Greek : autos = self
Akos = medicinal agents or remedy
•naturally occurring chemical substances
• produced within the body
•transported to the other parts of the body
where they exert their effects
• protect the body from adverse situations.
Classification of autacoids
In the basis of structure autacoids can be divided into three categories:
a) Decarboxylated amino-acid
Plasma kinins (Bradykinin and kallidin)
Platelet activating factor (PAF)
• Imidazole ethylamine
• Important inflammatory mediator
• potent biogenic amine and plays an important
role in inflammation, anaphylaxis, allergies,
gastric acid secretion and drug reaction
Enzyme histidine decarboxylase
Sites of histamine release
1) Mast cell site:
• Pulmonary tissue (mucosa of bronchial tree)
• GIT(intestinal mucosa)
• Conc. Of histamine is particularly high in these
2) Non-mast cell sites:
• CNS (neurons)
• Epidermis of skin.
• GIT(gastric cells)
• Cells in regenerating or rapidly growing tissues
• Basophils (in the blood)
Sites of histamine Storage
• Mast cell in most tissues.
• Basophils in the blood.
• Other storage site includes (non-mast cell
• Epidermis of skin.
• Cells in the gastric mucosa
• Neurons in the CNS.
Metabolism of histamine
• The bound form of histamine is biologically
• There are two major paths of histamine
metabolism in man. The more important of these
involves ring methylation. Alternatively histamine
undergoes oxidative deamination.
• The products of metabolism are imidazole acid
and its ribosides.
• The metabolites are excreted in urine.
• Granules of mast cell contain glycosaminoglycans,
acidic protein in histamine.
Release of histamine
Stings and venom.
Fragments of complements (c3a and c5a)
Lysosomal protein (protease)
Surface acting antigen (bile salt, lysolecithin)
High molecular weight compound(dextran,
a) Chemotherapeutic agents
b) Centrally acting drugs
c) Spasmolytic drugs
d) Sympathomimetic drugs
e) Vasodilator drugs
f) NM blocking agents
Mechanism of Histamine release
• lgE antibody sensitized mast or basophil cells +antigen> Fall of intracellular c AMP and an influx of ca++occurs> degranulation Histamine released
• Histamine held by an acidic protein and heparin within
intracellular granules, when granules are extruded by
exocytosis, Na+ gets exchanged for histamine
• Substance release during IgG or lgM immunoreactions
also release histamine from the mast cells & basophil.
• Chemical and mechanical mast cells injury causes degranulation of
cytoplasmic granules & histamine is released.
• Certain amines ( E.g. morphine, d-tubocurarine) accumulate in the
mast cells due to affinity for heparin, displace histamine and form a
heparin liberator complex. This complex increases the permeability
of the mast cell membrane and diffuse histamine.
• Loss of granules from mast cells relapsed histamine by ion
exchange. Na+ in the extra-cellular fluid rapidly displace histamine
from the complex.
• Compound 48/80 releases histamine from tissue from tissue mast
cells by an exocytotic degranulation process requiring energy and
Release of Ca++
Protein Kinase C activation
Gastric parietal cells
CNS (postsynaptic) some blood vessels
Impromadine> Histamine>Dimaprit> 4methylhistaine > Betazole.
H3 receptor (H3 -R )
Pre-synaptic ( Brain)
other neurons .
**G- protein coupled
H2 – R acts by increase cAMP
Adenyl cyclase activation---increase cAMP
**G protein coupled
Decrease Ca++ influx
K+ channel activation
Physiologic role of Histamine
• Play an important role in gastric HCl secretion by
stimulating H2 receptor.
• Endogenous histamine plays a central role in the immediate
hypersensitivity and allergic reaction.
• In regulation of microcirculation through its vasoactive
• Histamine acts as a neurotransmitter in the CNS.
• Tissue growth and repair
• Histamine helps in implantation of fertilized ovum by
increasing blood supply to the myometrium.
Role of Histamine in Inflammation
• Histamine induces action of prostaglandin as well as
bradykinin to produce pain.
• Histamine helps in the release of proteolytic & hydrolytic
enzymes from the lysosomes.
• Histamine causes vasodilation and increases capillary
• Increase exudation of serum & plasma to surrounding area
• Increase migration of polymorph leucocyte to the traumatic
• Increase migration of inflammatory cell to other places.
