histamineModerator: Dr. Pooja Shukla

Resident: Fariha Fatima JR-2

Overview:• Introduction• Synthesis, Storage, and Release• Clinical manifestations of histamine pathophysiology• Histamine Receptors• Drugs acting on histamine receptors

Introduction:

Histamine is a biogenic amine found in many tissues, including

mast cells, basophils, lymphocytes, neurons, and gastric

enterochromaffin-like cells.

It is an autacoid—that is, a molecule secreted locally to

increase or decrease the activity of nearby cells.

Histamine is a major mediator of allergic and inflammatory

processes.

It also has significant roles in the regulation of gastric acid

secretion, neurotransmission, and immune modulation.

Histamine Synthesis, Storage, and Release:

Histamine synthesis and storage can be divided into two “pools”: a slowly turning over pool a rapidly turning over poolThe slowly turning over pool is located in mast cells and basophils.Histamine is stored in large granules in these inflammatory cells, and the

release of histamine involves complete degranulation of the cells.

The rapidly turning over pool is located in gastric ECL cells

and in histaminergic CNS neurons.

These cells synthesize and release histamine as required for

gastric acid secretion and neurotransmission, respectively.

Clinical manifestations of histamine pathophysiology:

Receptors:

Actions of Histamine

Tissue and Organ System Effects of Histamine

The “triple response”

Intradermal injection of histamine causes a characteristic red spot,

edema, and flare response that was first described many years ago.

The effect involves three separate cell types: smooth muscle in the

microcirculation, capillary or venular endothelium, and sensory nerve

endings.

At the site of injection, a reddening appears owing to dilation of small

vessels, followed soon by an edematous wheal at the injection site and a

red irregular flare surrounding the wheal.

The flare is said to be caused by an axon reflex.

A sensation of itching may accompany these effects.

HISTAMINE ANTAGONISTS

The effects of histamine released in the body can be reduced in several

ways.

Physiologic antagonists , especially epinephrine, have smooth muscle

actions opposite to those of histamine, but they act at different receptors.

This is important clinically because injection of epinephrine can be

lifesaving in systemic anaphylaxis.

H-1 Antihistamines:The basic structure of 1st generation antihistamines

consists of 2 aromatic rings linked to a substituted ethylamine backbone.

These drugs are divided into 6 subgroups based on their substituted side chains:

Ethanolamines,Ethylenediamines,Alkylamines, Piperazines,Phenothiazines & Piperidines.

The H 1 antagonists are conveniently divided into :

first-generation second-generation

Neutral at physiological pH Cross bbb where they block

the actions of histaminergic neurons in the CNS.

Ionised at physiological pH

Do not cross bbb

Pharmacokinetics:

These agents are rapidly absorbed after oral administration,

with peak blood concentrations occurring in 1–2 hours.

They are widely distributed throughout the body, and the

first-generation drugs enter the central nervous system

readily.

Some of them are extensively metabolized, primarily by

microsomal systems in the liver.

Most of the drugs have an effective duration of action of 4–6

hours following a single dose,

meclizine and several second-generation agents are longer-

acting, with a duration of action of 12–24 hours.

The newer agents are considerably less lipid soluble than the

first-generation drugs and are substrates of the P-glycoprotein

transporter in the blood-brain barrier; as a result they enter the

central nervous system with difficulty or not at all.

Pharmacodynamics:

The first-generation H 1 -receptor antagonists have

many actions in addition to blockade of the actions of

histamine.

Some of these actions are of therapeutic value and

some are undesirable.

• Sedation

• Anti nausea and antiemetic actions

• Anti parkinsonism effects

• Anti cholinoceptor actions

• Adrenoceptor-blocking actions

• Serotonin-blocking action

• Local anesthesia

Other actions

Certain H 1 antagonists, eg, cetirizine, inhibit mast cell release

of histamine and some other mediators of inflammation.

