4. AUTOCOIDS
ā¢ The words "autos" (self) and "akos" (healing ingredient or remedy) are the origin of this phrase in Greek.
ā¢ Autacoids are a variety of manufactured chemicals.
ā¢ A wide range of biologically active cells in the body, however they often function locally (as in inflammatory pockets) at
the site of synthesis and release.
ā¢ They've also been referred to as "local hormones."
ā¢ They differ from "hormones" in two key respects, though: hormones are created by particular cells and are circulated to act
on distant target regions.
ā¢ Autacoids have a role in a variety of physiological and pathological processes, most notably the immune system's response
to damage and insult.
ā¢ system, although it is unclear exactly what their function is at many sites. Several helpful medications work by altering
their metabolism or function.
5. FUNCTION OF AUTOCOIDS
ā¢ Work as a neurotransmitter.
ā¢ Promote the gastric juice secretion.
ā¢ Work as a modulator in the nervous system.
ā¢ Role in physiological and pathological processes.
ā¢ Role in the allergic reaction to the body.
CLASSIFICATION ā1) Decarboxylated amino acids
a) Histamine
b) Serotonin
2) Polypeptide
a) Angiotensin
b) Plasmakinin
C) Substance P
D) Slow reacting substance of anaphylaxis
3) Eicosanoid
a) Leukotrienes
b) Thromboxanes
c) Prostaglandins
8. Histamine ā
ā¢ Histamine is an amine that is produced as part of a local immune response to cause inflammation. It also performs several
important functions in the bowel and acts as a neurotransmitter or chemical messenger that carries signals from one nerve
to another.
ā¢ Histamine is secreted by basophils and mast cells as part of a local immune response to the presence of invading bodies.
The basophils and mast cells are found in nearby connective tissue. This histamine release causes capillaries to become
more permeable to white blood cells and other proteins, which proceed to target and attack foreign bodies in the affected
tissue. Aside from humans, histamine is found in virtually all animals
ā¢ History-
ā¢ Histamine was first synthesized in 1907 and its pharmacological properties were demonstrated in 1911. Because the
substance was extracted from tissue, the word āhistoā was used to describe this āamineā. Receptor subtypes for histamine
were characterized in 1966 and the first antihistamine drugs were developed between 1943 and 1944.
ā¢ Chemistry -
9. Chemistry of Histamine
ā¢ Imidazole ethylamine.
ā¢ Formed from the amino acid histidine
ā¢ Important inflammatory mediator
ā¢ Potent biogenic amine and plays an important role in inflammation ,anaphylaxis ,allergies, gastric acid secretion and drug
reaction.
ā¢ As part of an immune response to foreign pathogens, produced by basophils and mast cells found in near by connective
tissue.
12. Release and Functions of Endogenous Histamine
ā¢ Important physiological functions of histamine. Histamine, which is released from storage granules as a result of a contact
between an antigen and immunoglobulin E (IgE) antibodies on the surface of mast cells, is a key component of allergic and
acute hypersensitivity reactions. Histamine's effects on
ā¢ The smooth muscle and blood vessels of the bronchial passages are responsible for numerous allergic reaction symptoms.
Moreover, several clinically effective medications have the potential to release histamine directly from mast cells, which
would account for some of their undesirable side effects.
ā¢ In addition to controlling the release of neurotransmitters, histamine plays a significant function in the regulation of
stomach acid output.
13. Role in Allergic Responses.
ā¢ The principal target cells of immediate hypersensitivity reactions are mast cells and basophils (Schwartz, 1994). As part of
the allergic response to an antigen, reaginic (IgE) antibodies are generated and bind to the surfaces of mast cells and
basophils via high-affinity Fc receptors that are specific for IgE. This receptor, FcĪµRI, consists of Ī±, Ī², and two Ī³ chains.
ā¢ Histamine is a modulator of both the humoral and cellular immune responses, as well as a major mediator of
hypersensitivity reactions. If applied in large doses or released during anaphylaxis, it causes an extreme decrease in blood
pressure.
ā¢ Additionally, histamine can act as a neuromodulator, regulating responses to other neurotransmitters. It interacts like
acetylcholine, opiates, GABA, etc. Furthermore, it increases the excitability of CNS neurons, regulates hypothalamic
functions, wake/sleep relationship, appetite, and vegetative functions
14. Release of Other Autacoids
The release of histamine only partially explains the biological effects that ensue from immediate hypersensitivity reactions.
