AUTACOIDS

T KATUNGA PHIRI
 AUTACOIDS
• These are biological molecules that act like local
hormones, produced by the body and acting near where
they are produced.
• They are also referred to as mediators or chemical
messengers.
• These messengers differ from other hormones produced
by glands, transported by the blood and acting on other
target tissues.
 Determination of local hormones

• A mediator is said to be released in response to a

stimulus of some kind, and produces a particular
biological effect.
• Within an appropriate time frame;
• that application of an authentic sample of the mediator
reproduces the original biological effect (agonist)
• that interference with the synthesis, release or action
ablates or modulates the original biological response.
(antagonists)
 HISTAMINE
• It is an amine formed from histidine by histidine
decarboxylase.
• It is present in high concentrations in tissues in contact
with the outside world (lungs, skin and gastrointestinal
tract).
• At cellular level, histamine is found in granules together
with heparin in mast cells and basophils.
• It is also found in the histaminergic neurons in the brain
and histaminocytes in the stomach.
.
.
 Histamine release
• Histamine is released from mast cells by exocytosis during inflammatory
or allergic reactions.
• Stimuli interact with specific surface receptors, and the combination of
antigen with cell-fixed immunoglobulin (Ig)E antibodies
• Histamine release is initiated by a rise in cytosolic [Ca2+ ].
• Various basic drugs, such as morphine and tubocurarine also release
histamine.
• Agents that increase cAMP formation (e.g. β-adrenoceptor agonists
adrenaline, salbutamol) inhibit histamine secretion and lead to
bronchodilation.
 Histamine receptors
• There are four histamine receptors which are all G-
coupled but differ in their downstream signaling system.
• H1 and H3 receptors elevate cAMP, whereas H2 and H4
receptors stimulate Phospholipase C (PLC).
• All four are implicated in the inflammatory response in
some capacity.
Histamine receptors
 Actions
• Smooth muscle effect- Histamine, acting on H1
receptors, contracts the smooth muscle of the ileum,
bronchi, bronchioles and uterus.
• The effect on the ileum is not as marked in humans as it
is in the guinea pig.
• Histamine reduces air flow in the first phase of bronchial
asthma but H1 antagonists are not of much benefit in the
human disease.
 Cardiovascular effects
• Histamine dilates human blood vessels and increases
permeability of postcapillary venules, by an action on H1
receptors.
• It also increases the rate and the output of the heart
mainly by an action on cardiac H2 receptors.
(pathological, rather than physiological state).
 Gastric secretion
• Histamine stimulates the secretion of gastric acid by
action on H2 receptors.
• In clinical terms, this is the most important action of
histamine, because it is implicated in the pathogenesis of
peptic ulcer
 Effects on skin (H1)
• When injected intradermally, histamine causes a reddening of
the skin, accompanied by a weal with a surrounding flare.
• The flare is an axon reflex: stimulation of sensory nerve fibres
evokes antidromic impulses through neighbouring branches of
the same nerve, releasing vasodilators such as calcitonin gene-
related peptide
• Histamine causes intense itch if injected into the skin or applied
to a blister base, because it stimulates sensory nerve endings
through an H1-dependent mechanism
 Pathophysiologic roles of
histamine
• as a stimulant of gastric acid secretion – H2 receptor
antagonist
• as a mediator of type I hypersensitivity reactions such as
urticaria and hay fever - H1
Histamine antagonism
• Histamine receptor antagonist,
• secretion blockers (cromolyn sodium),
• physiologic antagonist (adrenaline and salbutamol)
 H1 blockers
• Used mainly for the treatment of allergic reactions like
urticaria and hay fever, conjunctivitis and congetion.
• Some of them (promethazine) have antiemetic effect caused
by motion sickness, vestibular disorders, and pregnancy.
• Preoperative anxiety
• Insomnia
• Irritable bowel syndrome- can help with abdominal pain
(cramps)
 1st generation H1 blockers
• They are sedating as they penetrate the BBB. They also
poses M-cholinolytic effects.
Antagonist of H2-receptors
(H2-blockers) – for the treatment
of peptic ulcer:
•Cimetidine (? …)
•Famotidine
•Nizatidine
•Ranitidine
•Roxatidine
 Mast cell stabilizers
• Prevent transmembrane influx of calcium ions,
provoked by antigen-IgE antibody reaction on the
mast cell membrane.
• They prevent degranulation and release of
histamine and other autacoids from mast cells.
 Examples
• Sodium cromoglycate (cromolyn sodium)
• Nedocromil
• Lodoxamide
• Ketotifen fumarate
• Epinastine hydrochloride
SEROTONIN
 SEROTONIN
• 5-hydroxytryptamine (5-HT)
• It is both a neurotransmitter (in the brain) and local
hormone in the peripheral.
• It has three main sites of distribution;
• In the wall of the intestine (enterochromaffin cells)
• In the blood ( in platelets)
• In the CNS (mid brain)
 Biosynthesis
• It is formed from dietary tryptophan
• Synthesis occurs in chromaffin cells as well as neurons
• Platelets have a high affinity for 5-HT. they bind to
serotonin during luminal circulation.
• NOTE- Mechanism of biosynthesis and metabolism of
serotonin and adrenaline are similar.
 Important functions of 5-HT
• Increased GI motility
• Increased platelet aggregation
• Increased microvascular permeability
• Stimulation of nociceptive nerve endings
 Important functions of 5-HT
Control of
• Appetite
• Sleep
• Mood
• Hallucinations
• Pain perception
• Vomiting
 Clinical conditions where 5-HT
plays a role
• Migraine
• Mood disorders (depressive illnesses)
• Anxiety
• Vomiting
• Carcinoid syndrome (malignant tumors of
enterochromaffin cells in intestines). Associated with 20
fold increase of 5HT metabolite in urine.
 .
.
 5-HT receptors
• There are seven families (1-7) with subtypes (5-HT1 has A-F).
• All are G protein–coupled receptors, except 5-HT3, which are
ligand-gated cation channels.
• 5-HT1 receptors occur mainly in the central nervous system
(CNS) (all subtypes) and some blood vessels (5-HT1B/D
subtypes).
• Some effects are mediated through inhibition of adenylyl
cyclase, include neural inhibition and vasoconstriction.
(important for migraine control)
Migraine
 Migraine and 5HT
• There is a sharp increase in the urinary excretion of the
main 5-HT metabolite, 5-HIAA, during the attack.
• The blood concentration of 5-HT falls, probably because of
depletion of platelet 5-HT. 2.
• Many of the drugs that are effective in treating migraine
are 5-HT receptor agonists or antagonists.
 Rang
Ranget etal.
al.
Pharmacology
Pharmacology
––55ststEd.
Ed.(2003)
(2003)

