Antihistamines

At the end of the lecture, students must know the followings:
* the biosynthesis, functions, and location of histamine.
*Mechanism of action of antihistamines.
*Types of antihistamines.
*Clinical uses of antihistamines.
* side effects and drug interactions of antihistamines.



• Autacoids (histamine, prostaglandin and serotonin) are substances have different structures and pharmacological activities but they have the common feature that they are formed by the tissues on which they act. Thus, they act as local hormones.
• Autacoids also differ from hormones in that they are produced by many tissues rather than in specific endocrine glands.

Histamine

• Histamine mediates a wide range of cellular response including:
• allergic and inflammatory reactions,
• gastric acid secretion,
• and neurotransmission in the brain.
Location: Histamine found in all tissues of the body, but it is found in a large amounts in skin, lung, and GIT. It is found in mast cells or basophils. It is also a component of venoms.
Synthesis: Histamine is an amine formed by the decarboxylation of amino acid histidine by histidine decarboxylase. In mast cells, histamine stored in granules as inactive complex composed of histamine and heparin. If histamine is not stored, it is rapidly inactivated by amine oxidase enzymes.


Histidine Histamine
Release of histamine: It is released as a primary response to some stimuli such as destruction of cells as a result of cold, bacterial toxins, bee sting venom, or trauma.

Mechanism of action
• Histamine mediates its action via four types of histamine receptors: H1, H2, H3, and H4 receptors. H1, and H2 receptors are the targets of clinically useful drugs.
• All types of histamine receptors have seven transmembrane helical domines and transduce extracellular signals by way of G protein-mediated second-messenger system.

Actions of histamine

H1 receptor produce:

• Exocrine secretion: increase nasal and bronchial discharge.
• Bronchial smooth muscle: constriction of bronchial smooth muscle causes symptoms of asthma.
• Intestinal smooth muscle: constriction cause intestinal cramps and diarrhea.
• Sensory nerve ending: causes itching and pain.
• Cardiovascular system: lower blood pressure by reducing peripheral resistance .
• Skin: Dilation and increased permeability of capillaries result in leakage of proteins and fluids into the tissues. In the skin , this result in classic (triple response) wheal formation, reddening due to vasodilataion and flare (hallo).

Histamine H2

Histamine H2 receptors mediate gastric acid secretion.

Role in allergy and anaphylaxis:
• The symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock reaction. This include contraction of smooth muscle, stimulation of secretions, dilatation and increased the permeability of the capillaries, stimulation of sensory nerve ending.
• Symptoms associated with allergy and anaphylactic shock result from the release of certain mediators from their storage sites. Such mediators include histamine, serotonin, leukotrines, and eosinophil chemotactic factor of anaphylaxis.


H1 ANTIHISTAMINES

• The term antihistamine refers to the classic H1 receptor blockers. These compounds do not influence the formation or release of histamine, but they block H1 receptors.
• NOTE: ( Other drugs such as cromolyn and nedocromil inhibit the release of histamine from mast cells and are useful in the treatment of asthma).
• H1 receptor blockers can be divided into first and second generation drugs.
• The older first generation:
• Still widely used because they are effective and inexpensive.
• These drugs penetrate CNS and cause sedation.
• They interact with other receptors, producing unwanted adverse effects.
• such as: diphenhydramine (Allermine)
dimenhydramine
chlorpheniramine
dexchlorpheniramine
promethazine
dimetindene (Fenistil)
cyproheptadine (periactin)
triprolidine
Ketotifen


• The second generation:
• They are specific for H1 receptor.
• They do not penetrate CNS, so they cause less sedation than first generation.
• Such as: Loratadine
desloratadine
acrivastine
cetirizine
fexofenadine

Actions
• The action of all the H1-receptor blockers is similar.
• Most of these drugs block ,also, cholinergic, adrenergic, or serotonin receptors.
• Blocking H1-receptors causes:
• Reduce allergic inflammation, itching, sneezing, and rhinorrhea.
• Reduce neurotransmission in the CNS.
• Increase sedation.
• Reduce cognitive and psychomotor functions.
• Increase appetite.
• Blocking serotonin-receptors causes: increase appetite
• Blocking ?-adrenergic receptors causes:
• Hypotension
• Dizziness
• Reflex tachycardia
• Blocking cholinergic-receptors causes:
• Dry mouth
• Urinary retention
• Sinus tachycardia.


Therapeutic uses
1- Allergic and inflammatory conditions:
• H1 – receptor blockers are useful in treating E.g. allergic rhinitis and urticaria.
• H1 – receptor blockers are ineffective in treating bronchial asthma (except ketotifen), because histamine is only one of several mediators of that condition.
• Epinephrine opposite the action of histamine, and it acts at different receptors. Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis.
• Glucorticoids show greater anti-inflammatory effects than the H1 antihistamines.

2- Motion sickness and nausea
3- Insomnia
4- Parkinson`s disease.
5- Cyproheptadine can be used as appetite stimulant.
6- Antihistamines are used as expectorant.

Pharmacokinetics

• H1-receptor blockers are well absorbed after oral administration with maximum serum levels occurring at 1 to 2 hours.
• The t half-life is 4-6 hours.
• They have high bioavailability and are distributed in all tissues, including the CNS.
• Most H1-receptor blockers are metabolized by the hepatic cytochrome P450.
• The duration of action of many oral H1-receptor blockers is at least 24 hours, facilitating once-daily dose.
• They are most effective when used prophylactically before allergen exposure rather than as need.
• Tolerance to the action of H1 antihistamines has not been observed.

Adverse effects
First generation H1-receptor blockers have a low specificity ; that is, they interact not only with histamine receptors but also with muscarinic cholinergic receptors, ?-adrenergic receptors, and serotonin receptors. The interaction of H1-receptor blockers with these receptors causes different side effects.

1- CNS:
• First generation H1-receptor blockers bind to H1-receptors and block the effects of histamine in CNS. So, the adverse reactions are:
• Sedation
• Tinnitus
• vertigo
• Fatigue
• Dizziness
• Lassitude (sense of weariness)
• Uncoordination
• Tremors
• Second generation of H1-receptor blockers are specific for H1-receptor and penetrate CNS poorly. They show less sedation and other CNS side effects.

2- Dry mouth, urinary retention, and blurred vision.
3- Hypotension and tachycardia.
4- Increased appetite.

Drug interactions:

• H1-receptor blockers potentiate the effects of other CNS depressants such as alcohol.
• Monoamine oxidase (MAO) inhibitors exacerbate the anticholinergic effects of the antihistamines.
• H1-receptor blockers decrease the effectiveness of cholinesterase inhibitors (rivastigmine, galantamine, donepezil) in the treatment of Alzheimer`s disease.

Overdose
• H1-receptor blockers are safe drugs and the chronic use toxicity is rare.
• Acute poisoning include hallucinations, excitement, ataxia and convulsions.


HISTAMINE H2-RECEPTOR BLOCKERS

• Histamine H2-receptor blockers have no affinity for H1-receptors.
• H2-receptor blockers are used as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn.
• These drugs reduce intracellular concentration of cAMP and, thereby, secretion of gastric acid.
• This group includes cimetidine, ranitidine, famotidine, and nizatidine.