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HISTAMINE AND ANTIHISTAMINES

Histamine Content of Human Tissues

High in lung, mucous membrane, GI tract, skin, eosinophils. Range 1 to 100 µg/gStored in mast cells in some organs, in granules together with heparin and proteases. Turnover is slow. Basophils in blood are rich in histamineEpidermis, gastric mucosa, neurons and regenerating tissues contain histamine, but not in mast cells.Rapidly synthesized, but not taken up by cells.

Exocytosis without cell destructionNon-exocytotic pathways, lysis of cell membranes

Release of Histamine

Releasers of HistamineEndogenous

IgE antibodies- cause immediate hypersensitivityPeptides that contain basic amino acids arginine and/or lysine.Complement derivatives- anaphylatoxins such as C3a, 4a, 5a) and substance P.Bee and wasp venom constituents such as melittin, polistes kinin, etc.

Chemicals, Therapeutic Agents

48/80morphinecodeined-tubocurarinedextransblood substitutesplasma expanderspolymixin B

Dental Pharmacology, Spring, 2005Prof. Ervin Erdös

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Biosynthesis

Histidine is converted into histamine

HistidineHistidine decarboxylase

Histamine

Aromatic amino acid decarboxylase

Histamine (2-[4-imidazolyl]ethylamine)

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Consequences of mediator release

Antigen-induced IgE-dependent secretion leads to classic allergic reactions or immediate hypersensitivity. Atopic individuals develop IgE antibodies to commonly inhaled antigens heritable. Late phase reactions come later, initially at 2-8 hr. and are characterized pathologically by polymorphonuclear leukocyte infiltrations. A second phase of cellular infiltration consisting of mononuclear cells is apparent after 24-72 hr. IgE receptor activates phospholipase A2 and C, followed by release of mediators other than histamine. (E.g. Leukotriene D, platelet activating factor)

“Classic” allergic reaction (Immediate hypersensitivity) in minutes

Late phase reactions in hours (2-8)

Smooth muscle contraction

Vascular leakage

Flush

Hypotension

Mucus secretion

Pruritis

Infiltration with eosinophilsand neutrophils

Fibrin deposition

Days (1-2)

Infiltration with mononuclears(macrohages, fibroblasts)

Tissue destruction

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Pathways of Histamine Metabolism

(10-40 micrograms)

Histamine

2-3%

Methylhistamine

4-8%

Methylimidazoleacetic acid

42-47%

Imidazole acetic acid riboside

16-23%

Imidazoleacetic acid

9-11%

Acetylhistamine

<1%

46-55% 25-34%

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Acid production!Stomach

Negative feedbackMast cells

Slow dropBlood vessels, smooth muscles

Chronotropy, inotropyHeartGαS

cAMP increases (adenylyl cyclase)OverallH24-methylhistamine

ItchingPeripheral nerve endings

Increased exocrine secretionNose, bronchi

Release of catecholamines (Pheochromocytoma)

Adrenals

Smooth muscle contractionIleum

Smooth muscle contractionBronchi

Arterial vasodilation (NO); postcapillary venulesconstrict, endothelial gap, permeability change

Blood vessels, endothelial cells

Increased coronary flow, force of contractionHeart

Headache; neurotransmitter? wakefulness, arousal

CNS; hypothalamus Gαq/11

Cyclic GMP increases (NO)OverallH12-methylhistamine

EFFECTSLOCATIONRECEPTOR AND G-PROTEIN

AGONIST

Histamine receptors. G protein coupled receptors, cloned and characterized

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RegulationWhite blood cells

Immune functionImmune active cellsGi/o

May be involvedIncreased intra-cellular Ca2+

Intestine, bone marrowH4 *, **

Inhibitory action on some forms of bronchoconstriction

Airways, neurons, heart (arrhythmias)

Gi/o

CAMP decreases; sedative action Presynaptic nerve terminals. Modulates release of neurotransmitters, such as acetylcholine, norepinephrine, dopamine.

