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AUTOCOIDSAUTOCOIDS

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Prostaglandins, histamine and Prostaglandins, histamine and serotonin belong to this group.serotonin belong to this group.

Act as local hormonesAct as local hormones Mainly produced from diff. tissuesMainly produced from diff. tissues

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PROSTAGLANDINSPROSTAGLANDINS

Derived from unsaturated fatty Derived from unsaturated fatty acidsacids

Cause the arteries to dilate Cause the arteries to dilate  Influence blood clottingInfluence blood clotting Stimulate pain nerve endings  Stimulate pain nerve endings   Reduce stomach acid secretionReduce stomach acid secretion AbortifacientAbortifacient

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Prostaglandin receptors:Prostaglandin receptors:

Most affect other cells by interacting with Most affect other cells by interacting with plasma membrane plasma membrane G-protein coupled G-protein coupled receptorsreceptors. .

Depending on the cell type, the activated G-Depending on the cell type, the activated G-protein may stimulate or inhibit formation of protein may stimulate or inhibit formation of cAMPcAMP, or may activate a phosphatidyl inositol , or may activate a phosphatidyl inositol signal pathway leading to intracellular signal pathway leading to intracellular CaCa++++ release. release.

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PROSTAGLANDINSPROSTAGLANDINS

CARBOPROSTCARBOPROST DINOPROSTDINOPROST DINOPROSTONEDINOPROSTONE MISOPROSTOLMISOPROSTOL

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USESUSES

GITGIT PGEs and PGI2 inhibit gastric acid secretion, PGEs and PGI2 inhibit gastric acid secretion,

stimulated by feeding, histamine or gastrinstimulated by feeding, histamine or gastrin Maintainance of the gastric mucosa - stimulation Maintainance of the gastric mucosa - stimulation

of mucus secretionof mucus secretion

misoprostolmisoprostol (substituted PGE1) used for (substituted PGE1) used for NSAID-induced gastric ulcer;NSAID-induced gastric ulcer;

administered intra-vaginally with administered intra-vaginally with mifepristone(oral) for non-surgical abortionmifepristone(oral) for non-surgical abortion

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UterusUterus Certain Prostaglandins cause uterine Certain Prostaglandins cause uterine

contraction in pregnancy contraction in pregnancy clinically used as abortifacients or to clinically used as abortifacients or to

induce laborinduce labor Dinaprostone (PGE2) andDinaprostone (PGE2) and Carboprost (15-methyl-PGF2a)Carboprost (15-methyl-PGF2a) Misoprostol + MifepristoneMisoprostol + Mifepristone

Histamine Histamine Histamine is a chemical messenger that Histamine is a chemical messenger that

mediates a wide range of cellular mediates a wide range of cellular responses, including allergic and responses, including allergic and inflammatory reactions, gastric acid inflammatory reactions, gastric acid secretion and neurotransmission in parts secretion and neurotransmission in parts of the brainof the brain

Histamine has no clinical applications, but Histamine has no clinical applications, but agents that interfere with the action of agents that interfere with the action of histamine(antihistamines) have important histamine(antihistamines) have important therapeutic applicationstherapeutic applications

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Location: Location: occurs in all tissues but found in occurs in all tissues but found in high amounts in the lung, skin and GIT. high amounts in the lung, skin and GIT.

Found in high conc in mast cells or Found in high conc in mast cells or basophils by type-1 hypersensitivity basophils by type-1 hypersensitivity reactionsreactions

Histamine also occurs as a component of Histamine also occurs as a component of venoms and in secretions from insect stingsvenoms and in secretions from insect stings

SynthesisSynthesis: is an amine formed by : is an amine formed by decarboxylation of histidinedecarboxylation of histidine

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H1 receptors stimulate phosphoinositide H1 receptors stimulate phosphoinositide turnover and Ca++ influxturnover and Ca++ influx

LocationLocation: smooth muscle, endothelium and : smooth muscle, endothelium and CNS tissue CNS tissue

