Autacoids are locally acting hormones that are produced in tissues rather than glands. Histamine is an important amine autacoid that is synthesized and stored in mast cells and basophils. It is released upon stimulation and acts through four types of histamine receptors (H1-H4) to produce various effects. Histamine's actions are terminated by enzymatic degradation or receptor desensitization within minutes. Antihistamines competitively inhibit histamine receptors to treat allergic disorders and histamine-mediated conditions.

1. Autacoid
• Autacoids are the local hormone produced in tissues
rather than in glands.
• Autacoids are locally acting hormone like substance,
which originates from different tissue & produce
intense biological activities near their site of
synthesis or release.
• Classification of autacoids
A. Amine autacoids
B. Peptide autocoids
C. Eicosanoids

2. Amine autacoids
• Histamine
• Types of histamine receptor and their distribution
1. H1 receptor :Blood vessels, CNS, smooth muscles, Adrenal
medulla, autonomic ganglia
2. H2 receptor: Blood vessels(smaller ), CNS, heart, parietal
cell of stomach.
3. H3 receptor: Blood vessels( certain ), Brain(presynaptic),
lungs, spleen, skin, ileum.
4. H4 receptor: Bone marrow, Basophils, thymus , small
intestine, lungs, spleen & Colon.
Synthesis of histamine:
• L- Histidine decarboxylase converts L- Histidine into
Histamine.

3. • Metabolism:
• a. Diamine oxidase acts on histamine to form
imidazole acetic acid
• b. Histamine-N-methyl transferase acts on histamine
to form N-methyl histamine and monoamine oxidase
further converts N-methyl histamine into N-methyl
imidazole acetic acid.
• Storage:
• mainly occurs in mast cells or basophils where it is
held in intracellular storage granules in a complex form
with an acidic protein & a heparin of high molecular
weight.
• Its content is approx.:0.1 to 0.2 pmol per mast cel &
0.01 pmol per basophil

4. • Release:
from mast cell by secretory/degranulation process
during physiological, mechanical or chemical insult.
• initiated by a rise in intracellular ca2+ levels, which
triggers extrusion of the contents of granules by
exocytosis.
• Stimuli
• - interaction of antigen with cell fixed IgE antibodies.
• - interaction of complement component C3a & C5a with
specific receptors on cell surface.
• Excretion:
• Very little amount of unchanged histamine is excreted in
urine & Imidazole acetic acids is excreted in urine in large
amount.
The activity of histamine is terminated within 5 to 15
minutes after it's synthesis or release.

5. Pharmacology Of Histamine&
Analogue
• Histamine: It has no therapeutic use because of its profound
adverse effects. However, it is infrequently used as a diagnostic
tool to test acid secreting capacity of stomach & to distinguish
between pernicious anemia & other form of anemia.
•
→ Loss of gastric parietal cells in pernicious anemia results in
an inability to secrete gastric acid even in response to histamine
but in other types of anemia, gastric acid secretion increases in
response to histamine.
•
→Not given orally due to rapid inactivation in GI tract & liver.
Administered by parenteral route –virtually complete
absorption.

7. Betazole

8. Pentagastrin
• It has been used as a diagnostic aid. It is more
commonly used for gastric analysis because it is
short acting& has minimal side effects.
Dose:- Dogs-6μg/kg.sc
It stimulates gastric acid secretion, pepsin &
intrinsic factor secretion.
It also stimulates pancreatic secretion, inhibits
absorption of water & electrolyte & increases
blood flow in the gastric mucosa.

9. Histamine blocking drugs

11. First generation antihistaminic drugs

13. • Antidote:-
-There is no specific antidote of mepyramine.
Intravenous (IV). Sodium bicarbonate improves
wider of QRS that may result from
antihistamines with sodium channel blocking
properties (eg.pyrilamine )
•
Clinical use:-
- It is used occasionally to reduce or help
prevent histamine mediated adverse effects.
- It is also used topically as cream for the
treatment of insect bites& stings nettle rash.