• All the processes are in the favour of inflammation
Indications of Histamine
• Diagnostic use:
• Diagnosis of pernicious anaemia (vit-B12
• Pernicious anaemia -> Achlorohydria (no HCI) >Histamine administered -> if no HCI(diagnostic)
• Diagnosis of phaechromocytoma:
phaechromocytoma ->histamine administered ->
excessive adrenaline release from adrenal
medulla-> hypertensive crisis.
• Diagnosis of integrity of reflex arc.
• Therapeutic use
• Meniere's disease.( non suppurative disease of labyrinth ) --betahistine
• Various vascular headache.
Contraindication of histamine
Patient with active peptic ulcer disease .
Angina with hypotension.
Adverse effect of Histamine
Dyspnoea due to bronchospasm.
Hypotension (histaminic shock)
Itching and pain
Individual 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
b) Potent and moderate sedative:
• Tetrahydeoxy carboline
c) Less potent and less sedative:
2) Non-sedative (second generation )
antihistamines: Less lipid soluble therefore
cannot enter into the CNS:
3) Antihistamines having anti-cholinergic action
a) Anti-emetic and anti-motion sickness.
Central action: anti- emetic, anti-motion sickness and antiparkinsonism.
Peripheral action: Atropine like side effects.
4) Anti-histamines having anti-serotonin action
Cyproheptadine -5-HT antagonist action.
5) Antihistamine having local anaesthetic property:
Pharmacological action of H1blocker
• H1 receptor blockade action
• Action not caused by histamine receptor
Anti nausea and anti emetic
Alpha adrenoceptor block( orthostatic hypotension)
Local anesthetic action
Properties of newer antihistamine
• They are highly selective for H1 receptors
• Less lipid soluble; hence no or poor penetration into CNS.
• They are devoid of significant anti-cholinergic actions like
• They are usually active orally.
• Their metabolites are also active H1 antagonist
• Astemizole are extensively plasma protein
• These drugs are able to suppress the wheal and flare
response to histamine or allergen for more than 12hours
• Low incidence of side effects
Indication of H1 blockers
1)Dermatitis of all types.
2)Allergic reaction :Urticaria,Rhinitis,Conjunctivitis and
4)Anti-motion sickness: diphenhydramine
5)Anti-emetic:Cyclizine,Meclizine,Doxylamine (in pregnancy)
6) Anti-parkinsonism: Diphenhydramine is used.
7) Preanesthetic medication
8) As sedative agent: Promethazine
Adverse effect of H1 blockers
:disturbance of ocular accommodation
Dryness of mouth
Blurring of vision.
Doxylamine (no teratogenicity)
Dermatitis, skin rashes
– regulator of smooth muscle in the cardiovascular
system and the gastrointestinal tract, an enhancer of
platelet aggregation, and a neurotransmitter in the
– 5-HT is found in high concentrations in
enterochromaffin cells throughout the gastrointestinal
tract, in storage granules in platelets, and broadly
throughout the CNS
– widely distributed in the animal and plant kingdoms
– It occurs in vertebrates; mollusks, arthropods, and
coelenterates; and in fruits and nuts. It also is present
in venoms, including those of the common stinging
nettle and of wasps and scorpions
Synthesis and metabolism of
• essential amino acid tryptophan
• 2 steps
• Tryptophan hydroxylase, a mixed-function oxidase
converts tryptophan to 5-hydroxytryptophan.
• aromatic L-amino acid decarboxylase converts to
• Released by exocytosis from the serotonergic neurons
• metabolism of 5-HT involves oxidative deamination by
monoamine oxidase (MAO), forming an acetaldehyde
intermediate and then to 5-hydroxyindole acetic acid
(5-HIAA) by a ubiquitous enzyme, aldehyde
• The 5-HT1, 5-HT2, and 5-HT4-7 receptor families are
members of the superfamily of GPCRs. The 5-HT3 receptor,
on the other hand, is a ligand-gated ion channel that gates
Na+ and K+ similar to nicotinic receptors.
