Histamine is a biogenic amine present in many animal and plant tissues. It is implicated as a mediator in hypersensitivity and tissue injury reactions. Histamine is present and stored in mast cells, especially in the skin, lungs, and gastrointestinal mucosa. It is synthesized from the amino acid histidine and acts on H1, H2, and H3 receptors to cause various pharmacological effects like vasodilation, increased capillary permeability, smooth muscle contraction, and increased gastric acid secretion. Serotonin is another amine present in enterochromaffin cells of the gastrointestinal tract. It is synthesized from tryptophan and acts on multiple 5-HT receptor subtypes to cause vasoconstriction, intestinal per

1. Histamine
RVS Chaitanya Koppala

2. AUTOCOID
• Auto- self , akos –healing substance or remedy
• Acts locally ( with in inflammatory cells) at the site of synthesis and
release
• Also known as local hormones
• Differ from the hormones in two way?
• Acts as mediator in physiological and pathological processes, reaction to
injury and immunological insult)
• Serve as transmitter or modulator in nervous system

3. AUTOCOID
Classification of autocoids
 Amine autocoids: Histamine, 5-Hydroxytryptamine
 Lipid derived autocoids: prostaglandins, leukotrienes, platelet
activation factor
 Peptide autocoids: plasma kinins (bradykinins, kallidin),
Angiotensin
In addition Cytokines ( interleukins, TNFalpha, GM-CSF etc)
Several peptides Gastrin, somatostatin, vasoactive intestinal peptide

4. Histamine
• Histos: Tissue
N N
NH2
H
1
2
3
45
Histamine
•Present mostly in mast cells:
 skin, lungs, GIT Mucosa
•Non mast cell histamine:
Brain, Gastric Mucosa
Histamine is a biogenic amine present in many animal and plant tissues .

5. Histamine
• Meaning tissue amine, present in animal tissues and in certain plants eg: stinging
nettle
• Implicated as mediator in hypersentivity and tissue injury reactions
• Present almost and stored in mast cell
• Tissues rice in histamine are skin gastric mucosa and intestinal mucosa, lungs,
liver and placenta.
• Non mast cell histamine occurs in brain , epidermis, gastric mucosa and growing
regions
• Also presents in body secretions, venoms and pathological fluids

6. Synthesis, storage & metabolism of
histamine
• Synthesized by decarboxylation of
amino acid histidine

7. Pharmacological actions
• Blood vessels:
– Dilates arterioles, capillaries, venules,
• IV injection- decreased BP
• Intradermal- Triple response
Stimulating H1, H2, H3 Receptors
Red spot
(dilatation)
Wheal
(exudation of
fluids)
Flare(Reflex
arteriolar dilatation)

8. Pharmacological actions (Contd)
• CVS: rate as well as force of contraction is increased (H2)
• Visceral smooth muscles:
Bronchoconstriction, abdominal cramps, colic by intestinal contractions,
uterus is contracted in animals
Smooth muscle is H1 response, sometimes H2 mediated relaxation is
also seen
• Secretions:
– Increased gastric secretion (H2) primarly of gastric but also pepsin
mediated by increase cAMP generation
– Increased nasal secretions (H1)

9. Pharmacological actions (Contd)
• Sensory Nerve Endings: i.v/ Intracutaneosly occurs itching
Higher concentrations injected more deeply causes pain
• Autonomic ganglia and adrenal medulla: stimulated and release
Adr- causes secondary rise in BP
• CNS: Doesnot cross/ penetrate BBB- no central effects are seen on
i.v
– Wakefulness, rise in BP, cardiac stimulation, behavioral arousal,
hypothermia, vomiting and ADH release on intra
Cerebroventricular Injection (H1/H2)

10. Pathophysiological Roles
• Gastric secretion(H2)
• Allergic phenomena (H1)
• As transmitter : regulate body temperature, CVS, thirst etc (H1)
• Inflammation (p-selection adhesion of leukocytes)
• Tissue growth and repair
• Head ache