16. • Side/Adverse effects:-
Sedation, diminished alertness, lethargy,
somnolence& ataxia(Lack of coordinate in voluntary
movement ) due to central depression &dry mouth,
dysuria, constipation, increased heart rate & pupil
dilation due to anticholinergic effects.
•
Antidote:-
Overdose can be treated symptomatically & with
decontamination therapy.
Phenytoin IV is recommended in the treatment of
seizures caused by diphendramine & other
antihistamines over dosage.

17. • Phenytoin IV is recommended in the treatment of
seizures caused by diphendramine & other
antihistamines over dosage.
Dose Rate:-
In allergic disorder dogs and cats
a) 2-4mg/kg IM or slow IV, 2 times diary or as
needed.
b) 2mg/kg IM or slow IV, 2 times dairy or as
needed.
For adjunctive therapy of anaphylaxis
a) cattle: 0.5-1mg/kg IM or IV
b) Horse 0.25-1mg/kg IV or IM
Note: The Iv route shouldn’t be used routinely
because it carries risk of cardiac arrest.

20. • Pharmacokinetics:-
Hydroxyzine is rapidly absorbed after oral &
intramuscular administration. It is distributed through
the body & crosses blood brain barrier
It is metabolized in liver and the main metabolites
cetirizine
Duration of action:-
6-8 hours in dogs and up to 12 hours in cat.
Side effects:-
Sedation and gastric disturbances inn dog it produces
hyper excitability (tremors& rarely seizures)
Antidote:-
There is no specific antidote ECG monitoring is
recommended in case of hydroxyzine.
Drug rate:-
a) Dogs: 1-2mg, PO or IM, 3-4 times daily
b) horse: 0.5-1mg/kg, PO or IM, 2 times daily.

21. • Contraindication:-
It is contradicted in early pregnancy.
It is contradiction in patients with known hyperxyzine.
Contradiction in patient with a prolonged QT interval.
Clinical Use:-
Hydroxyzine is used primarily as antihistamine for the
treatment of itching, allergies, hyperalgesia, motion
sickness, induced nausea& insomnia. It is also used for
the treatment of mild anxiety.
In veterinary medicine hydroxyzine is mainly for
antihistaminic, antipruritic (anti itching) &
sedative/tranquilizing properties, often in atopic patient
(hereditary disease).
Allergic airway disease & Rhinitis.

25. • Side effects:-
Dry mouth constipation fatigue, drowsiness, sore
throat hepatic toxicity
Antidote:-
There is no specific antidote to cetirizine, not
effetely removed by dialysis.
Treatment is symptomatic& supportive therapy.
Clinical use:-
Used in the treatment of pruritus& allergic
conditions.
It may help in the treatment of eosinophils.
Dosage: Dogs& cats – 1mg/kg PO once daily.
Horse- 10mg/kg PO once daily.

27. • Terfenadine& its metabolites are excreted in feces
via biliary elimination& urine.
• Pharmacological effects:-
• It has rapid onset of action (1-2 hours& moderate
duration of action 12-24 hours)
• Side effects:-
• Dizziness, weakness, or muscle cramps, nausea,
diarrhea, upset stomach.
• Antidote:-
• It doesn’t have specific antidote.

28. • Drug interaction:-
• Never take terfenadine with antifungal drugs
such as ketaconazole, itraconazole .
• Antibiotic such as erythromycin, azithromycin
• ulcer drug such as cimetidine.
• Clinical uses:
• Dose:- 0.25-2.5mg/kg PO once daily.

29. • H2 receptor Antagonists
• The H2 receptor antagonists are a class of drugs
used to block the action of histamine on parietal
cells in the stomach, decreasing the production of
acid by these cells.
• The H2 receptor antagonist drugs are:
• a) Cimetidine
• Cimetidine was the first H2 receptor blocker to
be introduced clinically and was described as the
protype.
• Cimetidine HCl occurs as white, crystalline
powder and is soluble in water and alcohol. It
should be stored & protected from light anf kept at
room temperature. Cimetidine and other H2
receptor antagonists, so they reach the central
nervous system only to a limited extent.