This action is not due to H 1 -receptor blockade and may reflect

an H 4 -receptor effect

A few H 1 antagonists (eg, terfenadine, acrivastine) have been

shown to inhibit the P-glycoprotein transporter found in cancer

cells, the epithelium of the gut, and the capillaries of the brain.

Clinical Uses:First-generation H 1 -receptor blockers are among the most

extensively promoted and used over-the-counter drugs.

The prevalence of allergic conditions and the relative safety

of the drugs contribute to this heavy use.

The fact that they do cause sedation contributes to heavy

prescribing and over-the-counter use of second-generation

antihistamines.

1.Allergic Reactions

The H 1 antihistaminic agents are often the first drugs used to

prevent or treat the symptoms of allergic reactions.

In allergic rhinitis (hay fever), the H 1 antagonists are second-

line drugs after glucocorticoids administered by nasal spray.

In urticaria, in which histamine is the primary mediator, the H 1

antagonists are the drugs of choice and are often quite effective

if given before exposure.

For atopic dermatitis, antihistaminic drugs such as

diphenhydramine are used mostly for their sedative

side effect, which reduces awareness of itching.

The second-generation H 1 antagonists are used

mainly for the treatment of allergic rhinitis and chronic

urticaria.

2.Motion Sickness and Vestibular Disturbances

Scopolamine and certain first-generation H 1

antagonists are the most effective agents available for

the prevention of motion sickness.

The antihistaminic drugs with the greatest

effectiveness in this application are diphenhydramine

and promethazine.

The piperazines (cyclizine and meclizine) also have

significant activity in preventing motion sickness and

are less sedating than diphenhydramine in most

patients.

3.Nausea and Vomiting of Pregnancy

Doxylamine, an ethanolamine H 1 antagonist, was

promoted for this application as a component of

Bendectin, a prescription medication that also

contained pyridoxine.

Toxicity:Less common toxic effects of systemic use include

excitation and convulsions in children, postural

hypotension, and allergic responses.

Overdosage of astemizole or terfenadine may induce

cardiac arrhythmias; the same effect may be caused at

normal dosage by interaction with enzyme inhibitors.

Drug Interactions:Lethal ventricular arrhythmias occurred in several

patients taking either of the early second-generation agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole, or macrolide antibiotics such as erythromycin.

These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines.

H 2 -RECEPTOR ANTAGONISTS:H 2 receptor antagonists (also called H 2 blockers )

reversibly and competitively inhibit the binding of histamine to H 2 receptors, resulting in suppression of gastric acid secretion.

H 2 receptor antagonists also indirectly decrease gastrin and

acetylcholine-induced gastric acid secretion.

All four drugs are well tolerated in general. Occasional minor adverse effects include

diarrhea, headache, muscle pain, constipation, and fatigue.

H 2 receptor antagonists may induce confusion and hallucinations in some patients.

H 3 & H 4 RECEPTOR ANTAGONISTS:

Till date no drug directed against H3 &H4 have been approved for clinical use.

H3 receptors are thought to provide feedback inhibition of certain effects of histamine in CNS and in ECL use.

In animal studies, H3 receptor antagonists include wakefulness and improves attention.

Drugs used in animals are:

Thioperamide, Clobenpropit,Ciproxifan, Proxyfan.

H 4 receptor antagonists represent a promising area of drug development to treat inflammatory conditions that involve mast cells and eosinophils.

Conclusion:The more recent elucidation of the H 3 and H 4

receptor subtypes has renewed interest in the role of histamine in CNS-related disorders.

H 3 -specific receptor targeting may provide new therapies for a number of cognitive, neuroendocrine, and neuropsychiatric conditions.

The H 4 receptor is also an exciting molecular target for drug

development, as it is thought to play an important role ininflammatory conditions involving mast cells and

eosinophils. Agents directed against H 4 receptors might one day be employed to treat a variety of inflammatory conditions, such as asthma, allergic rhinitis, inflammatory bowel disease and rheumatoid arthritis.