Histamines

Question 1

What is a histamine?

Answer 1

An organic nitrogen compound made of:
- imidazole ring
- amino acid chain
Is a base as both sides have potentially unprotonated nitrogen.

At physiological pH partially protonated.

Question 2

Where are endogenous histamines produced?

Answer 2

Mast cells and basophils

Non-mast cell histamines also found in the brain

And in enterochromaffin cells in the stomach.

Question 3

What is scombroid poisoning?

Answer 3

From consumption of histamine produced by bacteria found in dark meat fish. Can result in bronchopasm in severe casee, commonly presents as flushing, facial flushing, urticaria, diarrhoea.

Question 4

How is endogenous histamine released)

Answer 4

IgE antibodies result from exposure to an antigen. Antigens then bind to existing IgE antibodies that are attached to mast cell membranes. This causes mast cell degranualtion and histamine release.

Question 5

What are the locations and roles of H1 and H2 receptors?

Answer 5

When activated

H1 - found in many organs. In the airways cause bronchoconstriction.
Bowel peristalsis. Leaky capillaries and oedema. Itching, pain, disturbed sleep, nausea and vomiting.

H2 - primarily involved with gastric acid secretion and gastrointestinal motility.

Question 6

What mechanism of action occurs on activation of H1 receptor?

Answer 6

• Gq protein linked receptor
• effects mediated by phospholipase, and phosphotidyl-inositol pathway.
• leads increased intracellular calcium released from endo plastic reticulum. The DAG leads to activation protein kinase C.

Question 7

How are antihistamines classified?

Answer 7

Three generations:

1st- across BBB therefore cause side effects of drowsiness, dizziness, poor concentration.
Eg. Chloraphenamine, promethazine, cyclizine.

2nd- do not cross BBB, zwittertonic- highly polar, therefore less lipophilic. More specific to H1. Some associated with QT prolongation leading to torsades de pointes.

3rd- active metabolite or enantiomer of 2nd gen drug Eg. Fexofenadine

Question 8

Chloraphenamine:
Bioavailability 
Protein binding 
Vd 
Metabolism 
Half life

Answer 8

Bio: 25-50

Protein: 70%

Vd: 7.5

Met: hepatic

Half life: 2-43 hours

Question 9

Cyclizine: 
Bioavailability 
Protein binding 
Vd
Metabolism 
Excretion 
Half life

Answer 9

Bioavailability: 75-80%

Protein and Vd unknown

Metabolism: N-demethylation to norcyclizine

Excretion: renal

Half life: 10-20 hours

Question 10

How does cyclizine work?

Answer 10

Acts at H1 present in chemoreceptors trigger zone (important to Tx of nausea and vomiting), and vestibular apparatus.

Is a piperazine 1st gen antihistamine. This class have some anticholinergic activity.

Question 11

Disadvantages of giving cyclizine IV?

Answer 11

Pain on injection, thrombophlebitis, local necrosis and tachycardia.

Question 12

Promethazine: mechanism of action, unique properties.

Answer 12

Tricyclic first generation antihistamine, primarily acts as reversible inverse agonist at H1 receptors but also has anticholinergic properties, anti-serotonergic activity, antidopaminergic activity. Acts at CTZ and vestibular apparatus.

Significant sedative and anxiolytics properties. Antiemetic. Anti-allergic.

Can have EPSE more than other antihistamines (dyskinesias, dystonic reactions)

Question 13

Main enzymes responsible for metabolism of Loratadine?

Answer 13

CYP3A
CYP2D6
Hepatic

Question 14

How is fexofenadine excreted?

Answer 14

80% unchanged in faeces, 12% unchanged in urine