Autacoid Drugs: Histamine and Serotonin

Autacoid Drugs Overview

• Autacoids are produced by both neural and non-neural tissues.
• Act locally to modulate the activity of smooth muscle, nerves, glands, and platelets.
• Some autacoids function as neurotransmitters in the central nervous system (CNS) or the enteric nervous system.
• Regulate gastro-intestinal, uterine, and renal function.
• Involved in pain, fever, inflammation, allergic conditions, asthma, and thromboembolic conditions.
• Includes monoamines like histamine and serotonin.
• Includes fatty acid derivatives like prostaglandins and leukotrienes.
• Usually have local effects, restricted to their tissue of origin.
• Massive systemic release can occur in conditions like carcinoid tumors (serotonin) or anaphylactic shock (histamine).

Histamine Biosynthesis and Release

• Histamine is a biogenic amine.
• Primarily produced by mast cells and basophils, and paracrine cells in the gastrointestinal tract (GIT).
• Functions as a neurotransmitter in the CNS.
• Formed when the amino acid histidine is decarboxylated by the enzyme L-histidine decarboxylase.
• Histamine is stored in granules within mast cells and basophils.
• Mast cell degranulation and histamine release can be triggered by various factors - IgE antigen interaction, bacterial toxins, drugs (morphine, tubocurarine…etc).
• Histamine release can be blocked by cromolyn sodium.

Histamine Receptors and Effects

• H1, H2, and H3 are the main histamine receptor subtypes.
• H1 receptor activation causes vasodilation and increased vascular permeability, leading to erythema, congestion, edema, inflammation, pruritus, and cough.
• Massive histamine release by H1 activation can lead to decreased peripheral resistance and blood pressure, potentially causing anaphylactic shock, bronchoconstriction, and contraction of GIT smooth muscle.
• H2 receptor stimulation increases gastric acid secretion and is involved in allergic reactions.
• H2 receptor activation increases heart rate and contractility, but these effects are generally not prominent.
• H3 receptors are found in various tissues in the periphery and on nerve terminals.
• Activation of presynaptic inhibits the release of histamine and other neurotransmitters in the brain.
• Dermatitis, Rhinitis, Conjunctivitis, Bronchoconstriction, Other forms of allergy, and Anaphylactic shock can active H1 receptors.

Antihistamine Drugs

• Two main groups: first-generation and second-generation antihistamines.
• First generation antihistamines (Chlorpheniramine, Diphenhydramine, Hydroxyzine, Meclizine, Promethazine).
• Second-generation antihistamines (Cetirizine, Fexofenadine, Loratadine, Desloratadine).
• Drugs in both groups are administered orally and intravenously.
• Major difference is CNS distribution: first-generation antihistamines distribute into the CNS and cause sedation.
• Second-generation antihistamines have limited CNS penetration (do not cross BBB significantly) and cause little sedation.
• Competitive antagonists at H1 receptors and block histamine's effects on vascular smooth muscle and nerves, preventing or counteracting allergic reactions.
• Good oral absorption and wide distribution through the body and are extensively metabolized in the liver by CYP450 enzymes.
• Hydroxyzine has an active metabolite available as cetirizine.
• H1 antihistamines are similarly effective in treating allergies.
• First-generation antihistamines: used for sedation, treatment of nausea and vomiting, motion sickness, and vertigo.
• Diphenhydramine, hydroxyzine, and promethazine have the highest sedation action to induce sleep, pre-operative sedation, and severe pruritus.
• Phenyramines, such as chlorpheniramine are are less sedating that are used to treat allergic reactions to pollen, fungal spores, and other environmental allergens.
• Antimuscarinic effects: Diphenhydramine and promethazine have the highest anticholinergic activity: dry mouth, blurred vision, tachycardia,urinary retention, and other atropine-like effects.
• Contraindicated in overdose situations.
• Promethazine is a phenothiazine derivative with antihistaminic, anticholinergic and sedative effects.
• Used for management of vertigo and nausea and vomiting.
• Interactions: Physostigmine, a choline esterase inhibitor that crosses the BBB, can counter the central anticholinergic effects of first-generation antihistamines.
• Second-generation drugs lack antiemetic activity and are indicated to treat allergies.
• Fexofenadine has a shorter half-life and is taken twice per day (some others are once per day).
• Loratadine is metabolized to an active metabolite, excreted in urine and feces.
• Terfenadine and Astemisole can prolong QT intervals so are now withdrawn.
• Fexofenadine, cetirizine, and loratadine do not have cardiac effects.
• Azelastine is administered as nasal spray for allergic rhinitis, blocks H1 receptors inhibiting histamine release from mast cells.
• Can cause drowsiness, with uncommon side effects include dizziness, tiredness, headache, nasal irritation, dry mouth, and weight gain.
• Selctive antagonists-levocabastine, epinastine, olopatadine are used topically for seasonal allergic conjunctivitis.
• Ketotifen is a non-competitive antagonist for itchiness of allergic conjunctivitis and limits side effects by burning eyes.
• First-generation antihistamines cross the BBB, block H1 receptors in the CNS causing sedation, cheap cost, sedating actions such as: sedation (block H₁-Rc), atropine like effect (block M-Rc→ anticholinergic S/E), orthostatic hypotension (block a₁-Rc), and weight gain (block 5HT-Rc esp. cyproheptadine).
• Second-generation antihistamines can but are more expensive with prolong QT intervals especially with terfenadine and astemizole so fexofenadine is safer to prescribe.

