HISTAMINE – SEROTONIN AND THEIR ANTAGONIST

SURYOSUTANTO Depart.of. Pharmacology & Therapy

Faculty Of Medicine – Padjadjaran University

Overview:

The word AUTACOID comes from the Greek : Autos (self) and Acos (medicinal

agent,or remedy).The autacoids are a variety of substances of widely differing structures and pharmacological activities.

They all have the common feature of being formed by the tissues on which they act; thus, they function as local hormones. The autacoids also differ from circulating hormones in that they are produced by many tissues rather than in specific endocrine glands.

Classification:I. Amino-decarboxylic acid:

Histamine and SerotoninII. Polypeptides:

Angiotensin, Kinins, P substance, Vasoactive Intestinal Polypeptides.

III.Eicosanoids: Prostaglandins, Leukotrienes, and Tromboxane

HISTAMINE AND ANTI HlSTAMINES

HISTAMINES:• is a chemical messenger that mediates a

wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and possibly neurotransmission in parts of the brain.

• has no clinical application

Location, synthesis and release of histamine :

Location : occurs in practically all tissues, but it is unevently distributed, with high amounts found in lung, skin and GIT. It is found in high concentration in mast cells or basophil.

Synthesis : Is an amine formed by decarboxylation of the amino acid histidine. This process occurs primarily in the mast cells, basophils, and in the lungs, skin and GIT mucosa.In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the polysulfated anion, heparin, along with an anionic protein. If histamin is not stored, it is rapidly inactivated by MAO.

Release of histamine : May be primary response to the stimuli, but most often, histamine is just one of several chemical mediators released. Stimuli causing the release of histamine from tissues include the following:

1. The destruction of cells as a result of cold, bacterial toxins, bee sting venoms,trauma and so forth.

2. The dissolution of cytoplasmic granules as a result of action of radiation or surfactants.

3. The action of histamine liberators, which include foreign proteins, drugs (such as curare and morphine), dextran, or radiograph contrast media.

4. Allergic and anaphylaxis.

Functions of Endogenous Histamine• Role in allergic responses• Release of other autacoids• Regulator of mediator release• Histamine release by drugs, peptides, venoms, and other agents.• Histamine release by other means• Growths of mast cells and basophils.• Gastric acid secretion• As a neurotransmitter in central nervous system

Mechanism of action of histamine : Its effects by binding to two types of receptors, designated HI and H2 receptors, located on the surfaces of cells.

Actions of histamine: HI Receptors• Exocrine excretion

increased production of nasal andbronchial mucus, resulting inrespiratory symptoms.

• Bronchial smooth muscle: constriction of bronchioles results in symptom of asthma, decreased lung capacity.

• Intestinal smooth muscle: constriction results in intestinal cramps and diarrhea

• Sensory nerve endings: act as a local anesthetic resulting in decreased pain and itch

H2 ReceptorsStomach: stimulation of gastric hydrochloric acid secretion

Hl and H2 ReceptorsCardiovascular System- lowers systemic blood pressure by

reducing peripheral resistance- causes positive chronotropism (mediated

by H2 R) and a positive inotropism (mediated by both HI and H2 R).

Skin:- dilation and increased permeability of the

capillaries results in leakage of protein and fluid into the tissues.

- in the skin this results in the classical "triple response".

- wheal formation, reddening due to vasodilation, and flare ("halo").

HI R Antagonists : Mechanism of actions : l. These compounds do not influence the

formation or release of histamine, but rather they block the receptor-mediated response of a target tissue, (contrasts with action of cromolyn)

2. The HIR blockers are classified according to their chemical structures

3. The histamnine receptors are distinct from those that bind serotonin, acetylcholine and the catecholamines

Pharmacological Properties: Their effects are largely predictable from knowledge of the responses to histamine that involve interaction with HI R.

Smooth muscle :- antagonism of the constrictor action of

histamine on respiratory smooth muscle (in guinea pig, but not so in human being,

because allergic bronchoconstriction is caused primarily by mediators such as leukotrienes, and platelet activating factor)

- within the vascular tree, the HI antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by HIR on endothelial cells.

Effects of the histamine antagonists on histamine-induced changes in systemic blood pressure parallel these vascular effects.

Capillary permeability:HI antagonists strongly block the action of histamine that results in increased capillary permeability and formation of edema and wheal.

Flare and itch: HI antagonists suppress both.Exocrine glands:• gastric secretion is not inhibited at all

by HI antagonists.

• they suppress histamine-evoked salivary, lacrimal and other exocrine secretions with variable responses.

• The atropine-like properties of many of these agents, however, may contribute to lessened secretion in cholinergically inervated glands and reduce on going secretion in, for example, the respiratory tree.

Immediate hvpersensitivity reactions:- edema formation and itch, are fairly well

controlled; others such as hypotension, are less so.

