Autacoids are locally acting substances that are secreted by specialized cells, act locally, and are quickly degraded. Histamine and serotonin are examples of amine autacoids that have roles in inflammation, allergic reactions, smooth muscle contraction, and mood regulation. Antihistamines work by competitively blocking the actions of histamine at the H1 receptor, with older first generation antihistamines having additional anticholinergic and sedative effects compared to newer second generation antihistamines. Serotonin has complex roles in various organ systems through its multiple receptor subtypes, and drugs that modify serotonin signaling are used to treat conditions like depression, anxiety, nausea, and migraines.

1. By- Mr. Shrikant Sir
Autacoids
Histamine and
Antihistaminic Drugs

2. AUTACOIDS
Autacoids are substances that have following features-
o Secreted by specialized cells
o Acts locally
o Protects the body from some adverse situations
o Degraded quickly are termed as autacoids. [autos
(self) coid (remedy) full meaning is 'self-remedy]
o Also known as Local hormone but differ from
hormones in following ways
 Hormones are produced by specific cells
 Transported through circulation to act on
specific target tissues.

3. CLASSIFICATIONS
Amine autacoids Lipid autacoids Peptide
autacoids
Miscellaneous
Histamine
5 Hydroxy tryptamine
(Serotonin)
Eicosanoids
Prostaglandins
Leukotrienes
Platelet
activating factor
Angiotensin
Kinnins
(Bradykinin,
Kallidin)
Cytokines
(interleukins,
TNFα) Gastrin
Somatostatin
Vasoactive
intestinal
peptide.

4. STRUCTURES & PHYSIOLOGICAL ROLE
Autacoids Structure Role
Histamine
 Histamine is a bio amine
derived principally from
dietary histidine.
 Histamine concentrated in
the granules of basophils
and mast cells.
 Mediates immediate allergic
 Inflammatory responses
 Gastric acid release
 Acting as a neurotransmitter
 Vasodilator

5. Serotonin
(5-HT)
 Responsible for maintaining mood
balance, and that a deficit of
serotonin leads to depression
 Constricting smooth muscles
 transmitting impulses between nerve
cells
 Acting as a neurotransmitter
 ↓ Decreased 5-HT level associated
with Depression
 Affect mood and social behavior,
appetite and digestion, sleep, memory
and sexual desire and function.

6. Prostaglandins  Reproduction
 Pain & Fever
 Inflammation
 Affect platelets functions
 Immunological action
 Vasoconstriction or Dilation
Function depend up on the
subtype of PGs
Leukotrienes  Regulate vasoconstrictions
 Strong vasoconstriction
 ↑ Vessels permeability

7. Lipoxins -  Retard inflammation contrast to
proinflamatory Eicosanoids (PG & LT)
Platelet
activating
factor(PAF)
-  Vasoconstrictions
 Bronchoconstriction
 ↑ Platelets aggregations
 ↑ Leukocyte adhesion and chemotaxis
 ↑ Vascular permeability

8. Angiotensin Polypeptide
(Main-
Angiotensin-II-
Octapeptide)
 Potent vasoconstrictor
 ↑ Na & Water reabsorptions
 ↑ Aldosterone
Bradykinin &
Kallidin
Polypeptide  Vasodilator
(10 time to histamine)
 Act locally to produce pain
 Smooth muscles Constrictions-
Bronchoconstriction
 ↑ PG synthesis
 ↑ Permeability
 Stimulate histamine release

9. HISTAMINE
 Histamine is a bio amine derived principally from dietary histidine.
 Histamine is synthesized throughout the body but is highly
concentrated in the granules of basophils and mast cells.

10. Synthesis, Storage, Release & Degradation
Synthesis- Histamine is 2-(4-imidazoyl) ethylamine is biosynthesized from
histidine by the action of L-histidine decarboxylase.

12. Storage–Stored in mast cells
histamine granules (Histamine
positively in combination with acidic
protein and negatively charged
heparin).
Release- Releases by exocytosis with
exchange with Na
Action on Postsynaptic membrane-
Pharmacological actions by binding to
histamine receptor.
Degradation- by Methyl transferase
and Diamine oxidase enzymes.

