Histamine and Antihistamines

• Autacoids are local hormones, including Histamine, Serotonin, Angiotensin, Kinins, Prostaglandins, and Leukotrienes.
• Agonists and antagonists exist for autacoids, and receptor types are specified in brackets.
• Histamine is stored in mast cells and basophils.
• Histamine acts on at least four receptor types: H1, H2, H3, and H4, with no current clinical applications.

Histamine (H1, H2)

• H1 blockers include Diphenhydramine, Chlorpheniramine, Promethazine, Cetirizine, and Loratadine.
• H2 blockers include Ranitidine, Famotidine, and Roxatidine.
• H1-receptor antagonists (antihistamines) are divided into first-generation and second-generation agents.
• First-generation drugs include Diphenhydramine and dimenhydrinate, Cyclizine, Meclizine, Chlorpheniramine and Cyproheptadine. First-generation drugs often have multiple side effects like sedation and anticholinergic symptoms due to cross-reactivity with muscarinic cholinergic and a-adrenergic receptors.
• Second-generation drugs include Loratidine, Fexofenadine, and Cetirizine. Second-generation H1-antihistamines (e.g., Loratadine (Claritin), Fexofenadine (Allegra), Desloratidine (Clarinex), Cetirizine (Zyrtec)) do not readily enter the CNS and are more specific for H1 receptors, leading to fever side effects.
• H1 antihistamines are competitive antagonists. Their effectiveness is best when administered before exposure to an allergen. H1 antihistamines are more effective against acute allergic reactions than chronic allergies.
• Clinical uses for H1 antihistamines include treatment of seasonal allergic rhinitis, acute urticaria, anxiety, insomnia, nausea, and Parkinson's disease.
• First-generation antihistamines cross the blood-brain barrier, acting centrally and peripherally, but second-generation do not.
• Diphenhydramine (Benadryl), promethazine (Phenergan), clemastine (Tavist), chlorpheniramine (chlor-trimetron), hydroxyzine (atarax, vistaril), and dimenhydrinate (Dramamine) are first-generation antihistamines.
• Fexofenadine (Allegra) which is terfenadine metabolite, Loratadine (Claritin) with a 24-hour duration, and Cetirizine (zyrtec) are second generation antihistamines.
• Terfenadine (seldane) and astemizole ( hismanal) have been withdrawn due to cardiac concerns.
• First-generation antihistamines cause high sedation and anti-cholinergic effects, while second-generation ones have either.

5-HT or Serotonin (5-HT1-7)

• Agonists include Sumatriptan, Buspirone, and Dexfenfluramine.
• Blockers include Cyproheptadine, Ketanserin, and Ondansetron.

Angiotensin (AT1, AT2)

• AT1 blockers include Losartan.
• ACE inhibitors include Captopril, Enalapril, and Ramipril.

Kinins (B1, B2)

• Kinins include Bradykinin and Kallidin.
• Antagonists are being developed.

Prostaglandins

• Analogs include Misoprostol, Dinoprostone, and Carboprost.
• Synthesis inhibitors include Aspirin, Indomethacin, and Paracetamol
• NSAIDs inhibit cyclooxygenase enzymes, reducing the synthesis of prostacyclin (PGI2), prostaglandins, and thromboxane (TXA2) but have no effect on lipoxygenase which synthesizes leukotrienes.

Leukotrienes

• Antagonists include Montelukast, Zafirlukast, and Pranlukast.
• Lipoxygenase inhibitors include Zileuton.

Eicosanoids

• Eicosanoids are a large group of autacoids that are widely distributed in the body.
• These are locally synthesized from arachidonic acid via de novo synthesis.
• Arachidonic acid is converted to HPETE by Lipoxygenase, which then turns into HETE and then Leukotrienes.
• Cyclooxygenase turns Arachidonic acid into Endoperoxides, then synthetases convert it to Prostacyclin (PGI2), Prostaglandins, and Thromboxanes (TXA2).
• Zileuton inhibits Leukotrienes production via LOX.
• Montelukast blocks Leukotrienes.
• LTB4 affects Chemotaxis, while LTC4, LTD4, and LTE4 cause Bronchoconstriction.
• Misoprostol is a PGE1 analog, displaying gastroprotective properties and maintaining ductus patency, in addition to vasodilation . Alprostadil is also PGE1.
• Dinoprostone is a PGE2 analog causing uterine contraction.
• Carboprost is a PGF2alpha analog causing uterine contraction and elevates uveoscleral outflow of aqueous humor.
• Ileoprost is a PGI2 analog causing vasodilation and anti-aggregation.
• Aspirin inhibits TXA2, causing vasodilation and aggregation.