11. Therapeutic Uses
• Betahistine
• H1 Selective histamine analogue
– To control vertigo in Meniere`s disease 8 mg tab ½
tablet QID (probably by vasodilatation in inner ear)
Histamine releasers
• stings and venom
•Ag-Ab reaction
•Drugs
 d-tubocurarine
Morphine

12. Histamine releasers
• Variety of mechanical , chemical and immunological
stimuli are capable of releasing histamine from mast
cell
• Tissue damage: trauma, stings and venoms, proteolytic
enzymes, phospholipase A
• Polymers like dextrans, polyvinyl pyrrolidone
• Basic drugs: tubocurarine, morphine, atropine,
pentamidine, plymyxin B, vancomycin

13. Adverse effects of histamine release
• Itching, Urticaria
• Flushing
• Hypotension
• Tachycardia
• Bronchospasm
• Angioedema
• Wakefullness
• Increased acidity (Gastric acid secretion)

14. Mechanism of Action of Histamine
Histamine
H1 Receptors H2 Receptors H3 Receptors
(presynaptic auto
receptors)
↑ Ca2+
Smooth muscle contraction
Increased capillary
permeability
Vasodilation
Sensory nerve endings pain
& itching
↑ cAMP
↑ Gastric acid secretion
Blood vessels:
vasodilation
Increased capillary
permeability
↓ histamine release
↓secretion
Vasodilation
↓ cAMP

15. Classification of H1 Antagonists

16. Mechanism of action
Competitive antagonism
Histamine General formula of H1 Blocker

18. Pharmacological actions
• CNS depression: (More with first generation)
– Sedation and drowsiness
– Some have antiemetic and antiparkinsonian
effects
• Antiallergic action
• Anticholinergic actions (More with first
generation)
– Dryness of mouth , Blurring of vision
– Constipation
– Urinary retention

19. Pharmacological Actions
• Local anesthetic
• BP: smooth muscle relaxation/ alpha
adrenergic blocade
• Antimotion sickness effect: Dimenhydrinate,
Promethazine
• Antiemetic: Promethazine
• Antiparkinsonism: Diphenhydramine,
orphenadrine, promethazine(IV)
• Antivertigo: cinnarizine

20. Preparations & dosage (Daily)
Drug Dose
1. Diphenhydramine 25-50 mg oral
2. Dimenhydrinate 25-50 mg oral
3. Promethazine 25-50 mg oral/injection
4. Chlorpheniramine 2-4 mg oral
5. Pheniramine 25- 50 mg oral/im
6. Cinnarizine 25-150 mg oral
7. Cyprohepatidine 4 mg oral

21. Therapeutic uses
1. Allergic rhinitis & common cold
2. Allergic dermatitis, itching, urticaria
3. Wasp stings/ bite: pain and itching decreases
4. Mild blood transfusion reactions
5. Allergic conjunctivitis
6. Motion sickness: dimenhydrinate, promethazine
7. Morning sickness: promethazine

22. 8. Vertigo: cinnarizine
9. Chronic urticaria
10. Appetite stimulant: cyprohepatidine
11.Drug induced parkinsonism: Diphenhydramine,
Therapeutic uses (Contd..)

23. Adverse effects
• Sedation
• Anticholinergic effects
• Dermatitis on local use
• Cyclizine, meclizine : teratogenicity

24. Second generation H1 Blockers
(Non Sedative:Less anticholinergic property)
• Fexofenadine
• Astemizole
• Loratidine
• Cetrizine
• Levocetrizine
• Azelastine
• Terfenadine
Uses:
• Allergic rhinitis
• Allergic Dermatitis
• Allergic conjunctivitis
• Urticaria
• Common cold

25. Advantages of second generation antihistaminics
• They have no anticholinergic side effects
• Do not cross blood brain barrier (BBB), hence
cause minimal or no drowsiness and sedation
• Do not impair Psychomotor performance

27. Serotonin
RVS Chaitanya Koppala

28. SEROTONIN
• Named after the vasoconstrictor substances which appeared in serum
when blood clotted
• Smooth muscle contracting substance present in enterchromaffin cell of
GIT
• About 95% of 5-HT receptors concentrated in Intestine remaining in
platelets and brain
• Wasp and scorpion sting also contains serotonin
• Widely distributed in invertebrates and plants (banana , pear, pineapple,
tomato, stinging)