13. HISTAMINE RECEPTOR
 All there types (H1,H2,H3,H4)) are 7-transmembraneGPCR.
H1 H2 H3
Mechanism Gq, IP3 DAG
↑ Ca++
Gs
↑ cAMP
Gi
↓ cAMP
Functions  Systemic vasodilatation
 Bronchoconstriction
 Itching inflammations
 Triple response &
Allergic reactions
 Gastric gland -↑
Acid secretions
 Presynaptic receptor ↓
Histamine release→
sedation
 ↓ NT (NE, Ach)
release
Nonselectiv
e agonist
Histamine Histamine Histamine

14. Selective
agonist
2-Methylhistamine
2-Pyridylethylamine 2-
Thiazolylethylamine
4-
Methylhistamine
Dimaprit,
Impromidine
(R)α-
Methylhistamine
Imetit
Selective
antagonist
Antihistaminic drugs
Diphenhydramine
Loratadine
Cetirizine
Fexofenadine
Antiulcer drugs
Ranitidine
Cimetidine
Famotidine
Nizatidine
Ciproxifan
Clobenpropit
Thioperamide
Impromidine
Pitolisant/Tiprolisa
nt
(Inverse agonist)
H1 H2 H3

15. H4 Receptor-
Recent type play role in mast cell chemotaxis &
located in the immune system (↑ Allergic
reaction).
H4-receptor antagonists- Thioperamide (Used to
treat allergic reactions)

16. Action of histamine
Organ Mechanism Action
Blood
vessels
H1-↑ NO & PGI2-
Vasodilation
H2-Direct relaxation-
Vasodilation
↓ BP Flushing and hypotension
Triple response by Intradermal
route
(Red spot- capillary dilatation
Wheal- exudation of fluid Flare-
redness)
Visceral
smooth
muscle
Contraction through H1 Bronchoconstriction
Intestinal contraction
Abdominal cramps

17. Glands ↑ Gastric acid secretion (H2) Acid secretion in stomach
Brian Stimulates reticular activating
system and maintains
wakefulness (H1)
wakefulness
Immune
system
H1 &H4
AG : AB reaction on their surface
(IgE antibodies)
Allergic reactions
Type-I (immediate hypersensitivity
reaction)
Anaphylactic shock
Sensory
nerve
endings
Stimulation (H1) Itching
Tissues
damage
Adhesion of leukocytes
Vasodilation
Inflammation
Head Due to vasodilation Headache

18. Histamine has no therapeutic value.
In the past used to test acid secreting capacity
of stomach, bronchial hyper reactivity in
asthmatics, and for diagnosis of
Pheochromocytoma, but due to high risk not
performed these test with histamine
Mediator of inflammation and immediate
type of hypersensitivity reactions-
o Betahistine (H1selective histamine
analogue) is an oral histamine analogue
used to control vertigo in Meniere’s disease

19. Histamine release increased by-
o Some basic drugs like d-tubocurarine, morphine, atropine,
vancomycin and polymyxin B
o Tissue damage, trauma, stings and venoms, proteolytic
enzymes, phospholipase A.
o Ag:Ab reaction (IgEAb)
o Polymers like dextran, polyvinyl pyrrolidone (PVP).
o Surface acting agents like Tween 80

20. Antihistaminic Drugs
Antagonize the actions of histamine through H1 receptors in Competitive
manners.
The H1-receptor antagonists, or antihistamines are classified into-
o First generation agents (older more sedating)
 Penetrate blood brain barrier (CNS action like sedation, psychomotor
impairment). Contraindicated in person required constant attention
(like truck drivers, machinery operators and swimmers).
 Anticholinergic activity
o Second-generation agents (newer less/non-sedating)
 Least CNS penetration (Non sedative)
 No anticholinergic activity except cetirizine and azelastine
 Selective action bind only to H1 receptor

21. o Third generation agents (Derived from Second generation drugs)
 Active enantiomer (like Levo-cetirizine) or metabolite (desloratidine
and fexofenadine) of 2nd generation drugs
First generation drugs classification
(A) On the basis of sedative action -

22. Promethazine
MECHANISM OF 1ST GEN ANTIHISTAMINIC DRUGS
Compitively antagonize the histamine action via
H1 receptor.
Anticholinergic action
Some serotonin antagonist like cyproheptadine

23. PHARMACOLOGICAL ACTION
Antagonism of histamine-
o Block bronchoconstriction & Contraction of other smooth
muscles
o Antagonize histamine induced triple response.
o Antagonize histamine induced reduction in BP.
o Anatomize all action of histamine by H1 receptor but not
inhibit the gastric acid secretion.
Antiallergic Action-Suppressed immediate hypersensitivity
(type I reactions)

24. Anticholinergic action
o Antagonize muscarinic
actions of ACh
o Drug have highest
anticholinergic action-
 Promethazine
 Diphenhydramine
ADVERSE EFFECT-
Anticholinergic
o Dryness of mouth,
o Blurred vision
o Urinary retention
o Constipation
Antidopeminergic
o Phenothiazines mainly
o Extra-pyramidal symptoms
Sedation
Photosensitivity (promethazine)
Jaundice
Psychomotor impairment

25. II GENERATION ANTIHISTAMINIC DRUGS
It is new drug with following advantages over 1st gen drugs-
o Minimum or No sedation due to least CNS penetration
o No anticholinergic activity except cetirizine and azelastine
o Selective action binds only to H1 receptor.
o Absence of CNS depressant property.
o Additional Antiallergic mechanism like
 Inhibit allergic reaction by acting on Leukotrienes or by antiplatelet
activating factor effect.

