This document discusses autacoids and serotonin. It defines autacoids as biological agents that act locally at the site of synthesis and release, like local hormones. Two important amine autacoids are histamine and serotonin. Histamine is stored in mast cell granules and plays roles in hypersensitivity, tissue injury, and gastric acid secretion. Serotonin is synthesized from tryptophan and acts as a neurotransmitter and in gastrointestinal functions. The document describes the receptors, biosynthesis, metabolism, and pharmacological actions of histamine and serotonin, as well as the mechanisms and uses of antihistamines and anti-serotonin drugs.

1. Autacoids & serotonin
By
Dr. Manoj Kumar
Assistant Professor
Department of Pharmacology
Adesh Medical College & Hospital Ambala Can’t

2. Autacoids
Greek: autos – self and akos – Remedy or healing
substance.
Biological agents
Act locally (e.g. within inflammatory pockets) at the site of
synthesis and release.
 Generally act locally also called “local hormones”( short
action)
Amine Autacoids:
Histamine and Serotonin
 Lipid derived: PG, LT and PAF
Peptides: Plasma kinins and Angiotensin

3. Histamine - Introduction
 Meaning “tissue amine” (histos – tissue)
 Physiological and Pathological role hypersensitivity &
tissue injury
The primary site, mast cell granules (or basophiles) –
skin, intestinal, gastric mucosa, lungs, liver and placenta
Other sites
 CNS: neurotransmitter
 Funds of the stomach: major acid secretagogues
epidermis, gastric mucosa, growing regions, poison.

4. Synthesis & metabolism of histamine
Synthesized by decarboxylation of amino acid histidine

5. Distribution & storage :
 Histamine - storage granules of mast cells.
 Tissues rich in histamine - skin, gastric and
intestinal mucosa, lungs, liver and placenta.
 Non-mast cell histamine occurs in brain, epidermis,
gastric mucosa.

6. Releasing Agents
Non-immune Releasers
• Morphine and other opioids
• Aspirin and other NSAIDs in some asthmatics
• Vancomycin i.v. (Red man syndrome), polymixin B
• Some x-ray contrast media
• Succinylcholine, d- tubocurarine
• Anaphylotoxins: Cold or solar urticaria
IgE - Mediated Releasers
• Food: eggs, peanuts, milk products, strawberries, grains.
• Drugs: penicillins, sulfonamides etc.
• Venoms: fire ants, snake, bee.
• Foreign proteins: nonhuman insulin, serum proteins.
• Enzymes: Chymopapain

9. Classification
•
•
1stGeneration: H1 ANTAGONIST
– Highly sedatives: Diphenhydramine, Promethazine and
Hydroxyzine
– Moderately sedatives : Pheniramine, Cyproheptadine,
Meclizine, Buclizine and Cinnarizine
– Mild sedatives : Chlorpheniramine,
Dexchlorpheniramine, Dimethindene, Cyclizine,
Clemastine
2ndGeneration:
Fexofenadine, Loratidine, Cetirizine, Levocetrizine, Azelastine,
Mizolastine, Desloratidine, Ebastine and Rupatidine

10. PATHOPHYSIOLOGICAL ROLES
1. Gastric secretion
Histamine - ↑ secretion of HCl(Acid and pepsin ) in
the stomach
• It is released – feeding, vagal stimulation.
• Act on H2 receptor stimulate parental cell.
2. Allergic phenomenon
3. Transmitter - start the sensation of itch and pain at
sensory nerve endings.
4. Inflammation -Histamine is a mediator of vasodilatation
5. Tissue growth and repair.
6. Headache

11. Exocrine Glands
 Salivary glands
 Sweat glands
 Pancreas
 Bronchial glands
 Lachrymal glands
 Gastric glands
↑ Secretion

