Histamine and Histamine Antagonists-08

7/27/2019 Histamine and Histamine Antagonists-08

1/26

Histamine and anti histamines


2/26

Synthesis and storage and release of

histamine

Mechanism of Synthesis:

histamine is synthesized by decarboxylation of the

amino acid histidine by the action of the enzyme

histidine decarboxylase. Once formed, histamine is stored at the site of

synthesis.


3/26

Site of synthesis and storage:

Histamine is synthesized and stored in the following

sites:

1- Neurons in the brain2- Enterochromaffin cells in the gastric mucosa

3- Mast cells


4/26

Sources of histamine release in the body

1- Mast cellsMast cells are of two types:

1- connective tissue mast cells (especially around blood vessels and in the skin)

2- mucosal mast cells (lungs, digestive tract, mouth, conjunctiva and nose)

Release of histamine from mast cells

1- Immune mediated2- Non immune mediated (chemical and mechanical release)

They synthesize andstore histamine in granules


5/26

Release of histamine from mast cells (1)

Immune mediated release = hypersensitivity reactions2 stages:

1- First exposure to an antigen (inhalation,ingestion)

results in the formation of antibodies (type IgE)

specific for that antigen. These antibodies are fixed on mast cells

2- Subsequent exposure to the same antigen

(may occur after a variable period, days,months)

Results in binding of the antigen to its specific IgE on mast cells and cross linking of IGE

receptors. This results in release of histamine


6/26

Non-immune mediated release = Chemical andmechanical release

Certain drugs such as morphine and tubocurarine,

can displace histamine from mast cells. This type ofrelease does not require prior exposure.


7/26

2- Non mast cell sources of histamine in

the body1- Brain: (functions as neurotransmitter)

2- Enterochromaffin cells (EC) in the stomach

(function: stimulates HCL secretion by parietal cells of

the stomach)


8/26

Pharmacological actions of histamine

The pharmacological actions of histamine depend onthe tissue and type of receptor present at the area

of release


9/26

Effect of histamine release

(pathophysiologic release)

Source of release Receptor Site of receptor Effect

Mast cells

(hypersensitivity)

H1 Smooth muscles 1. Bronchoconstriction

2. Contraction of GIT

H1 Endothelium 1. Vasodilatation

2. Increased capillary

permeability leading to

edema

H1 Sensory nerve endings 1. Pain and itch

H2 Smooth muscles of blood

vessels (only in large

doses)

1- Vasodilatation

H4 Immune active cells (as

eosinophils)

1. Chemotaxis


10/26

Effect of histamine release (physiologic

release)

Source of release Receptor Site of receptor Effect

ECL - cells in the

stomach

H2 Oxyntic cells of the

stomach

1. HCL secretion

Brain

(histaminergicneurons cell bodies

of these neurons are

found in the

hypothalamus and

axons extend to all

areas of the brain)

H1 and H2 Post synaptic neurons at

all areas of the rain

1. 1- Arousal

2. Decreased appetite

H3 Presynaptic histaminergic

neurons in the brain

1. Inhibit histamine

release producing sleep

2. Modulate the release

of other

neurotransmitters


11/26

Termination of Histamine Action

1. Cellular uptake

2. Metabolism by histamine N-methyltransferase and

histaminase enzymes in the liver.3. Very little amount is excreted


12/26

Symptoms associated with histamine

release from mast cells

Mild cutaneous release

Moderate release

Severe release (anaphylactic)

erythema, urticaria, and/or itching

skin reactions, tachycardia, moderate

hypotension, mild respiratory distress

severe hypotension, ventricularfibrillations, cardiac arrest, bronchospasrespiratory arrest


13/26

Urticaria

(due to the release of histamine)


14/26

Reduction of the effects of released

histamine

1. Physiologic antagonists:Epinephrine has smooth muscle actions opposite to

histamine but by actiong on different types of receptors.It is used in conditions of massive release of histamine

2. Histamine release inhibitors:Reduce immunologic release of histamine from mast cells

a) Mast cell stabilizers: Cromolyn and nedocromil

b) Beta 2 adrenergic agonists

3. Histamine receptor antagonists


15/26


16/26

Pharmacokinetics:

1- First Generation Agents:

Rapidly absorbed from the GIT

Widely distributed

Cross blood-brain barrier

Extensively metabolized by the cytochromeP450 and metabolites are active and are excretedby the kidney

Duration of action 4-6 hours.


