HISTAMINE

Biosynthesis: Decarboxylation of histidine

Source: Plants & animals (in all tissues)

Storage:High in skin/epidermis, GI mucosa, (non-mast cells) and lungs (mast cells). Bound to heparin in mast cells. Basophils in blood

Release: antigen antibody reaction leading to degranulation of cells (mast)

Effects: allergic response, exocrine secretion (gastric acid, pulmonary, lacrimal, salivary etc.), neurotransmission in CNS. Non-vascular smooth muscles contracted. Stimulates adrenal medulla (release epi); dilates cerebral vessels (histamine headache); capillary leak leads to hypotension/edema/histamine shock.

Receptors: H₁(contractile), coupled with phospholipase; H₂(gastric secretion, vessel relaxation), cAMP coupled; H₃(feed-back inhibition). Interact with G protein in the plasma membrane. In general, histamine constricts.large vessels; dilates capillaries and venules.

Histamine is one of the autacoids. It is a natural amine. It is a small molecule derived from the decarboxylation of the amino acid histidine. It is rapidly destroyed by the enzyme diamine oxidase (histiminase), which is also involved in the metabolism of other bioactive amines.

Common Allergens

ž Tree Pollen and Grass

ž Pet

ž Mold

ž Dust Mites

ž Foods

ž Hay fever and Asthma----To pollen, house dust, pets etc.

ž Urticaria(Hives)---Drugs,food. Reddening and itching of skin.

ž Systemic anaphylaxis---Inj. of Penicillin,Insect bites.

Symptoms

ž Allergic Rhinitis

ž Conjunctivitis

ž Bronchoconstriction

ž Urticaria

ž Atopic Dermatitis

ž Anaphylaxis

Histamine

ž Histamine is one of the most important autacoids, and is formed from the amino acid histidine and is stored in high concentrations in mast cells, and basophils.

ž Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. It may play a role in many brain functions such as neuroendocrine control, cardiovascular regulation, thermoregulation, and arousal.

Non – allergic release of histamines:

Drugs :

-Aspirin.

- ACE inhibitors.

- D-tubocurarine

Narcotics.

Radiocontrast media.

Many venoms

Antibiotics

RECEPTORS AND EFFECT

Two receptors for histamine, H₁ and H₂, mediate most of the well-defined actions;

1. H₁ receptor: important in smooth muscle effects, especially those caused by IgE-mediated responses

- IP₃ and DAG are released.

② Bronchoconstriction and vasodilation.

③ Vasodilation by release of endothelium-derived relaxing factor (EDRF), are typical responses of smooth muscle.

④ Capillary endothelium, in addition to releaseing EDRF, also contracts, opening gaps in the permeability barrier and resulting in the formation of local edema.

2. H₂ receptor: activation of adenylyl cyclase → cAMP↑

① Mediates gastric acid secretion by parietal cells in the stomach.

② Cardiac stimulant effect.

③ Reduce histamine release from mast cells -- a negative feedback effect.

3. H₃ receptor:

① involved mainly in presynaptic modulation of histaminergic neurotransmission in the central nervous system.

② In the periphery, it appears to be a presynaptic heteroreceptor with modulatory effects on the release of other transmitters.

Tissues and Organ System Effects of Histamine

ž Exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, and on the secretory cells of the stomach.

ž Sensitivity to histamine varies greatly among species. Humans, guinea pigs, dogs, and cats are quite sensitive, while mice and rats are much less so.

1. 1. Nervous system: histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching.

2. 2. Cardiovascular system:

a. Cardiac effects: increased contractility and increased pacemaker rate.——mediated chiefly by H₂-R. But H₁-R mediates the decrease of contractility in human atrial muscle.

b. Vascular effects: vasodilator action (H₁-R, H₂-R). endothelial cells contraction and increased permeability (H₁-R).

c. Platelet function: aggregation (H₁-R) anti-aggregatio

3. Smooth muscle: contraction (H₁-R) → bronchoconstriction, abort. histamine-induced contraction of guinea pig ileum is a standard bioassay for this amine.

4. Secretory tissues: stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. (H₂-R)

Histamine

Triple response: red spot (capillary dilation); wheal (edema fluid); red flare (arteriole dilation-axon reflex)

Fate: Gut absorption poor; metabolism by N-methyl transferase & histaminase

Symptoms: anaphylaxis, swelling (skin, mucosa); itching, bronchospasm, hypotension, shock, phospholipase C and A₂ activation.