30. • Pharmacological effects
• Cimetidine, like other H2 receptor antagonists, inhibits
the interaction of histamine with H2 receptors present
in numerous tissues, but its important action is
observed on gastric parietal cells. At the H2 receptors
of parietal cells, cimetidine competitively inhibits
histamine, thereby reducing gastric acid output both
during basal conditions and when stimulated by food,
pentagastrin, histamine, insulin, fundic distension and
to a lesser extent by muscarinic antagonists in a dose
dependent and to a lesser extent by muscarinic
agonists in a dose dependent manner. It reduces both
the secretion as well as the amount of pepsin induced
by a variety of secretogogues. Gastric emptying time,
pancreatic or biliary secretion, and lower oesophageal
pressure are not altered by cimetidine. Secretion of
intrinsic factor is also reduced.

31. • Pharmacokinetics
• Absorption: Cimetidine is rapidly absorbed
from the gastrointestinal tract. Bioavailability
is approximately 95%.
• Distribution: It is distributed throughout the
body, crosses placenta and reaches in milk but
penetration into the brain is poor due to it's
hydrophilic nature .
• Metabolism: It is metabolised in liver.
• Excretion: excreted in urine in both
unchanged and conjugated forms.

32. • Side effects
• - Very rare in animal at the dosage generally
used.
• - Thrombocytopenia
• - tachycardia and respiratory failure in lab
animals at very high dose.
• - prolonged use may produce gynaecomastia,
loss of libido, impotence and temporary
decrease in sperm count.
• - Rebound hypersecretion and relapse
gastroduodenal ulceration after the therapy is
discontinued ( in human)

33. • Drug interaction
• a. Cimetidine decreases the hepatic metabolism of
numerous drugs including theophylline, phenobarbitol,
warfarin, digitoxin, quinidine and phenytoin. Impaired
metabolism of other drugs can leads to their accumulation
to toxic levels in body.
• b.It impairs oral absorption of a number of drugs due to
alteration of GI pH and by binding to them.
• c.Cimetidine reduces hepatic blood flow by about 20% and
has shown to reduce the clearance of flow limited drugs
such as propranolol and lidocaine.
• d.Cimetidine can inhibit tubular secretion of procainamide,
with increase in plasma concentrations of the drug and its
cardioactive metabolite N-acetylprocainamide.
• e.Antacids and metoclopramide reduce absorption of
cimetidine and other H2- receptor antagonists. If used
concurrently, a gap of 2 hours should be allowed between
the dosing of two drugs.

34. • Dose:
• For gastric ulceration, oesophagitis or gastric hyperacidity.
• Dog & cats : 5-10 mg/kg, PO, SC, IM, or slow IV, 3 to 4 times daily
• Cattle : 8-16 mg/kg, 3 times daily
• Swine : 330 mg ( total ), 2 times daily
• Foals : 20 mg/kg, PO, 2 times daily ,
• For uraemic gastritis
• Dogs & cats : 2.5-5 mg/ kg, PO or slow IV, 2 to 3 times daily.
• For equine melanoma
• Horses : 2.5 mg/kg, PO, 3 times daily for 3 months.
• Clinical uses:
• cimetidine has been used for the treatment and prophylaxis of
gastric, abomasal and duodenal ulcers and in uremic gastritis, stress
related or drug induced erosive gastritis, duodenal gastric reflex and
oesophageal reflux.
• Cimetidinr is employed to treat hypersrcretory conditions
associated with gasrinomas and systemic mastocytosis.
• Cimetidine is used in the treatement of equine melanomas.

35. Rantidine
• Pharmacological effects
• Ranitidine is a H2 receptor antagonist that
possess pharmacological properties similar to
those of cimetidine. However, it is 5 to 12
times more potent as an inhibitor of gastric
acid secretion than cimetidine and doesn't
significantly inhibit hepatic metabolism of
other drugs.unlike cimetidine Ranitidine lacks
anti-androgenic effect and inhibit microsomal
P450 enzymes.