• 5-HT1 Receptors. All 5 members of the 5-HT1-receptor
subfamily inhibit adenylyl cyclase.decrease cAMP,
autoreceptors, inhibit serotonergic receptors
• 5-HT2 Receptors. The 3 subtypes of 5-HT2 receptors are
linked to phospholipase C with the generation of two
second messengers, diacylglycerol (a cofactor in the
activation of protein kinase C) and inositol trisphosphate
(which mobilizes intracellular stores of Ca2+).
• 5-HT3 receptor- corresponding to M type
receptor gating cation channel , present in
somatic and autonomic nerve endings, nerve
endings in myenteric plexus, and area postrema.
• 5-HT4 receptor is thought to evoke secretion in
the alimentary tract and to facilitate the
peristaltic reflex. 5-HT4 receptors couple to Gs to
activate adenylyl cyclase, leading to a rise in
intracellular levels of cyclic AMP (cAMP)
Sites of 5-HT Action
• 1) Enterochromaffin Cells: gi mucosa , highest
density in duodenum, synthesize 5-HT from
tryptophan and store 5-HT and other
autacoids. Basal release of enteric 5-HT is
augmented by mechanical stretching.
• 2) platelets: not synthesized in platelets, but is
taken up from the circulation and stored in
secretory granules by active transport,
regulates thrombosis and hemostasis (5-HT2a)
3) Cardiovascular System: The classical response of blood vessels to 5-HT is
contraction, particularly in the splanchnic, renal, pulmonary, and cerebral
Contraction – large vessels
Relaxation( due to release of EDRF)
Bradycardia- activation of coronary chemoreflex
Hypotension and apnoea
positive inotropic and chronotropic actions
4) Central Nervous System. A multitude of brain functions are influenced by 5-HT,
including sleep, cognition, sensory perception, motor activity, temperature
regulation, nociception, mood, appetite, sexual behavior, and hormone secretion.(
but injected serotonin doenot have CNS effects)
A) sleep and wake cycles
B) anxiety and depression
C) Aggression and Impulsivity
• Neurotransmitter-sleep, temperature regulation, thought, cognitive
function, behaviour and mood, vomiting and pain perception
• Precursor of melatonin
• Neuroendocrine function
• Nausea and vomiting
• Migraine-methysergide, sumatriptan
• Raynaud’s disease-ketanserin
• Variant angina
• Intestinal motility
• Carcinoid syndrome
• 5-HT1A receptor
Azapirones such as buspirone, gepirone, and tandospirone are 5HT1A agonists marketed primarily as anxiolytics, but also recently as
antidepressants, 8-OH DPAT( hydroxydipropylaminotetraline)
• 5-HT1B receptor
Triptans such as sumatriptan, rizatriptan, and naratriptan, are 5HT1B receptor agonists that are used to abort migraine and cluster
• 5-HT1D receptor
In addition to being 5-HT1B agonists, triptans are also agonists at the
5-HT1D receptor, which contributes to their antimigraine effect.
• 5-HT1F receptor.
Lasmiditan has successfully completed Phase II clinical trials in early
• 5-HT2A receptor
Psychedelic drugs such as LSD, mescaline, psilocin, , act as 5-HT2A
agonists. Their action at this receptor is responsible for their
It is now known that many of these drugs act as agonists at many
other 5HT receptors in addition to the 5-HT2A including the 5-HT2C
• 5-HT2C receptor
Lorcaserin is a thermogenic and anorectic weight-loss drug which
acts as a selective 5-HT2C agonist.
• 5-HT4 receptor
Cisapride is a 5-HT4 partial receptor agonist that has been used to
treat disorders of gastrointestinal motility. Prucalopride is a highly
selective 5-HT4 receptor agonist that can be used to treat certain
disorders of gastrointestinal motility
• 'Ketanserine' blocks 5 HT2A,5 HT2C and alpha 1 receptors.
• 'Ondansetron,Dolansetron,Granisetron' are 5 HT3 receptor
antagonist.they are efficacious in treating chemotherapy induced
• Clozapine' blocks 5 HT2A,5 HT2C,D4 receptors.
• Quetiapine' blocks 5 HT2A,5 HT1A,D1-2,HI,alpha 1 receptors.
• Methsergide' is 5 HT2A-2C antagonist and nonselective 5 HT 1
receptor blocker.it causes retrperitoneal fibrosis and mediastinal
• Cyproheptadine' blocks 5 HT2A, HI and it is a mild anticholinergic.
