1. AUTACOIDS

2. • The term derived from Greek word
Autos= Self
Akoid (Akos)= Medicinal agent
or Remedy

3. • Produced by wide variety of cells in the
body and released locally
• Act at site or near the site of their release
so called as local hormones

4. Classical autacoids are
• Amine autacoids:-
• Histamine (H),
• 5- Hydroxy tryptamine (Serotonin, 5HT)
• Lipid derived autacoids:-
• Prostaglandins (PG) ,
• Leuckotrines (LT),
• Platelet activating factors (PAF)
• Peptide hormones :-
• Plasmakinin (Bradykinin,Kalliidin),
• Angiotensin (AT).
Others:- VIP
Gastrin
Somatostatin
Cytokines

5. HISTAMINE
• Histamine tissue amine (Histo=Tissue),
also called as biogenic amine
• It was identified in 1907
• Pharmacology studied by Dales 20th
century.
N N
NH2
H
1
2
3
45
Histamine
Heterocyclic amine

6. • Naturally occurring imidazole derivative (ß-
imidazole ethylamine)
• synthesized locally & Storage granules of mast
cells.
• Tissues rich in histamine are
skin, Intestinal mucosa, Lungs,
Liver and placenta
• Non mast cell histamine occurs in brain,
epidermis, gastric mucosa.

7. L-Histidine
Synthesis
Histamine
Histidine de carbosylase
α Fluromethyl hisitidine
+
Gastrin, Nicotine, stress
L-A.A decarboxylase
Stored in
mast cells
N- Methyl histamine
Imidazole N- methyl transferees Di amine oxidase
Imidazole acetic acid
MAO-B Ribose
N- Methyl imidazole acetic acid Imidazole acetic acid riboside

8. Storage
• In mast cell histamine (+ve) and get ionically
complexed with acidic –ve protein and heparin
high molecular weight.
• Bounded form is biologically inactive
• Non mast cells stored in histaminocytes in the
stomach and histaminergic neuron in brain.
Histamine
Heparin/
protein

9. Release
• The stored histamine from the mast cells
released by 2 ways mechanisms.
– Immunological release (anaphylactic)
– Chemical mediators (anaphylactoid)

10. Immunological release
Allergen enter (Forgein body)
Immunological reaction (AG:AB Complex formation)
Circulation in blood
Basophiles, Neutrophilis engulf
Cause neutralization
Contd.,

11. Whenever same allergen re-exposed
Activation of AG:AB complex
Reacts with mast cells
(Degranulation of mast cells)
Spasmogens release
(Like Histamine,5HT,PGs,LT4, Cytokines)
Mast Cell
Degranulation

12. Chemical Release
• Chemical mediators:
Chemical injures mast cell
(Granules exposed)

13. Drugs or chemicals release histamine
• Morphine Hydralazine
• d-TC Dextran
• Pentamidine Bilesalts
• Trimethophan Detergents
• Tolazoline Substance –P
• Polymyxin –B Bradykinin
• SCh, component 48/80
• Polyvinylprolidone (PVP)

14. • Drugs decrease release of Histamine:-
– ß-Agonists
– Mast cell stabilizers
– Negative feed back control on mast cells.

15. Histamine receptor classification
• Histamine receptor were classified by
Asch and Schild (1966) into H1, H2.
• H3 receptor was postulated by Schwartz
1983, confirmed by Arang in 1987.
• H4 receptors also present , but clinical less
important.

16. Receptor Distribution Post receptor
mechanism
H1
Post
synaptic
a)Smooth muscle ( Intestine, bronchi, Uterus)
b) Blood vessels
c) CNS
d) Sensory nerve ending
e) Adrenal medulla
Gq
IP3, DAG
Release Ca+
PKC activation
H2
Post
synaptic
a) Gastric gland
b) Blood vessels
c) Heart
d) Brain
Gq
IP3, DAG
Release Ca+
PKC activation
H3
Pre synaptic
a) Brain presynaptic
b) Lung, Spleen, Gastric mucosa
c )Blood vessels
Gi
CAMP, Ca+2 influx ,
opening K+ channels
H4 a) Eosinophils
b) Neutrophils
CD4T Cells.
Gi
CAMP, Ca+2 influx ,
opening K+ channels

17. Pharmacological actions
H1 mediated pharmacological actions:-
Sensory nerve endings:- Powerful
stimulant on sensory nerve endings
especially those mediating pain and
itching.
H1 mediated effect is an important
component of utricarial response to insect
bites and stings.

18. Smooth muscle:-Bronchial:- Histamine
cause broncho constriction.
• GIT:-cause contraction of intestinal
smooth muscle result in intestinal cramps
and diarrhoea.
• Uterus:- spasmodic contractions of uterus
and ileum
• Glands:-Increases secretions of endocrine
glands in bronchioles, pancreas, salivary
and lacrimal glands.

