UNIVERSITY INSTITUTE OF PHARMA SCIENCES

Master of Pharmacy (Pharmacology)

Advanced Pharmacology-I (22PHT-622)

Topic:-Autacoids
Presented To:- Dr. Payal Mittal
DISCOVER . LEARN . EMPOWER
Presented By:- Pankaj(22MPH20016) 1
CONTENTS

1. Definition
2. Classification
3. Receptor
4. Function
5. Agonist
6. Antagonist
AUTACOIDS:
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This term is derived from Greek:autos—self, akos—

healing substance or remedy.

They have also been called ‘local hormones’

because they act locally at the site of production.
Autacoids are involved in a number of
physiological and pathological processes
(especially reaction to injury and immunological
insult).
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HISTAMINE:
4
Histamine is synthesized from histidine and is stored within the
storage granules of mast cells.
It acts mainly on H1 and H2 receptors. Recently H3 (presynaptic) and
H4 receptors have also been isolated.

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Action:-
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• It causes dilation of small blood vessels and can result in flushing and
hypotension.
• H1 receptor stimulation has negative dromotropic (decreases AV
conduction) effect whereas H2 stimulation increases the force of contraction
of isolated heart. Effect on intact heart is not prominent.
• Histamine increases gastric secretion by stimulation of H2 receptors.
• H3 receptors are pre-synaptic in location and inhibit the release of
histamine. Inverse agonist or antagonist of these receptors may increase
histamine leading to wakefulness.
• H4 receptors are present in hematopoietic cells like eosinophils, basophils
and mast cells. These promote chemotaxis. antagonists of these receptors
are being developed for allergic conditions.
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Important Drug:-
• Terfenadine
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is the fastest acting antihistaminic drug. In overdose, it blocks cardiac
delayed rectifier K+ channels and may result in polymorphic ventricular tachycardia
(torsades de’ pointes) manifested as prolongation of QTc interval.
• Astemizole is slowest and longest acting agent and possesses arrhythmogenic
property similar to terfenadine. Therefore, it should not be administered with
ketoconazole, erythromycin, clarithromycin and itraconazole..
• Cetirizine is an active metabolite of a first generation antihistaminic drug, hydroxyzine.
It possesses additional anti-allergic mechanisms like inhibition of
release of cytotoxic mediators from platelets and inhibition of
chemotaxis. Some persons acquire sedative effects with cetirizine.
Levocetirizine is l-isomer of cetirizine that is more potent and less
sedative.
• Olopatadine is a recently approved topical H1-antihistaminic used
as nasal spray for
seasonal allergic rhinitis.
SEROTONIN:-
5-hydroxytryptamine
9 (serotonin) is synthesized from
tryptophan. It is produced by hydroxylation followed by
decarboxylation of tryptophan; steps similar to catecholamine
synthesis. It is similarly stored in the vesicles and its action is
terminated by reuptake. It acts by activation of several
serotonin receptors (5- HT1 - HT7 receptors).
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Therapeutic Uses:-
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Serotonin Syndrome:-
Extremely high level of serotonin can cause a condition known as serotonin
syndrome , with toxic and potentially fatal effect.
Drug used to treat: 1.Non-specificblocking agents : Methysergide , Cyproheptadine
2.Beta blockers : Proparanolol , Pindolol
Migraine:-
It is unilateral pulsatile headache due to dilation and inflammation of the
affected cerebral vessels.
Drug used to treat: Sumatriptan -: 5HT1 Agonist , 1st line therapy for severe
migraine.
Ergotamine -: For acute attack of migraine.
Propanolol -: For prophylaxis of migraine attack.

Vomiting:-
5HT3 antagonist: Ondansetron is mostly used.
Eicosanoids (PGs, TXA2, LTs) :-
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Chemical mediators derived from oxygenation of polyunsaturated fatty acid.