12. Blood vessels:
Dilatation of small vessels – arterioles, capillaries and
venules
– SC administration – flushing, heat, increased HR and CO –
little fall in BP
– Rapid IV injection: Fall in BP early
– Larger arteries and veins – constriction mediated by H1
receptor
– Increased capillary permeability – exudation of plasma

13. Triple Response
Intradermal histamine injection causes:
1. Red spot (few mm) in seconds: direct vasodilation effect ,
H1 receptor mediated
2. Flare (1cm beyond site): axonal reflexes, indirect
vasodilation, and itching,
H1 receptor mediated
3. Wheal (1-2 min) same area as original spot, oedema due
to increased capillary permeability
H1 receptor mediated

14. Heart
Direct effects of histamine are not prominent,
but the isolated heart,
especially of guinea pig, is stimulated—rate as
well as force of contraction.
These are primarily H2 responses.
Visceral smooth muscles:
Bronchoconstriction, intestinal contractions
increased (colic), Uterus not affected

15. Sensory Nerve endings:
Itching on injected, High doses – pain
Autonomic ganglia and Adrenal Medulla:
Adrenaline release – rise in BP
CNS:
IV injection Does not cross BBB – no CNS effects
intracerebral injection: Rise in BP, Cardiac stimulation,
hypothermia, vomiting

16. General Mechanism of Action of Antihistamines
 Blocks action of histamine at receptor
 Competes with histamine binding
 Displaces histamine from receptor
 Most beneficial when given early

17. Pharmacological actions
Antagonism of Histamine:
– The block bronchoconstriction, contraction of intestinal and
other smooth muscles and triple response
– Low dose BP fall antagonized
– Constriction of large vessels also antagonized
– Gastric secretion – unchanged
Antiallergic action:
Type 1 hypersensitivity reactions – suppressed
– Urticaria, itching, angioedema – controlled
– Anaphylactic fall in BP – partially prevented
– Asthma in human – not affected

18. CNS:
CNS depression (sedation), dizziness , decrees
concentration depends on individual drugs – ability
to cross BBB
Promethazine
 Controls motion sickness and vomiting of
pregnancy
 Controls rigidity and tremor in Parkinsonism

19. .
Anticholinergic:
Anticholinergic properties – Promethazine highest –
additive action with Atropine, TCAs etc.
Local anaesthetic:
Pheniramine – membrane stabilizing effects – LA – but
not used
BP:
Fall in BP with IV injection (all) but not with Oral

20. Pharmacokinetics
Lipid soluble, well absorbed orally and
parenterally, metabolized in Liver and excreted in
urine
– Widely distributed in body and enters Brain and crosses
BBB
– Induce microsomal hepatic enzyme
– Duration of action 4-6 Hours except …..
– Cetirizine (C), loratadine (L), fexofenadine (F) - well
absorbed and excreted mainly unmetabolized form
– C and L are primarily excreted in the urine
– F is primarily excreted in the feces

21. Clinical Uses of Antihistamines
■ Allergic rhinitis (common cold)
■ Allergic conjunctivitis (pink eye)
■ Allergic dermatological conditions
■ Urticaria (hives)
■ Angioedema (swelling of lips-eyelids )
■ Puritus (atopic dermatitis, insect bites)
■ Anaphylactic reactions (severe allergies)
■ Seasonal Hay fever
■ Nausea and vomiting (first generation H1-
antihistamines)
■ Sedation (first generation H1-antihistamines)

22. 2nd Generation antihistaminics
•
(SGAs) – after 1980s
– Higher affinity for H1 receptors: no anticholinergic side
effects
– No CNS depressant property
– Additional antiallergic – LT and PAF inhibition
Advantages over 1stgeneration:
– No psychomotor impairment – driving etc. can be allowed
– No subjective effect
– No sleep induction
– Do not potentiate BDZ and alcohol etc.

