what is Autocoid? Histamine and antihistaminic agent Serotonin and anti 5-HT agent Prostaglandins

1. AUTOCOIDS
SUJIT T. KARPE
PRINCIPAL,
SOJAR COLLEGE OF PHARMACY

2. INTRODUCTION
• AUTACOIDS auto=self
• Local Hormones
akos=healing/remedy
“An organic substance, such as a hormone, produced
in one part of organism and transported by the
blood or lymph to another part of the organism
where it exerts a physiologic effect on that part”.

3. CLASSIFICATION
Amine derived: Histamine (amino acid:
Serotonin (Tryptophan)
Histidine),
Peptide derived: Angiotensin, Bradykinin
Lipid derived: Prostaglandins, Leukotrienes, Interleukins,
Platelet Activating Factor

4. AMINE AUTACOIDS
• DERIVED FROM NATURAL AMINO ACIDS
• HISTAMINE AND SEROTONIN are the major autacoids in this
class

5. HISTAMINE
Imidazole ethylamine
Formed from the amino acid Histidine
Important inflammatory mediator
Potent biogenic amine and plays an
important role in inflammation,
anaphylaxis, allergies, gastric acid
secretion and drug reaction
As part of an immune response to
foreign pathogens, produced by
Basophils and mast cells found in
nearby connective tissues.

6. Site of Histamine release
Mast cell site
Pulmonary tissue
Skin
GIT (Intestinal Mucosa)
Non mast cell site
CNS (Neuron)
Epidermis of skin
GIT (Gastric cell)
Cells in regenerating and rapidly growing tissue
Basophil (In blood)

7. The synthesis and breakdown of histamine

8. MECHANISM OF ACTION
Histamine is an autacoid, which means it acts similarly to a local
hormone, near its site of synthesis. It is produced as part of the
local immune response to invading bodies and triggers
inflammation.
Histamine exerts its effects by binding to histamine receptors on
cells’ surfaces.

11. ROLE IN ALLERGY:
Allergies are caused by a hypersensitivity reaction of
the antibody class IgE (which located on mast cells in
the tissues and basophils in the blood)
When an allergen is encountered, it binds to IgE,
which excessively activates the mast cells or basophils,
leading them to release massive amounts of
histamines
These histamines lead to inflammatory responses
ranging from
runny nose to anaphylactic shock
If both parents have allergies, you have a 70% chance
of having them, if only one parent does, you have a
48% chance, statistics suggested by American Academy
of Asthma, Allergies and Immunology.

12. HISTAMINE ANTAGONISTS
Anithistamines are drugs used to block the activity of histamines, by
preventing the ability of histamine to bind to histamine receptors.
These agents are therefore referred to as histamine antagonists /
Antihistaminics

13. HISTAMINE ANTAGONISTS
H1 receptor antagonist
1) Sedative (first generation) antihistamines: Highly lipid soluble and easily enters into the CNS:
a) Potent and marked sedative:
• Promethazine (phenergan) widely used • Diphenhydramine Dimenhydrinate
b) Potent and moderate sedative:
• Chloryclizine • Chlorpheniramine • Tetrahydeoxy carboline
c) Less potent and less sedative: • Mepyramine • Pheniramine(avil)
2) Non-sedative (second generation ) antihistamines: Less lipid soluble therefore cannot enter into the CNS:
• Cetrizine • Terfenadine • Astemizole • Ketotifen • Cyclizine

14. H1 RECEPTOR ANTAGONISTS
Pharmacodynamic
 Blocks triple response of histamine
 Antagonize stimulant action on smooth muscle of GIT
 Inhibit histamine induced salivary secretion.
 Antagonize histamine induced bronchospasm.
 By acting on vestibular apparatus, prevent vomiting
due to motion sickness.
 Posses local anesthetic effect.
 Shows pharmacological activity resembling atropine.

15. H1 RECEPTOR ANTAGONISTS
Pharmacokinetics:
Well absorbed from GIT (oral)
Onset – 30 minutes, duration – 3 to
Biotransformed in the liver
Excretion – kidneys
6 hours

16. ADVERSE EFFECTS
CNS : sedation, agitation, nervousness, delirium, tremors, incoordination,
hallucinations, & convulsions - common in first generation antihistamines
GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipation
- dryness of mouth, throat & airway, urinary retention - first generation
Headache, faintness
Chest tightness, palpitations, hypotension
Visual disturbances

17. THERAPEUTIC USES:
Dermatosis
Allergic rhinitis
Motion sickness & emesis (cyclizine, meclizine)
Parkinson’s disease (Diphenhydramine)
Sedative Agent (Promethazine)
Preanesthetic Medication

18. H2 RECEPTOR ANTAGONISTS
H2 blockers are a group of medicines that
acid produced by the cells in the lining of
commonly called H2 blockers. They include
nizatidine and ranitidine.
reduce the amount of
the stomach. They are
cimetidine, famotidine,

19. INDICATIONS
H2-antagonists are used by clinicians in the treatment
related gastrointestinal conditions, including:
Peptic ulcer disease (PUD)
Gastroesophageal reflux disease (GERD/GORD)
Dyspepsia
Prevention of stress ulcer (ranitidine)

20. Serotonin (5-HT) and anti-serotonin
Serotonin is one of most important autacoid , has many
physiological roles and serotonin agonists and
antagonists have many clinical applications .
Serotonin is widely distributed in plants and animal tissues.
In human , about 90% of total body serotonin present in
enterochromaffin tissues , 8% in platelets and 2% in CNS
.

