Autacoids

Dr. Nirbhay Kumar

Asstt. Professor & Head
Deptt. of Veterinary Pharmacology & Toxicology
Bihar Veterinary College, Bihar Animal Sciences University, Patna
 Autacoids

 The term ‘autacoid’ is derived from Greek words –

‘autos’ meaning self and ‘akos’ meaning remedy or
healing substance.

 Autacoids are locally acting hormone like substances

produced by a wide variety of cells in the body, having
intense biological activity which act briefly at the site
of synthesis and release (i.e. on adjacent cells).
 Autacoids contd…
 Autacoids are also known as tissue hormones or local
hormones. These are formed, released and inactivated
within tissues.
 They are usually vasoactive and mediators of
inflammation.
 Autacoids differ from hormones in following ways:
(i) Hormones are produced by specific cells; and
(ii) They are transported through circulation to
act on distant target tissues.
 Classification of Autacoids
(I) Classification based on chemical structure:
(1)Amine autacoids: Histamine, 5-Hydroxytryptamine
(5-HT) or Serotonin.
(2)Lipid derived autacoids: Eicosanoids {Prostaglandins,
Leucotrienes (LTs) and Thromboxanes (TXs)}, Platelet
activating factor (PAF).
(3)Peptide autacoids: Plasma kinins (Bradykinin and
Kallidin), Angiotensin, Vasoactive Intestinal
Polypeptide (VIP) and Substance P.
 Classification of Autacoids contd…

Classification based on origin:

1. Precursor molecules in plasma: Bradykinin, Kallidin

and Angiotensin.

2. Preformed & stored in the cell: Histamine, 5-HT,

VIP and Substance P.

3. Precursor molecules in cell membrane phospholipids:

Prostaglandins, LTs and PAF.
 Histamine (Tissue Amine)

 It is an amine present in a variety of animal

tissues, venoms, bacteria and certain plants (e.g.
stinging nettle).

 The amine is involved in inflammations,

anaphylaxis, allergies and certain types of drug
reactions, and it regulates gastric secretion.
 Synthesis, Storage & Catabolism of Histamine

 Chemically, histamine is β-imidazolylethylamine.

 It is synthesized from the decarboxylation of amino
acid histidine by a specific enzyme, histidine
decarboxylase.
 This enzyme is present in all cell types that contain
histamine.
 Histamine is widely distributed throughout mammalian
tissues.
 Synthesis, Storage & Catabolism of Histamine contd…

 It is generally accepted that most of histamine stored

within the body is synthesized locally.
 Dietary histamine & histamine produced by enteric
bacteria are disposed off rapidly after absorption into
the portal circulation and contribute little or nothing to
tissue storage sites.
 In the animal body, histamine (basic) is found
complexed with heparin (acidic) and protein in the
granules of mast cells.
 Catabolism of Histamine

 The catabolism of histamine

includes ring methylation (to form
N-methylhistamine) catalyzed by
N-methyltransferase and oxidative
deamination catalyzed by diamine
oxidase (histaminase) forming
imidazolylacetic acid and its
riboside.
 The metabolites of histamine are
pharmacologically inert and are
excreted in urine.
 Histamine Stores
Mast cell pool Non-mast cell pool
(i) Made up of mast cells (i) Made up of histaminocytes
(connective tissue) and basophils localized in GI tract, CNS, dermis
(blood). and other organs.
(ii) Turnover of histamine is slow. (ii) Fast turnover.
(iii) The mast cell pool represents (iii) It is synthesized and released
the histamine that participates continuously rather than being
in inflammatory responses, stored.
allergic phenomena, shock, some Functions:
adverse drug reactions and CNS – Neurotransmitter
other forms of cellular insult. GIT – Control of gastric
(iv) Effect of histamine liberating secretion.
drug 48/80 – complete emptying (iv) Resistant to histamine releasing
of storage granules & release of drugs such as compound 48/80.
histamine.
 Histamine Receptors
Selective H1 H2 H3
Agonist 2-methylhistamine 4-methylhistamine a-methylhistamine