Phospholipids

Phospholipase A2

LTs LOX Arachidonic acid COX PGs & TX A2

MOA of eicosanoids:
Binds their G-protein receptors, where
PGE & PGI cause ↑cAMP → ↓IC Ca2+
PGF2α & TX A2 cause ↑IP3 & DAG → ↑IC Ca2+.
Prostaglandins (PGs):-
These are present as:
A) Physiologic PGs normally occur, important for vital physiologic functions.
B) Pathologic PGs synthesized during inflammation, act as inflammatory mediators - COX

COX enzyme present in 3 isoforms:

1. COX-1: Constitutive normally occur, important for RBF & mucus secretion.
Serves housekeeping function e.g. gastro-protective.
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2. COX-2: Inducible during inflammation.
Constitutive in brain, endothelium and kidney.
3. COX-3: Recently isolated from cerebral cortex.
Involved in pain perception and fever.
Not involved in inflammation.
Paracetamol targets COX-3.
Uses of PG’s:-
1. PGE1 16 –:

"Misoprostol", orally for medical abortion in 1st trimester (alone or with

mifepristone) & NSAIDs-induced ulcer.
"Alprostadil", intra-urethral for erectile dysfunction (replaced by sildenafil) &
IV for patency of ductus arteriosus in child with congenital heart disease (TAG)
until corrective surgery within 4-6 wks after delivery.
2. PGE2 -:
"Dinoprostone", IV to induce labor at term & medical abortion in 2nd
trimester; & aerosols as bronchodilator.
3. PGI2 -:
"Prostacyclin/Epoprostenol", IV as antiplatelets & in open heart surgery (DOC
since it is natural & immediate action); & as inhaler in severe pulmonary
hypertension.
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4. PGF2α -:
"Latanoprost, Travoprost, Bimatoprost", topically for open angle glaucoma [since
↑aqueous humor drainage via uveosclera by dilating IC spaces in ophthalmic
tissue 'nonconventional pathway 30% drainage'; but not via canal of schlem
'conventional pathway 70% drainage'].
"Dinoprost", IV to induce labor at term.
"Carboprost", IV for medical abortion in 2nd trimester.
Leukotrienes:-
• These are synthesized from arachidonic acid with the help of the
enzyme, 5-lipoxygenase.
• This enzyme must associate with 5-lipoxygenase activating protein
(FLAP) for leukotriene synthesis.
• First step is the production of LTA4 that is converted either to LTB4 or
to cysteinyl leukotrienes (LTC4, D4 and E4). LTC4 and LTD4 are also
known as slow reacting substance of anaphylaxis (SRS-A) due to their
powerful bronchoconstricting action.
• LTB4 is a powerful chemotactic agent and is an important mediator of
all types of inflammation.
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Action of LTs can be inhibited by:

• Corticosteroids (decrease the production of LTs by inhibiting
phospholipase A2).
• Lipoxygenase inhibitors (zileuton).
• LT receptor antagonists (zafirlukast, montelukast, iralukast).
Key Points:-
• Histamine is synthesized from histidine.
• Histamine induced fall in blood pressure is mediated by both
H1(early) as well as H2 (delayed and persistent) receptors.
• Doxepin is a tricyclic antidepressant having most potent H1blocking
action (800 times more potent than diphenhydramine).
• Terfenadine and Astemizole result in polymorphic ventricular
tachycardia (Torsades de’ pointes) manifested as prolongation of QTc
interval.
• Sumatriptan is the drug of choice for aborting acute attack of
migraine.
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• Triptans and ergotamine should not be administered within 24 hours
of each other.
• Propanolol is the most commonly used drug for prophylaxis of
migraine attacks.
• Phospholipase A2 is rate limiting enzyme in synthesis of
prostaglandins.
• Recently it has been found that aspirin acetylated COX-2 enzyme can
convert arachidonic acid to 15-HETE (15-hydroxyeicosatetraenoic
acid). In WBCs,15-HETE is converted to epilipoxins (15-epi-LXA4 or
15-epi LXB4). These are called aspirin triggered lipoxins and have
powerful bronchoconstrictor action. This finding can explain
induction of asthma with aspirin.
 Recent Discovered Drug:-
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1.Omlonti (omidenepag isopropyl) Ophthalmic Solution
Company: Santen Inc.
Date of Approval: September 22, 2022
Treatment for: Glaucoma/Intraocular Hypertension
Omlonti (omidenepag isopropyl) is a relatively selective prostaglandin E2 (EP2)
receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in
patients with open-angle glaucoma or ocular hypertension.