Pathogenesis of migraine and drug treatment

 5-HT1
• Specific agonists include triptans (used in migraine
therapy)
• Examples: Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan
• Buspirone (used in anxiety) a partial agonist.
• Specific antagonists include spiperone and
methiothepin.
 5-HT2
• 5-HT2 receptors occur in the CNS and many peripheral
sites (especially blood vessels, platelets, autonomic
neurons).
• Neuronal and smooth muscle effects are excitatory and
some blood vessels are dilated as a result of nitric oxide
release from endothelial cells.
• 5-HT2 receptors act through the phospholipase C/inositol
trisphosphate pathway. Ligands include lysergic acid
diethylamide (LSD; agonist in CNS, antagonist in
periphery). Specific antagonists include ketanserin,
Ergotamine and methysergine (migraine)
 Adverse effects
of methysergide

• retroperitoneal fibrosis
• renal failure
SSRIs (selective serotonin
reuptake inhibitors):
• Examples:
Fluvoxamine,Citalopram,
Fluoxetine, Paroxetine, Sertraline
• Are used in humans to treat:
chronic anxiety, depression,
bulimia
 5-HT3-receptors

• Located in enteric neurons and in CNS

• Act by stimulating adenylate cyclase
• Effects are excitatory, causing GI motility and
vomiting
• Also stimulates nociceptive nerve ending and
causes pain
 5-HT3-receptors

• Antagonists of 5-HT3 receptors are very powerful

antiemetics (associated with chemotherapy)
• Examples: Dolasetron, Granisetron, Ondansetron,
Tropisetron
 Agonists of
5-HT4-receptors