21. Synthesis and Metabolism

22. Physiological roles of serotonin:
1- It acts as a neurotransmitter in the brain.
2- Regulation of temperature.
3- Pain perception .
4- In pathogenesis (manner of development of a disease) of migraine.
5- In pathogenesis of depression.
6- In pathogenesis of anxiety.
7- Involved in intestinal motility .
8- Control of vomiting.
9- Control of appetite.
10- Pathogenesis of carcinoid syndrome.

23. Mechanism of action of serotonin:
Serotonin exerts its action by binding to 7
subtypes of receptor [ 6 of them are G-
protein coupled and one of them "5-
HT3" is ionic channels coupled.
The second messenger of G-protein
coupled receptors is either cyclic AMP or
IP3 (Inositol-1,4,5-triphosphate) and DAG (diacyl glycerol).

24. Pharmacological action of serotonin:
1- CVS: - On heart : serotonin has small +ve inotropic and +ve chronotropic effect on the
heart. Elevated plasma level of serotonin in carcinoid syndrome lead to pathogenic
endocardial changes. -
On blood vessels : serotonin produces triphasic response which includes:
1- early depressor phase due to ↓ heart rate and cardiac output due to
chemoreceptor reflex.
2- Presser effect due to ↑ peripheral vascular resistance and cardiac output.
3- Late depressor phase : related to vasodilatation in skeletal muscle.

25. 2- Respiratory system: Serotonin produces a small direct
stimulation to bronchial smooth muscle in normal person but
produce a bronchospasm in patients with carcinoid syndrome.
Serotonin produces hyperventilation due to stimulation of bronchial
sensory nerve endings.
3- GIT: serotonin has a potent stimulation on the smooth muscle of the
gut which increases the tone and facilitate peristalsis that related to the
action of serotonin on 5HT receptor in smooth muscle and ganglionic
stimulation of the enteric plexus .
4- CNS : Stimulation of sensory nerve endings leads to pain and
itching.

26. 5- Glandular secretion: Serotonin has little inhibitory effects on
exocrine glands.
6- Uterus: Large dose of serotonin impairs placental blood supply
and may lead to fetal distress.

27. Serotonin agonists :
1- Buspirone : acts on 5-HT1A receptor .It is an anxiolytic drug ( non benzodiazepines
non barbiturates anxiolytic).
2- Dexfenfluramine : Suppresses appetite and used to ↓ body weight.
3- Sumatriptan ,Amlotriptan , Eletriptan , Naratriptan , Rizatriptan , Zolmitryptan :
They act on 5-HT 1 B and D receptors and used in treatment of acute migraine.
4- Cisapride : It is used in the management of reflux esophagitis but now rarely used
because it causes serious ventricular arrhythmias .It acts on 5-HT4 receptors
.Other 5-HT4 receptor agonists are: Tagaserol and metaclopromide .

28. Serotonin antagonists:
1- Cyproheptadine (periactin): It is H1 and 5-HT2 blocker , used mainly
as appetite stimulant. Other uses include : Allergic rhinitis , cold
urticaria , prophylaxis of migraine , in Dumping syndrome after
gasterectomy and in carcinoid syndrome.
2- Ketanserin: It is 5-HT 2 and α-blocker . It was used in the treatment
of hypertension .
3- Ritanserin : It is 5-HT2 blocker and has no α- blocking effect.

29. 4- Ondansetron , Granisetron ,Tropisetron and
Alosetron:
Acts on 5-HT3 receptor as antagonists and used mainly in cytotoxic
induced nausea and vomiting.
5- Ergot Alkaloids : They are produced by fungus that infects grain .
Ergots act on the following receptors:
a- Serotonin receptor.
b- α adrenoceptor.
c- Dopamine receptor.
Ergots act as agonist , partial agonist or antagonist.
Serotonin antagonists:

30. Migraine Syndrome
It is a syndrome of recurrent throbbing unilateral headache with or
without aura ( visual halos) with nausea , vomiting , phonophobia
and photophobia.
It is poorly understood , it is precipitated by stress , anger , fatigue ,
diet , rich in chocolate and cheese , alcohol , menses in female or
using contraceptive , hypoglycemia.
Changes in vascularity between intra and extra- cranial blood vessels
and stimulation of trigeminal nerve by calcitonin genes related
peptides are the most popular concept concerning etiology of
migraine.
Migraine Etiology

31. Pathogenesisofmigraineanddrug
treatment

32. Treatment of migraine
1- Treatment of acute attack : by using Paracetamol , NSAIDs (aspirin),
serotonin agonists like Sumatriptan , ……..other serotonin agonists or
by ergot alkaloid derivatives like ergotamine.
Other supportive treatment like anti-emetic , sedative.
2- prophylactic treatment : many drugs are used with different outcome
like calcium channel blockers ( Verapamil), B-blockers
(propranolol ) , ergot alkaloid ( Methysergide) , clonidine, tricyclic anti-
depressant (imipramine), anti-serotonin ( cyproheptadine and
pizotifen) .

