AUTOCOIDS

Prostaglandins, histamine and serotonin belong to this group. Act as local hormones Mainly produced from diff. tissues

PROSTAGLANDINS Derived from unsaturated fatty acids Cause the arteries to dilate  Influence blood clotting Stimulate pain nerve endings   Reduce stomach acid secretion Abortifacient

Prostaglandin receptors: Most affect other cells by interacting with plasma membrane G-protein coupled receptors. Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP, or may activate a phosphatidyl inositol signal pathway leading to intracellular Ca++ release.

PROSTAGLANDINS CARBOPROST DINOPROST DINOPROSTONE MISOPROSTOL

USES GIT PGEs and PGI2 inhibit gastric acid secretion, stimulated by feeding, histamine or gastrin Maintainance of the gastric mucosa - stimulation of mucus secretion misoprostol (substituted PGE1) used for NSAID-induced gastric ulcer; administered intra-vaginally with mifepristone(oral) for non-surgical abortion

Uterus Certain Prostaglandins cause uterine contraction in pregnancy clinically used as abortifacients or to induce labor Dinaprostone (PGE2) and Carboprost (15-methyl-PGF2a) Misoprostol + Mifepristone

Histamine Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion and neurotransmission in parts of the brain Histamine has no clinical applications, but agents that interfere with the action of histamine(antihistamines) have important therapeutic applications

Location: occurs in all tissues but found in high amounts in the lung, skin and GIT. Found in high conc in mast cells or basophils by type-1 hypersensitivity reactions Histamine also occurs as a component of venoms and in secretions from insect stings Synthesis: is an amine formed by decarboxylation of histidine

H1 receptors stimulate phosphoinositide turnover and Ca++ influx Location: smooth muscle, endothelium and CNS tissue H2 receptors stimulate adenylate cyclase resulting in increase cAMP Location: parietal cells of the stomach, vascular smooth muscle

H₁ ACTIVATION ↑ capillary dilation (via NO) → ↓BP ↑ capillary permeability → ↑edema ↑ bronchiolar smooth muscle contraction ↑ activation of peripheral nociceptive receptors → ↑ pain and pruritus ↓AV nodal conduction Responsible for allergic rhinitis and motion sickness

H₂ ACTIVATION (GS) ↑ gastric acid secretion → ↑ GI ulcers ↑ SA nodal rate, positive inotropism and automaticity

H1- BLOCKERS 1ST generation First-generation agents tend to be relatively more sedating and more likely than second-generation drugs to block autonomic receptors -- for example blockade of cholinergic, α-adrenergic and serotonin receptor

Chlorpheniramine Dexchlorpheniramine Clemastine Dimenhydrinate Diphenhydramine Doxylamine Methdilazine Promethazine Cyclizine Hydroxyzine Azatadine First generation

Second-generation agents   are relatively less sedating compared to the earlier first-generation agents and exhibit less CNS penetration, which accounts for reduced sedation.

2nd Generation Terfenadine Astemazole Loratidine (Claritin) Cetirizine Fexofenadine (Allegra)

USES Allergic conditions Motion sickness – Dimenhydrinate, Diphenhydramine, Cyclizine, Meclizine. Preoperative sedation Nausea and vomiting with pregnancy Acute EPS Parkinson disease Insomnia & cold– Diphenhydramine Meclizine – long duration of action

Astemazole – long duration of action Terfenadine & Astemazole – CI with Macrolides, antifungals, which can cause severe ventricular arrhythmias

SE Drowsiness Fatigue Tremors Vertigo Blurred vision Dry mouth with some Overdoses – hallucinations, excitement, ataxia.