36. • Pharmacokinetics
• Absorption: well absorbed through the GI tract,
bioavailability is approximately 80% .
• Distribution: volume of distribution is 2.6 L/kg.
• Metabolism: metabolised in liver
• Excretion: excreted in urine and bile
• Side effects
• Side effects of ranitidine appear to be very rare in
animals at the dosages generally used. Although
some side effects like- confusion, headache,
diarrhoea /constipation have been reported in
human.

37. • Contraindications and precautions
• Ranitidine should not be used in animals with known
hypersensitivity or allergy to the drug. Ranitidine should be
avoided in animals with liver or kidney disease.
• Drug interactions
• Unlike cimetidine, ranitidine appears to have only minimal
effects on the hepatic metabolism of drugs and is unlikely to
cause clinically relevant drug interaction via this metabolism.
The relative bioavailability of ranitidine may be increased with
high peak serum level when propantheline is administered
concomitantly with ranitidine. Antacids may decrease
absorption of ranitidine.
• Dose:
• Dogs & cats : 0.5 - 2 mg/kg, PO ,IV, IM, or SC, 2 to 3 times
daily.
• Horses : 4-6 mg/kg, PO, 2 times daily
• : 1 mg/kg, IV, 3 times daily.

38. SEROTONIN AND ITS ANTAGONIST

39. SEROTONIN(5-HT)
 Serotonin is a biogenic amine i.e monoamine
neurotransmitter and an autacoides.
 Primarily found in the GI tract mostly
enterochromaffin cells,platelates and CNS.
 These regulates sleep,body temperature & mood.
 A hormone melatonin is derived from serotonin.

40. SYNTHESIS AND DEGRADATION
L-TRYPTOPHAN
T.Hydroxylase
5-HYDROXYTRYPTOPHAN
Decarboxylase
5-HT(SEROTONIN)
MAO Dehydrogenase
5-HIAA 5-Hydroxytryptophol

41. Storage and Release
 After synthesis ,it is stored in storage vesicles
mainly in enterochromaffin cells and often stored in
neurons.
 Platelets do not synthesis serotonin due to lack of
decarboxylase enzyme.
 But collect the autacoid from blood by an active
transport mechanism.

42. PATHOPHYSIOLOGICAL ROLES
 Neurotransmitter
 Precursor for melatonin
 Neuroendocrine Function
 Nausea and Vomiting
 Migraine
 Haemostasis

43. MECHANISM OF ACTION
 Action mediated through a variety of serotonin receptor
called 5-HT receptors.
 Receptors are classified into 5-HT1 to 5-HT7 receptor on
the basis of pharmacological characteristics.
 5-HT receptor induced membrane hyperpolarization and
reduction in input resistance from an increase in k-ion
conductance.
 Slow depolarization induced by receptors activation in
area such as the facial motor neuron involves a decrease
in K-ion conductance.

44. A second distinct mechanism involving Ca-ion
activated membrane current enhances neuronal
excitability and potentiality the response to
excitatory signals such as glutamate.
The fast depolarization elicited by 5-HT receptors
reflect direct gating of an ion channel instrinsic to
the receptor structure itself.
5-HT receptors acts through the G-protein couple
receptors which activates an intracellular second
messenger or ionotropic receptors that directly
regulates Na-K channels.

45. PHARMACOLOGICAL ACTIONS
 Action on GIT
5-HT act as a local hormone & to regulate peristalsis movement.
 Action on CNS
It act as neurotransmitter in CNS.
 Action on smooth muslcles
It constricts the smooth muscle of bronchia and GIT.
 Action on blood vessels
5-HT dilates the blood vessels of skeleton muscles,coronary arteries
& capillary of skin.
 Action on platelets
It enhances the aggregation of platelates & haemostasis.
 Depression
Low brain cells production of serotonin, a lack of receptor sites able
to receive the serotonin that is made inability of receptor to reach
the receptoer site or shortage of tryptophan lead to depression.

46. SEROTONIN ANTAGONIST
Non selective serotonin antagonist
1.Cyproheptadine
• It is combine serotonin and cholinergic antagonist.
• Its anti-serotonin activity utilized in intestinal manifestation
of carcinoid.
• It also has been used in the treatment of cyclical vomiting
syndrome and stimulate appetite.
• Side effects: drowsiness,dry mouth,ataxin confusion.