2.Ryaltris (mometasone furoate and olopatadine hydrochloride) Nasal Spray

Date of Approval: January 13, 2022
Company: Glenmark Pharmaceuticals, Inc.
Treatment for: Allergic Rhinitis
Ryaltris (mometasone and olopatadine) nasal spray is a corticosteroid and
antihistamine combination for the treatment of seasonal allergic rhinitis (SAR) in
patients 12 years of age and older.
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3.Astepro Allergy (azelastine) Nasal Spray

Date of Approval: June 17, 2021
Company: Bayer HealthCare LLC
Treatment for: Allergic Rhinitis
Astepro Allergy (azelastine) is a nasal antihistamine for the treatment of seasonal
allergic rhinitis.
4.Tosymra (sumatriptan) Nasal Spray
Date of Approval: January 25, 2019
Company: Dr. Reddy's Laboratories, Inc.
Treatment for: Migraine
Tosymra (sumatriptan) is a serotonin (5-HT1B/1D) receptor agonist (triptan)
indicated for the acute treatment of migraine with or without aura in adults.
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5.Wakix (pitolisant) Tablets

Date of Approval: August 14, 2019
Company: Harmony Biosciences, LLC
Treatment for: Narcolepsy
Wakix (pitolisant) is a histamine-3 (H₃) receptor antagonist/inverse agonist for the
treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with
narcolepsy.
6.Quzyttir (cetirizine hydrochloride) Injection
Date of Approval: October 4, 2019
Company: TerSera Therapeutics LLC
Treatment for: Urticaria
Quzyttir (cetirizine hydrochloride) is a histamine-1 (H1) receptor antagonist indicated for
the treatment of acute urticaria in adults and children 6 months of age and older.
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7.Motegrity (prucalopride) Tablets

Date of Approval: December 14, 2018
Company: Shire plc
Treatment for: Chronic Idiopathic Constipation
Motegrity (prucalopride) is a selective serotonin type 4 (5‑HT4) receptor agonist for the
treatment of chronic idiopathic constipation (CIC) in adults.
8.Sustol (granisetron) Extended-Release Injection
Date of Approval: August 9, 2016
Company: Heron Therapeutics, Inc.
Treatment for: Nausea/Vomiting, Chemotherapy Induced
Sustol (granisetron) is a long-acting 5-HT3 antagonist indicated for the prevention of
chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic
chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy
regimens.

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• Histamine H3 receptor ligands in clinical evaluation

Disorder Compound Phase

Narcolepsy BF2.649 III
GSK‐189254 II
JNJ‐17216498 II
ADHD MK‐0249 II
PF‐03654746 II
Alzheimer’s
Disease GSK‐239512 II
MK‐0249 I
MK‐0249 II
Parkinson’s
Disease BF2.649 II
BF2.649 III

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REFERENCES:
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1. FDA approved drug/Drugs.com/New Drugs.

2. Tripathi K.D “Essential of Medical Pharmacology” Jaypee brothers medical
publishers,8th edition , page no.174-197.
3. Gupta Sparsh & Garg Rai Gobind “Review of Pharmacology” Jaypee brothers
medical publishers , 15th edition , page no.86-96.
4. Tiligada E, Kyriakidis K, Chazot PL, Passani MB. Histamine pharmacology and new
CNS drug targets. CNS Neurosci Ther. 2011 Dec;17(6):620-8. doi: 10.1111/j.1755-
5949.2010.00212.x. Epub 2010 Nov 22. PMID: 22070192; PMCID: PMC6493842.

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