- Mast cells in most tissue, basophils in blood

- In granules, histamine is bound to heparin or chondroitin sulfate proteoglycans (inactive)

- Mast cells enriched in surface tissues

- Non-mast cell histamine is in brain as a neurotransmitter and as ECL in stomach as gastric acid secreter.

-Exocytosis, lysis or displacement of cell membrane

-Antigen binds to IgE (Fc, FceRI) on mast cell surface -> mobilization of Ca+ and exocytosis/degranulization of histamine

- IgE is central to type I hypersensitivity rxn

- Released in large quantities (ug/10^6 cells)

- Mast cell injury, Ca+ dependent exocytosis and energy dependent exocytosis release granules

- Bind receptors on tissue surfaces

- H1, H2, H3, H4 are to G-protein coupled

-Receptors have inactive and active states from spontaneous isomerization

- Agonists preferably bind active state pushing equilibrium to active

- Antihistamines prefer inactive and push equilibrium to inactive

H1:

Distribution: Smooth muscle, endothelium, brain

2nd messenger: Increase IP3, DAG (Gq); Increased Ca+

Fxn: Increase itching, pain, vasodilation, vascular permeability, hypotension, flushing, headache, tachycardia, brochoconstriction, stim of airway vagal nerves and cough receptor, excitatory transmission via post-synaptic H1 receptors

H2:

Distribution: Gastric mucosa, cardiac muscle, mast cells, brain

2nd messengers: Increased CAMP (Gs)

Fxn: Increase gastric secretion, hypotension, flushing, tachycardia, headache, bronchodilation, mucous production, excitatory post-synaptic transmission

H3:

Distribution: Presynaptic histaminergic neurons, myenteric plexus, other neurons

2nd messenger: Decreased CAMP (Gi), Increased Ca+

Fxn: prevents excessive bronchoconstriction, mediates itching (no mast cells), decrease presynaptic histamine synthesis and release

H4:

Distribution: Bone marrow, peripheral hematopoietic cells (eosinophils, neutrophils, CD4+ T cells)

2nd messenger: decrease CAMP (Gi), increase Ca+

Fxn: Differentiation of myeloblasts from promyelocytes

- Stimulant of sensory nerve endings

- Component of urticarial rxn to bees and nettle (H1)

- Experimental: respiratory, memory, and cognition regulation (H1)

- H3 modulates transmitter release centrally and peripherally (reduce Ach, amine, and peptide)

- H1 and H3 sense pain peripherally

-H2 stimulates A, V, and pacemaker muscle contraction = increased heart rate

- H1 decreases AV node conduction

- H1 and H2 cause vasodilation of arterioles and precapillary sphincters by the release of NO = hypotension

- H1 on venules = increased permeability = edema and extravasation of fluid and protien

- Anaphylaxis: increased capillary permeability causes profound drop in blood pressure 

H1 - bronchoconstriction

H2 - bronchodilation 

Asthma - histamine hypersensativity

Contraction can cause diarrhea (H1)

- Gastric acid mediated by H2 (parietal cells)

- Activation of parietal H2 = increased CAMP

- Small and large intestinal secretion

- H3 agonists can inhibit acid secretion

-H1 and H3 knockouts = increased obesity

- H3 = sleep cycle regulation

- Red spot from vasodilatory effect

- bright red flush/flare from histamine induced stimulation of axon reflex that causes vasodilation

- wheel in area of red spot due to capillary permeability

No applications

Adverse effects are dose related: flushing, hypotension, vasodilation, headache, bronchoconstriction, wheals, GI upset

Can be blocked by antihistamines 

Physiologic antagonist

Opposite effect on smooth muscle

Bronchodilator

Given during anaphylaxis

All are reversible, competitive H1 or H2

Potent and experimental H3 are being developed

Negligible potency in the H2 and H3 receptors

Reverses actions on smooth muscle, especially GI, and bronchiolar contraction

Blocks capillary permeability - prevents edema

Blocks peripheral nerve endings - itch and flare

-old, effective, non-specific

- lipid soluble and can cross the BBB

- strong sedative with cholinergic/muscarinic antagonist activity (atropine like)