H2 receptors stimulate adenylate cyclase H2 receptors stimulate adenylate cyclase resulting in increase cAMPresulting in increase cAMP

Location: Location: parietal cells of the stomach, parietal cells of the stomach, vascular smooth musclevascular smooth muscle

HH₁ ACTIVATION ₁ ACTIVATION

↑ ↑ capillary dilation (via NO) → ↓BPcapillary dilation (via NO) → ↓BP ↑ ↑ capillary permeability → ↑edemacapillary permeability → ↑edema ↑ ↑ bronchiolar smooth muscle contraction bronchiolar smooth muscle contraction ↑ ↑ activation of peripheral nociceptive activation of peripheral nociceptive

receptors → ↑ pain and pruritusreceptors → ↑ pain and pruritus ↓↓AV nodal conductionAV nodal conduction Responsible for allergic rhinitis and motion Responsible for allergic rhinitis and motion

sicknesssickness1111

HH₂ ACTIVATION (GS)₂ ACTIVATION (GS)

↑ ↑ gastric acid secretion → ↑ GI ulcersgastric acid secretion → ↑ GI ulcers ↑ ↑ SA nodal rate, positive inotropism and SA nodal rate, positive inotropism and

automaticityautomaticity

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H1- BLOCKERSH1- BLOCKERS

11STST generation generation First-generation agents tend to be First-generation agents tend to be

relatively relatively more sedating more sedating and more and more likely than second-generation drugs to likely than second-generation drugs to block autonomic receptors -- for block autonomic receptors -- for example example blockade of cholinergic, blockade of cholinergic, αα--adrenergic and serotonin receptoradrenergic and serotonin receptor

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ChlorpheniramineChlorpheniramine DexchlorpheniramineDexchlorpheniramine ClemastineClemastine DimenhydrinateDimenhydrinate DiphenhydramineDiphenhydramine DoxylamineDoxylamine MethdilazineMethdilazine PromethazinePromethazine CyclizineCyclizine HydroxyzineHydroxyzine AzatadineAzatadine

First First generationgeneration

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

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22ndnd Generation Generation

TerfenadineTerfenadine AstemazoleAstemazole Loratidine (Claritin)Loratidine (Claritin) CetirizineCetirizine Fexofenadine (Allegra) Fexofenadine (Allegra)

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USESUSES Allergic conditionsAllergic conditions Motion sickness – Dimenhydrinate, Motion sickness – Dimenhydrinate,

Diphenhydramine, Cyclizine, Meclizine.Diphenhydramine, Cyclizine, Meclizine. Preoperative sedationPreoperative sedation Nausea and vomiting with pregnancyNausea and vomiting with pregnancy Acute EPSAcute EPS Parkinson diseaseParkinson disease Insomnia & cold– DiphenhydramineInsomnia & cold– Diphenhydramine Meclizine – long duration of actionMeclizine – long duration of action

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Astemazole – long duration of actionAstemazole – long duration of action Terfenadine & Astemazole – CI with Terfenadine & Astemazole – CI with

Macrolides, antifungals, which can Macrolides, antifungals, which can cause severe ventricular arrhythmiascause severe ventricular arrhythmias

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SESE

DrowsinessDrowsiness FatigueFatigue TremorsTremors VertigoVertigo Blurred visionBlurred vision Dry mouth with someDry mouth with some Overdoses – hallucinations, Overdoses – hallucinations,

excitement, ataxia.excitement, ataxia.

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H 2 - BLOCKERSH 2 - BLOCKERS

H2 receptor antagonists inhibit histamine-H2 receptor antagonists inhibit histamine-induced stomach acid secretion induced stomach acid secretion

Mainly used in the treatment of the peptic Mainly used in the treatment of the peptic ulcers.ulcers.