19. • Autonomic ganglia:- Stimulates, cause
release adrenaline.
• CNS:- Histamine does not penetrate BBB.
No central effect.
• Intra cerebroventricular administration
produces BP, cardiac stimulation,
behavioral arousal, hypothermia, vomiting
and ADH release.
• H1 mediate the maintenance of
wakefulness.

20. H2 mediated action:-
• powerful stimulant of gastric acid on
activation of H2 receptors on gastric cells.
• It associated with cAMP & intracellular
Ca+2 concentration
H3 mediated action:- CNS and ANS ,
presynaptic H3 receptors act as feed back
inhibitor for the release of histamine, NE
and Ach.
• H3 receptor activation by histamine, it
inhibits gastric acid release and block
inflammatory process.

21. H1 and H2 actions:-
• Stimulation of both receptor cause dilatation
of arterioles and post capillary venules.
Result remarkable fall in BP.
• Vasodilation is mediated by the release of
Endothelium Derived Relaxing Factor
(EDRF).
• Dilatation of post capillary venules cause
headache due to stretching of sensory nerve
fibers around the cranial arteries.

22. • Histamine inj intradermally, atypical triple
response is produced
• It characterized by an immediate redding
of skin (Flush) , formation of edematous
patch (Wheal) and a red irregular halo
surround the wheal (Flare)
Flare
Wheal
Flush

23. • Flush:- Due to vasodilatation
• Wheal:-Exudation of fluid from capillaries
and venules due to inc. permeability
• Flare: Consequence of axon reflex causing
vasodilatation through the release of
vasodilatory neuromediators.

24. CVS:- + ve chronotrophic (H2) and positive
inotropic effect (H1+ H2) on heart
• These effect occurs reflexly due to fall in
BP.

25. Receptor Distribution Function
H1
Post
synaptic
a)Smooth muscle ( Intestine, bronchi, Uterus)
b) Blood vessels
c) CNS
d) Sensory nerve ending
e) Adrenal medulla
Contraction
Dilatation
NT
Stimulation( Pain)
Release catecholamines
H2
Post
synaptic
a) Gastric gland
b) Blood vessels
c) Heart
d) Brain
Inc. acid secretion
Dilatation
Atria +ve chronctrophic
Ventricle +ve inotrophic
NT
H3
Pre
synaptic
a) Brain presynaptic
b) Lung, Spleen, Gastric mucosa
c )Blood vessels
Inhibitor dec.Ach, NE, H,
release
Dilatation
H4 a) Eosinophils
b) Neutrophils
CD4T Cells.

26. Histamine antagonists
• Histamine released in the body reduced by
3ways.
• Release inhibitors:-Disodium cromoglycate,
Nedocromic sodium prevent the degranulation of
mast cell.
• Prevent the release of histamine & other
inflammatory mediators from mast cells.
• Iodoxasmide, Tromethamine are newer mast
cell stabilizers.
• Ketotifen fumarate H1 blcoker + Mast cell
stabilizer

27. Physiological antagonists:- Ex:- Epinephrine
It have smooth muscle action opp. to
histamine; but they acts at different
receptors.
Histamine receptor antagonists: These are
antagonize the effect of histamine by
competitively blocking the receptors.

28. H1 antagonists
• Called as conventional anti histamines.
(Old)
• These are introduced at 1930s.
• These are conveniently divided into 1st &
2nd generations
• These group are distinguished by the
relatively strong side effects most 1st
generations.

29. 1st generation 2nd generations
• Short to intermediate
action
• BBB cross
• Sedative action
• Produce anti muscurnic
side effects
• Also block auonomic
receptors
• Cheap
• Long acting
• Poor penetration
• No
• No
• No
• Relatively expensive

30. Name Adult
dose Oral
in mg
Duration
of action
(hr)
Anti
cholinergic
activity
Uses
Highly sedative
Dimenhydrinate
Diphenhydramine
Doxylamine
Hydroxyzine
Promethazine
25-50
25-50
15-25
25-50
10-25
4-6
4-6
4-6
4-6
+++
+++
++
+++
+++
Anti motion sickness activity
Anti motion sickness activity
Sleep aid
Antiemetic
Antiemetic
Moderate sedative
Pyralamine
Tripelennamine
Cyproheptadine
Carbinoxamine(Clistin)
Clemastine
25-50
25-50
4
4-8
2-6
4-6
4-6
4-6
4-6
12
+
+
++
+++
+++
Sleep aid
-
Anti serotonin effects
-
-
Mild sedatives
Cyclizine
Meclizine
Chlorphenaramine
Dexchlorphenaramine
Triprolidine
25-50
25-50
4-8
4-6
2.5-65
4-6
12-20
4-6
4-6
4-6
++
++
+
+
+
-
-
-
Anti motion sickness activity
-

31. Pharmacological actions
• Antagonism of histamine:- Blocks
• Histamine induced broncho constriction
• Contraction of intestinal other smooth muscle
• Triple response.
• Fall in BP is blocked, but H2 antagonists are
required.
• Release of Adr form adrenal medulla in
response to histamine is abolished.