• Pizotifen' is a 5 HT2A-2C , H1 blocker and anticholinergic used for
5-HT2a, H1 antagonist
Increase appetite in children
Postgastrectomy dumping syndromes
Antagonise priapism and orgasmic delays
caused by SSRIs
• Clozapine , a 5-HT2A/2C-receptor antagonist,
represents a class of atypical antipsychotic
• reduced incidence of extrapyramidal side
effects compared to the classical neuroleptics,
and possibly a greater efficacy for reducing
negative symptoms of schizophrenia
• Also has a high affinity for subtypes of
• Selective serotonin (5-HT3) receptor
antagonist that inhibits serotonin receptors in
GI tract or chemoreceptor trigger zone.
• Prevention of nausea and vomiting with initial
and repeat courses of emetogenic cancer
chemotherapy, including high-dose cisplatin;
• prevention of postoperative nausea or
• Eicosanoids are 20-carbon fatty acid
• Consist of prostaglandins, related
thromoboxanes and leukotrienes
• derived from the oxidative metabolism of
arachidonic acid (5, 8, 11, 14-eicosatetraenoic
• arachidonic acid cascade
Products of Prostaglandin
PGG2, and PGH2
COX-1 – constitutive, levels always same
COX-2---normally insignificant but induced by
cytokines, and growth factors
• COX-1 inhibitors:
• COX-2 inhibitors:
• The prostaglandins, thromboxane, and prostacyclin,
collectively termed the prostanoids, are generated
from PGH2 through the action of isomerases and
Products of Lipoxygenase
• Lungs, WBC, and platelets
• hydroperoxyeicosatetraenoic acids (HPETEs), which
rapidly convert to hydroxy derivatives (HETEs) and
• FLAP (5-lipo-oxygenase activating protein)
• associated with asthma, anaphylactic shock, and
• LTA4, the primary product of 5-LOX, can be converted
via 12-LOX in platelets to the lipoxins LXA4 and LXB4
Lipo-oxygenase inhibitor: zileuton
Epoxygenase Products (cytp450
• four epoxyeicosatrienoic acids (EETs)
• The epoxygenase products are synthesized in
endothelial cells, and cause vasodilation in a
number of vascular beds by activating the
smooth muscle large conductance Ca2+activated K+ channels
• Prostaglandin isomers
• Degradation of eicosanoids:
• Fastest in lungs
• Oxidation of side chains and reduction of double
• Metabolites excreted in urine
Prostaglandin synthesis inhibitors
• Nonsteroidal anti-inflammatory drugs NSAIDS
, block enzymes that convert arachidonic acid
• Corticosteroids: by stimulating the synthesis
of several inhibitory proteins collectively
called annexins or lipocortins. inhibit
phospholipase A2 activity, probably by
interfering with phospholipid binding and thus
preventing the release of arachidonic acid.
• Basic structural unit is referred to as a prostanoic
or prostenoic acid.
• Each PG differs from the others in the
substitution pattern in the cyclopentane ring and
• Prostaglandins are broadly classified as PGA,
PGB,PGC, PGD, PGE, PGF, PGG, and PGH based on
their cyclopentane/pentene ring substitution
• subclassified based on the degree of unsaturation
(i.e. PGE1, PGE2)
• eight prostanoid receptors have been cloned
• receptors are coupled to either
phospholipase C (PLC) or adenylate cyclase
• in the case of adenylate cyclase, the action of
the PGs may be stimulatory or inhibitory.
• powerful vasodilators; especially PGI2 and PGE2, promote
vasodilation by increasing cAMP and decreasing smooth
muscle intracellular calcium,
• In kidney: increased excretion of salt in the urine.
• inhibit the action of vasopressin on the kidney tubules,
• mediate the control of GnRH over LH secretion, modulate
ovulation, and stimulate uterine muscle contraction and
• inducing labor in pregnant
• Administration of either PGE2 or PGF2 results in colicky
• Low concentrations of PGE2 enhance, whereas
higher concentrations inhibit, platelet
aggregation. Both PGD2 and PGI2 inhibit
• PGE2 promotes the release of growth hormone,
prolactin, TSH, ACTH, FSH, and LH.