Cimetidine Cimetidine Ranitidine Ranitidine Famotidine Famotidine Nizatidine Nizatidine

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serotoninsserotonins

Pharmacologic actionsPharmacologic actions serotonin has profound effects on serotonin has profound effects on

gastrointestinal, cardiovascular, gastrointestinal, cardiovascular, respiratory, and central and peripheral respiratory, and central and peripheral nervous system functionnervous system function

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Serotonin receptor subtype Serotonin receptor subtype

pharmacology and therapeutic agentspharmacology and therapeutic agents 5-HT1 Receptors5-HT1 Receptors Agonist binding to Agonist binding to

these receptors results in the inhibition of these receptors results in the inhibition of adenylate cyclase via the inhibitory GTP-adenylate cyclase via the inhibitory GTP-binding protein (Gi). binding protein (Gi).

for 5-HT1A Effects in generalized anxiety for 5-HT1A Effects in generalized anxiety BuspironeBuspirone - partial-agonist for 5-HT1A - partial-agonist for 5-HT1A

receptor, the first specific non-receptor, the first specific non-benzodiazepine anxiolytic benzodiazepine anxiolytic

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5-HT1D Receptor5-HT1D Receptor SumatriptanSumatriptan - used in acute treatment of - used in acute treatment of

migraine headaches a highly selective agonist migraine headaches a highly selective agonist of the 5-HT1D subtype receptorof the 5-HT1D subtype receptor

Sumatriptan blocks the neuropetide-mediated Sumatriptan blocks the neuropetide-mediated inflammatory response after trigeminal inflammatory response after trigeminal stimulation and may block trigeminal stimulation and may block trigeminal neurotransmission. neurotransmission.

vasoconstriction of intracranial arteriesvasoconstriction of intracranial arteries

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Ergotamine and dihydroergotamineErgotamine and dihydroergotamine have high have high affinity 5-HT1 receptorsaffinity 5-HT1 receptors

They are used for the They are used for the treatmenttreatment of migraine. of migraine.

MethysergideMethysergide a semi-synthetic ergot alkaloid is a semi-synthetic ergot alkaloid is a 5-HT2 antagonist with greater potency than a 5-HT2 antagonist with greater potency than ergotamine and dihydroergotamine that is used ergotamine and dihydroergotamine that is used for migraine for migraine prophylaxisprophylaxis..

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5-HT2 receptors have a role in 5-HT2 receptors have a role in depression and anxietydepression and anxiety

RisperidoneRisperidone, a new antispychotic , a new antispychotic blocks 5-HT2 receptors blocks 5-HT2 receptors

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5-HT3 receptors are located peripherally on 5-HT3 receptors are located peripherally on vagal nerve terminals and centrally at the vagal nerve terminals and centrally at the Chemoreceptor Trigger zone (CTZ). Chemoreceptor Trigger zone (CTZ).

Antagonists of these receptors are potent Antagonists of these receptors are potent inhibitors of chemotherapy and radiation -inhibitors of chemotherapy and radiation -induced emesis.induced emesis.

Ondansetron and GranisetronOndansetron and Granisetron are currently are currently available in the U.S. as an anti-emetics. available in the U.S. as an anti-emetics.

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5-HT4 receptors5-HT4 receptors These receptors are positively coupled to These receptors are positively coupled to

adenylate cyclase, opposite of 5-HT1 receptorsadenylate cyclase, opposite of 5-HT1 receptors CisaprideCisapride is a specific 5-HT4 receptor agonist, is a specific 5-HT4 receptor agonist,

similar to metoclopramide but with much weaker similar to metoclopramide but with much weaker dopaminergic action. dopaminergic action.

It also enhances release of Ach from nerve It also enhances release of Ach from nerve terminals in the myenteric plexus. terminals in the myenteric plexus.

It is a prokinetic agent that enhances and It is a prokinetic agent that enhances and promote motility in the GI tract.promote motility in the GI tract.

It relieves Gastroesophageal reflux disease by It relieves Gastroesophageal reflux disease by increasing lower esophageal sphincter pressureincreasing lower esophageal sphincter pressure..