Selective Chlorpheniramine Ranitidine Thioperamide

Antagonist
 Smooth muscle (GIT, RT &  Gastric glands:  Brain: Inhibition
uterus): Contraction. Acid secretion. of histamine
 Blood vessels: Endothelium-  Blood vessels: release
Vasodilatation & increased Dilatation. (sedation).
Distribution capillary permeability.  Heart:  Lung, spleen,
In Smooth muscle- + ve inotropy skin, gastric
The Vasoconstriction. + chronotropy mucosa: ↓
Body  Afferent nerve endings:  Brain: histamine
And stimulation (itching & pain) Transmitter content.
Actions  Ganglionic cell: Stimulation. function.  Primarily serves
Mediated  Adrenal medulla: Release of as autoreceptors
catecholamines controlling
 Brain: Transmitter histamine release
function. from neurons in
 Pathophysiological Functions of Endogenous
Histamine
 HCl secretion in the stomach.
 Released from mast cells following Ag - Ab interactions during
hypersensitive reactions (Type-1 hypersensitivity).
 Neurotransmitter in CNS: Regulates water intake, body temperature,
release of ADH, blood pressure and pain perception.
 Regulates GI tone and motility : helps to maintain normal peristalsis.
 Released in extensive tissue damage: Mediates local circulatory
response to injury and inflammatory reactions.
 Play an essential role in the process of tissue growth and repair
because these tissues contain high concentrations of histamine.
 Histamine Release

Various factors are responsible for release of histamine from

mast cells:-

1. Tissue damage by trauma, stings, venoms, proteolytic

enzymes etc.

2. Antigen – antibody reactions involving IgE antibodies.

3. Some drugs like tubocurarine, morphine, atropine,

polymyxin B, vancomycin etc. release histamine without
an immunological reaction.
 Pharmacological Effects of Histamine
[1]. Blood Vessels:
 Marked dilatation of smaller blood vessels including arterioles, capillaries
and venules. Constrictor effect on large blood vessels.
 In rabbits, histamine is a “pressor agent” as a result of pronounced
constriction of blood vessels.

Histamine Shock:
 Intense dilatation of capillary bed → Increase in capillary permeability.
 The dilated arterioles, capillaries and venules that tag large volumes of
blood and reduce venous return to heart and thus the cardiac output.
 Histamine release during allergic or anaphylactic reactions.
 The condition may cause death due to vascular shock as seen in acute
surgical or haemorrhagic shock.
 Pharmacological Effects of Histamine contd…
Triple Response:
Histamine produces a characteristic triple response in skin
following intradermal injection. It consists of the following:-
1. A localized red spot : due to intense capillary dilatation
developing within a few seconds and attaining maximum hue
within a minute.
2. Wheal : Localized oedema fluid forming a wheal in about 90
seconds due to exudation of fluid from capillaries and venules;
and
3. Flare (Diffuse redness) : i.e. redness in the surrounding area
due to arteriolar dilatation mediated by axonal reflex.
 Pharmacological Effects of Histamine contd…
[II]. Non-vascular smooth muscles:
 Acute bronchial constriction (via H1 receptors) in most of the
species. However, guinea pigs are exceptionally sensitive and even
minute doses of histamine can evoke bronchoconstriction leading to
death.
 Tracheal relaxation in cat (both H1 & H2), bronchial relaxation in
sheep (H2) and uterine relaxation in rat (H 2) but uterus is
generally contracted in other species.
[III]. Exocrine glands: ↑ gastric acid secretion (due to H2 receptors).

[IV]. Sensory nerve endings: Nerve ending stimulation→ Itching &

pain.
[V]. Autonomic ganglia and adrenal medulla: Adrenaline release, ↑ B.P.
 Medical Uses of Histamine

 Histamine has no therapeutic application, but used in

experimental pharmacology.

 Clinical applications in human include –

(i) Use of histamine as a test agent for achlorhydria.
(ii) Used in diagnosis of phaechromocytoma, and
(iii) Used for production of triple response to evaluate
integrity of sensory innervations and circulatory
competency.
 Antihistamines
 Drugs used to antagonize the effects of histamine liberation.
The antihistamines act as competitive antagonists of histamine
at receptor sites.

 The antihistamines of clinical value in veterinary medicine are

H1 antagonists.

 H1 Antagonists: These are the drugs which competitively

antagonize actions of histamine at H1 receptors. These are also
known as Conventional Antihistaminics.
 Classification of H1 antagonists
Drug Trade Name
First Generation
(1) Ethanolamines : Diphenhydramine HCl Benadryl (Parke-Davis)
(2) Ethylene diamines : Pyrilamine maleate Histosol
(3) Alkylamines : Chlorpheniramine maleate Jeet (Alembic),
Pheniramine maleate Avil (Intervet)
(4) Piperazines : Hydroxyzine HCL Atarax (UCB Pharma)
(5) Phenothiazines : Promethazine HCl Phenergan (Rhone Poulenc)
(6) Piperidines : Cyproheptadine HCl Practin (Merind)
Second Generation
(1) Piperazines : Cetirizine HCl Cetzine (Glaxo)
(2) Piperidines : Loratadine HCl Loridin (Cadila)
Fexofenadine HCl Allegra (Hoechst)
Terfenadine HCl Terin (Wockardth)
 H1 antihistaminics

 Highly Sedative : Diphenhydramine, Promethazine

& Hydroxyzine.

