Dermatographic urticaria
Condition in which the triple response of lewis is exaggerated. Largely idiopathic. Treatment: H1 receptor antagonist and omalizumab (recognises IgE and reduces activation of mast cells)
Synthesis and storage of histamine
Formed from the amino acid histidine by histidine decarboxylase. Found in 4 cell types: Mast cells, basophils, ECL cells in the gut, histaminergic neurons in the brain Packaged in acidic granules with macroheparin
How is histamine released from mast cells?
Exocytosis from secretory granules following Ca2+ induced degranulation by c3a/c5a, SP and IgE
- c3a and c5a are Gi coupled. βγ subunit activates PLCβ → IP3 → Ca2+
- SP binds mas-related gene x2 (Mrgx2) receptor which is Gq coupled. PLCβ → IP3 → Ca2+
- Allergen induced crosslinking of IgE with FcεR1 (high affinity receptor). Phosphorylation of adaptor protein linker for activation of T cells ( LAT) causing activation of PLCγ/ IP3 mediated Ca2+ release
Histamine receptor activation
- H1R = Gq: PLCβ → IP3 + DAG/PKC (importan in inflammtion)
- H2R = Gs: inc AC →inc cAMP/PKA (gastric acid secretion)
- H3R = Gi: dec AC →dec cAMP (important inhibitory autoreceptor in the CNS)
- H4R = Gi: dec AC →dec cAMP (chemotaxis/cytokine release)
Physiological effects of histamine
- smooth muscles contraction in ileum, bronchioles and uterus (H1)
- Blood vessel dilatation via endothelial NO release (H1)
- Itching evoked by activation of distinct sensory nerves (puritoceptors, H1)
- Triple response (H1)
- Increased HR (H1)
- Gastric acid secretion (H2)
- Brain neurotransmitter (mainly H1-3 but also H4)
Physiological roles of histamine
- Involved in allergic reactions e.g. rhinitis, urticaria
- responses include swelling, itchiness, nasal congestion, watery eyes
- In severe anaphylaxis throat swells, inc HR, dec BP (rapid adrenaline treatment required)
- Driver of some symptoms of mastocytosis: too many mast cells present leading to excessive allergic type reactions triggered by various factors (temp, stress, infection etc) Often due to mutation in c-kit (receptor tyr kimase causing mast cell proliferation)
Histamine metabolism
2 enzymes can metabolise histamine
- Hiastaminase (aka diamine oxidase) : oxidative deamination of hist to produce imidazole acetaldehyde
- Histamine N-methyltransferase: transfer of methyl group on to the nitrogen of the imidazole ring to produce NT-methylhistamine
Both products are inactive at histamine receptors
Sodium Cromoglycate
Mast cell stabiliser - unclear mechanism
Reduced Ca2+ influx upon mast cell stimulation. May inhibit the inward Cl- current which is required to maintain a negative enough membrane potential to allow sustained influxes of Ca2+
Used in eye drosp for hayfever and prophylactically for asthma and mastocytosis
Drugs that increase cAMP to treat histamine associated pathology
increasing cAMP inhibits mast cell degranulation
- β2 receptor agonists e.g. salbutamol (short acting) and formoterol (long acting)
- Phosphodiesterase inhibitors e.g theophylline (partially effective in mast cell inhibition but main role in bronchdilatation therefore used in asthma
- omalizumab - anti IgE antibody. Allergen bound IgE induces mast cell degranulation wehn bound to FcεR1
First generation H1R antagonists
Mepyramine
rapidly permeated the BBB and caused drowsiness so problematic for systemic use
- still used topically for insect bites
- used in some cold/flu medication to aid sleeping
Second generation H1R antagonists
Terfenadine
Did not cross BBB however reports of death due to long QT syndrome
- shown to inhibit kv11.1/hERG which is important for repolarisation of the AP
- terfenadine is a prodrug metabolised to fexofenadine by CYP3A4. Reduced CYP3A4 = increased risk of death (avoid grapefruit juice)
3rd generation H1R antagonists
Fexofenadine and loratadine
Non-drowsy and lack cardiac side effects.
Treatment of allergies, hayfever and urticaria
Use of adrenaline in anaphylactic shock
Adrenaline administered i.m. to counteract systemic vasodilataion (NA unsuitablel as it causes reflex bradycardia)
Adrenaline also relieves bronchospasm and is often coadministered with hydrocortisone for its anti-inflam effects
Treatment of mastocytosis
Inhibitors of mast cell degranulation and histamine receptor antagonists used
Potential for use of receptor tyr kinase inhibitors eg imatinib (only efficacious in patients without the common c-kit mutation)
Pathway of H2 action in the stomach
G cells secrete gastrin on to ECL cells where it binds CCK2 (CCK receptor)
inc Ca2+ in ECL cells
histamine secretion
histamine acts at Gs receptors on parietal cells causing inc cAMP and PKA
PKA phosphorylates proteins involved in the trafficking of K+/H+ pumps on the apical membrane and therefore H+ release
What is a negative regulator of gastric H+ release?
Somatostatin
Drugs that inhibit gastric acid secretion
- Proglumide: CCK2R antagonist. Reduces histamine secretion, no longer used
- H2 antagonists e.g cimetidine. However soon replaced by ranitidine as it inhibits CYP450
Omeprazole
PPIs convert to the actice form in the acidic environment of the parietal cell and form disulphide bonds with the K+/H +pump
However, it is broken down by H+ and slo onset to max effectiveness. Predominantly metabolised by CYP2C19 which shows significant genetic polymorphisms (1% Europeans and 30% of asians are poor metabolisers)
New K+/H+ blockers
- Vonoprazin is a potassium competitive acid blocker (P-CAB) that competes for the K+ binding site. It has greater stabilty in H+ and CYP2C19 is less important in its metabolism
- Antacids eg. gaviscon neutralise stomach acid
- Cholinergic blockade and vagotomy (both virtually obselete). Inhibits ACh M3R stimulation of parietal cells and reduces acid release
- Eradication of H pylori by antibiotics eg. clarithromycin
NSAIDs use and PPIs
NSAIDs inhibit PG synthesis
PGE2 acts on ECL cell EP2/3R to inhibit gastric acid secretion and enhance mucin (EP4R) and bicarbonate (EP1/2R)
- Patients at risk of peptic ulcers who are prescribed NSAIDs are also given PGE1 analogue misopristol or omeprazole
- Arthrotec = disclofenac (NSAID) and misopristol