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5-HT Reuptake Inhibitors5-HT Reuptake Inhibitors Many drugs useful as antidepressant block the Many drugs useful as antidepressant block the

reuptake of serotonin. reuptake of serotonin. These include many tricyclic agents (eg. These include many tricyclic agents (eg.

amitryptilline, nortryptilline, imipramine) which amitryptilline, nortryptilline, imipramine) which may also inhibit catecholamine reuptake.may also inhibit catecholamine reuptake.

Newer agents which selectively block the Newer agents which selectively block the reuptake of serotonins include reuptake of serotonins include fluoxetine,fluoxetine, sertraline, fluvoxamine, paroxetine, sertraline, fluvoxamine, paroxetine, venlafaxine, and citalopramvenlafaxine, and citalopram..

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MIGRAINEMIGRAINE

Family history is thereFamily history is there May be there life longMay be there life long A symptom complex occurring A symptom complex occurring

periodically and characterized by pain periodically and characterized by pain (pulsating & throbbing) in the head (pulsating & throbbing) in the head (usually unilateral), vertigo, nausea (usually unilateral), vertigo, nausea and vomiting, photophobia, and and vomiting, photophobia, and scintillating appearances of light.scintillating appearances of light.

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SumatriptanSumatriptan ErgotamineErgotamine DihydroergotamineDihydroergotamine NSAID’sNSAID’s Beta blockersBeta blockers MethysergideMethysergide

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SumatriptanSumatriptan Serotonin agonist acts at 5 –HT 1d Serotonin agonist acts at 5 –HT 1d

receptors – found in peripheral nerves receptors – found in peripheral nerves that innervate the cerebral vessels – that innervate the cerebral vessels – vasoconstriction vasoconstriction

Oral or SCOral or SC Rapidly and effectively aborts the Rapidly and effectively aborts the

severity of the migraine headaches. severity of the migraine headaches. SE: dizziness, flushing nausea, SE: dizziness, flushing nausea,

hypertension.hypertension. CI – heart diseasesCI – heart diseases

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ErgotamineErgotamine

Serotonin agonist of 5HT1-D – Serotonin agonist of 5HT1-D – vasoconstrictorvasoconstrictor

Caffeine potentiates the actionsCaffeine potentiates the actions So mostly used in combined form.So mostly used in combined form. Oral, Sublingually, Rectally, NasallyOral, Sublingually, Rectally, Nasally Most effective – early phase of an attackMost effective – early phase of an attack CI – preg, vascular diseases CI – preg, vascular diseases SE: Diarrhea , nausea & vomitingSE: Diarrhea , nausea & vomiting

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

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NSAID’sNSAID’s

May be sufficient for mild /moderate May be sufficient for mild /moderate migraine migraine

AspirinAspirin AcetaminophenAcetaminophen NaproxenNaproxen Aspirin combination (Aspirin + Caffeine + Aspirin combination (Aspirin + Caffeine +

butalbital) butalbital) If severe pain may need – opioids If severe pain may need – opioids

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ProphylaxisProphylaxis

Methysergide (Sansert)Methysergide (Sansert) Effective in about 60% of patients Effective in about 60% of patients

Toxicity: Toxicity: Retroperitoneal fibroplasia Retroperitoneal fibroplasia Subendocardial fibrosis Subendocardial fibrosis The side effects are the basis of The side effects are the basis of

recommending a 3-4 week drug holiday recommending a 3-4 week drug holiday every six months. every six months.

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Beta - Blockers Beta - Blockers Propranolol (Inderal) -- Prophylaxis- Most Propranolol (Inderal) -- Prophylaxis- Most

common for continuous prophylaxis common for continuous prophylaxis Nadolol and Timolol can also be used.Nadolol and Timolol can also be used. all beta2-blockers: contraindicated in all beta2-blockers: contraindicated in

asthmatics asthmatics Best established drug for migraine attack Best established drug for migraine attack

prevention. prevention.

Other drugs for Other drugs for prophylaxisprophylaxis

Calcium channel blocker Calcium channel blocker such as such as verapamil can be used also as verapamil can be used also as prophylaxis.prophylaxis.

AntidepressantAntidepressant such as amitriptyline. such as amitriptyline.

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