• metoclopramide, Tegaserod (Zelmac®)

activates 5-HT4- receptors in the intestine
and stimulates peristalsis and secretion.
• Stimulates gastric emptying.
• Indication: colon irritable syndrome
EICOSANOIDS
 2. EICOSANOIDS
(20 carbon atoms!)
(eicosi = 20) •prostanoids (5,8,11,14-eicosatetraenoic acid)

- prostaglandins (PGs)
- thromboxanes (Txs)
•leucotrienes (LTs)
•lipoxins
 Biosynthesis and release
• These are commonly known as inflammatory modulators.
• They are not stored in cells but once synthesized are
released into the general circulation.
• Cytosolic PLA2 is activated by phosphorylation. (triggered
by inflammatory stimuli)
• This enzyme catalyzes the release of arachnodic acid from
phospholid membrane.
• Arachnodic acid is metabolized via 2 pathways; COX or
Lipoxyginases.
 COX
• Fatty acid cyclo-oxygenase
• Two isoforms; COX-1 & COX-2
• Responsible for producing prostanoids.
• COX-1 is present in most cells as a constitutive enzyme.
• It is mainly responsible for homeostatic regulation (e.g.
modulating vascular responses, regulating gastric acid
secretion).
• COX-2 is induced by inflammatory stimuli.
 COX
• Both enzymes catalyse the incorporation of two molecules of oxygen
into two of the unsaturated double bonds in each arachidonate
molecule, forming the highly unstable endoperoxides prostaglandin
(PG)G2 and PGH2.
• The suffix ‘2’ indicates that the product contains only two double bonds.
• rapidly transformed in a tissue-specific manner by endoperoxide
isomerase or synthase enzymes to PGE2, PGI2 (prostacyclin), PGD2,
PGF2α and thromboxane (TX)A2.
• In platelets TXA2 predominates, whereas in vascular endothelium PGI2
is the main product.
• Macrophages, neutrophils and mast cells synthesise a mixture of
products.
 CATABOLISM
• Most prostaglandins are rapidly inactivated by prostaglandin
dehydrogenase and reductase enzymes.
• The inactive products are further degraded by general fatty acid-
oxidising enzymes and excreted in the urine.
• The enzymes are present in high concentration in the lungs.
• The half-life of most prostaglandins in the circulation is less than
1 minute.
• TXA2 and PGI2 are slightly different. Both are inherently
unstable and decay rapidly and spontaneously within 30s and
5min respectively.
 PROSTANOIDS
• PGD2 causes vasodilatation in many vascular beds
• inhibition of platelet aggregation,
• relaxation of gastrointestinal and uterine muscle

• PGF2α causes uterine contraction in humans

 PROSTANOIDS
• PGI2 causes vasodilatation,
• inhibition of platelet aggregation
• renin release and natriuresis through effects on tubular
reabsorption of Na+
• TXA2 causes vasoconstriction and platelet aggregation
 PROSTANOIDS
• PGE2 is the predominant ‘inflammatory prostanoid.
• EP1 receptors, it causes contraction of bronchial and
gastrointestinal smooth muscle
• EP2 receptors, it causes bronchodilatation, vasodilatation,
stimulation of intestinal fluid secretion and relaxation of
gastrointestinal smooth muscle
• at EP3 receptors, it causes contraction of intestinal smooth
muscle, inhibition of gastric acid with increased mucus secretion,
inhibition of lipolysis, inhibition of autonomic neurotransmitter
release and contraction of the pregnant human uterus.
 PROSTANOIDS
• EP4 receptors, it causes similar effects to those of EP2
stimulation .
• Also causes vascular relaxation and cervical ‘ripening’.
• Some inhibitory effects of PGE2 on leukocyte activation
are probably mediated through this receptor
• Misoprostol, an EP2/EP3 agonist.
 Dorland’s
Dorland’sIllustrated
Illustrated
Medical Dictionary
Medical Dictionary
(2003,
(2003,2004)
2004)

PGE1, PGF2α, PGE2

• PGE1 (gemeprost
• PGF2α (dinoprost)
• PGE2 (dinoprostone)
are given for:
• induction of labour
• termination of pregnancy
 INFLAMMATION
• PGE2 predominates, although PGI2 is also important.
• In areas of acute inflammation, PGE2 and PGI2 are generated
by the local tissues and blood vessels, while mast cells release
mainly PGD2.
• In chronic inflammation, cells of the monocyte/macrophage
series also release PGE2 and TXA2
• PGE2, PGI2 and PGD2 are themselves powerful vasodilators
• Prostaglandins of the E series are also pyrogenic.
 Arachidonic acid
5-Lipoxygenase