29. SYNTHESIS, STORAGE AND DESTRUCTION
• 5-HT is ß-aminoethyl-5-hydroxyindole.
• It is synthesized from the amino acid tryptophan and
degraded primarily by MAO and to a small extent by a
dehydrogenase

30. SEROTONERGIC (5-HT) RECEPTORS
• Gaddum and Picarelli (1957) classified 5-HT receptors into musculotropic (D type)
and neurotropic (M type).
• Four families of 5-HT receptors (5-HT1, 5HT2, 5-HT3, 5-HT4-7) comprising of 14
receptor subtypes have so far been recognized.
• All 5-HT receptors (except 5-HT3) are G protein coupled receptors
• which function through decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-HT7)
cAMP production or by generating IP3/ DAG (5-HT2) as second messengers.
• The 5-HT3 expresses large number of 5-HT2C receptors

31. Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7
Subtypes A/B/D/E/F 2A/B/C 3A/B 5A/B
Signaling
pathway
cAMP↓ IP3-DAG Ion channel cAMP↑ cAMP↓ cAMP↑ cAMP↑
Location Brain stem,
raphe nucleaus,
nerve ending
vascular
visceral smooth
muscle,
platelets and
cerebral
Neurones.
Somatic
autonomic,
myenteric
plexus, Area
postrema
nucleus
tractus
solitarious
mucosa,
plexuses and
smooth
muscle of the
Gut, brain,
hippocampus,
colliculi
mucosa,
plexuses and
smooth
muscle of the
Gut, brain,
hippocampus,
colliculi
mucosa,
plexuses and
smooth
muscle of the
Gut, brain,
hippocampus,
colliculi
mucosa,
plexuses and
smooth
muscle of the
Gut, brain,
hippocampus,
colliculi
Agonist Buspirone,
sumatriptin
Alpha-methyl
5-HT
Alpha-
methyl 5-HT
Cisapride,
renzapride
----- Clozapine Clozapine
Antagonist Pindolol Ketenserin Odansetron ---- ----- ----

32. Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7
Actions Antimigraine platelets,
aggregation,
bronchial
contriction
Antiemetic, gut
wall and brain
Intestinal
secretions and
peristalsis
Cloned
receptors of
5HT4
Cloned
receptors
of 5HT4
Cloned
receptors of
5HT4
Roles Constricts
cranial blood
vessels and
inhibits release
of inflammatory
neuropeptides in
them;
sumatriptan
(antimigraine)
acts through
these receptors
vascular and
visceral smooth
muscle
contraction,
platelet
aggregation,
neuronal
activation
in brain
depolarizes
neurones by
gating cation
channels; elicits
reflex effects
of 5-HT—
emesis, gut
peristalsis,
bradycardia,
transient
hypotension,
apnoea, pain,
itch
Mediate
intestinal
secretion,
augmentation
of peristalsis
unknown Unknown unknown
Drugs
acting
Sumatriptan
(antimigraine)
Ketanserin Odansetron Renzapride Unknown Unknown Unknown

33. Pharmacological action of serotonin
1. CVS Arteries are constricted (by direct action on vascular smooth muscle) as well
as dilated (through EDRF release) by 5-HT, depending on the vascular bed and the
basal tone
BP: a triphasic response is classically seen on i.v. injection of 5-HT in animals.
2.Vascular smooth muscle: potent stimulator of g.i.t., both by direct action as well as
through enteric plexuses. Peristalsis is increased and diarrhoea can occur
3. Glands 5-HT inhibits gastric secretion: (both acid and pepsin), but increases mucus,
It thus has ulcer protective property. Effect on other glandular secretions is not
significant.

