Eicosanoids And Histamine

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Eicosanoids

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- Prostaglandins and related compounds are synthesized from arachidonic acids (membrane phospholipids)
- Specific effects on target cells close to formation.
- Prostaglandins, prostacyclins, thromboxane, leukotriene

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Eicosanoids: Physiological effects

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Profound physiological effects at low concentrations:

- Inflammatory response (rheumatoid arthritis).
- Production of pain and fever.
- Regulation of blood pressure.
- Induction of blood clotting.
- Control of several reproductive functions such as the induction of labor.
- Regulation of the sleep / wake cycle.

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Eicosanoids: Pathway

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Eicosanoids: Cox-1 isoform

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- COX-1: constitutively expressed- "housekeeping" processes, homeostatic regulation.

- COX-1 catalyzes the synthesis of PGE2 and PGI 2 that have cytoprotective actions and play an important role in maintaining the integrity of the gastroduodenal mucosa.

- COX-1 maintains renal function (vasomotor tone)

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Eicosanoids: Cox-2 isoform

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- COX-2 levels increase in inflammatory diseases (arthritis).
- Inflammation is associated with up-regulation of COX-2 & increased amounts of particular prostaglandins.
- COX-2 expression is increased in some cancer cells.
- Angiogenesis (blood vessel development), which is essential to tumor growth, requires COX-2.

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Eicosanoids: Cox-2 isoform cont...

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- COX-2, is an inducible isoform that is found mainly in inflammatory and immune cells (neutrophils, macrophages, mast cells, etc).

- Pro-inflammatory cytokines and growth factors induce COX-2.

- At the site of inflammation, COX-2 is responsible for the generation of the hyperalgesic and pro-inflammatory prostaglandins.

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Eicosanoids: Cox-1/Cox-2 Flowchart

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Eicosanoids: Lipoxygenase pathway

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- Lipoxygenase synthesizes Leukotriene B4, C4, D4 and E4.
- Occurs predominantly in leukocytes, in response to a variety of immunological stimuli.
- The primary target of LTB4 is the leukocyte where it elicits chemotaxis, adherence, and aggregation.

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Eicosanoids: Lipoxygenase B4

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- Causes neutrophils to adhere to vascular endothelial cells and enhances the rate of migration of neutrophils into extra-vascular tissues.

- Activates phospholipases, the production of diacylglycerols and phosphoinositides, and the release of either anti- or pro-inflammatory agents.

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Eicosanoids: Lipoxygenase C4

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- Leukotriene C4, together with LTD4 and LTE4, cause contraction of the bronchial smooth muscle in asthma and play a role in bronchospasm.

- Leukotriene antagonists play a potential therapeutic role in asthma.

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Eicosanoids: Thromboxane

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- Synthesized primarily in platelets.
- Potent inducer of platelet aggregation
- Causes vasoconstriction.
- Indicated in the pathophysiology of thrombotic events, myocardial infarction and ischemia.
- What Aspirin targets.

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Pain Neurochemistry

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Central/Peripheral sensation of Pain

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Injured Cell Pain pathway

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Eicosanoids: Antagonists - Corticosteroids

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Corticosteroids:
- Potent anti-inflammatory agents.
- Inhibit phospholipase A2
- Inhibit cyclooxygenase 2
- Indicated in treatment of rheumatoid arthiritis, gout, asthma, eczema,
- Available as oral, inhaled and topical agents.
- Long-term use has profound adverse effects


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Eicosanoids: Antagonists - Non-Steroidal Anti-Inflammatory Drugs:

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Non-Steroidal Anti-Inflammatory Drugs:
- Inhibition of cyclooxygenase enzymes.
- Inhibition of prostaglandins involved in fever, pain and inflammation.
- Blockade of thromboxane formation platelets inhibits clotting.
- Indicated for inflammatory conditions, pyresis and analgesia.
- Generally targets both Cox-1 & Cox-2

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Eicosanoids: Antagonists- Aspirin

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Thromboxane A2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting.
Aspirin’s anti-clotting effect, attributed to inhibition of thromboxane formation in blood platelets.
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Prophylaxis for MI and prevention of recurrence of MI, embolism and stroke.
Aspirin forms a covalent bond making it effective at low doses. At high doses it works as an anti-inflammatory, but causes the worst GI side-effects at high dose.