- bronchokonstriction is reduced little

Central nervous system :- The first generation HI antagonists can both stimulate

and depress the CNS.- The second-generation antagonists (terfenadine,

astemizole loratadine) are largely excluded from the brain when given in therapeutic doses, because they do not cross the blood-brain barrier appreciably

- An interesting and useful property of certain HI antagonists (dimenhydrinate and subsequently with diphenhydramine, various piperazine derivates, and promethazine) is the capacity to counter motion sickness.

Anticholinergic effects:- Many of the first generation HI antagonists tend to

inhibit responses to acetylcholine that are mediated by muscarinic receptors.

- The second-generation HI antagonists have no effect on muscarinic receptor.

Local anesthetic effect:Some HI antagonists, dimenhydrinate and promethazine have local anesthetic activity. However, the concentrations required for this effect are several orders higher than those that antagonize histamine.

Classification a. First-generation agents: 1. Ethanolamines: - include dimenhydrinate, diphenhydramine,

clemastin, carbinoxamine, doxylamine. - produce mark sedation; doxylamine marketed only as a

sleeping aid. - also act as antiemetics.

2. Ethylenediamines: - include pyrilamine. tripelennamine, and antazoline. - produce moderate sedation and gastrointestinal upset.

3. Alkylamines : - include chlorpheniramine and brompheniramine. - produce slight sedation.

4. Piperazines: - include hydroxyzine. cyclizine, and meclizine

- produce marked adverse gastrointestinal effects and moderate sedation.

- are antiemetics

5. Phenothiazines : - include promethazine and cyproheptadine. - produce marked sedation - are antiemetics

B. Second generation agents (nonsedating) : Piperidines: - Astemizole

- Levocabastine - Loratadine - Terfenadine

Absorption, Fate and Excretion : – are well absorbed after oral administration ;

effects are usually seen in 30 minutes, duration of action 4-6 hours.

– are lipid-soluble; most first-generation agents cross the blood-brain barrier, a property reduced with second-generation agents.

• are metabolized in the liver ; many induce microsomal enzymes and alter their own metabolism and that of other drugs.

• the second generation HI antagonists are rapidly absorbed, from GIT, and metabolized in the liver to active metabolites by hepatic microsomal P450 system.

• excreted in the urine

Side Effects : 1. Sedation : the most frequently, and other common adverse

effects include tinnitus, fatique, dizziness, lassitude, incoordination, blured vision, and tremors.

2. Dry mouth;3. Drug interactions : the potentiation with CNS depressants, MAO

Inhibitors -> can exacerbate the anticholinergic effects of the antihistamines.

4. Mutagenicity; only in animals.5. Drug allergy; more commonly it results from topical application.6. Overdoses : hallucinations, excitement, ataxia, and

convulsion -> coma and collaps CRS.

Therapeutic Uses; 1. Allergic conditions:

- are drugs of choice in controlling the symptoms of allergic rhinitis and urticaria because histamine is the principal mediator. - are ineffective in treating bronchial asthma.2. Motion sickness and nausea; diphenhydramine, dimenhydrinate, cyclizine and meclizine.3. Somnifacient: diphenhydramine

H2 R Antagonists :

1. Actions: • acts on H2 R in the stomach, blood vessels,

and other sites• completely inhibits gastric acid secretion

induced by histamine, gastrin or pentagastrin

• only partially inhibits gastric acid secretion induced by acetylcholine or betanechol.

2. Therapeutic Uses: - duodenal ulcer, nonmalignant gastric ulcer,

gastroesophageal reflux disease, - small maintanace doses are effective against recurrences.

3. Pharmacology; - Absorption: GIT -> almost 80 % Unevenly distributed in various organs of the body. Only

small amount cross the blood- brain barrier.

- Inactivated by the liver's microsomal mixed function oxygenase system (30%)

- Excreted unchanged in the urine (70%)

4. Adverse reactions: - are usually minor

- the most common side effects are headache, dizziness, diarrhea, and muscular pain. - can also have endocrine effects, since it acts as a nonsteroidal antiandrogen -> gynecomastia, galactorrhea, and reduced sperm count.5. Drug interactions: blocks hepatic mixed function oxygenase, and thus inhibits

the microsomal metabolism of several other drugs, causing higher blood levels and enhancement of their effects.

1. Actions:• is a new, potent, H2 R blocker• compared to cimetidine, ranitidine is longer acting and is five to ten times as potent.

2. Therapeutic Uses and Pharmacokinetics : are similar to those described for cimetidine.

3. Adverse effects :• has minimal side effects.• it does not produce the antiandrogenic or prolacting-

stimulating effects of cimetidine.• it does not inhibit the mixed function oxygenase

system in the liver, it does not affect the concentration of other drugs

Famotidine:• is similar to ranitidine in its

pharmacological action, but it is 20-160 times more potent than cimetidine and 3-20 times more potent than ranitidine

Nizatidine:• is similar to ranitidine in its

pharmacological action and potency.• in contrast to cimetidine, ranitidine, and

famotidine(which are metabolized by the liver), nizatidine is eliminated principally by the kidney.

• its bioavailability is nearly 100%.