23. Fexofenadine:
 First non-sedating SGA -
 when co-administered with CYP3A4 inhibitors –
erythromycin, clarithromycin, ketoconazole and
itraconazole etc
 Terfenadine, Astimazole etc. – banned

24. Loratidine:
 Long acting, selective peripheral H1 blocker – fast
acting and lacks CNS depression – metabolized by
CYP3A4
 No interaction with macrolides and no
arrhythmias
 Uses: Urticaria and atopic dermatitis.
 Desloratidine: Metabolite like Loratidine – with
its double potency

25. Cetirizine:
Most commonly used(Levocetirizine – same with lesser S/E)
High affinity for Peripheral H1 receptor, but poor cross BBB at
high dose
Not metabolized in body, no cardiac action.
Other anti-allergic action – inhibits histamine and cytotoxic
material release for platelets and eosinophils
High skin concentration – beneficial urticaria and atopic dermatitis
Longer half life 7-10 hr – once daily dosing
Uses: Upper respiratory allergies, pollinosis, urticaria and
atopic dermatitis and seasonal asthma

26. Azelastine:
H1 blocker with topical action – also inhibitor of inflammatory
response mediated by LT and PAF.
- Nasal mucosa – Intranasal application
- Half-life 24 hours but action longer due to active metabolites
- Used intranasal in seasonal and perennial rhinitis
Mizolastine: Non-sedating – effective in rhinitis and urticaria.
– Half-life 8-10 Hours but single dosing
Ebastine: Newer SGA – converts to carbastine
- Half-life: 10-16 Hrs and non-sedating
– Used in nasal and skin allergies

27. Adverse effects
 First generation H1-antihistamines Side effects are due to CNS depression:
 Sedation
 Dizziness
 Tinnitus (ringing in the ear)
 Blurred vision
 Euphoria
 Uncoordination
 Anxiety
 Insomnia
 Tremor
 Nausea/vomitting
 Dry mouth/dry cough
 Second generation H1-antihistamines side effects (drowsiness, fatigue,
headache, nausea and dry mouth)

28. H2-receptor antagonists
Cimetidine, Ranitidine, Famotidine and
Roxatidine …….
….. “Drugs for Peptic Ulcer”

29. Serotonin and Anti-serotonin
drugs

30. Serotonin
• Monoamine neurotransmitter
• Synthesized from tryptophan
• 90 % present in gastro-intestinal
enterochromaffin cells and 10 % in platelets
and brain.
• Role in mood, sleep, sexual activity,
thermoregulation, pain.

32. Biosynthesis
Tryptophan (From diet)
Tryptophan hydroxylase
5Hydroxytryptophan
Aromatic Amino Acid decardoxylase
5-Hydroxy tryptamine
Monoamine oxidase(MAO)
5 Hydroxyindole acetaldehyde
Aldehyde dehydrogenase
5Hydroxyindole acetic acid (5HIAA)

33. Storage and release

34. Distribution
• GIT enterochromaffin cells (90%)and
myentric plexus.
• Platelets
• Lungs
• Bone marrow
• Pineal gland
• CNS

35. Serotonin Receptors
• seven main types
• (5-HT1 to 5-HT7).
• 5-HT1, 5-HT2 subdivided
• Total 14 types of 5-HT receptors present.
Different monoamine transporters
• Dopamine transporter
• Norepinephrine transporter
• Serotonin transporter

36. Agents can inhibit 5-HT reuptake
•
•
•
Cocaine
Tricyclic antidepressants
Selective serotonin reuptake
inhibitors(SSRIs)
e.g. Fluoxetine

37. Elimination
• Metabolized by MAO and then
Aldehyde dehydrogenase to form
5-hydroxyindole acetic acid(5-HIAA)
• Excreted in urine

38. CNS – As Neurotransmitter
• Behavioral responses
• Feeding behavior
• Mood and emotion control
• Sleep / wakefulness control
• Emetic reflex (esp. chemical triggered)
• Control of sensory pathways
Pharmacological Actions