47. 2.Ketanserin
• Non selective 5HT receptor blocking property
blocks 5HT2𝐴 and 5𝐻𝑇2𝐵.receptors.
• It induced vasoconstriction, platelets
aggregation & contraction of smooth muscles.
• Ketanserin also lowers the blood pressure in
hypertensive patients and its effects is likely
related to the blockage of alpha-1 adrenergic
receptors.

48. 3. Ergot Alkaloides
• it acts as patrtial agonist and antagonist at
serotonin receptors at 5𝐻𝑇2𝐵.
• Antagonist action of 5HT on smooth muscles
including that of blood vessels.
• Used for migraine prophylaxis.

49. Selective Serotonin Antagonists
1.Ritanserin
• It is more selective 5𝐻𝑇2𝐴 and less 5𝐻𝑇2𝐶 receptor.
• It posses low affinity for alpha-1 adrenergic receptor.
• It is used together with typical antipsychotics in the
treatment of schizophrenia.

50. 2.Odansetron
• Selectively 5𝐻𝑇3antagonist
• Remarkable efficacy in controlling nausea & vomiting
following administration of highly emetic anticancer drug
and radiotherapy.
3.Agometaline
• It is an antidepressant that acts as a melatonergic
MT1 and MT2 receptor agonist and serotonin 5𝐻𝑇2𝐶
receptor antagonist.
• Agomelatine is indicated for the treatment of major
depressive disorder in human medicine.

51. Thank you

52. PROSTAGLANDINS

53. INTRODUCTION
Prostaglandins and related compounds are collectively known as
eicosanoids.
Most are produced from arachidonic acid, a 20-carbon
polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid).
The eicosanoids are considered "local hormones."
 They have specific effects on target cells close to their
site of formation.
 They are rapidly degraded, so they are not transported
to distal sites within the body.
But in addition to participating in intercellular signaling, there is
evidence for involvement of eicosanoids in intracellular signal
cascades.

55. ROLE OF EICOSANOID
– Inflammation
– Fever
– Regulation of blood pressure
– Blood clotting
– Immune system modulation
– Control of reproductive processes & tissue
growth
– Regulation of sleep/wake cycle.

56. PGE2 (prostaglandin E2)
It is an example of a prostaglandin, produced from
arachidonic acid.

57. Prostaglandins all have a cyclopentane ring.
A letter code is based on ring modifications (e.g.,
hydroxyl or keto groups).
A subscript refers to the number of double bonds in the
two side-chains.
Thromboxanes are similar but have instead a 6-member
ring.
PGE2 (prostaglandin E2).

58. Prostaglandin receptors:
 Prostaglandins & related compounds are
transported out of the cells that synthesize them.
 Most affect other cells by interacting with plasma
membrane G-protein coupled receptors.
♦ Depending on the cell type, the activated G-protein
may stimulate or inhibit formation of cAMP, or may
activate a phosphatidylinositol signal pathway
leading to intracellular Ca++ release.

61.  Prostaglandin receptors are specified by the same letter code.
E.g., receptors for E-class prostaglandins are EP.
Thromboxane receptors are designated TP.
 Multiple receptors for a prostaglandin are specified by
subscripts (E.g., EP1, EP2, EP3, etc.).
Different receptors for a particular prostaglandin may activate
different signal cascades.
Effects of a particular prostaglandin may vary in different tissues,
depending on which receptors are expressed.
E.g., in different cells PGE2 may activate either stimulatory or
inhibitory or G-proteins, leading to either increase or decrease in
cAMP formation

62. Prostaglandin H2 Synthase catalyzes the committed step in the
“cyclic pathway” that leads to production of prostaglandins,
prostacyclins, & thromboxanes.
Different cell types convert PGH2 to different compounds.
leukotrienes
phospholipids arachidonate diacylglycerol
prostaglandin H2
prostacyclins thromboxanes
other prostaglandins
Lipoxyganase
PGH2 Synthase
Prostacyclin
Synthase
Thromboxane
Synthase
Linear pathway
Cyclic pathway
Two major
pathways of
eicosanoid
metabolism.
Cyclic
pathway:

63. Role of prostaglandin

64. Role of prostaglandin

65. Role of prostaglandin

66. Role of prostaglandin

67. Thromboxane A2
It stimulates blood platelet aggregation,
essential to the role of platelets in blood
clotting.
 Many people take a daily aspirin for its anti-
clotting effect, attributed to inhibition of
thromboxane formation in blood platelets.
 This effect of aspirin is long-lived because
platelets lack a nucleus and do not make new
enzyme.