Serotonin Synthesis and Release

• Serotonin (5-HT) is an autacoid and neurotransmitter.
• Primarily produced from platelets, enterochromaffin cells in the GIT, and neurons.
• Highest concentration is in enterochromaffin cells in the GIT.
• Synthesized from the amino acid tryptophan.
• Tryptophan hydroxylase (rate limiting enzyme) converts tryptophan to 5-hydroxytryptophan, then aromatic L-amino acid decarboxylase converts it to serotonin.
• Monoamine oxidase and aldehyde dehydrogenase convert serotonin to 5-hydroxy-indole acetic acid (5-HIAA).
• Serotonin is stored in vesicles within cells and released by calcium-mediated endocytosis.

Physiological Effects of Serotonin

• Peripheral tissues effects platelet aggregation, stimulates GI motility, modulates vascular smooth muscle contraction, and vasoconstriction.
• CNS regulates mood, appetite, pain and emotional processing, and sleep.
• Exerts effects via several subtypes e.g.., 5-HT1A and 5-HT1D.

Classification of Drugs Affecting Serotonin

• Serotonin agonists directly activate serotonin receptors.
• Serotonin antagonists block serotonin receptors.
• Serotonin reuptake inhibitors block the reabsorption and increase the amount of serotonin in the synaptic cleft.

Serotonin Agonists

• Buspirone is a partial agonist at 5-HT1A receptor for anxiety and depression.
• Sumatriptan and related triptans are 5-HT1D/1B receptor agonists to treat migraine headaches.
• Cisapride is a 5-HT4receptor agonist to treat gastro-esophageal reflux disease and gastrointestinal hypomotility.
• Cisapride was withdrawn in FDA 2000 due to QT prolongation.

5-HT Antagonists

• Clozapine,an atypical antipsychotic.
• Act partially by inhibition of 5-HT2 receptors in the CNS and used in schizophrenia.
• Cyproheptadine is a 5-HT2 receptor antagonist with H1 antihistamine activity, used to treat urticaria (hives) and other allergic rxns- pruritus and can cause mild to moderate drowsiness.
• Cyproheptadine and metisergide are useful in carcinoid tumors , which produce serotonin, histamine, other vasoactive substances to carcinoid syndrome. Presents with malabsorption, serve watery diarrhoea, cramps and paroxysmal vasomotor attacks of sudden purple blushing of face and neck.
• Ondansetron is a selective 5-HT3 receptor antagonist.
• It Prevents nausea and vomiting by blocking the effects of serotonin in the chemoreceptor trigger zone and the vagal afferents in the GIT.