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Role of antagonists Chart:

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Eicosanoids: Prostaglandin Analogs

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- Alprostadil (PGE1): Treatment of erectile dysfunction
- Misoprostol (Cytotec): Prevention of peptic ulcers in patients on high dose of 
NSAID’S
- Epoprostenol: Severe pulmonary hypertension

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Histamine

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- Formed from the amino acid histidine
- Stored in high concentrations in vesicles in mast cells and basophils
- Metabolized by
-- Monoamine oxidase and diamine oxidase

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Histamine causes:

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- Stimulation of gastric secretion H2
- Smooth muscle contraction (bronchioles) H1
- Cardiovascular (vasodilation) H1
- Pruritis
- Urticaria
- Mucosal Congestion H1

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Histamine: H1 receptors

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- Bronchoconstriction and vasodilation (via the release of nitric oxide and EDRF)
- Local edema is caused by capillary endothelial cells releasing EDRF and contracting, opening gaps in the permeability barrier-vasodilation
- Manifested in allergic reactions and mastocytosis

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Histamine: H2 receptors

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- G-coupled receptor that mediates gastric acid secretion by the parietal cells in the stomach
- Actions are mediated by activation of adenyl cyclase, which increases intracellular cAMP.
- Excessive gastric acid production:
-- Gastroesophageal reflux disease (GERD)
-- Peptic ulcer
-- Zollinger Ellison Syndrome

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Histamine: Typical Release

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- Released from mast cells in response to IgE-mediated (immediate) allergic reactions

- Histamine blockade plays an important role in treatment of seasonal rhinitis, urticaria, and angioneurootic edema

- Histamine receptors in gastric parietal cells control gastric acid secretion.

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Histamine: Distribution

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Histamine: MOA of release

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Histamine: Allergen mediated release

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Pollen
Dust mites
Mold
Latex
Drugs
Insect Venom

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Histamine: Drug Mediated Relsease

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Penicillin
Cepahalosporin
Vancomycin
Tubocurarine
Succinylcholine
Radiocontrast media
Aspirin & NSAID’s
Insulin

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Histamine: Effect on vascular smooth muscle

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Histamine: Anaphylaxis

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- Most acute and potentially severe allergic reaction.

- Symptoms include hypotension, vasodilation, myocardial depression, dysrhythmia, urticaria, angioedema and bronchospasm.
- Drug of choice is epinephrine (produces bronchodilation and increases blood pressure)

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Histamine: Anaphylaxis triple response

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Triple Response:
- This denotes the response to intradermal administration of histamine
a. Localized red spot forms around the side of injection
-- Histamine - induced vasodilatory effect
b. Brighter red flush or " flare" extending beyond original red spot.
-- histamine- induced axon reflexes cause vasodilation indirectly
c. Wheal (lump) is discernible in 1-2 min occupying the original red spot.
-- caused by increased capillary permeability - reflects edema.

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Histamine: characteristics of histamine receptor activation

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Histamine: Agents overview

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Histamine: H1 Antagonists, 1st Gen

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- Indicated for the treatment of allergies, rhinitis, inflammation and nausea associated with motion sickness.
- Interaction with muscarinic, cholinergic and adrenergic receptors (low specificity)

- Produce strong sedative effects

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Histamine: H1 Antagonists, 1st Gen: Examples

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Hydroxyzine (Vistaril)
Cyclizine (Marezene)
Diphenhydramine (Benadryl)
Dimenhydrinate (Dramamine)
Clemastine (Tavist)
Carbinoxamine (Histex)
Promethazine (Phenergan)
Azelastine (Optiva)
Meclizine (Antivert)

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Histamine: H1 Antagonists, 1st Gen: Hydroxyzine

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Hydroxyzine is a long-acting drug that is widely used for skin allergies, also used as a mild anxiolytic

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Histamine: H1 Antagonists, 1st Gen:
Cyclizine

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Cyclizine and meclizine are indicated for motion sickness.