Analgesic Antipyretics

• Most analgesic antipyretics reduce prostaglandin synthesis by inhibiting cyclooxygenase (COX).
• Aspirin (acetylsalicylic acid) acetylates and irreversibly inhibits COX-1 and COX-2.
• The COX-2 efficacy approximates conventional NSAIDs, reducing GI ulcerations compared to COX1, but there is not antithrombotic activity. Renal complications at least the same but there are cardiovascular complications.
• Aspirin's main therapeutic effects include:
• Mild analgesia comes from reduced prostaglandin synthesis blocking pain in sensory nerve endings.
• Antipyresis comes from reduced prostaglandin synthesis in the hypothalamic temperature control center.
• Anti-inflammatory effects come from reduced prostaglandins at inflammation sites (high doses).
• Aspirin side effects include:
• Gastric ulcerations and hemorrhaging: increased by ingesting ethanol, decreased by taking with food or misoprostol.
• Reduced platelet aggregation by inhibiting thromboxane A2 formation.
• Hypersensitivity reactions may be due to increased leukotrienes.
• Reduced renal uric acid secretion at low doses and reduced uric acid reabsorption (uricosuria) at high doses.
• Aspirin is best avoided in children due to Reye’s syndrome, involving a fatal hepatitis and cerebral edema, in children with chicken pox (varicella) or influenza viral infections
• NSAIDs block conversion of Arachidonic acid to PG2.
• Common NSAID adverse effects include upper GI (dyspepsia, erosions, anemia, ulcers) and renal issues (dysfunction, failure, high blood pressure, heart failure), plus antiplatelet actions that increases blood loss.
• Aspirin, at 2-3 g/day, inhibits PGI2 and TXA2, causing vasodilation and inhibiting platelet aggregation. Low-dose aspirin (50-325 mg) also inhibits TXA2.

Aspirin vs. Other NSAIDs

• Aspirin differs from other NSAIDs in kinetics, toxicity, and antiplatelet effects.
• Aspirin inhibits prostaglandins in the gastric mucosa, increasing HCl production and causing loss of protective action, leading to gastric irritation and potential peptic ulcers.
• Aspirin exists in a unionized form at the acidic pH of the stomach. It enters mucosal cells then becomes ionized at pH 7.1, where it will become stiff and indigestible.
• Arachidonic acid is converted into inflammatory PGs by COX-2 enzyme and PG2s regulation function in the stomach, kidney and intestinal function via COX-1 enzyme.
• Aspirin is an antipyretic drug. Long-term use of Aspirin can cause nephropathy or overdose.
• it increases the risk of bleeding, and decreases platelet aggregation and has high plasma protein binding.
• Aspirin leads to GI bleeding and respiratory issues and is contraindicated in peptic ulcer disease. It has anti-inflammatory properties and impacts the CNS and peripheral nervous system (CNS,peripheral).
• Acetaminophen is another type of antipyretic drug that has no effect on nephropathy, doesn't affect or impact platelet aggregation or bleeding risk. It does not cause GI bleeds or respiratory issues and is hepatotoxic, impacting only the CNS.
• Non-selective COX inhibitors inhibit both COX-1 (non-inducible) and COX-2 (inducible) enzymes, while selective COX-2 inhibitors only act on the COX-2 (inducible) enzyme.
• Both classes of drugs have equal analgesic and antipyretic effects.
• Nonselective COX inhibitors have more frequent gastric side effects, increased renal side effects, and increased decreased CVS but frequent hypersensitivity reactions. Selective COX-2 inhibitors have less frequent gastric side effects, frequent increased renal side effects, increased CVS and less frequent hypersensitivity reactions.
• Unlike aspirin, Paracetamol does not have anti platelet properties which is usually the antidote.
• Aspirin is contraindicated, particularly in children with viral infection, peptic ulcers, or sensitivity to asthma. Examples of propionic acid derivatives include which are NSAIDS, and ibuprofen (Indomethacin) is an indol derivative.