• increase bone turnover, ie, stimulation of bone
resorption and formation
• PGE and PGF derivatives lower intraocular
• Mediate fever and malaise
• produces vasodilation,
• inhibits platelet aggregation and stimulates intestinal and uterine smooth muscle.
• ductus arteriosus
• erectile dysfunction
♦ Cardiovascular: Flushing, bradycardia, hypotension, tachycardia, edema , less
commonly more severe effects such as cardiac arrest, congestive heart failure,
second degree heart block, shock, supraventricular tachycardia and ventricular
♦ CNS: Fever, seizures, cerebral bleeding, hyperextension of the neck, hyperirritability,
hypothermia,lethargy and stiffness .
♦ GI: Diarrhea, gastric regurgitation and hyperbilirubinemia.
Hematologic: Disseminated intravascular coagulation, anemia, bleeding,
♦ Renal: Anuria and hematuria
♦ Respiratory: Apnea, bradypnea, bronchial wheezing, hypercapnia, respiratory
depression, respiratory distress and tachypnea
2) Prostaglandin E2 (Dinoprostone)
• PGE2 stimulates the production of PGF2α which in turn
sensitizes the myometrium to endogenous or
exogenously administered oxytocin.
• 1)initiation or continuation of cervical ripening in
pregnant women at or near term with a medical or
obstetrical need for labor induction (cervical ripening)
• 2) the management of missed abortion or intrauterine
fetal death up to 28 weeks gestational age and,
• 3) management of nonmetastatic gestational
trophoblastic disease (benign hydatidiform mole).
3) Misoprostol, Enprostilfor peptic ulcer as anti secretory and cytoprotective agents)
• Antisecretory Actions: decreased HCl and pepsin secretion( basal or
• Cytoprotective Activities: increased gastric blood flow, increased mucous
and bicarbonate protection
• Immunologic Actions: inhibit basophilhistamine release, thus it has a
potential role as immunotherapy designed to reduce early-phase and latephase allergic inflammation
• Reproductive Effects: Misoprostol produces uterine contractions that may
• 4) Prostaglandins for Treatment of Pulmonary
Hypertension: Epoprostenol, Treprostinil and
CLINICAL PHARMACOLOGY OF
1) Female reproductive system:
a) Abortion—mifepristone pretreatment
b) Post partum hemorrhage– carboprost,
c) Facilitation of labour -d) Dysmenorrhoea
e) Menstruation inducing contraceptive--
2) Male reproductive system:
erectile dysfunction-- alprostadil
3) Pulmonary hypertension
4) Patent ductus arteriosus
5) Peripheral vascular diseases
6) Blood platelet aggregation
8 ) Immune system
a) Cell-mediated organ transplant rejection
c) Rheumatoid arthritis
10) Bronchial asthma
• process of clot formation begins with an
aggregation of blood platelets (TXA2). This
process is strongly stimulated by
thromboxanes and inhibited by prostacyclin.
• Prostacyclin--- vasodilation and lowers BP
• LTB4- neutrophils
• LTC4 and LTD4- macrophages
• LTC4 and LTD4 are potent bronchoconstrictors
and are recognized as the primary
components of the slow-reacting substance
of anaphylaxis (SRS-A) that is secreted in
asthma and anaphylaxis
Effects of leukotrienes :
1) CVS and blood: brief rise in BP followed by a prolonged
fall, due to coronary constriction induced decrease in
cardiac output and reduction in circulating volume due
to increased capillary permeability
2) Inflammation = redness (rubor), heat (calor), pain (dolor),
migration of neutrophils to the inflammatory site
promoted by LTB4
3) Smooth muscle- contraction, potent bronchoconstrictors,
and also increase bronchial secretions
4) Afferent nerves- sensitizes afferent neurons carrying pain
• All function through IP3/DAG transducer
neuropeptide Y, and
bradykinin and related kinins,
vasoactive intestinal peptide,
calcitonin gene-related peptide(CGRP), and
RENIN AND ANGIOTENSIN
• pathophysiology of hypertension, congestive
heart failure, myocardial infarction, and
• Circulating renin angiotensin system
• Tissue (local) renin-angiotensin system
• Extrinsic local RAS- blood vessels
• Intrinsic local RAS- heart , blood vessels, brain, kidneys,
• Synthesized in liver
• Glycoprotein with a molecular weight 57, 000
• Synthesis increased by:
c) thyroid hormones
d) angiotensin II
Elevated during pregnancy and in women taking