26. II Gen antihistaminic drugs
o Fexofenadine (Piperidine derivatives)
o Loratadine(Piperidine derivatives)
o Desloratidine(Piperidine derivatives)
o Cetirizine (Piperazine derivative)
o Levocetirizine (Piperazine derivative)
o Azelastine
o Mizolastine
o Ebastine (Piperidine ring)
o Rupatadine (Piperidine derivatives)
Cetirizine

27. Terfenadine Fastest acting antihistaminic drug
At overdose block cardiac K channel hence caused ventricular
tachycardia
(Torsades de’ pointes) & QT prolongation.
Microsomal enzyme inhibitors (ketoconazole, erythromycin,
clarithromycin and Iitraconazole) → ↑ risk of this arrhythmia.
Terfenadine is metabolized to an active metabolite “fexofenadine”
(available as a separate drug) that lacks K+ channel blocking property.
Astemizole It is slowest and longest acting agent
At overdose block cardiac K channel hence caused ventricular
tachycardia
(torsades de’ pointes) & QT prolongation.
Microsomal enzyme inhibitors (ketoconazole, erythromycin,
clarithromycin and itraconazole) → ↑ risk of this arrhythmia.

28. Loratidine Long acting second generation antihistaminic
Metabolized to desloratidine (available as a separate drug)
Cetirizine Active metabolite of a first generation antihistaminic
hydroxyzine
Inhibits release of histamine and of cytotoxic mediators from
platelets as well as eosinophil chemotaxis during the
secondary phase of the allergic response.
Levocetiriz
ine
It is the active R(–) enantiomer of cetirizine.
Azelastine Used in nasal spray due to good topical action

29. NOTE-
Doxepin is a tricyclic antidepressant having most potent H1 blocking
action (800 times more potent than diphenhydramine).
Tiprolisant is H3 inverse agonist used for Narcolepsy.

30. SAR OF ANTIHISTAMINIC DRUGS
•Essential pharmacophore required for histamine H1 antagonistic activity is
• The nitrogen should be 3° in nature for
maximum antihistaminic activity.
• The group present between nitrogen
atom and group X may be saturated or
unsaturated or substituted.
• The Ar group may be aryl or hetero
aryl, which may be substituted.
• The group (X) can be carbon, oxygen or
nitrogen

31. Serotonin and Related Drugs
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine
neurotransmitter and Biochemically derived from tryptophan.
Serotonin is primarily found in the gastrointestinal tract (GI tract
enterochromaffin cells 90%), blood platelets (8%), and the central
nervous system (2%) and a contributor to feelings of well-being and
happiness.
Serotonin is naturally produced in the Pineal gland which lies deep at the
Centre of the human brain.

32. Functions
o Control of appetite,
o Sleep,
o Memory and learning,
o temperature regulation
o Mood & behavior
o Cardiovascular function
o Muscle contraction,
o Endocrine regulation and
o Depression.

33. Serotonin receptors
Seven families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-
HT6, 5-HT7)
All are GPCRs except 5-HT3 (5-HT3 is a ligand gated Na+ channel)
All are GPCRs follow cAMP pathway except 5-HT2 (IP3-DAG).
5-HT1 inhibits cAMP and 5-HT4, 5-HT6 and 5- HT7 increases cAMP.

34. Pharmacological action of Serotonin
On i.v. injection, it produces triphasic response on blood pressure. Early
sharp fall then brief rise (due to vasoconstriction) followed by prolonged fall
(due to arteriolar dilation) in blood pressure is seen.
Serotonin is a powerful stimulator of smooth muscles. It increases
peristalsis and constricts bronchi.
It has gastro protective action by decreasing acid secretion and increasing
mucus production.
5-HT is involved in regulation of sleep, cognition, behavior and mood.
Serotonin increases platelet aggregation

35. Agonist /Increase the action Antagonist
• Sumatriptan: 5-HT1D agonist;
contraindicated in patients with angina
• Fluoxetine: Selective serotonin uptake
inhibitors for depression and other
indications
• Buspirone: 5-HT1A agonist for anxiety
• Cisapride: 5-HT4 agonist to ↑ GI motility
and decrease G-E reflux (Removed from
US market due to fatal arrhythmias)
• LSD: 5HT1A – hallucinogen
• Ergot alkaloids: 5-HT1 and 2 and other
receptors
• Methysergide and Cyproheptadine.
5HT2 antagonists. In carcinoid, migraine.
• Ketanserin: 5HT2 and Alpha antagonist –
used as antihypertensive.
• Ondansetron: 5-HT3 antagonist for
chemotherapy induced nausea and
vomiting
• Clozapine: 5HT2A/2C antagonist: for
schizophrenia.