68. Leukotrienes have roles in inflammation.
They are produced in areas of inflammation in blood vessel walls as
part of the pathology of atherosclerosis.
Leukotrienes are also implicated in asthmatic constriction of the
bronchioles.
Some leukotrienes act via specific G-protein coupled receptors
(GPCRs) in the plasma membrane.
Anti-asthma medications include:
 inhibitors of 5-Lipoxygenase, e.g., Zyflo (zileuton)
 drugs that block leukotriene-receptor interactions.
E.g., Singulair (montelukast) & Accolate (zafirlukast) block binding
of leukotrienes to their receptors on the plasma membranes of
airway smooth muscle cells.

69. 1) Prostaglandins and analogues
a) misoprostol:
synthetic analogue of prostaglandin E1
Pharmacological effect:
Cytoprotective and antiulcer effect on gastric mucosa.
Inhibits gastric acid secretion by a direct action on gastric parietal cells.
Increase production of gastric mucus and bicarbonate and enhances
blood supply to gastric mucosal cells.
Pharmacokinetics:
Effectively absorbed from the GI tract
Rapidly metabolized to misoprostol acid which is primary active
metabolite. Further biotransformed to inactive metabolites

70. Side effects:
Includes diarrhoe, nausea, vomiting, abdominal cramps
Potentially uterine contractions and vaginal bleeding may
occur In bithches
Contraindications
It is contraindicated during pregnancy due to its uterine
stimulant activity.
Should be used cautiously in patients sensitive to
prostaglandins and in cerebral or coronary vascular disease
Drug interaction:
Non-systemic antacids reduce absorption of misoprostol .
Dose:
Dogs: 2-5 ug/, po,2-3 times daily

71. • Horses: 0.5ug/kg,po,4 times daily
PROSTAGLANDINS E2 AND ANALOGUES
Dinoprostone:
Synthetic prostaglandin E2
Promotes ripening and dilation of cervix and
causes contraction of uterus.
Also stimulates osteoblasts to release factors
which stimulate bone resorption
Sulprostone:
Selective agonist for EP3 receptors
Potent stimulator of uterine smooth muscle
contractions.

72. PROSTAGLANDIN F AND ANALOGUES
Dinoprost
Pharmacological effects:
Causes stimulation of uterus , relaxation of cervix and regression of
corpus luteum.
Side effects:
Transient sweating, decreased body temperature, tachycardia,
abdominal pain, ataxia in horses
Transient salivation, increased body temperaure , restlessness,
tremor and mild diarrhoea in cattle
Contraindication:
Not to be used during pregnancy.
Contraindicated in animals with bronchoconstrictive respiratory
disease and disordersof vascular sytem

73. Drug interaction
Should not be administered along with other oxytocic agents
because of enhancement of pharmacological effects
Inhibitors of eicosanoid synthesis
1) Glucocorticoids :
important class of therapeutic agents which inhibit the release of
arachidonic acid from membrane phospholipids, which in turn
inhibits synthesis of all eicosanoids.
Glucocorticoids are widely used in therapeutic for anti-
inflammatory actions.
2) Non –steroidal anti-inflammatory drugs(NSAIDS)
NSAIDS are important class of therapeutic agents which inhibits
cyclooxygenase enzyme (COX) and blocks the synthesis of
prostaglandins which in turn prevents the inhibition of gastric
acid production.