BrainHistaminergic neuronsTransmission decreased

H3 *α-methylhistamine

*Results based mainly on laboratory experiments in animals.** Related to H3

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Histamine Actions

Cardiovascular: Drop in blood pressure, tachycardia, flush, headache, permeability increaseRespiration: Bronchoconstriction, prostaglandin release.Glandular tissue: Adrenals - catecholamine release (pheochromocytoma); stomach -acid secretion; mucosa - nasal secretion.Skin: Lewis triple reflex (flush, flare, wheal); itching; leukocyte recruitment

Conditions for which H3 antagonists may in the future be applied therapeutically:

Attention deficit, hyperactive disorder, epilepsy, obesity, migraine (?) and arrhythmias

Release Inhibitors

Mechanism: β adrenergic-receptor activation and cAMP accumulation

• isoproterenol• epinephrine• theophylline

Current techniques to study functions of histamine and its receptors

Overexpression in mice

Transgenic mice: They can have several copies of a gene to express a desired protein. Transgenic constructed with recombinant DNA and injected into one-celled embryos.

Knockout mice

DNA construct containing mutated gene injected into mouse embryonic stem cell. Cells incorporate altered genetic material, resulting in deletion of the endogenous gene from all cells.

H1 knockout: Suggestion: histamine may suppress seizures; impairment of neurological functions

H1 knockout: Itching; antihistamine did not prevent scratching.

H2 knockout: Impaired gastric acid production and secretion.

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Antihistamines

H1 Blockers: Substituted EthylaminesX-C-C-NEthanolamine derivatives: diphenhydramine (Benadryl; X=0 sleep); dimenhydrinate(dramamine; X=0 motion sickness)Alkylamine derivatives: chlorpheniramine (Chlortrimeton)Ethyleneamine: tripelenamine (PBZ)Piperazine: cyclizine (Morezine)Phenothiazine: Promethazine (Phenergan)40 available world-wide

They are called “inverse agonists” stabilize inactive form of H1 receptor. Mode of action: may involve inhibition of calcium-ion channels and down regulation ofpro-inflammatory cytokines.

Therapeutic Applications

Diseases of allergyPollinosisUrticariaAllergic rhinitisTransfusion reactionSerum sicknessHay feverItchingAtopic contact dermatitisInsect bitesIvy poisoningMotion sicknessConjunctivitis

Not recommended for

AsthmaCommon coldLocal administration on skin

Myelogenic leukemia (basophils)

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Prototypes of First Generation Antihistamines

All H1-antihistamines cause a parallel shift to the right of the log dose-response curve for a given histamine effect with no change in the maximal effect. None of the H1 antihistamines in therapeutic doses affect metabolism of histamine, nor do they block its release.

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H1 Blockers: Absorption

Well absorbed after oral administration. Therapeutic effects 4-12 hrs.Although they are metabolized in liver by cytochrome P450, some are excreted unchanged, most of them excreted as metabolites.

Side Effects

Lessened effect after chronic administration: induction of microsomal enzymes in liver, increased metabolism.Drowsiness; additive with alcohol, accidents with first generation of H1 blockersCan stimulate and depress CNS.Drying salivary bronchial secretion (anticholinergic; antimuscarinic)Loss of appetite, nausea, vomiting.

Warnings

Use of topical application in allergic dermatitis is questionable.Poisoning in children: CNS effects are similar to atropine poisoning of some histamines. Barbiturates contraindicated. Confusion, delirium, respiratory depression, dilated pupils. Treatment supportive.

Cytochrome P450

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Fexofenadine (Allegra)Active metabolite of terfenadineDoes not cross the blood-brain barrier, no anticholinergic or a1-adrenergic receptor blocking effectHalf life of 14 hrs., 95% excreted in urine unmetabolized.

