Histamine & Antihistamines - PowerPoint Presentation

Slide1

Histamine & Antihistamines

Slide2

Histamine is an autacoid chemical messenger mostly generated in mast cells that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain.

Histamine has no clinical applications, but agents that interfere with the action of histamine (antihistamines) have important therapeutic applications.

Slide3

Location, synthesis, and release:

Location

:

Histamine occurs in practically all tissues, but it is unevenly distributed, with high amounts found in nose, lung, skin, and the gastrointestinal tract (sites where the “inside” of the body meets the “outside”).

It is found at high concentration in mast cells or basophils. Histamine also occurs as a component of venoms and in secretions from insect stings.

Synthesis:

Histamine is an amine formed by the decarboxylation of the amino acid L -histidine by

histidine decarboxylase

an enzyme that is expressed in cells throughout the body, including central nervous system (CNS) neurons, gastric mucosa parietal cells, mast cells, and basophils .

Slide4

Once formed, histamine is either stored or rapidly inactivated. 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 histamine is not stored,

it is rapidly inactivated by methylation and oxidation reactions that are catalyzed by a

methyltransferase

enzyme and

diamine

oxidase, respectively.

Release of histamine:

The release of histamine may be the primary response to some stimuli, but, most often, histamine is just one of several chemical mediators released.

The release of histamine from tissues is caused by: the destruction of cells as a result of cold, bacterial toxins, bee sting venoms, or trauma. Allergies and anaphylaxis also cause histamine release.

Stimuli include complement components C3a and

C5a,

which interact with specific surface receptors, and the combination of antigen with cell-fixed immunoglobulin (

Ig

)E antibodies. In common with many secretory

processes,

histamine release is initiated by a rise in cytosolic [Ca2+]. Various basic drugs, such as morphine and

tubocurarine

, release histamine

Slide5

Slide6

Mechanism of action:

Histamine is released

in response to various stimuli exerts its effects by binding to one or more of four types of histamine receptors:

H1, H2 ,H3

and

H4

receptors

.

H1 and H2 receptors are widely expressed and are the targets of clinically useful

drugs. While H3 receptors are located in various tissues in the periphery and on nerve terminals. Activation of these presynaptic receptors(H3) in the brain inhibits the release of histamine and other neurotransmitters.

The

H4 receptors are located on leukocytes especially eosinophils and mast cells and is involved in

chemotactic responses

by these cells

.

Histamine binds to G protein-coupled

H1

receptors and stimulates the inositol phospholipid signaling pathways, resulting in the formation of inositol-1,4,5-trisphosphate (IP3) and

diacylglycerol

and an increase in intracellular calcium.

Stimulation of

H2

receptors enhances the production of cyclic adenosine monophosphate (

cAMP

) by adenylyl cyclase.

All four histamine receptors have been shown to have constitutive activity in some systems; thus, some antihistamines previously considered to be traditional pharmacologic antagonists must now be considered to be

inverse agonists

Slide7

Actions:

Smooth muscle effects:

Histamine, acting on H

1

receptors, contracts the smooth muscle of the ileum, bronchi, bronchioles and uterus. Histamine reduces air flow in the first phase of bronchial asthma .

Cardiovascular effects:

Histamine promotes vasodilatation of small blood vessels by causing vascular endothelium to release nitric oxide by an action on H

1

receptors & also increasing capillary permeability .

It also increases the heart rate and the output of the heart by action on cardiac H

2

receptors.

Gastric secretion:

Histamine stimulates the secretion of gastric acid by action on H

2

receptors. So, it is implicated in the pathogenesis of peptic ulcer.

Exocrine excretion:

Increased

production of nasal and bronchial mucus, resulting in respiratory symptoms

Slide8

Nervous system effects :

Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H1-mediated effect is an important component of the

urticarial

response and reactions to insect and nettle stings.

Histamine is a transmitter in the CNS. It has effects on

neuroendocrine

control, cardiovascular regulation, thermal and body weight regulation, arousal, appetite & vomiting.