74. • Others inhibitors includes
• Zileuton: inhibits 5-lipoxygenase enzyme ,prevents generation of
leukotrienes
• Piriprost: also blocks synthesis of leukotrienes
• Dazoxiben: selective thromboxane synthase inhibitor, hence prevents
platelets aggregation
2) inhibitors of eicosanoids receptors:
Montelukast :
Leukotriene CysLT1 receptor antagonist. Reduces inflammatory conditions
in respiratory tract and decreases bronchoconstriction.
Has been indicated for the maintenance treatment of asthma and to
relieve symptoms of seasonal allergies.
Zafirlukast:
Leukotriene CysLT1 receptor antagonist with pharmacological effects
similar of montelukast
Ramatroban :
Thromboxane A2 receptor antagonist. Indicated for the treatment of
coronary artery diseases and treatment of asthma

76. Thank you

77. PEPTIDE AUTACOIDES
77

78. PEPTIDE AUTACOIDES
(Locally Acting hormone like
peptides)Exert important effect on blood vessels and smooth
muscles
Some are involved in tissue damage , allergic reaction
and other inflammatory condition
78
Peptide
Autacoids
Kinins
Angiotensin
Tachykinins
Cytokines

79. A. KININS
 Involve in vasodilation, increase vascular permeability ,
nociception and prostaglandins synthesis.
BRADYKININ and KALLIDIN
• Vasodilator peptide autacoids originated from kininogens
have effect on vascular smooth muscles, capillary
permeability and bronchioles and intestinal muscles.
CHEMISTRY AND DISTRIBUTION:
o Bradykinin is a nonapeptide and kallidin is decapeptide as
lysine residue is at amino-terminal portion so sometimes
called as Lysyl-bradykinin.
o Widely distributed in human , animal’s body ,certain snake
venoms , etc.
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
fig:Bradykinin 79

80. Synthesis and Metabolism
 Synthesized from circulating alpha 2 globulins called
kininogens of proteolytic enzyme, kallikreins.
 Rapidly metabolized(t12=60sec) mainly in lungs but
also in other tissues by enzyme called kininases
(specially kininase II) splitting off 2aminoacid from
carboxy terminal to form inactive kinin metabolite
80

81. Mechanism of action
 Act through two types of kinin receptor B1
and B2.
a) B1 receptors : major role at inflamed sites.
b) B2 receptors: mediate majority effects in
absence of inflammation.
Bradykinin has more affinity to B2 than
B1 but kinin is equipotent to both B1 and
B2.
B2 receptor is coupled to G-proteins and
activates phospholipase C and A2 that leads to
increase in inositol 1,4,5-triphosphate and
diacylglycerol,which in turn increase cytosolic
calcium ion and protein kinase activity
,respectively.
81

82. Pathophysiological Roles
1.Mediation of Inflammation:
• Produce all signs of inflammation-redness,exudation,pain
and leukocyte mobilization.
• Activation of B2 receptors on macrophages
inducesproduction of IL-1 and TNF-alpha and other
inflammatory mediators.
2.Mediation of Pain:
• Directly stimulating nerve ending and increasing PG
production ,
substance P, kinins appear to serve as mediator of pain.
• B2 antagonists block the acute pain produced by
bradykinin but induced B1 receptors appear to mediate
pain of chronic inflammation.
82

83. Continued…
3.Functional Hypermia :
• Functional Hypermia in glands during secretion.
 Regulation of micro circulation-especially in
kidney may be occurring through local kinin
production.
4.Other:
• Vital role in Rhinitis, Angiodema,Asthma and
Carcinoid Syndrome.
• Blood Coagulation:
Liberated Kalikrein activates Factor XII by positive
feedback mechanism, independent of kinin production. 83

84. Kinin
No therapeutic but some drugs that alter their activities are
available.
KININ AGONIST
1) RMP-7:
 Bradykinin analogue resistant to kinin metabolizing
enzyme.
 Increases permeability of blood barrier to certain drugs.
 In the treatment of primary brain tumours.
84

85. 2. Angiotensin Converting
enzymes inhibitors
 Known as Kininase II Inhibitors.
 Prevent the degradation of
endogeneous kinins.
 Prolong their duration of action.
 Clinically not used to prolong kinin
duration of action but their
antihypertensive effects are
mediated through vasodilation.
85