Clinical Uses

1. Pulmonary Function Testing: Histamine aerosol is sometimes used as a provocative test of bronchial hyperreactivity.
2. Tesing Gastric Acid Secretion: However, pentagastrin is currently used for this purpose, with a much lower incidence of adverse effests.
3. Diagnosis of Pheochromocytoma: Histamine can cause release of catecholamine from adrenal medullary cells. This hazardous provocative test is now obsolete.

Toxicity & Contraindications

ž Like those of histamine release, dose-related.

ž Flushing, hypotension, tachycardial, headache, wheals, bronchoconstriction, and gastrointestinal upset.

Other Histamine Agonists

ž Betahistine: H₁-R agonists

ž Impromidine: H₂-R agonists

ž (R) α-methylhistamine: H₃-R agonists

H₁ Receptor Antagonists

ž Divided into first-generation and second-generation agents.

ž The first-generation drugs are distinguished by the relatively strong sedative effects and more likely to block autonomic receptors.

ž The second-generation drugs are less sedating characteristic owing to less lipid-soluble to enter the CNS with difficulty or not at all. They are longer-acting.

Mechanism & Effects

1. H₁-R Blockade:
2. Sedation:
3. Antinausea and antiemetic actions: preventing motion sickness.
4. Antiparkinsonism effects:
5. Anticholinoceptor action: atropine-like effects on peripheral muscarinic receptors.
6. Adrenoceptor-blocking actions:
7. Serotonin-blocking actions:
8. Local anesthesia: block Na⁺-channel

Diphenhydramine (Benadryl)

- H₁ antagonist: competes with free histamine for the H₁ binding sites

- Good for allergic symptoms – also treats irritant cough

- Effective in relief of nausea, vomiting, and vertigo from motion sickness (anticholinergic)

- Produces marked sedation in most patients

- May suppress edema, flare, and pruritis from histaminic activity

Promethazine

- H₁ antagonist with considerable anticholinergic, sedative, and antiemetic effects

- Often seen in combinations with cough and cold products

Azelastine (Astelin)

- Nasal spray that treats seasonal allergic rhinitis (almost equally effective as oral Certerizine)

- Dual mechanism of action: H₁ receptor antagonism as well as inhibition of histamine release from mast cells

Loratadine (Claritin)

- 2^nd generation non-sedating H₁ blocker

- Poor penetration to CNS and low affinity for CNS H₁ receptors

- Not associated with QT prolongation

- - -Toxicity: drowsiness, fatigue, headache, restlessness, sinus tachycardia, wheezing, xerostomia, etc. (anticholinergic

Cetirizine (Zyrtec)

- 2^nd generation non-sedating H₁ blocker (high affinity)

- Relieves seasonal allergic rhinitis

- Under investigation for treatment of allergic asthma, physical urticaria, and symptomatic relief of atopic dermatitis

- This 2^nd generation H₁ blocker has higher incidence of somnolence than Fexofenadine and Loratadine

- Labeled for use in infants as young as 6 months of age

- Questionable dual action: may prevent the release of mast cell mediators

Cyproheptadine (Periactin)

- A serotonin receptor blocker

- Typically used to treat anorexia

- Also used to prevent anorgasmia in young males

Pharmacokinetics

ž Second generation antihistamines:

— Relatively rapid onset

— Elimination Half-Lives:

○ Loratadine-up to 28 hours

○ Fexofenadine-14 hours

○ Cetirizine-8 hours

— Children metabolize Cetirizine faster, but rates are similar for the others

Clinical Uses

1. Allergic Reaction:
2. Motion Sickness and Vestibular Disturbances:

Toxicity

ž Sedation

ž Antimuscarinic effects such as dry mouth and blurred vision

ž α-blocking actions may cause orthostatic hypotension

H₂ Receptor Antagonists

ž Presently available H₂-R antagonists reversibly compete with histamine at H₂-R sites.

ž Relatively selective and have no significant blocking action at H₁ or autonomic receptors.

ž The only therapeutic effect of clinical importance is the reduction of gastric acid secretion. Blockade of cardiovascular H₂-R mediated effects has no clinical significance.

ž Immunomodulating effect.

Pharmacokinetics

ž Rapidly absorbed after oral administration

ž Serum concentrations peak in 1-3 hr

ž Therapeutic levels maintained up to 12 hrs

ž Small percentage is protein bound

ž 10% to 35 % metabolized by the liver

ž Drugs and metabolites primarily excreted by kidneys (**reduce doses in renal disease)

ž inhibit 90% acid secretion in basal state as well as food-induced and nocturnal acid production.

ž they are helpful in healing gastric and duodenal ulcers and prevent their recurrence. Have benefits in preventing increased gastric acid secretion in Zollinger-Ellison syndrome.

-Cimetidine Has several side effects, not a choice now - Under Prescription.