 Moderately Sedative : Pheniramine and

Cyproheptadine.

 Mildly Sedative : Chlorpheniramine and pyrilamine

 Non- Sedative : Second generation

antihistaminics.
 H1 antihistaminics contd…
Cetirizine:
 It is a metabolite of hydroxyzine (1st generation antihistaminic)
with marked affinity for peripheral H1 receptors.
 It penetrates blood brain barrier poorly, so is very less sedative.
 It attains high and longer lasting concentration in skin, which
may be responsible for its superior efficacy in urticaria/ atopic
dermatitis.
 It is indicated in upper respiratory allergies, pollinosis,
urticaria and atopic dermatitis; also used as adjuvant in
seasonal asthma.
 H1 antihistaminics contd…

Cyclizine, Meclizine, Promethazine, Diphenhydramine

(Anti-motion sickness):

 These agents have prophylactic value in milder types of motion

sickness; should be taken one hour before starting journey.

 Promethazine can also be used in morning sickness, drug

induced and post-operative vomiting, radiation sickness.

 H1 receptors mediate emesis in emetic centre.

 H1 antihistaminics contd…

Clinical Uses :
i. In allergic and anaphylactic reactions.
ii. In bronchial asthma, laminitis, azoturia and pulmonary
emphysema in horses.
iii. In asthma, bloat, acetonaemia, gangrenous mastitis,
metritis and retained placenta.
iv. In the treatment of skin affections like dermatitis, pruritis
and eczema (their mild local anaesthetic action helps in
pruritis).
 H2 antihistaminics
 These drugs block the effects of histamine that are mediated
through H2 receptor stimulation, such as increase in gastric
acid secretion and increase in heart rate and automaticity of
auricles and ventricles.
 The H2 antagonists also act as competitive antagonists of
histamine for H2 receptors.
 The H2 antagonists : Cimetidine, Ranitidine, Famotidine,
Roxatidine, Nizatidine etc.
 These drugs are of value in the treatment of peptic ulcer in
man and animals.
 5-Hydroxytryptamine (5-HT) or Serotonin

 Serotonin was the name given to the vasoconstrictor

substance which appeared in serum when blood clotted.
 Enteramine was the name given to the smooth muscle
contracting substance present in enterochromaffin cells of
gut mucosa.
 Source of 5-HT
 5-HT is formed and localized in three essential pools in the body:
i. Enterochromaffin cells of intestine (about 90%).
ii. Small number of neurons in CNS and mast cells of rodents
(rat, mice, hamsters) along with histamine and heparin.
iii. Blood platelets.
 In addition to the endogenous 5-HT reserve, it is also found in
invertebrates and plants (banana, pear, pineapple, tomato,
stinging nettle etc).
 In the pineal gland, 5-HT is converted to melatonin after
acetylation and methylation.
 Role of endogenous 5-HT

 Neurotransmitter in brain in tryptaminergic nerves. Its

deficiency causes depression and excess causes excitement.

 It is a precursor molecule of melatonin hormone.

 It helps to regulate the tone and motility of GIT.

 Platelet 5-HT serves as one of the mediators of blood clot

formation.
 Synthesis, storage and degradation of 5-HT
 5-HT is synthesized from dietary tryptophan in a two stage
chemical reaction:-
(i) Tryptophan is hydroxylated by the enzyme tryptophan-5-
hydroxylase to give 5-hydroxytryptophan (5-HTP).
(ii) 5-HTP is then decarboxylated to yield 5-HT.

 Like catecholamines, 5-HT is also stored in storage granules

and its uptake is also inhibited by Reserpine.