34. Pharmacological action of serotonin
4. Nerve endings and adrenal medulla Afferent nerve endings are activated causing
tingling and pricking sensation, as well as pain.
5. Respiration A brief stimulation of respiration (mostly reflex from bronchial
afferents) and hyperventilation are the usual response
6. Platelets By acting on 5-HT2A receptors 5-HT causes changes in shape of platelets,
but is a weak aggregator.
7. CNS Injected i.v. 5-HT does not produce central effects
Direct injection in the brain Produces sleepiness, changes in body temperature and a
variety of behavioural effects

35. Pathophysiological roles
• Neurotransmitter (sleep, temperature regulation, thought,
cognitive function, behaviour and mood, appetite, vomiting and
pain perception)
• Precursor of melatonin(regulate the biological clock and
maintain circadian rhythm)
• Neuroendocrine function (anterior pituitary hormones are
probably regulated by serotonergic mechanism)
• Nausea and vomiting (evoked by cytotoxic drugs or
radiotherapy is mediated by release of 5-HT)

36. Pathophysiological roles
Migraine:5-HT is said to initiate the vasoconstrictor phase of migraine
Haemostasis (5-HT accelerates platelet aggregation and clot formation
Angina (5-HT released from platelets has been implicated in causing
coronary spasm and variant angina)
Hypertension (Increased responsiveness to 5-HT as well as its reduced
uptake and clearance by platelets has been demonstrated in
hypertensive Patients)
Intestinal motility (5-HT containing neurones may regulate peristalsis
and local reflexes in the gut)
Carcinoid syndrome (Bowel hypermotility and bronchoconstriction in
carcinoid is due to 5-HT)

37. Drugs affecting serotonin system
•Drugs Action/activity
5-HT precursor Increase level of serotonin (tryptophan)
Synthesis inhibitor P-chloropheniramine –reduce 5-HT level
Uptake inhibitor TCA- antidepressant/antianxiety
Storage inhibitor Reserpine – anorectic property
Degradation inhibitor NON-MAO/ SELECTIVE MAO antidepressant
Neural degeneration 5-6-dihydoxy tryptamine
5-HT receptor agonist Azapirones, sumatriptin, cisapride
5-HT receptor antagonist Cyproheptadine, methysergide, ketanserin

38. Serotonin antagonist
S.NO Drug Activity Adverse effect
1 Methysergide (5-HT2 and 5HT1) Migraine prophylazxis, Abdominal, intestinal,
endocarial fibrosis
2 Ketanserin (5HT2) Antihypertensive,
vasoconstriction,
bronchoconstriction
Vasospastic
3 Clozapine (5HT blocker) Efficient cases in
schizophrenia
4 Risperidone (5-HT2A-D2) Ameloriative negative
symptoms
Extrapyramidal symptoms
5 Odansetron (5-HT3) Nausea and vomiting Anticancer and
radiotherapy
6 Ergotamine (5-HT1 /2) (agonist) Vascular, visceral
constractions, potent emetic
Damage to capillary
endothelium

39. Migraine
Migraine is a mysterious disorder characterized by pulsating
headache, usually restricted to one side,lasting 4–48 hours
Associated with nausea, vomiting, sensitivity to light and sound,
flashes of light, vertigo, loose motions and other symptoms.
Two major types are—
• migraine with aura (classical migraine) in which headache is
preceded by visual or other neurological symptoms
• migraine without aura (common migraine).

40. Pathogenesis
• Pulsatile dilatation of certain large cranial vessels is the immediate cause of pain.
• Initial vasoconstriction or shunting of blood through carotid arteriovenous anastomoses
produces cerebral ischaemia and starts the attack.
• Inflammation of the affected blood vessel wall which is amplified by retrograde
transmission in the afferent nerves and release of mediators like 5-HT, neurokinin,
substance P, calcitonin gene related peptide (CGRP), nitric oxide, etc.

41. Specific antimigraine drugs
• Ergotamine (partial agonism of 5HT1 receptor vasoconstriction)
• Dihydroergotamine (DHE)
• Selective 5HT1 (agonist)
–Sumatriptans (5HT1 only and only)
–Rizatriptan

42. Prophylaxis of migraine
• Beta adrenergic blockers (propranolol)
• Calcium channel blockers
• Tricyclic antidepressants
• Anticonvulsants