This is so because a broad spectrum of other inflammatory mediators is released on mast cell activation.
stimulation of IgE receptors also activates phospholipase A2 (PLA2), leading to the production of a host of mediators,
including platelet-activating factor (PAF) and metabolites of arachidonic acid.
Regulation of Mediator Release-
The wide variety of mediators released during the allergic response explains the ineffectiveness of drug therapy focused on a
single mediator. Considerable emphasis has been placed on the regulation of mediator release from mast cells and basophils,
and these cells do contain receptors linked to signaling systems that can enhance or block the IgE-induced release of
mediators. Agents that act at muscarinic or Ī± adrenergic receptors increase the release of mediators, although this effect is of
little clinical significance.
15. ā¢ Epinephrine and related drugs that act through Ī²2 adrenergic receptors increase cellular cyclic AMP and thereby inhibit the secretory
activities of mast cells. However, the beneficial effects of Ī² adrenergic agonists in allergic states such as asthma are due mainly to their
relaxant effect on bronchial smooth muscle.
ā¢ Cromolyn sodium is used clinically because it inhibits the release of mediators from mast and other cells in the lungs.
ā¢ Histamine Release by Drugs, Peptides, Venoms, and Other Agents
ā¢ Many substances, including a huge number of medicinal medicines, directly and without previous sensitization stimulate the release of
histamine from mast cells. This type of reaction is most likely to happen after intravenous injections of certain chemical classes,
particularly;
ā¢ amides, amidines, quaternary ammonium compounds, pyridinium compounds, piperidines, and alkaloids are examples of organic bases.
The reaction may also be induced by tubocurarine, succinylcholine, morphine, certain antibiotics, radiocontrast media, and specific
carbohydrate plasma expanders.
16. ā¢ Clinical experts are concerned about the phenomena because it could be the cause of unforeseen anaphylactoid reactions.
Histamine release may be a mediator of the "red-man syndrome" brought on by vancomycin, which includes hypotension,
upper body and face flushing.
ā¢ And In addition to medicinal drugs, certain experimental substances have histamine release stimulation as their primary
pharmacological feature. The polybasic chemical known as compound 48/80 serves as the archetype. This is a mixture of p-
methoxy-N-methylphenethylamine low-molecular weight polymers, with the hexamer being the most active.
ā¢ Histamine release from basic polypeptides is frequently efficient, and over a narrow range, its potency typically rises with
the number of basic groups. Bradykinin, for instance, releases histamine poorly, but kallidin (Lys-bradykinin) and
substance P, with its
ā¢ Amino acids with higher positive charges are more active. Certain venoms, like the wasp's, include strong peptides that
release histamine. Furthermore particularly active is polymyxin B.
17. Histamine Release by Other Means.
ā¢ The clinical conditions cold urticaria, cholinergic urticaria, and solar urticaria all involve the production of histamine in reaction to external
stimuli. certain of these
ā¢ entail distinct mast cell secretory reactions and cell-fixed IgE . Nevertheless, histamine is also released anytime there is generalised cell
damage due to any factor. A well-known example is the redness and urticaria that occur after scratching the skin.
ā¢ Increased Proliferation of Mast Cells and Basophils and Gastric Carcinoid Tumors.
ā¢ In urticaria pigmentosa (cutaneous mastocytosis), mast cells aggregate in the upper corium and give rise to pigmented cutaneous lesions that
urticate (i.e., sting) when stroked. In systemic mastocytosis, overproliferation of mast cells also is found in other organs. Patients with these
syndromes suffer a constellation of signs and symptoms attributable to excessive histamine release, including urticaria, dermographism,
pruritus, headache, weakness, hypotension, flushing of the face, and a variety of gastrointestinal effects such as peptic ulceration. Episodes
of mast cell activation with attendant systemic histamine release are precipitated by a variety of stimuli, including exertion, emotional upset,
exposure to heat, and exposure to drugs that release histamine directly or to which patients are allergic. In myelogenous leukemia, excessive
numbers of basophils are present in the blood, raising its histamine content to high levels that may contribute to chronic pruritus. Gastric
carcinoid tumors secrete histamine, which is responsible for episodes of vasodilation as part of the patchy āgeographicalā flush
18.