H 2 - BLOCKERS H2 receptor antagonists inhibit histamine-induced stomach acid secretion Mainly used in the treatment of the peptic ulcers. Cimetidine Ranitidine Famotidine Nizatidine

serotonins Pharmacologic actions serotonin has profound effects on gastrointestinal, cardiovascular, respiratory, and central and peripheral nervous system function

Serotonin receptor subtype pharmacology and therapeutic agents 5-HT1 Receptors Agonist binding to these receptors results in the inhibition of adenylate cyclase via the inhibitory GTP-binding protein (Gi). for 5-HT1A Effects in generalized anxiety Buspirone - partial-agonist for 5-HT1A receptor, the first specific non-benzodiazepine anxiolytic

5-HT1D Receptor Sumatriptan - used in acute treatment of migraine headaches a highly selective agonist of the 5-HT1D subtype receptor Sumatriptan blocks the neuropetide-mediated inflammatory response after trigeminal stimulation and may block trigeminal neurotransmission. vasoconstriction of intracranial arteries

Ergotamine and dihydroergotamine have high affinity 5-HT1 receptors They are used for the treatment of migraine. Methysergide a semi-synthetic ergot alkaloid is a 5-HT2 antagonist with greater potency than ergotamine and dihydroergotamine that is used for migraine prophylaxis.

5-HT2 receptors have a role in depression and anxiety Risperidone, a new antispychotic blocks 5-HT2 receptors

5-HT3 receptors are located peripherally on vagal nerve terminals and centrally at the Chemoreceptor Trigger zone (CTZ). Antagonists of these receptors are potent inhibitors of chemotherapy and radiation -induced emesis. Ondansetron and Granisetron are currently available in the U.S. as an anti-emetics.

5-HT4 receptors These receptors are positively coupled to adenylate cyclase, opposite of 5-HT1 receptors Cisapride is a specific 5-HT4 receptor agonist, similar to metoclopramide but with much weaker dopaminergic action. It also enhances release of Ach from nerve terminals in the myenteric plexus. It is a prokinetic agent that enhances and promote motility in the GI tract. It relieves Gastroesophageal reflux disease by increasing lower esophageal sphincter pressure.

5-HT Reuptake Inhibitors Many drugs useful as antidepressant block the reuptake of serotonin. These include many tricyclic agents (eg. amitryptilline, nortryptilline, imipramine) which may also inhibit catecholamine reuptake. Newer agents which selectively block the reuptake of serotonins include fluoxetine, sertraline, fluvoxamine, paroxetine, venlafaxine, and citalopram.

MIGRAINE Family history is there May be there life long A symptom complex occurring periodically and characterized by pain (pulsating & throbbing) in the head (usually unilateral), vertigo, nausea and vomiting, photophobia, and scintillating appearances of light.

Sumatriptan Ergotamine Dihydroergotamine NSAID’s Beta blockers Methysergide

Sumatriptan Serotonin agonist acts at 5 –HT 1d receptors – found in peripheral nerves that innervate the cerebral vessels – vasoconstriction Oral or SC Rapidly and effectively aborts the severity of the migraine headaches. SE: dizziness, flushing nausea, hypertension. CI – heart diseases

Ergotamine Serotonin agonist of 5HT1-D – vasoconstrictor Caffeine potentiates the actions So mostly used in combined form. Oral, Sublingually, Rectally, Nasally Most effective – early phase of an attack CI – preg, vascular diseases SE: Diarrhea , nausea & vomiting

Dihydroergotamine (IV administration mainly) may be appropriate for intractable migraine.

NSAID’s May be sufficient for mild /moderate migraine Aspirin Acetaminophen Naproxen Aspirin combination (Aspirin + Caffeine + butalbital) If severe pain may need – opioids

Prophylaxis Methysergide (Sansert) Effective in about 60% of patients Toxicity: Retroperitoneal fibroplasia Subendocardial fibrosis The side effects are the basis of recommending a 3-4 week drug holiday every six months.

Beta - Blockers Propranolol (Inderal) -- Prophylaxis- Most common for continuous prophylaxis Nadolol and Timolol can also be used. all beta2-blockers: contraindicated in asthmatics Best established drug for migraine attack prevention.

Other drugs for prophylaxis Calcium channel blocker such as verapamil can be used also as prophylaxis. Antidepressant such as amitriptyline.