- antiemetic from H1 binding

- block autonomics

- metabolized by p450

- OTC cold meds, sleep aids, and antiemetics

- cheap and large margin of safety

-More selective

-Minor antiemetic, sedative, and anticholinergic

- Hydrophilic - do not pass BBB

- Orally effective

- More expensive

Allergic rxns: rhinitis 2g, eczema, hay fever 2g, insect bites, poison ivy

NOT for asthma

Motion sickness: better with ephedrine (Meclizine, cyclizine, diphenhydramine)

Nausea: Morning sickness, Doxylamine (pulled), and 5-HT3-receptor antagonist Ondansetron

Diphenhydramine - an Ethanolamine

H1 1g antihistamine

sedative, sleep aid

OTC

Tripelennamine - an Ethylenediamine

H1 1g antihistamine

mildly sedative

Chlorpheniramine - an Alkylamine

H1 1g antihistamine

OTC cold meds, less sedative

Can inhibit re-uptake of Serotonin (antidepressant)

Hydroxyzine - a 1st g Piperazine

H1 1g antihistamine

chronic urticaria, derm allergies

sedation common

contraindicated in early pregnancy

Cyclizine and Meclizine

H1 1g antihistamines

Antiemetics

Cyprohepadine and Phenidamine - 1st generation piperidines

H1 1g antihistamines

antihistamines and antiserotonins - can cause drowsiness and severe anticholinergic effect

CNS: effect transmission through the H1 receptor: drowsiness, fatigue, dizziness, cog/memory impairment, agitation, hallucinations

OD may stimulate: convulsions, restlessness, anxiety

Cardiac: blockade of muscarinic, adrenergic, and Ikr channel: sinus tach, reflex tach, and SVT; prolonged QT and ventricular arrhythmia

Other:  Pupillary dilation, dry eye, dry mouth, urinary retention, hesitancy 

Contraindicated in glaucoma/BPH

Promethazine - a Phenothiazine

H1 1g antihistamine

Antiemetic, sedative

not for children under 2 due to respiratory depression

Fexofenadine - a Piperadine

H1 2g antihistamine

metabolite of terfenadine

lower risk of arrhythmia

excreted unchanged

no CNS effect

Loratadine - a Piperidine

H1 2g antihistamine

Metabolized by p450 to active

Prolonged by antifungal

No CNS effects at daily dose, but maybe at higher

Cetirizine Hydrochloride - a Piperazine

H2 2g antihistamine

carboxylated hydroxyzine

excreted in urine

high doses = sedation

use of meds that cause CNS affects or H1 1g antihistamines can cause more CNS problems

Loratadine and terfenadine are metabolized by p450, inhibited by grapefruit juice

-Promote healing of gastric/duodenal ulcers

-Treat GERD

-Prophylaxis of bleeding from stress induced gastritis

-Zollinger-Ellison syndrome (H2 inhibitors now) - gastrin secreting tumor of non-b cells of the pancreas

Cimetidine

H2 antihistamine

-Oldest, least potent (t1/2 6 hours)

-Renal clearance so side effects if renally impaired: confusion, slurring, hallucinations, delirium, coma

-Antiandrogen

-Diarrhea, headache, dizziness, rash

Ranitidine

H2 antihistimine

-Binds less to p450

-Highly effective blocking gastric secretion

-Long lasting

Famotidine

H2 antihistimine

Does not interfere with hepatic met of other drugs

Most potent

Long lasting 12 hours

OTC

Nizatidine

H2 antihistimine

Does not interfere with hepatic met of other drugs

Little 1st pass met, 100% bioavailable

Highly potent x8 hours

Last introduced before the proton pump and H2 blocker for GERD

-Interference with hepatic cytochrome P450 drug metabolism pathways (due to the presence of 

imidazole), thus the half-lives of drugs metabolized by these pathways may be prolonged. These 

drugs include warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, 

metaprolol, tricyclic antidepressants, several benzodiazepines, calcium channel blockers, 

sulfonylureas, metronidazole and ethanol 

-H2 antagonists compete with certain drugs (e.g. procainamide) for renal tubular secretion 

-H2 antagonists but famotidine inhibit gastric first-pass metabolism of ethanol 

-Selective H2 receptor blockade on parietal cells

- Reversibly competes with histamine and prevents acid secretion

-Prevents acid secretion by histamine, Ach (vagus) (indirect effect), and gastrin secreting tumor of pancreatic islets (Zollinger-Ellison)

-Prevents basal acid secretion more than during feeding

-Absorbed by intestine

-Eliminated renally

-Can cross placenta, no known effects, still don't give