• Components of RENIN-ANGIOTENSIN SYSTEM
3) Angiotensin I
4) Angiotensin coverting enzyme
5) Angiotensin II
within kidney synthesized by JG cells
Renin secretion controlled by:
a) Renal vascular receptor: decreased stretch =increased renin
b) Macula densa: sensitive to Na+ and Cl- delivery to distal tubule, signal
transmission by: adenosine( inhibits renin) , prostaglandins ( stimulates renin)
and nitric oxide. Decrease= increased renin
Sympathetic nervous system:
increased nerve activity= increased renin
beta1 receptors (renal)
etrarenal beta receptors
d) angiotensin: Angiotensin II inhibits renin secretion
e) Pharmacologic alteration of renin release:
stimulated by : vasodilators
Phosphodiesterase enzyme inhibitors ( theophylline, milrinone,
No biologic activity
Must be converted to angiotensin II
Angiotensin converting enzyme
Peptidyl dipeptidase ( PDP)
Substrates: angiotensin I
also cleaves enkephalins and substance P
• Distributed widely in body , mostly on luminal
surface of vascular endothelial cells
• Potent pressor agent
• 40 times more potent than norepinephrine
• Pressor response due to
a) Direct contraction of vascular smooth muscle
b) Reset baroreceptor reflex control
c) Stimulates autonomic ganglia
d) Facilitate sympathetic transmission
e) Direct positive inotropic action on heart
• In adrenal cortex:
acts on zona glomerulosa to stimulate
aldosterone biosynthesis, also glucocorticoid
• In Kidney:
increase proximal tubular reabsorption
inhibit secretion of renin
stimulate drinking (dypsogenic )
increased secretion of vasopressin and ACTH
• Cell Growth:
causes cardiovascular hypertrophy
• high affinity for losartan and low for PD123177,
predominant in vascular smooth muscle ,
• activation of phospholipase C and IP3/DAGsmooth muscle contraction
• Vascular and cardiac growth mediated by
tyrosine kinases and increased transcription of
• Fetal tissue development
• Inhibition of growth and proliferation
• Cell differentiation
Angiotensin II having very short half life
Most vascular beds ( except lungs)
Metabolites biologically inactive
aminopeptidases, endopeptidases, and
Drugs acting on renin angiotensin
1) Drugs blocking renin secretion: clonidine ,
2) Direct renin inhibitors: remikiren, enalkiren
3) ACE inhibitors captopril, enalapril
4) Angiotensin antagonists :
a) peptide: saralasin
b) non peptide: losartan , valsartan, erposartan,
irbesartan, candensartan, telmesartan
• potent vasodilator peptides
• formed enzymatically by the action of
enzymes known as kallikreins or
kininogenases acting on protein substrates
• metabolised by nonspecific exopeptidases or
endopeptidases, commonly referred to as
present in plasma and in several tissues, including the kidneys,
pancreas, intestine, sweat glands, and salivary glands.
Plasma prekallikrein can be activated to kallikrein by trypsin,
Hageman factor, and possibly kallikrein itself.
Kallikreins can convert prorenin to active renin
• precursors of kinins and substrates of kallikreins
• present in plasma, lymph, and interstitial fluid.
• Two kininogens are known to be present in plasma:
• A) low-molecular-weight form (LMW kininogen)- crosses capillary walls
and serves as the substrate for tissue kallikreins
• B) high-molecular-weight form (HMW kininogen)(15–20% of the total
plasma kininogen). confined to the bloodstream and serves as the
substrate for plasma kallikrein.
• Three kinins have been identified in mammals:
bradykinin, lysylbradykinin (also known as
kallidin), and methionyl-lysylbradykinin
• Bradykinin is released by plasma kallikrein,
lysylbradykinin by tissue kallikrein, and
methionyl-lysylbradykinin by pepsin and
Actions of kinins
Effects on the Cardiovascular System
direct inhibitory effect of kinins on arteriolar smooth muscle
mediated by the release of nitric oxide or vasodilator
prostaglandins such as PGE2 and PGI2
• direct stimulation of venous smooth muscle or from the release of
venoconstrictor prostaglandins such as PGF2
• Bradykinin also increases blood pressure when injected into the central
• water and solutes pass from the blood to the extracellular fluid, lymph
flow increases, and edema may result.
