Dental Pharmacology, Spring, 2005 Prof.

Ervin Erds

HISTAMINE AND ANTIHISTAMINES

Histamine Content of Human Tissues

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

Release of Histamine
Exocytosis without cell destruction Non-exocytotic pathways, lysis of cell membranes

Releasers of Histamine Endogenous

IgE antibodies- cause immediate hypersensitivity Peptides 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

48/80 morphine codeine d-tubocurarine dextrans blood substitutes plasma expanders polymixin B

Biosynthesis
Histidine is converted into histamine

Histidine
Histidine decarboxylase

Histamine

Aromatic amino acid decarboxylase

Histamine (2-[4-imidazolyl]ethylamine)

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 eosinophils and neutrophils Fibrin deposition Days (1-2) Infiltration with mononuclears (macrohages, fibroblasts) Tissue destruction

Pathways of Histamine Metabolism

Histamine 2-3%

Methylhistamine 4-8%

Methylimidazole acetic acid 42-47%

Imidazole acetic acid riboside 16-23%

Imidazole acetic acid 9-11%

Acetylhistamine <1%

46-55%

25-34%

(10-40 micrograms)

Histamine receptors. G protein coupled receptors, cloned and characterized

AGONIST

RECEPTOR AND GPROTEIN H1 Gq/11

LOCATION

EFFECTS

2-methylhistamine

Overall CNS; hypothalamus Heart Blood vessels, endothelial cells Bronchi Ileum Adrenals Nose, bronchi Peripheral nerve endings

Cyclic GMP increases (NO) Headache; neurotransmitter? wakefulness, arousal Increased coronary flow, force of contraction Arterial vasodilation (NO); postcapillary venules constrict, endothelial gap, permeability change Smooth muscle contraction Smooth muscle contraction Release of catecholamines (Pheochromocytoma) Increased exocrine secretion Itching cAMP increases (adenylyl cyclase) Chronotropy, inotropy Slow drop Negative feedback Acid production!

4-methylhistamine

H2 GS

Overall Heart Blood vessels, smooth muscles Mast cells Stomach

-methylhistamine

H3 *

Brain Histaminergic neurons Transmission decreased

CAMP decreases; sedative action Presynaptic nerve terminals. Modulates release of neurotransmitters, such as acetylcholine, norepinephrine, dopamine. Inhibitory action on some forms of bronchoconstriction May be involved Increased intra-cellular Ca2+ Immune function

Gi/o

Airways, neurons, heart (arrhythmias) Intestine, bone marrow

H4 *, **

Gi/o

Immune active cells

White blood cells

Regulation

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

Release Inhibitors Mechanism: adrenergic-receptor activation and cAMP accumulation isoproterenol epinephrine theophylline

Conditions for which H3 antagonists may in the future be applied therapeutically: Attention deficit, hyperactive disorder, epilepsy, obesity, migraine (?) and arrhythmias

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.

Histamine Actions
Cardiovascular: Drop in blood pressure, tachycardia, flush, headache, permeability increase Respiration: 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

Antihistamines

H1 Blockers: Substituted Ethylamines X-C-C-N Ethanolamine 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 of pro-inflammatory cytokines.

Therapeutic Applications
Myelogenic leukemia (basophils)

Diseases of allergy Pollinosis Urticaria Allergic rhinitis Transfusion reaction Serum sickness Hay fever Itching Atopic contact dermatitis Insect bites Ivy poisoning Motion sickness Conjunctivitis

Not recommended for

Asthma Common cold Local administration on skin

Prototypes of First Generation Antihistamines

All H1-antihistamines cause a parallel shift to the right of the log doseresponse 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.

Cytochrome P450

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 blockers Can 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.

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Nonsedating Antihistamines Second Generation

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.

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

Cetirizine (Zyrtec)
No anticholinergic or antiserotininergic activity Rapidly absorbed, only slightly metabolized in liver. Others in this group: loratidine (Claritin), astemizole (Hismanal) Approved: desloratadine (Clarinex), active metabolite of loratidine

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H2 Blockers
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: Histamine Acetylcholine (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.

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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 effects Cimetidine 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 prolactin secretion); 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

CIMETIDINE RANITIDINE FAMOTIDINE NIZATIDINE

Bioavailability (%)

80

50

40

>90

Potency

5-10

32

5-10

Plasma half-life (hrs.) Approximate duration of therapeutic effect (hrs.) Relative effect on cytochrome P450 activity

1.5-2.3

1.6-2.4

2.5-4

1.1-1.6

12

0.1

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

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