Eicosanoids and Related Drugs

• Eicosanoids are autocoids derived from arachidonic acid.
• Prostaglandins are formed by cyclo-oxygenase (COX).
• Leukotrienes are formed by 5-lipooxygenase (LOX). -Thromboxanes act on smooth muscle and platelet aggregation:Platelet aggregation stimulated by thromboxane A2 (TXA2 ), inhibited by prostacyclin (PGI2 ) -Prostacyclin released by vascular endothelial cells: Prevents platelet aggregation
• Blood vessel injury →platelets stick to vascular endothelium →activates platelets → synthesis and release of TXA2 Thromboxane A3 (TXA3 ), synthesized from omega3 fatty acids in fish oils→Relatively little platelet aggregation or vasoconstriction compared to TXA2 .

Prostaglandins

• PGE2, PGI2 maintain pulmonary blood flow and renal vasodilation and glomerular filtration.
• Inhibits PG synthesis: may cause or aggravate renal dysfunction, counter act antihypertensive medication
• PGE2 and PGF2α stimulates uterine contractions and ↑ GIT motility
• Several PGs have a cytoprotective effect on GIT mucosa.

Eicosanoid Effects - Leukotrienes

• Secreted from inflammatory cells and is a product if anaphylaxis that is triggered by Leukotrienes C4 and D4 (LTC4 and LTD4 ).
• Secreted in asthma and anaphylaxis because of there main role in bronchospastic disease.
• Leukotriene inhibitors inhibit 5-lipo-oxygenase or blocks leukotriene receptors used in management of asthma
• NSAIDs Inhibit cyclo-oxygenase and relieves pain and inflammation
• Corticosteroids Inhibits formation of all eicosanoids, partially by inhibition of phospholipase A2 which are anti-inflammatory, antiallergic, antineoplastic effects and can treat a wide range of diseases.
• Prostaglandin E1: Alprostadil is identical to natural PGE1 and prevents closure of ductus arteriosus in neonates waiting for surgery.

Prostaglandin E1 Derivatives

• Misoprostol is a synthetic PGE1 analogue, cytoprotectiveEffect by inhibiting gastric acid secretion and increases bicarbonate secretion and is for NSAID induced gastric and duodenal ulcers, side effects include diarrhea and will trigger uterine contractions .
• Dinoprostone:natural PGE2 for ripening of cervix before induction of labour and causes terminations of pregnancy in intrauterine fetal death.
• CarboprostSynthetic PGF2α:Termination of pregnancy and control of postpartum bleeding only if measures have failed with side effect includes, vomiting and diarrhoea, changes in BP, blurred vision, resp. distress.
• a PGF2α analogue to treat open angle glaucoma, and increases ↑aqueous humour via the uveoscleral pathway but permanently triggers permanent change in colour of the iris by ↑melanin in melanocytes).
• Epoprostenol is a treatment of pulmonary hypertension, common side effects include Blushing, tachycardia, hypotension, nausea, vomiting, diarrhoea, and flu-like symptoms.
• Treprostinil is a analogue of prostacyclin and relieves symptoms of short breath and pulmonary hypertensions.

Endothelin-1

• Endothelin-1 (ET-1): peptide autacoid produced by vascular endothelial cells.
• ETA receptors → vasoconstriction and cell proliferation and contributes to dysfunction when triggered in pulmonary hypertension or during acute MI. ETA receptors → vasoconstriction and cell proliferation
• Bosentan: dual ETA and ETB receptor antagonist used to treat and approved for pulmonary arterial hypertension but has effects on the liver and should be monitored with contraception.
• Ambrisentan has More selectivity for ETA receptors (>4000-times), so you should monitor liver function too.