32. Anti allergic action:-
– Immediate hypersensitivity (type I) are suppressed.
– Itching, angioedema are controlled.
– Rhinitis, common cold
CNS:- 1st generation anti histamines produce variable
degree of CNS depression.
– Dec. alertness
– Inc. reaction time
- 2nd generation antihistamine are poor penetration to
BBB so no sedative action.

33. • Motion sickness:-
– Some antihistamine drugs acts Labyrinthine (H1) and
decrease motion sickness (Dimenhydrinate,
Diphenhydramine)
• Chlorpromazine (2-5mg ), Diphenhydramine(15-25mg)
and promethazine(15-25mg) are added to antitussive
agents.
• Doxylamine is used to prevent nausea and vomiting due
to pregnancy.

34. Pharmacokinetics :-
• Well absorbed by oral and parental routes.
• Metabolized in liver by microsomal system
• Wide distribution and enter brain
• Repeated use induce their own metabolism
Side effects:- Sedation, diminished alteration and
concentration, light headache, motor in
coordination, fatigue, tendency to fall sleep are
most common.
• Acute overdose produce central excitation, tremors,
convolutions, flushing, hypotension and fever.
• Death is due to respiratory CVS failure.

35. 2nd generation (1980)
Name Adult dose
Oral in mg
Duration
of action
(hr)
Anti
cholinergic
activity
Remarks
Astemizole
Fexofenadine
Cetrizine
Loratadine
Desloratadine
Levocetrizine
Ebastine
10mg OD
120-180mg
10mg OD
10mg OD
5mg OD
5mg OD
10mg
24
12
12-24
24
24
24
-
-
-
-
-
-
-
Anti inflammatory action

36. • Cetrizine is an active metabolite of hydroxyzine (1st G)
• Levo cetrizine is L-isomer of cetrizine more potent less
sedative .
• Cetrizine:- poorly penetrate to BBB
• Inhibits release of histamine and cytotoxic mediators from
platelets and eosinophil chemotaxis during 2nd phase of
allergic response
• Once daily , Elimination t1/2 7-10hr
• It is indicated for upper respiratory tract.

37. Fexofenadine
• dose not cross BBB
• free anti cholinergic side effect.
• Rapidly absorbed, excreted in urine and bile.
• t1/2 11-16hr, duration of action is 24hr.
Astemizole:-
• 97% plasma protein bound
• t1/2 20hr. Its metabolite t1/2 is 12-19days
• Excretion in faeces.
• Used for maintenance therapy.

38. Uses
• Allergic reactions:- effectively control
– immediately type of allergies like itching, urticaria,
– Allergic conjunctivitis
– Angioedema (DOC glucocorti).
– lay fever (2nd G),
– symptomatic relief in insect bite
• Pruritides:- first choice of drugs for idopathic
pruritides.
• Common cold:- produce symptomatic relief by
sedative and anticholinergic actions

39. Motion sickness:- Promethazine, Dimenhydrinate useful
for prophylaxis.
• Used in morning sickness, drug induced and post
operative vomiting.
Preanaesthetic medication
• promethazine used for its anticholinergic and sedative
action (specially in childrens)
Cough
• Chlorpromazine , Diphenhydramine and promethazine are
added to antitussive agents.
Motion Vomiting
centre
M,H1
Vestibular
apparatus
M,H1
Cerebellum
Anti cholinergic
activity

40. • Parkinsonism
• promethazine used due to anticholinergic activity
and sedative action.
• Acute muscle dystonia
• parentral promethazine or hydroxyzine.
• As a sedative, hypnotic, anxiolytic
• CNS depressant action
• Vertigo
• Cinnarizine widely used
• used to control mild blood transfusion and saline
infusion reactions like rigors and chills and
adjunct in anaphylaxis.

41. H2 antagonists
These are over the counter drugs OTC
• Mechanism of action:- competitively inhibit H2
receptors cells and suppress basal and food
stimulated acid secretions.
• They block the actions of histamine released
from ECL
• They inhibit stimulation of parietal cells.
• Reduced cAMP levels

42. Clinical uses:
• Peptic ulcer:-
– H2 blockers are one of the commonly used drugs is
peptic ulcer.
– H2 blockers produce sympathetic relief within days
and ulcer healing with in weeks.
• Zollinger Ellison syndrome:
– PPIs are drug of choice, H2 blockers are used to
control hypersecretions.
• GERD:
– PPIs are used. H2 blcokers also effective.
• Stress ulcers:- H2 blockers or PPIs are used

43. • Expect astemazole all are competitive
blcokers
• Antihistamines absorbed from gut.
• Metabolised by liver
• Metabolites are long half life