Leukotrienes (LTs)

LTC4- LTD4- LTE4-

receptor receptor receptor

(-) (-)
Montelukast, Zafirlukast
 LEUKOTRIENES
• Comprise two main categories, chemoattractant (LTB4)
and cysteinyl (or sufidopeptide) leukotrienes (LTC4, D4,
E4 and F4).
• The cysteinyl leukotrienes cause: – contraction of
bronchial muscle – vasodilatation in most vessels, but
coronary vasoconstriction.
• the CysLT-receptor antagonists zafirlukast and
montelukast used in asthma
 3. Platelet activating
factor (PAF)
•PLA2 releases PAF in inflammation.
•PAF causes vasodilatation,
increases vascular permeability,
activates platelet aggregation.
 PAF
• The anti-inflammatory actions of the glucocorticoids may
be caused, at least in part, by inhibition of PAF synthesis
• Rupatadine is a combined H1 and PAF antagonist for
allergies
• The PAF antagonist lexipafant is approved for the
treatment of acute pancreatitis.
PEPTIDES AND PROTEINS
 PEPTIDES AND PROTEINS
• They are made up of amino acids, a minimum of 2 amino
acids.
• Peptides have a range of 2-50 amino acids
• Proteins need to adopt a complex folded structure to exert
their specific function.
 Bradykinin
• A nonpeptide which is part of the inflammation mediators.
• It has 2 types of receptors ; B1 and B2
• The action of bradykinin leads to cough. (antagonists can manage
cough)
• It also causes vasodilation and increased pearmeability.
• It causes pain through activation of nociceptive nerve terminals.
• Contracts intestinal, uterine and bronchial smooth muscles
• Stimulates nasopharyngeal secretion in allergic rhinitis
 CYTOKINES
• These are protein or polypeptide mediators synthesised
and released by cells of the immune system during
inflammation.
• They amplify inflammation by inducing the formation of
other inflammatory mediators.
• Four main functional groups, namely interleukins,
chemokines, interferons and colony-stimulating
factors.
 INTERLEUKINS
• Describe mediators that signal between leukocytes.
• The primary pro-inflammatory species are tumour
necrosis factor (TNF)-α and interleukin 1 (IL-1).
• In auto-immune disease (e.g. rheumatoid arthritis, where
the adaptive immune system is activated) TNF plays a role
and can be targeted.
• Auto-inflammatory diseases (e.g. gout, where only the
innate system is involved) IL-1
• Transforming growth factor (TGF)-β, IL-4, IL-10 and IL-13
are potent anti-inflammatory substances
 CHEMOKINES
• Chemoattractant cytokines that control the migration of
leukocytes.
• Other functions include causing mast cell degranulation or
promoting angiogenesis.
• These are usually exploited in some diseases and by some viruses
leading to damage of the immune system.
• Including HIV virus.
• Drugs like maraviroc an antiretroviral therapy blocks the HIV virus
from attaching itself to Tcells to affect the CD4 count.
 INTERFERONS
• They interfere with viral replication.
• Three main types of interferon, termed IFN-α, IFN-β and
IFN-γ
• IFN-α and IFN-β have antiviral activity whereas IFN-α also
has some antitumour action.
• Both are released from virus infected cells and activate
antiviral mechanisms in neighbouring cells.
• IFN-γ has a role in induction of Th1 responses
 INTERFERONS (INFs)
•Interferon alpha-2b (Intron©):

- in chronic hepatitis B and C

- lymphomas, melanomas, etc.
•Interferon beta-1b (Betaferon©)
s.c. in multiple sclerosis.

•Interferon gamma –
in the regulation of
the immune system.
 COLONY STIMULATING
FACTORS
• They are glycoproteins that stimulate the production of blood cells
by binding to bone marrow cells and activating signaling pathways.
• Granulocyte CSF- filgrastim
• Granulocyte- macrophage CSF- sargramostim
• Macrophage CSF

• They are used in blood conditions like neutropenia and

agranulocytosis