histamine Flashcards
Synthesis of histamine
comes from essential amino acid L-Histidine
An inducible enzyme, histidine decarboxylase and pyridoxal 5-phosphate as a cofactor. Inhibited by methyl-histidine
localization of histamines
everywhere, highest amounts of lung, skin, and stomach
pools of histamine- tissues (mast cells), blood (basophils). Histamine is synthesized and stored in secretory granules as a complex with heparin sulfate and ATP (mast cells) or chondroitin (basophils)
turnover of histamines in these cells is slow
non mast cell stores (epidermal cells, gastric mucosa cells, brain neurons, regenerative and tumor cells). Rapid turnover, no granules continuously released.
Levels of histamine are correlated with the activity of histidine decarboxylase
metabolism of histamine
defects in the metabolism of histamine by the diamine oxidase or acetaldehyde dehydrogenase contributes to the flushing seen during alcohol intake
release of histamine
within second following an agent that releases histamine or after injection of histamine, humans get a burning, itching sensation. Marked in the palms, face, scalp, ears. Followed by an intense warmth, the skin reddens, blood pressure falls, and HR increases. Headaches are also common, within minutes, BP recovers and hives will appear on skin.
Ag-Ab reaction release of mast cell histamine (vasoactive amine), lots of drugs, peptides, venoms promote release of histamine from the mast cell (w/o prior sensitization)
can account for unexpected anaphylactoid reactions
mechanism of action of histamine
increase intracellular calcium via a number of different pathways
omalizumab
MOA, admin, adverse, therapeutics
inhibit the release of histamine, monoclonal antibodies
MOA: decreases amount of Ag specifi IgE that normally binds to and sensitizes mast cells
admin: sub Q
adverse effect: life threatening anaphylaxis
Therapy: sever allergic asthma
inhaled corticosteroids\
most often used for asthma treatment, they reduce histamine release but only at high concentration
histamine-receptors
4 subtypes H1 H2, h3 h4
H1: smooth muscle, endothelial cells, CNS-Gq
H2: gastric parietal cells, cardiac muscle, mast cells, CNS-Gs
H3: CNS-presynaptic-Gi
H4: cells of hematopoietic origin-Gi
CV system and histamine
Histamine- dilates resistance vessels, increases capillary permeability, and causes an overall fall in BP
in some vascular beds, histamine constricts veins-> contributing to edema
Vasodilation: in endothelial cells-H1 activation increases intracellular Ca and activation of NO synthase, in vascular smooth muscle cells- H2 activation is coupled to increase cAMP
vasoconstriction of large vessels- not a lot (H1 R located on vascular smooth muscle cells results in increase in intracellular Ca)
BP- IV injection of histamine, both H1 and H2 mediated effects on resistance sized vessels
increased vascular permeability: H1 Rs- located on post-capillary venules; causes endothelial cells to contract. This exposes the basement membrane which is freely permeable to plasma protein and fluid
heart: affects both cardiac contractility and electrical events, predominantly H2
non-vascular smooth muscle and histamine
bronchioles,
intestinal smooth muscle
bronchioles: H1 contraction minor, H2 relaxation effects are more pronounced in asthma/pulm diseases
intestinal smooth muscle
exocrine glands, peripheral nerves, neuroendocrine effects and histamine
exocrine glands, GI secretory tissue: H2 mediated gastric secretion
Peripheral nerve endings: H1 pain and itching
Neuroendocrine effects: H1, arousal and decreased appetite
H1 receptor blockers
major anti histamines First generation(sedating): ethanolamines (diphenhydramine, dimenhydrinate), alkylamine (Chlorpheniramine), phenothiazines (promethazine)
second generation (non sedating): piperidines (Fexofenadine, loratadine), piperazine (Cetirizine)
2nd gen drugs have little to no anti cholinergic side effects, dont cross BBB to CNS
Pharmacology of H1 blockers
specific reversible competitive antagonism of H1 R located in periphery and CNS. An inverse agonist because reduction of constitutive activity of the receptor and compete with histamine
inhibit capillary permeability, suppress the immediate hypersensitivity reactions seen in anaphylaxis and allergy. No effect on BP or bronchoconstriction
CNS effectsL 1st gen: diphenhydramine, dimennhydrinate, chlorpheniramin- can stimulate and depress the CNS. CNS stim=overdose, CNS depression= more commone
some 1sr gens prevent motion sickness (CNS anticholinergic, promethazine, dimenhydrinate, diphenhydramine)
PNS and CNS anticholinergic effect: atropine like: dry mucous membranes, UT retention
Local anesthetic effect (Promethazine)
pharmacokinetics of H1 blockers
well absorbed following oral admin, nasal and ophthalmic formulations
distributed widely throughout the body (2nd gens Fexofenadine, Loratadine, Cetirizine)- less likely to enter the brain
Extensive liver metabolism 2nd generation metabolized via CYP 3A4/ 2D6, some have active metabolites. Terfenadine is metabolized to fexofenadine
loratadine is metabolized to desloratadine. Cetirizine is active metabolite of hydroxyzine
Toxicity and Major side effects and H1 receptor blocker
- sedation- CNS effects are the most common SEs of 1st gen (Diphenhydramine, dimenhydrinate, chlopheniramine). Mechanism- inhibition of BOTH cholinergic and histaminergic pathway . 2nd gen clain to have no sedative effect (cetrizine has a little). 1st gen drugs can have CNS stimulation paradoxically in high doses
- GI side effects: loss of appetite, nausea, vomiting etc
rarly increased appetite and weight gain - dry mouth, dryness of respiratoy passages (only with 1st gen)
loratadine: metabolized by CYP 3A4 and 2D6 to desloratadine –no cardiac toxicity has been associated