Cetirizine (Zyrtec)No anticholinergic or antiserotininergic activityRapidly absorbed, only slightly metabolized in liver.

Others in this group: loratidine (Claritin), astemizole (Hismanal)Approved: desloratadine (Clarinex), active metabolite of loratidine

Terfenadine (Seldane)Low lipid solubility, does not cross the blood-brain barrier, no atropine-like effect, binds to plasma proteins, long half-life. Metabolized by cytochrome P450. If excretion impaired, may be toxic to CNS.Ineffective in motion sickness. Serious side effects in case of hepatic dysfunction, concomitant administration of some drugs (erythromycin) or overdose. Erythromycin inhibits cytochrome P450.Effects: ventricular arrhythmias, EKG, QT prolongation. Polymorphic ventricular tachycardia.Replaced with Fexofenadine (Allegra), withdrawn from the market.

Nonsedating AntihistaminesSecond Generation

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Gastric acid secretion by parietal (oxyntic) cell is not blocked by antihistamines acting on H1 receptors.Gastric acid secretion, blocked by antihistamines acting on H2 receptors, is stimulated by:HistamineAcetylcholine (vagus)Gastrin; 17-amino acid peptide hormone of antral mucosa. Tumor of the pancreas: Zollinger-Ellison syndrome, gastrin production.Commercial preparation: pentagastrin H2 receptor agonist; used to test gastric acid secretion.James Black discovered H2 blocking antihistamines.Chemically, retained imidazole ring, long side chain first, later changes in ring structure.Inhibit effect on stomach secretion, in addition to some effects on blood pressure and heart.First drugs, serious side effects: myelosuppression (burinamide).Application: gastric, duodenal ulcer.

H2 Blockers

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Cimetidine (Tagamet)

Application: To inhibit secretion, especially nocturnal, caused by histamine, gastrin or acetylcholine. Used to treat ulcer (duodenal, gastric and stress) and in Zollinger-Ellison syndrome.

Absorption and side effectsCimetidine is rapidly absorbed after oral administration, effective for 4-5 hrs. Renal excretion is important. Sulfoxide is a metabolite, half is excreted unchanged Generally well tolerated, but can cause headache.Although penetration into CNS is poor, neural side effects occur in the elderly with impaired kidney function: confusion, slurred speech, delirium, hallucination and coma.Other side effects include anti-androgen action at receptor (gynecomastia, impotence, enhanced prolactinsecretion); reduced metabolism of estrogen.Interferes with hepatic metabolism of other drugs such as warfarin, lidocaine or phenobarbital. This is due to binding of cytochrome P450, the mixed function oxidase, vital in drug metabolism.Newer derivatives developed to reduce side effects and interactions with other drugs.

Ranitidine (Zantac)Ranitidine was developed because it binds less to P450, has far fewer side effects, and acts longer than cimetidine. Ranitidine is structurally different because it has furan instead of imidazole ring. It is four to ten times more effective in blocking gastric secretion. Ranitidine is eliminated by the kidney but its duration of action is 8-12 hr. Thus, less frequent administration is required.

Famotidine (Pepcid)

Thiazole replaces imidazole. More effective than ranitidine, less than 45% of an oral dose is absorbed. Excreted (70%) unchanged in urine. Does not interfere with hepatic drug metabolism.

Nizatidine (Axid)

90% absorbed, 65% excreted unchanged. Does not interfere with hepatic metabolism of other drugs.

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Properties of Histamine H2 Receptor Antagonists

000.11Relative effect on cytochrome P450 activity

81286Approximate duration of therapeutic effect (hrs.)

1.1-1.62.5-41.6-2.41.5-2.3Plasma half-life (hrs.)

5-10325-101Potency

>90405080Bioavailability (%)

NIZATIDINEFAMOTIDINERANITIDINECIMETIDINE

Low doses approved for over-the-counter sales (heartburn; gastroesophageal reflux disease (GERD)