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Histamine: H1 Antagonists, 1st Gen:
Promethazine

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Promethazine indicated for allergic reactions and prophylaxis and treatment of motion sickness & postoperative pain (adjunct to analgesics)

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Histamine: H1 Antagonists, 1st Gen:
Azelastine

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- Inhibits release of histamine and other mediators and intranasally, reduces hyper-reactivity of the airways and increase the motility of bronchial cilia.
- Azelastine may be administered as a nasal spray and ophthalmic agent.
- Metabolized to desmethylazelastine (active metabolite)
- Commonly used as a nasal spray and has an active metabolite

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Histamine H1 Antagonists:
Adverse Effects

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- Sedation.
- GI distress
- Nausea
- Vomiting
- Extrapyramidal reactions.

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Histamine H1 Antagonists:
Second-Generation

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- Far less lipid soluble than the first generation
- Almost free of sedation and autonomic effects
- Developed for use in chronic conditions
- Most are extensively metabolized in the liver
- Half-life of 12-24 hours

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Histamine H1 Antagonists:
Second-Generation Examples

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- Fexofenadine (Allegra)
- Loratadine (Claritin)
- Cetrizine (Zyrtec)

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Histamine H1 Antagonists:
Second-Generation Indications

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- Allergic Reactions (allergic rhinitis, urticaria, dermatitis, hay fever)
- Motion Sickness and Vestibular Disturbances
- Nausea and Vomiting
- Sedation

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Histamine H1 Antagonists: receptor diagram

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Histamine H1 Antagonists:
Interactions

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- Potentiation of effects of CNS depressants and alcohol
- Contraindicated with monoamine oxidase inhibitors.

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Histamine H2 Antagonists: 4 on the market

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Classification and prototype:
Four H2 receptor blocking agents are currently available on the market:

- Cimetidine (Tagamet)
- Ranitidine (Zantac®)
- Famotidine (Pepcid®),
- Nizatidine (Axid®)

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Histamine H2 Antagonists:

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- Structurally different from the H1 receptor blocking agents
- Typical half-life of 1-3 hours
- Relatively nontoxic
- Can be given in large doses
- Extend the duration of action to 12-24 hours via multiple dosing

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Histamine H2 Antagonists: MOA

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- Produce a surmountable pharmacologic blockade of histamine H2 receptors

- Relatively selective and have no actions on H1 receptors or autonomic receptors

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Histamine H2 Antagonists:
Clinical Uses

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- Duodenal ulcer
- Gastric ulcer
- Zollinger Ellison Syndrome
- GERD
- Reflux esophagitis

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Histamine H2 Antagonists:
Clinical Uses

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Acid-peptic disorders:
- Specifically duodenal ulcer
- Reduce symptoms, accelerate healing, and prevent recurrences
- Acute ulcers are usually treated with 2 or more doses per day
- Recurring ulcers can be treated with a bedtime dose
- H2-blocking agents are also effective in accelerating the healing and prevention of recurrence of gastric peptic ulcers

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Which one of the follwoing anti-histamines would be indicated for treatement of zollinger-ellison sydndrome?

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Nizatidine

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Histamine H2 Antagonists
Clinical Uses: Zollinger-Ellison syndrome

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Zollinger-Ellison syndrome:
- Characterized by acid hypersecretion, severe recurrent peptic ulceration, GI bleeding, and diarrhea
- H2-blockers may be helpful but large doses are required.
- Not as effective as proton pump inhibitors. (PPI’s)

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Histamine H2 Antagonists:
Toxicity

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Cimetidine is an inhibitor of CYP-450 isoenzyme system in the liver (causes number of drug interactions)
- May also reduce hepatic blood flow
- Also has significant antiandrogen effects (at high doses)

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Drug Interactions (very important)

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