39. Pharmacological Actions
CVS
– Contraction of vascular smooth muscle except in
skeletal muscle and heart
IV injection causes triple response
BP Triphasic response :
fall – Coronary chemoreflex
rise – Vasoconstriction,↑co
fall - Vasodilation in skeletal M.& arterioles

40. • GIT
– Stimulates peristalsis
– ↑ mucus production ↓acid and pepsin
• Others
– Stimulates perception of pain and itch
by activating 5HT3 receptors
• ↓ food intake
• Bronchi - Bronchoconstriction (5HT2A)
• Platelets – platelet aggregation (5HT2A)
Pharmacological Actions

41. 5 HT receptor agonists
1. Buspirone: 5HT 1A used in anxiety
2. Sumatriptan: 5HT 1B/D used in migraine
3. Cisapride, mosapride: 5 HT4 used in GERD
4. Dexfenfluramine: Non selective 5HT2 Agonist
(BANNED)
5. Lorcaserin: 5HT2C used inobesity

42. 5 HT receptor antagonists
• Cyproheptadine: 5 HT2A
• Methysergide: 5HT2A/2C
• Ketanserin: 5HT2A/2C
• Clozapine: 5HT2A/2C (D2 to lesser
extent)
• Risperidone: 5HT2A+ D2 antagonist
• Ondansetron: 5 HT3 antagonist

43. Cisapride
• Has peripheral 5HT4 agonist action
• Useful in GERD, Diabetic gastroparesis
• Releases Ach from cholinergic neurones in
myenteric plexus
• Oral bioavailabilty ~30%
• T ½ 10 hrs
• Reported to cause serious ventricular arrhythmias
• Others are Renzapride, Mosapride

44. • Allergies
• Appetite stimulant
• Serotonin syndrome
• Carcinoid syndrome
• Priapism
– Adverse effects:
• Dryness of mouth,
• Weight gain,
• Drowsiness
Used

45. Sumatriptan
• Selective agonist for 5HT1D and 5HT1B
• Useful in acute migraine attack
• Bioavailability ~ 15%
• Half life 2-3 hrs
• Can be given orally, S/C or as nasal spray
• Can cause chest pain in 5% patients
• Zolmitriptan, Naratriptan can be given orally,
longer acting, safer

46. Buspirone
• Partial agonist at presynaptic 5HT1A receptors
• Weak D2blocker
• Useful as anxiolytic
• Rapidly absorbed , undergoes extensive
first pass metabolism
• t ½ 2-4 hrs
• Excreted in urine and faeces

47. Ketanserin
• Selective 5HT2 blocker
• No partial agonistic activity
• Weak α1,H1, Dopaminergic blocker
• Useful in Raynaud’s diasease
• Has antihypertensive activity
• Congener is Ritanserin more selective for 5HT2A

48. Cyproheptadine
• 5HT2Aantagonist
• Has additional H1 blocking as well as anticholinergic activity
• Useful in
Carcinoid tumor
Post-gastrectomy dumping syndrome
Pruritis Allergies
↑Appetite in children

49. Ondansetron
• Selective 5HT3 antagonist
• Useful as antiemetic agent
• Others are
Granisetron
Tropisetron

50. Methysergide
• Chemically related to ergot alkaloids
• Potent 5HT2A /2C antagonist
• Acts on 5HT1receptors also
• Useful in
Migraine prophylaxis
Carcinoid tumor
Post-gastrectomy dumping syndrome
Prolonged use in endocardial, pulmonary fibrosis

51. Ergot alkaloids
• Natural ergot alkaloids
– Ergometrine
– Ergotamine
• Synthetic
– Dihydroergotamine
– Dihydroergotoxine
– Bromocriptine

52. Ergot related drugs
• Ergotamine :
– Partial agonist & antagonist at, 5 HT1 & 5 HT2 receptors
– Produces sustained vasoconstriction , visceral
smooth muscle contraction , vasomotor centre
depression
– Chronic exposure can cause gangrene
• Bromocriptine:
• D2 agonist inhibits prolactin release
• Ergometrine:
– Oxytocic drug