86. KININ
ANTAGONIST
1. Aprotinin:
 Polypeptide from bovine lungs.
Inhibits kalikriens and blocks synthesis of
kinin and factor XIIa.
Hence,inhibition of intrinsic pathway of
coagulation as well as fibrinolysis.
Use in open heart surgery and
hyperplasminaemia.
Withdrawn worldwide from 2007 due to
hypersensitivity.
86

87. B.ANGIOTENSIN
Involve in electrolyte , blood volume and blood
pressure homeostasis.
Types:
i. Angiotensin I
ii. Angiotensin II
(most active biologically commonly called
angiotensins)
iii. Angiotensin III
Collectively are called Renin-
Angiotensin System that serve as circulating link
between kidney and systemic haemodynamic
control system.

88. Synthesis and Metabolism
Angiotensinogen (alpha 2 globulin)
Renin
Angiotensin I(NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-
Leu-COOH)
ACE 1 2 3 4 5 6 7 8 9
10
Angiotensin II (NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-
COOH)
Angiotensinase 1 2 3 4 5 6 7
8
Angiotensin III(NH2-Arg-Val-Tyr-Ile-His-Pro-Phe-
COOH)
+ 1 2 3 4 5 6 7
Inactive fragment
Fig: Biosynthesis and metabolism of Angiotensin(structure shown is in rat, pig,horse and
human but bovine contains valine in position 5)
88

89. • Two main types of G protein coupled
receptors: AT1 and AT2 .
• They are important in the renin-
angiotensin system: they are responsible
for the signal transduction of
the vasoconstriction stimulus of the
main effector hormone, angiotensin II.
Mechanism of action

91. PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTS:
1.Blood pressure homeostasis
Long term and short term pressure regulation.
Also has positive ionotropic and chronotopic effect on
heart.
2. Electroyte and blood volume
Increases Na⁺ and water reabsorption in kidney
Plays imp role in electrolyte and ecf balance
3. Mineralocorticoid secretion
Stimulate aldosterone secretion from adrenal cortex
4 . Cardiovascular disease
Involve in development of congestive heart failure, left
ventricular dysfunction following infarction
5 CNS
Function as neurotransmitter or neuromodulator
and regulation of thirst , release of hormones like ADH
&ACTH
Its most of functions is via renin angiotensin system

92. Renin-angiotensin system :

93. Pharmacology of angiotensin:
ANGIOTENSIN AGONIST :
1. Angiotensin II is not commercially
marketed as a drug and is not approved
for veterinary use .
2.Angiotensin II amide is a synthetic
compound that produce sustained rise in
blood pressure when given IV. However ,
it cause vasoconstriction that may
decrease tissue perfusion.

94. On the basis of action and chemical structures , inhibitors
of renin – angiotensin are of four classes :
I. Renin secretion inhibitor:
• Antagonist of sympathetic nervous system.
• Block renal sympathetic activity by beta adrenoceptor
blocker e.g propanolol
II . Renin inhibitors:
• Interfere with the generation of angiotensin I from
angiotensinogen
• All the drugs , except inhibitors of renin , has low
bioavailability and short duration of action .
• They produce dose dependent reduction in plasma
renin activity .So, used occasionally for reduction of
elevated blood pressure. E.g Aliskiren, Remikerin
Angiotensin
antagonist:

95. ContinuED...
III. Angiotensin converting enzyme inhibitor :
ACE inhibitors are easily identifiable by
their common suffix, '-pril'. ACE inhibitors
can be divided into three groups based on
their molecular structure:
a. Sulfhydryl-containing agents
eg .Captopril Zofenopril
b. dicarboxyl containing ACE inhibitors:
eg Enalapril Ramipril Quinapril
Perindopril Lisinopril Benazepril Imidapril
Trandolapril Cilazapril

96. • IV. Angiotensin receptor antagonists :
a.Peptide antagonists
• e.g saralasin
b.Non-peptide antagonists
• e.g. losartan , irbesartan , candesartan ,
eprosartan, valsartan, olmesartan and telmisartan
Contin
ueD...

97. 97