 Enzymes like MAO, dehydrogenase and aldehyde reductase

help to metabolize 5-HT.
Synthesis and Destruction of
5-HT
 5-HT Receptors
Four families of 5-HT receptors comprising of total 14 receptor
subtypes:-
(1) 5-HT1 {Five subtypes i.e. 5-HT1A, 1B, 1C, 1D, 1E}: Autoreceptors;
inhibit serotonergic neural activity in brain. Functions are
neural inhibition and vasoconstriction.
(2) 5-HT2 {Three subtypes i.e. 5-HT2A, 2B, 2C}: CNS and peripheral
sites (esp. vascular and visceral smooth muscles, platelets
and ANS neurons). Effects are vasoconstriction, intestinal,
bronchial and uterine contraction and platelet aggregation.
 5-HT Receptors contd…
(1) 5-HT3 {No subtype}: Peripheral Nervous System – Emesis, gut
peristalsis, bradycardia, transient hypotension, apnoea, pain,
itching etc.
(2) 5-HT4-7:

(i) 5-HT4: (No subtype) Enteric nervous system.

Mediate intestinal secretion and augments peristalsis.
(ii) 5-HT5: Two subtypes i.e. 5-HT5A, 5B
(iii) 5-HT6: No subtype. Not much is known about
5-HT5-7
(iv) 5-HT7: No subtype.
 Pharmacological effects of 5-HT
[I]. C.V.S.:
 Vasoconstriction on major arteries and veins.
 Activation of 5-HT receptors in endothelial cells and local
release of EDRF and prostaglandins.
 Triphasic Response (produced by Rapid i.v. infusion of 5-HT):-
(a) An initial fall of systemic arterial B.P. accompanied by
paradoxical bradycardia caused mainly by reflex
chemoreceptor stimulation (Bezod – Jarisch Effect).
(b) A short period of pressure effect; and
(c) A prolonged fall in systemic B.P. attributed to a
vasodilator effect in the vascular bed of skeletal muscle.
 Pharmacological effects of 5-HT contd…

[II]. Gastrointestinal tract (GIT):

 5-HT increases motility of small intestines and inhibits the

motility of stomach and large intestines.

[III]. Respiratory tract (RT) and Uterus:

 Constriction of bronchi and uterine contraction.

 5-HT Antagonists & Uses
 LSD, Ergot alkaloids, Methysergide,
 Cyproheptadine : Antiallergic and antipruritic; appetite
enhancer in children and helps to gain body weight.
 5-HT has negative effect on hunger centre and positive effect
on growth hormone secretion),
 Ketanserin,
 Clozapine (effective in schizophrenia),
 Risperidone
 The therapeutic value of 5-HT antagonists in veterinary
medicine is not yet established.
 Eicosanoids (PG, PGI, TXA & LT)

 The biologically active substances that are derived

from 20 carbon polyunsaturated fatty acids
(mainly arachiodonic acid) which share a prefix
‘eicosa’ (means twenty) are termed eicosanoids.

 These include prostaglandins (PG), prostacyclins

(PGI), thromboxane (TXA) and leucotrienes (LT).
Synthesis of Eicosanoids
 Synthesis of Eicosanoids
 Every cell in the body is capable of synthesizing eicosanoids.
 Arachiodonic acid from the phospholipids of cell membrane
and tissue triglycerides by the action of the enzymes
phospholipases and acylhydrolases are released for synthesis
of eicosanoids.
 Several factors are associated with activation of these
enzymes which include physiological, pharmacological and
pathological stimuli.
 Other autacoids like angiotensin and kinins activate
acylhydrolases and promote PG synthesis.
 Prostaglandins

 Two American Gynaecologists, Kurzrok and Lieb, in

1930, reported that human semen contained a
substance which was found to contract isolated
uterine and other smooth muscle strips and caused
a fall in blood pressure in animals.

 The active principle was termed ‘prostaglandin’,

thinking that it was derived from prostate gland.
Classification of Prostaglandins (PGs)
 Classification of Prostaglandins
 The classification of PGs is according to substituents on the
cyclopentane ring of prostaglandin molecule. Some newer PG
related compounds are PGG, PGH, PGI (prostacyclin) and
thromboxane.
 The PGs are further categorized as mono, di or
triunsaturated depending on the number of double bonds in
the side chains. This classification appears as a subscript to
the letter.
 Examples are –
PGE1 → one double bond.
PGE2 → two double bonds.
PGE3 → three double bonds.
 Cyclooxygenase (COX)
 Metabolizes arachiodonic acid to its PG derivatives.

 Two major isoforms : COX-1 and COX-2.

 COX-1:

• Constitutive. Synthesizes the small amounts of PGs that

participate in normal physiologic functions.

• Have protective actions on GI mucosa.