19. Gastric Acid Secretion.
ā¢ Acting at H2 receptors, histamine is a powerful gastric secretagogue and evokes a copious secretion of acid from parietal cells it also
increases the output of pepsin Histamine, Bradykinin, and Their Antagonists and intrinsic factor.
ā¢ Central Nervous System.
ā¢ There is substantial evidence that histamine functions as a neurotransmitter in the CNS. Histamine, histidine decarboxylase, and enzymes that
catalyze the degradation of histamine are distributed nonuniformly in the CNS and are concentrated in synaptosomal fractions of brain
homogenates.
ā¢ H1 receptors are found throughout the CNS and are densely concentrated in the hypothalamus. Histamine increases wakefulness via H1
receptors, explaining the potential for sedation by classical antihistamines. Histamine acting through H1 receptors inhibits appetite .
ā¢ Histamine-containing neurons may participate in the regulation of drinking, body temperature, and the secretion of antidiuretic hormone, as
well as in the control of blood pressure and the perception of pain. Both H1 and H2 receptors seem to be involved in these responses .
Knockout of the H1 receptor in mice by genetic engineering was associated with increased aggression, locomotion problems, and other
neurological symptoms.
21. Pharmacological action H1 and H2 receptor
ā¢ Histamine Toxicity from Ingestion- Histamine is the toxin in food poisoning from spoiled scombroid fish such as tuna in which high
histidine content combines with a large bacterial capacity to decarboxylate histidine to form large quantities of histamine.
ā¢ Ingestion of the fish causes severe nausea, vomiting, headache, flushing, and sweating. Histamine toxicity, manifested by headache and
other symptoms, also can follow red wine consumption in persons who possibly have a diminished ability to degrade histamine. The
symptoms of histamine poisoning can be suppressed by H1-receptor antagonists.
ā¢ Triple Response of Lewis s. If histamine is injected intradermally, it elicits a characteristic phenomenon known as the triple response .
(1) a localized red spot extending for a few millimeters around the site of injection that appears within a fewseconds and reaches a maximum
in about a minute;
(2) a brighter red flush, or āflare,ā extending about 1 cm or so beyond the original redspot and developing more slowly; and
(3) a wheal that is discerniblein 1 to 2 minutes and occupies the same area as the original small red spot at the injection site.
22. Pharmacological action H1 and H2 receptor
ā¢ Histamine Shock. Histamine given in large doses or release during systemic anaphylaxis causes a profound and progressive fall
in blood pressure. As the small blood vessels dilate, they trap large amounts of blood, and as their permeability increases, plasma escapes
from the circulation. Resembling surgical or traumatic shock, these effects diminish effective blood volume, reduce venous return, and greatly
lower cardiac output.
Clinical Uses The practical applications of histamine are limited to uses as a diagnostic agent. Histamine (histamine phosphate) is used to
assess nonspecific bronchial hyperreactivity in asthmatics and as a positive control injection during allergy skin testing.
24. H1-RECEPTOR ANTAGONISTS
ā¢ The discovery of H2 antagonists by Black and colleagues provided a new class of agents that antagonized histamine-induced acid secretion .
The pharmacology of these drugs (cimetidine, famotidine, etc.)
ā¢ Antihistamines are drugs used to block the activity of histamines by preventing the ability of histamine to bind to histamine receptors. These
agents are therefore referd to as histamine antagonists.
ā¢ H1receptor antagonist-well absorbed from git Onset- 30 minutes,duration-3 to 6 hours Biotransformed in liver ,Excretion-kidneys
Pharmacological Properties-
ā¢ Smooth Muscle-The majority of histamine's actions on smooth muscles, particularly the constriction of respiratory smooth muscle, are
inhibited by H1 antagonists. the guinea pigFor instance, the animal may survive 100 fatal doses of histamine if given an H1 antagonist, even
if death by suffocation occurs after fairly tiny doses of histamine. The same species also offers remarkable defence against anaphylactic
bronchospasm. In contrast, allergic bronchoconstriction in humans appears to be brought on by a range of mediators, including leukotrienes
and PAF Within the vascular tree,
ā¢ Capillary Permeability- H1 antagonists strongly block the increased capillary permeability and formation of edema and wheal brought
about by histamine.