33. 2. EICOSANOIDS
(20 carbon atoms!)
•prostanoids
- prostaglandins (PGs)
- thromboxanes (Txs)
•leucotrienes (LTs)
•lipoxins

34. •The eicоsanoids are important
mediators of inflammation
and allergy.
•The main source of
eicosanoids is arachidonic acid.
It is a 20-carbon unsaturated
fatty acid.

36. NOTE : Non-steroidal anti-inflammatory drugs [NSAIDs] exert
their effects through inhibition of COX I and II.
COX I and II produce both PGs and TXs.
PGs are widely distributed in brain , lung , liver, kidney ,
adrenals , uterus , testis , and prostate .
We have PGE1, PGE2 , PGE3 , PGF1α , PGF2α,……..
NOTE : Other types of PGs are derived from the above
compounds.

37. Mechanism of action of PGs:
They bind to G-protein coupled
receptor --------- ↑ cAMP
Mechanism of action of thromboxane
A2:
They bind to G-protein coupled
-----------↑ IP3 and DAG

38. Pharmacological actions of PGs and TX:
1- GIT: PGE2 and PGF2α cause contraction of the longitudinal muscle
of the gut while PGI2 and PGF2α cause contraction of the circular
muscle of the gut.PGE2 relaxes the circular muscles. In general , large
dose of PGs inhibits gastric acid secretion.
2- vascular smooth muscles : PGE2 and PGI2 cause
vasodilatation , while PGF2α and TX cause vasoconstriction
3- platelets : PGE1 and PGI2 inhibit platelets aggregation while TX
induces platelets aggregation.
4- Respiratory system: PGE1 , PGE2 and PGI2 cause bronchi dilatation
while PGF2α and TX cause bronchi constriction.

39. 5- Renal system: PGE1, PGE2 and PGI2 increase GFR (vasodilating
effect ) and increase the Na excretion , also enhance the release of
rennin.
PGE2 is involved in renal phosphate excretion.
TX reduces renal function and GFR.
6- Reproductive system: PGE2 and PGF2α causes contraction of
uterus , PGI2 increases penile erection.
NOTE: Seminal fluid containing less than 400 ug/ml of PG is
considered an infertile man

40. 7- CNS:
-Fever : PGE1 and PGE2 when are injected into cerebral ventricles ,
they increase the body temperature.
PGD2 when infused into cerebral ventricles produces sleepiness .
- Neurotransmission: PG compounds inhibit the release of Nor-
adrenalin from post-ganglionic sympathetic nerve endings.
- Neuro-endocrine: PG compounds promote the secretion of
prolactine , GH, TSH, ACTH, FSH and LH.

41. 8- Bone : PGD2 increases bone turnover (bone formation and
resorption) .
PG is involved in bone loss in post-menopausal women.
9- Eyes: PGF2α decreases intra-ocular pressure .

42. Clinical indications of PG preparations :
1- Reproductive indications:
PGE2 and PGF2α when used in early pregnancy , they will cause abortion , they
terminate pregnancy at any stage , facilitates labor if given at time of labor.
Advantages of PG over Oxytocin [ which also used in labor] :
a- PGs are more safe in pregnant women with pre-eclampsia , cardiac and renal
diseases .
b- PGs unlike Oxytocin, having no anti-diuretic effect.
PGE2 and PGF2α are involved in primary dysmenorrhia.
PGE1 is used in sexual dysfunction , injection of PGE1 in cavernosa is important in
management of impotence in man.

43. 2-CVS indications :
PG compounds have anti-hypertensive effect due to their
vasodilating and natriuretic effects.
PGI2 is used in pulmonary hypertension.
PGE1 and PGI2 are used in Ryanaud disease.
3- Blood: PGI2 is very effective in preventing platelets
aggregation .

44. 4- Respiratory indications: PGE2 is used as aerosol to relieve
bronchiospasm.
5- GIT indications : PGE1 analogue (Misoprostol)is
cytoprotective and used for treatment of gastric ulcer.
6- Immune indications: PGE2 and PGI2 inhibit T-cell
proliferation and clonal expansion by inhibiting interleukin I and
II.
While TX and platelet activating factor (PAF)stimulate T-cell
proliferation and clonal expansion by stimulating IL-I and II.
NOTE: PGs in general decrease incidence of organ
transplantation rejection .

45. 7- Eyes : PGF2α analogue is used in treatment of glaucoma .
Side effects of PGs :
GIT upset , headache , dizziness , bronchiospasm , allergic
reactions , syncope , hypo or hypertension , uterine laceration .

46. Some PGs preparations :
Dinoprost = PGF2α
Dinoprostone = PGE2
Alprostadil = PGE1
Epoprostenol = Prostacyclin = PGI2
Misoprostol = PGE1 analogue
Latanoprost = PGF2α ( eye preparation)