Download Antihistamines II

By Omar Durani
Prof. Buynak
04/13/06
Allergy = An abnormally high sensitivity to certain
substances, such as pollens, foods, or microorganisms.
Common indications of mild allergy may include sneezing,
itching, and skin rashes.
A severe allergic reaction is known as an
anaphylactic shock which can be lifethreatening (airway constriction & extreme
hypotension. Immediate medical attention
needs to be administered.
•People with allergies have immune systems that overreacts when exposed
to substances.
•These substances (ex. Pollen) causes the body to respond with release of
Histamine which is main proponent of allergic reactions in individuals.
• Discovered in 1911 by Sir Henry Dale, identified as a potent
vasoactive substance in guinea pigs and dogs through experiments.
•Soon recognized to be major mediator of allergic reactions such as
rhinitis, asthma, urticaria (hives), pruritis (itching) and anaphylaxis
HISTAMINE
Histamine stored in special granules, and to
exert its action, must be released.
Mast Cells – Tissue
Basophils – Blood
ACTIVE SITE
Histamine released from: Tissue injury, allergic reactions, drugs (antibiotics, toxins).
Histamine once released interacts with specific receptors on the cell surface.
There 4 histamine receptors found on cells:
H1 Receptor: Endothelial and smooth muscle cells, adrenal medulla, brain; histamine
increases Ca2+ intake.
H1 receptor is the target of Antihistamines
H2 Receptor: Gastric mucosa cells; histamine induces gastric acid released.
A form of antihistamine drugs bind to H2 receptors to treat for GERD (ex. Nexium,
Prevacid)
H3 Receptor: CNS neurotransmitter properties as a neural presynaptic receptor; may
somehow regulate histamine release.
H4 Receptor: Found in immune active cells and involved in their chemotaxis.
•These are drugs that directly compete with histamine for specific
receptor sites.
•Antihistamines compete for typically H1 and H2 receptors.
Common structural features of classical antihistamine*
- ETHYLAMINE GROUP
- 3O AMINE
- LINKED TO 2 AROMATIC GROUPS
X = N, R1 = R2 = small alkyl groups
X=C
X = CO
•Chirality at X can increase both the potency and selectivity for H1-receptors
•For maximum potency, the two aromatic rings should be orientated in different planes.
•BLOCK action of histamine at the receptor sites
•Compete with histamine for binding at unoccupied receptors.
If histamine is already bound, antihistamines cannot remove
histamine.
•The binding of H1 blockers to the histamine receptors prevents the
adverse consequences of histamine stimulation:
•Vasodilation
•Increased gastrointestinal and respiratory secretions
•Increased capillary permeability
• Absorbed well by GI tract with a maximum absorption – 1-2 Hr
and a high safety margin.
Cardiovascular (small blood vessels)
Histamine effects:
•Dilation
•Increased permeability
(allowing substances to leak into tissues)
Antihistamine effects:
•Prevent dilation of blood vessels
•Prevent increased permeability
Immune System
Histamine effects:
Mast cells release histamine and other substances, resulting
in allergic reaction.
Antihistamine effects:
Bind to histamine receptors, preventing histamine from causing
the allergic response.
Smooth Muscle
Histamine effects:
Stimulate salivary, gastric and bronchial secretions.
Antihistamine effects:
Prevent salivery, gastric and bronchial secretions.
Antihistamines effects…
Skin:
Block capillary permeability
itching
Anticholinergic:
Drying effect that reduces nasal, salivary, and lacrimal gland
secretions (runny nose, tearing, and itching eyes)
Sedative:
Some antihistamines cause drowsiness (1st generation
antihistamines)
Management of:
Seasonal allergic rhinitis (Hay fever)
•Nasal allergies
•Allergic reactions to food, microbes, dust, etc.
•Motion sickness
•Sinus congestions
•Sleep disorders
• 1st Generation or Traditional
antihistamines
•2nd Generation or Non-sedative
antihistamines
•Older drugs
•Work both peripherally and centrally
•Have anticholinergic effects, and in some cases more
effective than nonsedating agents
• Examples:
diphenhydramine (Benadryl),
chlorpheniramine (Chlor-Trimeton)
Different Classes:
1. Alkylamines - (Chlor Trimeton®)
2. Ethanolamines - Diphenhydramine HCl (Benadryl®)
3. Ethylenediamines
4. Piperazines – Hydroxyzine HCl (Atarax®)
5. Phenothiazines - Promethazine HCl (Phenergan®)
6. Piperadines - Azatadine (Optimine®)
•Nonsedating antihistamines
•Developed to eliminate side effects, (sedation)
•Bulky and not as lipophilic and thus does not readily cross BBB,
fewer CNS side effects
•Longer duration of action (increases compliance)
•Better specificity for H1 and/or H2 receptor to block histamines
effects
•Examples:
fexofenadine (Allegra)
loratadine (Claritin)
•CNS depression (mainly in first generation agents).
•Appetite loss,
•nausea and vomiting,
•constipation or diarrhea.
•Insomnia
•Tachycardia
•dry mouth
•blurred vision
•Urinary retention
•Secreted in breast milk and can cross the placenta.
http://www.medinfo.co.uk/drugs/antihistamines.html
http://en.wikipedia.org/wiki/Histamine
http://en.wikipedia.org/wiki/H1_receptor
http://www.medterms.com/script/main/art.asp?articlekey=10092
Ash, Schild. Receptors Mediating Actions of Histamine. J. Pharmacol, 1966. 427-429.
Bachert, C. "Histamine: a Major Role in Allergy?" Abstract. Clinical and Experimental Allergy 28 (1998): 15-19.
Huttrer CP, Leonard F. Histamine Antagonists. Washington DC: National Research Council 1950.
http://en.wikipedia.org/wiki/antihistamine
Hardman JG, Limbird LE (ed’s). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. McGraw-Hill, NY, NY; 1996, p 673.