Skin effects:

When injected

intradermally

, histamine causes a

reddening

of the skin, accompanied by a

wheal

with a surrounding

flare

. This is the triple response.

This

mimics the

'triple response of Lewis' to scratching of the

skin. The

reddening reflects vasodilatation of the small arterioles and

precapillary

sphincters, and the wheal: the increased permeability of the

postcapillary

venules

. These effects are mainly mediated through activation of H1 receptors. The flare is an axon reflex: stimulation of sensory nerve fibers evokes

antidromic

impulses through

neighbouring

branches of the same nerve, releasing vasodilators such as

calcitonin

gene-related peptide causing arteriolar dilatation & redness in the surrounding area.

Itching

occurs if histamine is injected into the skin because it stimulates sensory nerve endings by an H1-dependent mechanism.

Slide9

Slide10

Role in allergy and anaphylaxis:

The symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include contraction of airway smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings.

Symptoms

associated with

allergy and anaphylactic shock result from the release of certain mediators from their storage sites. Such mediators include

histamine, serotonin, leukotrienes, and the eosinophil chemotactic factor of

anaphylaxis

. In some cases, these mediators cause a localized allergic reaction, producing, for example, actions on the skin or respiratory tract. Under other conditions, these mediators may cause a full-blown anaphylactic response.

Slide11

It is thought that the difference between these two situations results from differences in the sites from which mediators are released and in their rates of release. For example, if the release of histamine is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for efficient inactivation, a full-blown anaphylactic reaction occurs.

Despite

the fact that histamine release is evidently capable of reproducing many of the inflammatory signs and symptoms, histamine H1 antagonists do not have much clinical importance in the acute inflammatory response, because other mediators are more important. However, histamine and through action on H1 receptor is implicated in type I hypersensitivity

reactions such as allergic

rhinitis ,

urticaria

.

Slide12

Slide13

H1 Antihistamines

The term "antihistamine" refers to the classic H

1

-receptor neutral antagonists or inverse agonists. These compounds do not influence the formation or release of histamine. Rather, they block the receptor-mediated response of a target tissue (

The H

1

antihistamines contain an

alkylamine

group that resembles the side chain of histamine and permits them to bind to the

H

1

receptor

and act as

competitive receptor antagonists

.).

[Note: This contrasts with the action of

cromolyn

&

nedocromil

(

mast cell stabilizers

), which inhibit the release of histamine from mast cells and are useful in the treatment of asthma.]

The H

1

-receptor blockers can be divided into first- and second-generation drugs:

Slide14

The older first-generation drugs are still widely used because they are

effective

and

inexpensive

. However, most of these drugs penetrate the CNS and cause sedation. Furthermore, they tend to interact with other receptors, producing a variety of unwanted adverse effects.

The

second-generation agents are

specific

for H

1

receptors and because they carry polar groups ,mainly by adding carboxyl groups (for example, cetirizine is the

carboxylated

derivative of hydroxyzine), they do not penetrate the blood-brain barrier, causing less CNS depression than the first-generation drugs. Among these

agents:

desloratadine

,

fexofenadine

and

loratadine

show the least sedation.

Slide15

Slide16

Actions:

The action of all the H1-receptor blockers is qualitatively similar. They are much more effective in

preventing symptoms

than reversing them once they have occurred. However, first-generation H

1

-receptor blockers have a low specificity, interacting not only with histamine receptors but also with muscarinic cholinergic receptors,

α

-adrenergic receptors, and serotonin receptors. Some of these actions are of therapeutic value and some are undesirable (adverse effects).

Slide17

Slide18

Therapeutic uses:

First-generation H

1

-receptor blockers are among the most extensively promoted and used

over-the-counter (OTC)

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 of second-generation antihistamines.

1.

Allergic and inflammatory conditions:

H1-receptor blockers are useful in treating

and

preventing allergies

caused by antigens acting on immunoglobulin E antibody–sensitized mast cells. For example, antihistamines are

used in

controlling the symptoms of allergic rhinitis(hay fever) and

urticaria

because histamine is the principal mediator.