• Inhibition of COX-1 activity : Loss of GI protection of

mucosal epithelial cells.
 Cyclooxygenase (COX) contd…

 COX-2:
• Not constitutive; rather it is inducible in nature.
• Bacterial lipopolysachharide and certain inflammatory
cytokines & growth factors induces synthesis of COX-2.
• Participate in inflammatory reactions.
 Other Eicosanoids

Prostacyclin (PGI2):

 It is a potent vasodilator.

 Exerts antiaggregatory activity on blood platelets.

 PGI2 has a very brief half life of 2-3 minutes.

 Other Eicosanoids contd…

Thromboxane A2:

 It is synthesized in platelets (thrombocytes).

 Thromboxane A2 plays an important physiological

role as :-
• a vasoconstrictor and
• pro-aggregatory in thrombus formation.
 Other Eicosanoids
Leucotriene:

 It is synthesized in lung, platelets and white

blood cells by metabolism of arachiodonic acid via
lipoxygenase pathway.

 Leucotrienes are thought to be chemotactic in

nature for leucocytes and participate in
inflammatory responses.
 Functions of Eicosanoids

 Prostacyclin: Antagonist of prostaglandins and

thromboxane A2 on blood platelets.

 Prostaglandins & Prostacyclins: Promote vasodilatation

and regulate tone of vasculature and control blood flow in
the vital organs.

 TXA2: A potent vasoconstrictor.

 Functions of Eicosanoids contd…

 Prostaglandins & Leucotrienes: Released during

allergic reactions and contribute to the
bronchoconstriction and other signs.

 Prostacyclin: Controls renal blood flow, urine

formation, renin secretion and checks the action of
ADH.
 Functions of Eicosanoids contd…

 Prostaglandins in semen may have a role in facilitating

conception following coitus.

 They also help in termination of pregnancy at the term.

 PGF2α elaborated by uterus (mare, cow, sow & ewe) functions

like luteolytic hormone and used for synchronizing oestrous.

 Aspirin, antagonist of PGF2α inhibits uterine contractions

during parturition by interfering with prostaglandin synthesis.
 Functions of Eicosanoids contd…

 PGs & LTs are produced during tissue injury are

responsible for reactions of inflammations. Increase
in vascular permeability, oedema and leukocyte
infiltration and potentiate the pain inducing effect of
bradykinin.

 Leucocytes release leucotrienes which help in

migration of leucocytes.
 Clinical Uses of Eicosanoids

 PGF2a analogues (Dinoprost, Tiaprost) are used for:-

 Oestrous synchronization (cow, ewe, goat, buffalo etc.)

 Induction of oestrous in anoestrous animals.

 Expulsion of mummified foetus; and

 Expulsion of pus in pyometra.

 Clinical Uses of Eicosanoids contd…

 Therapeutic abortion in human females – PGE2 analogue

(Dinoprostone) is used for abortion during first trimester.

 Impotency – PGE1 analogue (Alprostadil) may be used in

the treatment of impotency.

 Maintenance of patent Ductus Arteriosus: PGE 1 analogue

(Alprostadil) is used in the treatment of congenital
malformations of the heart in neonates.
 Platelet Activating Factor (PAF)

 PAF is another autacoid derived from membrane

phospholipids, and is therefore related to the eicosanoid
family.

 Whereas the eicosanoids are formed from a wide variety of

cell types, PAF is synthesized principally by platelets,
endothelial cells and circulating leucocytes.
 Functions of PAF
 Mediator of thrombin-induced platelet aggregation (by
forming TXA2).
 Contributes to the reactions of inflammation (increased
vascular permeability, oedema, pain, infiltration of leucocytes
and release of lysosomal enzymes).
 PAF is the most potent agent known to increase vascular
permeability.
 Although PAF lowers blood pressure due to its relaxing effect
on vascular smooth muscle, it markedly contracts smooth
muscle of the gut, stomach, uterus and peripheral airways of
the lungs.
 Functions of PAF contd…
 PAF is considered to be one of the most active endogenous
activators of PGs and related eicosanoids. Thus, biological roles of
PAF are often linked to those exhibited by the eicosanoid family.
 Role in ovulation, implantation and parturition. In absence of PAF,
ovulation does not occur.
 After fertilization, the embryo produces PAF which helps in
implantation of the blastocyst.
 At the time of parturition, PAF aids in increasing uterine
contractions. Just before parturition, PAF is found in the amniotic
fluid (released from foetal lungs).
 Despite the wealth of physiologic and pathophysiologic activities
proposed for PAF, pharmacologic manipulation of PAF synthesis and
receptors is at a preliminary stage. The clinical significance of PAF
antagonists is currently unknown for veterinary medicine.
 Cytokines
 In response to certain inflammatory and immunological
stimuli, many types of mammalian cells produce one or more
of a variety of small proteins termed cytokines.
 Cytokines have a vital role in the initiation and regulation of
various inflammatory and immunological responses.
 The important cytokines include:
Tumour necrosis factor-a (TNF-a)
γ-Interferon, and
Interleukins (ILs).
 Currently, monoclonal antibodies raised against these
specific proteins represent the primary
pharmacotherapeutic intervention relevant to the area of
cytokines.
 Polypeptides

