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Histamine

 

  1. Histamine (hista=tissues, amine=biogenic amine)
  2. Formed via decarboxylation of L-Histidine
  3. Metabolised to methylhistamine

ROLE: Histamine is an important mediator of immediate allergic (such as urticaria) and inflammatory reactions, although it plays only a modest role in anaphylaxis.
Histamine plays an important role in gastric acid secretion and functions as a neurotransmitter and neuromodulator.
Newer evidence indicates that histamine also plays a role in immune functions and chemotaxis of white blood cells.

 

Histamine receptors

  • All are GPCRs

SUBTYPE

LOCATION

MOA

ANTAGONIST

CLINICAL USE OF ANTAGONIST

H1

Smooth muscle, endothelium, brain

Gq, IP3, DAG

Cetirizine

Sedation, Antiallergic, Antiemetic, Anticholinergic, Antiparkinsonism, Local anesthetic, Antiadrenergic, Antiserotonergic, Ativertigo.

H2

Gastric mucosa, cardiac muscle, mast cells, brain

Gs, cAMP

Cimetidine, ranitidine,

Prevents gastric acid secreation.

H3

Presynaptic autoreceptors and heteroreceptors: brain, myenteric plexus, other neurons

Gi, cAMP
 

Thioperamide
 

Potentially useful in asthma, chronic inflammatory conditions

H4

Eosinophils, neutrophils, CD4 T cells

Gi, cAMP
 

Thioperamide
 

Potentially useful in pruritus, asthma, allergic rhinitis, and pain conditions.

 

Antihistaminc Drugs:                                               

  1. First Generation (Older)         
  2. Second Generation (Newer)

Classification

  1. First Generation
    1. Tripelennamine    
    2. Pheneramine               
    3. CPM             
    4. Cyclizine              
    5. Meclizine              
    6. Cyproheptadine    
    7. Trazdone             
    8. Hydroxyzine       
    9. Promethazine
  2. B. Second Generation
    1. Terfenadine         
    2. Astemazole          
    3. Cetrizine              
    4. Levocetrizine               
    5. Azalastine           
    6. Mezalastine          
    7. Fexofenadine              
    8. Loratidine            
    9. Desloratidine

Seond Generation Antihistaminics

  1. Higher H1 selectivitiy: no anticholinergic side effects.
  2. Absence of CNS depressant property (LESS SEDATION).
  3. Additional anti-allergic mechanisms apart from histamine blockade: some also inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet activating factor effect.
  4.  They have poor antipruritic, antiemetic and antitussive actions.

 

P/K

  1. well absorbed
  2. High first pass metabolism
  3. Short acting (half life=12-24 hours)
  4. Older generations (First Generation) are lipid soluble while newer generation are water soluble. There become ionized at physiological pH therefore do not enter blood brain barrier (hence first generation are sedatives while second generation are not).  
  5. Astemazole achieves steady state=1 week
  6. Not effective therefore in acute states
  7. Loratidine-longest acting
  8. Least entry into blood brain barrier
  9. Pro-drugs
    1. Hydroxyzine            
    2. Cetirizine
    3. Terfenadine          
    4. Fexofenadine

Uses:

  1. Chlorpheniramine & Pheniramine
    1. Common component of cold remedy medication
    2. Also used in Urticaria
  2. Promethazine
    1. Marked Sedation          
    2. Antiemetic
    3. Antiadrenergic property – Orthostatic hypotension (alpha blocker)
    4. Antiparkinsonism- used in Drug induced Parkinsonism
  3. Cyproheptadine; also has Anti-serotonergic activity

Uses:

  1. Cold urticaria                       
  2. Cholinergic urticaria
  3. Carcinoid syndrome             
  4. SSRI induced sexual dysfunction          
  5. Poor eaters with GH deficiency  
  6. Prophylaxis of Migraine
  1. Meclizine & Cyclizine
    1. Motion sickness (MCD: Meclizine, Cyclizine, Diphenhydramine)          
  2. New drugs (Second Generation)
    Uses: ONLY IN ALLERGIC CONDITIONS and CHRONIC URTICARIA
    Less sedative than First Generation
    1. Fexofenadine (ALLEGRA)
    2. Cetrizine/Levocetrizine
    3. Loratidine/Desloratidine
    4. Alcaftadine: Used in Allergic conjuctivitis
    5. Olapatidine: Used in Allergic rhinitis
    6. Azelastine/Mizolastine
    7. Rupatidine

Highly sedative

Moderately sedative

Least sedative

Diphenhydramine
Dimenhydrinate
Hydroxyzine
Promethazine
 

Pheniramine
Cyproheptadine
Meclizine
Buclizine
Cinnarizine

Chlorpheniramine
Dexchlorpheniramine
Dimethindene
Triprolidine
Mebhydroline
Cyclizine
Clemastine
 

 

HIGHLY ANTICHOLINERGIC

LOW ANTICHOLINERGIC

ABSENT ANTICHOLINERGIC

Diphenhydramine
Dimenhydrinate
Pheniramine
Promethazine
Cyproheptadine

Chlorpheniramine
Hydroxyzine
Triprolidine
Cyclizine
 

Fexofenadine
Astemizole
Loratadine
Cetirizine
Mizolastine

 

Side effects

  1. Sedation (loratadine least sedative)             
  2. Weight gain
  3. Photosensitivity                                    
  4. Hepatotoxicity-terfenadine
  5. Torsa de depointes-terfenadine/astemazole

 *Fexofenadine it does not increase in QT interval.

 

Poisoning (3C) 
a. Coma                 
b. Convulsions                     
c. Cardiotoxicity

  • Rx-symptomatic & supportive

 





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