase CNS effects of

barbiturates,opioids, general anesthetics

OTHER ACTIONS BY H RECEPTOR BLOCKERS

SedationAntinausea and antiemetic actionsAntiparkinson effectAnticholinoceptor actionSerotonin blocker actionLocal anesthesia

TOXICITYSedation, antimuscarinic action most common.Less common toxic effects are excitation and

convulsions in children, postural hypotension, and allergic responses (which is more common after topical use of H1 antagonists).