 The pharmacologically active polypeptides include –

1. Angiotensins
2. Kinins
3. Substance P and
4. Vasoactive Intestinal Polypeptide (VIP).
 The polypeptides have a variety of extremely potent
effects.
 Angiotensins
 Angiotensin is a blood borne polypeptide that serves as a
circulating link between the kidney and systemic
haemodynamic control systems.
 It is formed from angiotensinogen. It exists as angiotensin I,
angiotensin II and angiotensin III.
 Angiotensin II is a powerful vasoconstrictor having 40 times
the potency of NE and causes blood pressure to rise due to
direct action on vascular smooth muscles.
 Angiotensin is not a mediator of inflammation. It is discussed
here because of its chemical relationship to the kinins. Its
activation is terminated rapidly in blood. Its half life is less
than one minute.
Synthesis of Angiotensins
 Renin Angiotensin Aldosterone System
 The system has homeostatic role in maintaining
haemodynamics and water and sodium balance.
 Secretion of renin from the juxtaglomerular cells, which is
stimulated by renal as well as extrarenal factors.
 Renal factors: Reduced renal blood flow and lowered Na+
concentration in upper tubular fluid.
 Extrarenal factors: Enhanced sympathetic outflow as a result
of reduced blood volume, cardiac output and blood pressure,
causing release of NE from sympathetic nerve endings.
 NE activates β1 adrenergic receptors on juxtaglomerular cells
causing renin secretion.
 Renin Angiotensin Aldosterone System contd…

 Prostacyclin also causes release of renin.

 Renin accelerates formation of angiotensins, which cause
intense vasoconstriction and increase in blood pressure.
 Angiotensin also promotes aldosterone secretion, which helps
in Na+ retention and increase in the volume of extracellular
fluid.
 The vasoconstriction also contributes to Na+ retention. The
antagonists of the system [Angiotensin Converting Enzyme
(ACE) antagonists] are used as vasodilators in renal
hypertensive human subjects (captopril, enalpril etc).
Renin Angiotensin System
 Plasma Kinins
 Bradykinin & Kallidin: Mediates pain (nociception) and inflammatory
responses; regulates B.P., haemodynamics and fluid & electrolyte
balance.
 Bradykinin is a nonapeptide while Kallidin is a decapeptide.
 Prekallikreins (found in plasma, GIT and pancreas) are activated to
kallikreins by the Hageman factor (factor XII) or plasmin, and
others such as tissue damage, contact with glass, collagen and skin,
pH changes etc. which disrupt normal haemodynamics.
 The kallikreins are present in plasma, exocrine glands (pancreas &
salivary) and other organs.
 These are proteinases which convert a high molecular weight
kininogen to bradykinin and a low molecular weight kininogen to
Kallidin.
Kallikrein – Kininogen – Kinin System
 Pathophysiological and pharmacological actions of kinins
 The kinins are responsible for production of pain sensation
during tissue injury.
 They cause hypotension (about 10 fold more potent than
histamine) following marked peripheral vasodilatation and
increase in permeability in the minute blood vessels with oedema
formation as seen with histamine.
 The kinins also mediate inflammatory responses.
 They cause constriction of non-vascular smooth muscles
(intestine, uterus, bronchi) causing pain.
 Renal effects of kinins are opposite to those of renin
angiotensin system (increase of urine volume & excretion of Na+)
 Vasoactive Intestinal Polypeptide (VIP)

 VIP is present in small intestine and also widely

distributed in peripheral nerves and the CNS.

 Although, VIP exerts multiple pharmacological actions in

different tissues, its physiologic relevance remains
questionable.
 Substance P
 Substance P was first extracted from horse intestine and
brain.

 It is an endecapeptide.

 It has some bradykinin like action and is a potent stimulator

of the gut.

 Apart from VIP and substance P, several other vasoactive

peptides of which the actions in pathophysiologic states are
less known, are Eledoisin, Physalamin, Coerulein, Colostrokinin,
Urokinin and kinins of wasp and hornet venoms.
Thank You