Effects on Endocrine & Exocrine Glands
• prekallikreins and kallikreins are present in several glands,
including the pancreas, kidney, intestine, salivary glands,
and sweat glands
• Local modulators of blood flow
• modulate the tone of salivary and pancreatic ducts and
help regulate gastrointestinal motility
• influence the transepithelial transport of water,
electrolytes, glucose,and amino acids, and may regulate the
transport of these substances in the gastrointestinal tract
• physiologic activation of various prohormones, including
proinsulin and prorenin
• Role in Inflammation
Kallikreins and kinins can produce redness,
local heat, swelling, and pain
• Effects on Sensory Nerves
elicit pain by stimulating nociceptive afferents
in the skin and viscera.
KININ RECEPTORS & MECHANISMS OF
• B1 and B2
– widespread distribution
– G protein–coupled and agonist binding sets in motion
multiple signal transduction events, including calcium
mobilization, chloride transport, formation of nitric
oxide, and activation of phospholipase C,
phospholipase A2, and adenylyl cyclase
– Limited distribution
– important in long-lasting kinin effects such as collagen
synthesis and cell multiplication.
DRUGS AFFECTING THE KALLIKREINKININ SYSTEM
• anti-inflammatory and antinociceptive agents.
• Peptides• Icatibant is a second-generation B2 receptor
• third generation of B2-receptor antagonists
was developed; examples are FR 173657, FR
172357, and NPC 18884
• the kallikrein inhibitor aprotinin
• a synthetic polypeptide that has effects like
gastrin when given parenterally.
• stimulates the secretion of gastric acid, pepsin,
and intrinsic factor,
• used as a diagnostic aid in the pentagastrinstimulated calcitonin test.
• binds to the cholecystokinin-B receptor, which is
expressed widely in the brain. Activation of these
receptors activates the phospholipase C second
• When given intravenously it causes panic attacks.
• is a peptide hormone of the gastrointestinal
system responsible for stimulating the digestion
of fat and protein.
• Also called pancreozymin
• CCK also causes the increased production of
hepatic bile, and stimulates the contraction of the
gall bladder and the relaxation of the Sphincter of
Oddi, resulting in the delivery of bile into the
duodenal part of the small intestine.
• CCK administration causes nausea and anxiety,
and induces a satiating effect
• influence neurotransmission in the brain, regulating
anxiety, feeding, and locomotion.
• regulation of dopamine activity in the brain. CCK-B
activation appears to possess a general inhibitory
action on dopamine activity in the brain, opposing the
dopamine-enhancing effects of CCK-A.
• Activation enhances GABA release
• CCK-B receptors modulate dopamine release, and
influence the development of tolerance to opioids
• CCK-B activation decreases amphetamine-induced DA
release, and contributes to individual variability in
response to amphetamine.
• belongs to the tachykinin family of peptides, Other members of this
family are neurokinin A and neurokinin B. Substance P is an
undecapeptide, while neurokinins A and B are decapeptides.
• present in the central nervous system, where it is a
neurotransmitter, and in the gastrointestinal tract, where it may
play a role as a transmitter in the enteric nervous system and as a
local hormone .
• Effects in behavior, anxiety, depression, nausea, and emesis.
• It is a potent arteriolar vasodilator, producing marked hypotension .
The vasodilation is mediated by release of nitric oxide from the
• substance P causes contraction of venous, intestinal, and bronchial
• It also stimulates secretion of the salivary glands and causes
diuresis and natriuresis by the kidneys.
• The actions of substance P and neurokinins A and B are mediated
by three G protein-coupled tachykinin receptors designated NK1,
NK2, and NK3.
• Substance P is the preferred ligand for the NK1 receptor, the
predominant tachykinin receptor in the human brain.
• neurokinins A and B also possess considerable affinity for this
receptor. In humans, most of the central and peripheral effects of
substance P are mediated by NK1 receptors.
• Several nonpeptide NK1 receptor antagonists have been developed.
These compounds are highly selective and orally active, and enter
• these antagonists may be useful in treating depression and other
disorders and in preventing chemotherapy-induced emesis. Eg.