However, the H1-receptor blockers are not used in treating bronchial asthma because histamine is only one of several mediators of that condition

.

Slide19

[

Note

:

Epinephrine

has actions on smooth muscle that are opposite to those of histamine, and it acts at different receptors. This is called

(

Physiologic antagonism

) Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine.].

2. Motion sickness and nausea:

Along with the

antimuscarinic

agent

scopolamine

, certain H1-receptor blockers, such as

diphenhydramine

,

dimenhydrinate

,

cyclizine

,

meclizine

,

cinnarizine

and

promethazine

are

the most effective agents for

prevention

of the symptoms of motion sickness. They are usually not effective if symptoms are already

present and

, thus, should be taken prior to expected travel.

The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways

. not effective if symptoms are already present and, thus, should be taken prior to expected travel. The antihistamines prevent or diminish nausea and vomiting mediated by both the chemoreceptor and vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 and M1 muscarinic receptors.

Meclizine

and

cinnarizine

are

also useful for the treatment of vertigo associated with vestibular disorders.

Slide20

3.

Sleeping aids :

Although they are not the medications of choice, many first- generation antihistamines, such as

hydroxyzine

and

doxylamine

, have strong sedative properties and are used in the treatment of insomnia.

The

use of first-generation H

1

antihistamines is contraindicated in the treatment of individuals working in jobs in which wakefulness is critical.

Slide21

Pharmacokinetics:

First

and second generation drugs are administered orally or

parenterally

.

Azelastine

,

olopatadine

,

ketotifen

,

alcaftadine

,

bepotastine

,

and

emedastine

are

available in ophthalmic formulations that allow for more targeted tissue delivery.

Azelastine

and

olopatadine

have intranasal formulations, as

well

.

H1-receptor blockers are well absorbed after oral administration, with maximum serum levels occurring at 1 to 2 hours.

The average plasma half-life is 4 to 6 hours, except for that of meclizine and the second- generation agents, which is 12 to 24 hours.

The duration of action for many oral H

1

antihistamines is at least 24 hours, allowing once-daily dosing.

First-generation H

1

-receptor blockers have high bioavailability and are distributed in all tissues, including the CNS.

They are mainly metabolized in the liver and excreted in the urine.

Slide22

Adverse effects:

1. Sedation:

First-generation H

1

antihistamines, such as

chlorpheniramine

, hydroxyzine, diphenhydramine and promethazine

bind to H

1

receptors and block the neurotransmitter effect of histamine in the CNS. The most frequently observed adverse reaction is sedation. {At ordinary dosages, children occasionally (and adults rarely) manifest excitation rather than

sedation especially with diphenhydramine.}

Other central actions include tinnitus, fatigue, dizziness,

uncoordination

, blurred vision, and tremors

. coordination, and tremors. Elderly patients are more sensitive to these effects. Sedation is less common with the second-generation drugs, since they do not readily enter the CNS. Second-generation H1 antihistamines are specific for peripheral H1 receptors.

Regular use of

first-generation

antihistamines is not advisable in children, because the CNS depressant property may interfere with learning tasks.

Slide23

2. Anticholinergic adverse effects:

Oral antihistamines also exert anticholinergic effects (more with diphenhydramine,

dimenhydrinate

& promethazine) leading to dry mouth , blurred vision, constipation and retention of urine.

3.

Other adverse effects :

gastrointestinal disturbances which are fairly common, allergic dermatitis which can follow topical application

. The most common adverse reaction associated with second-generation antihistamines is headache.

 

Drug interactions:

Interaction of H

1

-receptor blockers with other drugs can cause serious consequences, such as potentiation of the effects of all other CNS depressants, including alcohol. Persons taking monoamine

oxidase

inhibitors (MAOIs) should not take antihistamines because the MAOIs can exacerbate the

anticholinergic

effects of the antihistamines.

Slide24

Overdoses:

Although the margin of safety of H1-receptor blockers is relatively high, and chronic toxicity is rare, acute poisoning is relatively common, especially in young children.

The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions. If untreated, the patient may experience a deepening coma and collapse of the cardiorespiratory system.