17/26

Pharmacokinetics:

2- Second GenerationRapidly absorbed from the GITWidely distributedDo not cross the blood-brain barrier (less lipidsoluble)Elimination: Cetirizine (urine) and fexofenadine (bile)


18/26

Pharmacological Properties

I- Effects related to reversible competitive antagonism of H1

receptors (present in both first and second generations)

1- On smooth Muscles:

inhibit effects of histamine on smooth muscles, especially the constriction

of the bronchi.

2- On blood vessels:

inhibit the vasodilator effects that are mediated by activation of H1

receptors on endothelial cells (synthesis/release of NO and other

mediators). Residual vasodilation is due to H2 receptors on smooth

muscle and can be suppressed by administration of an H2 antagonist.

3- On capillary permeability:

inhibit the increased capillary permeability and formation of edema

brought about by histamine.


19/26

II- Effects not related to blockade of H1 receptors (present in

some of the first generation drugs)

1- Anticholinergic Effects: Many of the first-generation H1 antagonists inhibit responses to acetylcholine

that are mediated by muscarinic receptors (have atropine-like actions) e.g.,

promethazine. The second-generation H1 antagonists have no effect on

muscarinic receptors.

Anticholinergic effects include dry mouth, blurred vision, constipation and

urinary retention

Perhaps because of their anticholinergic effects, some of the H1 antagonists

have suppressant effects on drug-induced parkinsonism symptoms.


20/26

Effects not related to blockade of H1 receptors

(present in some of the first generation drugs)

2-On the central nervous system:

Therapeutic doses of most of the first generation histamine H1 receptor

antagonists produce CNS depression manifest as sedation.

Excitation rather than sedation may occur in children and rarely in adults

Overdoses produce central excitation resulting in convulsions, particularly in

children. Individual variability as regards the CNS exist. Some of the first generation drugs can prevent motion sickness

The second-generation ("nonsedating") H1 antagonists do not affect the CNS

because they do not cross the blood-brain barrier when given in therapeutic

doses.


21/26

Summary of effects not related to reversible

competitive antagonism of H1 receptors

Anticholinergicactivity Sedation Other actions

First generation

Carbinoxamine +++ Slight to moderate -

Diphenhydramine +++ Marked Anti-motion sickness

Dimenhydrinate +++ Marked Anti-motion sickness

Cyclizine - Slight Anti-motion sickness

Chlorpheniramine + Slight -

Promethazine +++ Marked 1. Antiemetic

2. Alpha adrenergic blocker

Second generation

Fexofenadine - -

Loratadine - - Long duration of antihistamine action

Cetirizine - - Mast cell stabilizer


22/26

Uses:

1- Prevention and treatment of allergic diseases as allergicrhinitis and chronic urticaria : both first and secondgenerations (but the non-sedating drugs are preferred)

Histamine H1 receptor antagonists are ineffective in

bronchial asthma as other mediators of allergy arepresent

2-Treatment of atopic dermatitis: Sedative histamine H1receptor antagonists are preferred.

3- Motion sickness: diphenhydramine, dimenhydrinate orcyclizine.


23/26

Adverse effects:

1- Sedation (with first generation)1. Anticholinergic action in the form of dry mouth, blurred

vision, tachycardia, constipation and urinary retention

occur with diphenhydramine, dimenhydrinate or cyclizine,

chlorpheniramine, promethazine and carbinoxamine.2. Sedation occurs with the first generation drugs

3. Excitation and convulsions (mostly in children treated with

first generation drugs)

4. Allergy


24/26

Drug interactions

1) Co administering first generation H1 antihistaminestogether with cytochrome P450 inducers such as the

benzodiazepines will decrease their activity.

2) Co administering first generation H1antihistamines with drugs that competitively inhibit

P450 such as the macrolides, antifungals or calcium

antagonists will increase their activity.


25/26

Drug interactions

3) First generation H1 antihistamines produce additive CNSdepression with CNS depressants as:

1. opioids

2. sedatives

3. narcotic analgesics4. Alcohol

4) First generation H1 antihistamines produce additive

anticholinergic action with anticholinergic drugs


26/26

Cromolyn and Nedocromyl

Not absorbed orally Given as powder by inhalation for prophylaxis

against bronchial asthma and allergic rhinitis

Inhibit histamine release by inhibiting chloridechannels on mast cells

Side effects are local in the form of dry mouth,

throat irritation, cough or wheezes.

Documents

Histamine and Histamine Antagonists-08