53. Ergot related drugs
• Adverse events:
– Nausea, vomiting
– abdominal pain, muscle cramps
– weakness, paresthesia
– Chest pain
– coronary artery & other vascular spasm
• Contraindications:
– Sepsis, IHD, PVD, Pregnancy, liver & kidney disease

54. Serotonergic drugs: actions & uses
Sr.
no
Receptor Drug action Drug example Clinical disorder
1. 5HT1A partial agonist Buspirone,
ipsapirone
Anxiety,
Depression
2. 5 HT1B/1D Agonist Sumatriptan Migraine
3. 5 HT2A/2C Antagonists Methysergide,
Trazadone,
Risperidone,
ketanserin
Migraine
Depression
Schizophrenia
4. 5 HT3 Antagonists Ondansetron Chemotherapy ,
radiotherapy induced emesis
5. 5 HT4 Agonists Cisapride,
tegaserod
GIT disorders

56. What is Migraine?
 Repeated attacks of headache
 Moderately or severely painful
 Frequent or infrequent
 Last a few hours to a couple of days
 Often only one side of the head hurts

57. What You Might Experience During an Attack
 Nausea
 Vomiting
 Diarrhea
 Sweating
 Cold hands
 Sensitivity to light
 Sensitivity to sound
 Scalp tenderness
 Pressure pain

58. Triggers: Changes in Daily Cycles

59. Triggers: Environment or Diet

60. Triggers: Mental

61. Drugs for Migraine
• Mild Migraine (NSAIDS and antiemetics)
– Ibuprofen 400 mg TDS
– Paracetamol 500 mg TDS
– Naproxen 500 mg TDS
– Antiemetics: Metoclopramide 10 mg oral/ Domperidone
10 mg Oral
• Moderate migraine
– NSAIDS combination / triptans like sumatriptan +
antiemetic
• Severe : triptans/ ergotamine + Prophylaxis +
antiemetic

62. Prophylaxis of migraine
• Necessary when attacks are frequent ( 2 or
more attacks per month)
• Discontinue every 4-6 months and observe
• Drugs for prophylaxis of migraine
– Propranolol 40 mg BD
– Amitryptilline 25 mg BD
– Flunnarizine
– Valproic acid, gabapentin , topiramate (Anti-epileptics)

63. Sumatriptan
• Selective 5HT1B/1D receptor agonist
– Constriction of dilated extracerebral blood
vessels
– Inhibition of release of 5HT and
inflammatory neuropeptides around the
affected vessels
– Supression of neurogenic inflammation
• Dose: 50-100 mg

64. Sumatriptan
• Adverse effects
– Dose related: Tightness of chest, feeling of
heat, paresthesias, dizziness, weakness
– Risk of Myocardial infarction, seizure and
death
• Contraindications:
– Ischemic heart disease, epilepsy,
hypertension, pregnancy, hepatic and
renal imairment
Other triptans: Rizatriptan, zolmitriptan, naratriptan,
almotriptan

65. Case study
• A 28-year-old male, Ajay Kumar develops a runny
nose, itchy eyes, and sneezing every winter.
• To relieve his symptoms, he takes an OTC antihistamine
• Ajay Kumar is annoyed by the unpleasant effects that
accompany his allergy medication. Every time he takes
this antihistamine, he feels drowsy and his mouth feels
dry.
• He makes an appointment with his doctor who, advises
him to take loratadine. Upon taking new allergy
medication, his symptoms are relieved, and he
experiences no drowsiness or other adverse effects.

66. Questions
• What Is Ajay Kumar Problem?
• Which OTC is probably Ajay Kumar
taking?
• What is the reason of drowsiness and
dryness of mouth in Ajay Kumar ?
• What is loratadine? Why did Physician
prescribe it for Ajay Kumar ?