Migraine

• Migraines are more prevalent in women than in men and often run in families. There are two main types:
  • Migraines preceded by an aura.
  • Migraines without aura, which account for 85% of cases, preceded by fatigue and irritability. Migraineurs can have visual symptoms such as flickering lights, spots, or loss of vision with Sensory symptoms include needles or numbness. Migraines can present other neurological symptoms such as speech problems.
• Trigeminal nerve (CN V) activation, leading to neuropeptide release (VIP, Sub P, CGRP), vasodilation, plasma protein extravasation, and mast cell degranulation activates nociceptors.
• Migraine triggers include diet, changes in sleep patterns, fluctuation of estrogen, increased stress and dietary sources such as aged cheese and chocolate.
• Pharmacological treatments for Migraines with ergots and triptans decrease neuropeptide release and cause direct vasoconstriction.
• Nonpharmacologic treatments include avoiding triggers, having regular sleeping habits, and retiring to darkened rooms.
• The drugs for treatment and side effects include NSAIDs, antiemetics, D2 antagonists (Chlorpromazine, Prochlorperazine, Metoclopramide)
• Specific treatments are drugs agonists at 5-HT1D receptors that cause vasodilation and release of calcitonin gene-related peptide at the trigeminal nerve, along with opoids (Rescue medication), such as Triptan Zolmitriptan tablets are used when other drugs do not achieve the desired response. Opioids can also be used via (Intranasally) and (Parenteral route).
• Specific triptans exhibit variable individual responses, variant absorption, and variant protein binding capacity as one or more drugs are needed for successful pain relief.
• Fast-acting medications are Rizatriptan 10mg tablets and Eletriptan 40mg tablets. Slow acting are Sumatriptan tablets and Almotriptan Film-coated Tablets which are better tolerated.
• Agonists at 5-HT 1D receptors (serotonin receptors) on the small peripheral nerves innervating intracranial vasculature are used for the TOC - acute attacks of migraine. Side effects include vasoconstriction & nausea due to ergot alkaloids > triptans).

Ergots for Acute Migraine

• Acute migraine treatment with Ergots act as agonists at 5-HT 1B & 5-HT 1D receptors, diminishing release of neuropeptides & vasoconstriction. It's also a partial agonists @ alpha-1 receptors, causing vasoconstriction, and can be used IV, IM, SC, & intranasal.
• Ergotamine & dihydroergotamine (Derivative of ergotamine) is used for acute attacks of migraine, It is indicated when headaches occur greater than or equal to 2 times a month and severe headaches & is complicated. It acts similarly to triptans and has used for IV/ intranasal route.

Migraine Prophylaxis

• Prophylaxis includes Propranolol, and beta blockers. It also includes Calcium channel blocker Flunarizine and Ergot alkaloid Methysergide Drugs used in prophylaxis Flunarizine, Cyproheptadine, Clonidine. Dr.G.Bhanu Prakash, Pizotifen, Release of Gabapentine, Valproate, Nortriptyline, and is often a drug of choice.
• Treatment for Mild cases are simple analgesics/NSAIDs or their combinations (± antiemetic). Treatment for Moderate cases are NSAIDs combinations/ triptan/ergot alkaloids (+ antiemetic). For Severe cases are Triptan/ergot alkaloids (+antiemetic + prophylaxis and Amitriptyline/other tricyclic antidepressants Flu/ Ca22 blocker and valproate/topiramate

Triptans Side Effects

• Triptans can cause Side effects such as fluctuations in Blood pressure, Flushing, heightened Sweating and pain and Pressure in chest, neck, throat & jaw.
• Opioids are powerful pain relievers often used for severe pain but come with a higher risk of side effects and dependence. Analgesic antipyretics, on the other hand, are used for both pain relief and fever reductionand are generally safer for mild to moderate pain.
• Narcotic analgesics (morphine), act potent in all pain types, except itching and have central action opioid receptors and cause Euphoria-drowsiness with Long term use leading to tolerance and dependence. Antipyretic analgesics (Aspirin) is Less potent, works on musculoskeletal pain and is anti-inflammatory working on the Thalamus and periphery, Lowering elevated body temperature to normal NNNNNNNNNNoooooooooooooo