Histamine and anti histamines

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.

Site of synthesis and storage: Histamine is synthesized and stored in the following sites: 1- Neurons in the brain 2- Enterochromaffin cells in the gastric mucosa 3- Mast cells

Sources of histamine release in the body

1- Mast cells Mast 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)

They synthesize and store histamine in granules

Release of histamine from mast cells 1- Immune mediated 2- Non immune mediated (chemical and mechanical release)

Release of histamine from mast cells (1)

Immune mediated release = hypersensitivity reactions
2 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

Non-immune mediated release = Chemical and mechanical release

Certain drugs such as morphine and tubocurarine, can displace histamine from mast cells. This type of release does not require prior exposure.

1- Brain: (functions as neurotransmitter) 2- Enterochromaffin cells (EC) in the stomach (function: stimulates HCL secretion by parietal cells of the stomach)

2- Non mast cell sources of histamine in the body

Pharmacological actions of histamine

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

Effect of histamine release (pathophysiologic release)

Source of release Receptor
H1 H1

Site of receptor
Smooth muscles Endothelium

Effect
1. Bronchoconstriction 2. Contraction of GIT 1. Vasodilatation 2. Increased capillary permeability leading to edema 1. Pain and itch 1- Vasodilatation

Mast cells (hypersensitivity)

H1 H2

Sensory nerve endings Smooth muscles of blood vessels (only in large doses) Immune active cells (as eosinophils)

H4

1. Chemotaxis

Effect of histamine release (physiologic release)

Source of release
ECL - cells in the stomach Brain (histaminergic neurons cell bodies of these neurons are found in the hypothalamus and axons extend to all areas of the brain)

Receptor
H2 H1 and H2

Site of receptor
Oxyntic cells of the stomach Post synaptic neurons at all areas of the rain

Effect
1. HCL secretion 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

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

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, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest

Urticaria (due to the release of histamine)

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

Histamine H1- Antagonists

First Generation: Sedating (lipophilic compounds that readily cross the blood-brain barrier) Second Generation: Non-sedating (poorly penetrate the blood-brain barrier)

Pharmacokinetics:
1- First Generation Agents: Rapidly absorbed from the GIT Widely distributed Cross blood-brain barrier Extensively metabolized by the cytochrome P450 and metabolites are active and are excreted by the kidney Duration of action 4-6 hours.

Pharmacokinetics:
2- Second Generation Rapidly absorbed from the GIT Widely distributed Do not cross the blood-brain barrier (less lipid soluble) Elimination: Cetirizine (urine) and fexofenadine (bile)

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.

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.

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.

Summary of effects not related to reversible competitive antagonism of H1 receptors

Anticholinergic activity Carbinoxamine Diphenhydramine Dimenhydrinate Cyclizine +++ +++ +++ Sedation First generation Slight to moderate Marked Marked Slight Anti-motion sickness Anti-motion sickness Anti-motion sickness Other actions

Chlorpheniramine
Promethazine

+
+++

Slight
Marked Second generation

1. Antiemetic 2. Alpha adrenergic blocker Long duration of antihistamine action Mast cell stabilizer

Fexofenadine Loratadine Cetirizine

Uses:
1- Prevention and treatment of allergic diseases as allergic rhinitis and chronic urticaria : both first and second generations (but the non-sedating drugs are preferred) Histamine H1 receptor antagonists are ineffective in bronchial asthma as other mediators of allergy are present 2-Treatment of atopic dermatitis: Sedative histamine H1 receptor antagonists are preferred. 3- Motion sickness: diphenhydramine, dimenhydrinate or cyclizine.

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

Drug interactions
1) Co administering first generation H1 antihistamines together with cytochrome P450 inducers such as the benzodiazepines will decrease their activity. 2) Co administering first generation H1 antihistamines with drugs that competitively inhibit P450 such as the macrolides, antifungals or calcium antagonists will increase their activity.

Drug interactions
3) First generation H1 antihistamines produce additive CNS depression with CNS depressants as: 1. opioids 2. sedatives 3. narcotic analgesics 4. Alcohol 4) First generation H1 antihistamines produce additive anticholinergic action with anticholinergic drugs

Cromolyn and Nedocromyl

Not absorbed orally Given as powder by inhalation for prophylaxis against bronchial asthma and allergic rhinitis Inhibit histamine release by inhibiting chloride channels on mast cells Side effects are local in the form of dry mouth, throat irritation, cough or wheezes.