25. ā¢ Flare and Itch. The flare component of the triple response and the itching caused by intradermal injection of histamine are two different
manifestations of the action of histamine on nerve endings. H1 antagonists suppress both.
ā¢ Exocrine Glands H1 antagonists have varying degrees of efficacy in reducing histamine-induced salivary, lacrimal, and other exocrine
secretions, but they do not inhibit stomach secretion. However, the antimuscarinic properties of many of these drugs may help to decrease
ongoing secretion in places like the respiratory tree and cholinergically innervated glands.
ā¢ Immediate Hypersensitivity Reactions: Anaphylaxis and Allergy-
ā¢ During hypersensitivity reactions, histamine is one of the many potent autacoids released , and its relative contribution to the ensuing
symptoms varies widely with species and tissue. The protection afforded by histamine antagonists thus also varies accordingly. In humans,
edema formation and itch are effectively suppressed. Other effects, such as hypotension, are less well antagonized.
ā¢ Central Nervous System- Both stimulation and depression of the CNS are possible with first-generation H1 antagonists. Patients receiving
traditional doses occasionally experience stimulation, which causes them to become agitated, anxious, and unable to fall asleep.A
remarkable aspect of overdosing, which frequently results in convulsions, especially in newborns, is central excitement. On the other hand,
the earlier H1 antagonists frequently accompany therapeutic doses with central depression.Common symptoms include diminished
awareness, decreased reaction times, and sleepiness. Patients differ in their susceptibility to and responsiveness to specific medications, and
some H1 antagonists are more likely than others to depress the CNS. The ethanolamines, such as diphenhydramine, are especially likely to
result in sedation.
ā¢ When administered in therapeutic dosages, the second-generation ("nonsedating") H1 antagonists (such as loratadine, cetirizine, and
fexofenadine) are mostly excluded from the brain since they do not significantly pass the blood-brain barrier. Similar to placebo, they have
sedative effects . First-generation antihistamines cause drowsiness, which makes it difficult for many patients to tolerate them or use them
properly unless they are only taken at night. Even so, patients may have an antihistamine "hangover" the next day, which could cause
drowsiness or impairment of the psychomotor process . Therefore, the creation of non-sedating antihistamines was a significant
development that permitted the widespread application of these substances.
ā¢ Anticholinergic Effects.
ā¢ Local Anesthetic Effect.
31. ā¢ H2blocker are a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach. They
are commonly called H2blocker. Include cimetidine,famotidine,nizatidine and ranitidine.
ā¢ INDICATION-
ā¢ H2antagonist are used by clinicians in the treatment of acid-related gastrointestinal condition ,including
ā¢ Peptic ulcer
ā¢ Dyspepsia disease
ā¢ Gastroesophageal reflux disease
ā¢ Prevention of stress ulcer [ranitidine]
33. ā¢ the enterochromaffinlike cells of the stomach, H3 receptors suppress gastrin-induced histamine release and subsequently reduce
HCl secretion mediated by H2 receptors, although the effect is not sufficient to warrant the development of therapeutic drugs. The
H3 receptors on other cell types, in contrast to histaminergic neurons, may not be tonically activated by endogenous histamine or
exhibit constitutive activity because inverse agonists/antagonists do not have distinct effects. The receptors do, however, react to
agonists; for instance, H3 agonists lessen the release of tachykinin from capsaicin-sensitive C-fiber terminals, which reduces the
extravasation of plasma caused by capsaicin and has antinociceptive properties. Additionally, H3 agonists suppress the heart's
excessive catecholamine release, such as during ischemia.
ā¢ The H3 receptors are found on histaminergic neurons in the hypothalamic tuberomammillary nucleus, both on their terminals and
on their cell bodies/dendrites. The active H3 receptor reduces histamine release from depolarized terminals and suppresses neuronal
activity at the level of cell bodies and dendrites by impairing Ca2+ conductance.As a result, agonists and antagonists of the H3-
receptor are the only drugs that can change histaminergic neurotransmission in the brain. Along with sensitive C-fibers, H3
receptors are presynaptic heteroreceptors on a number of neurons in the brain and peripheral tissues, including noradrenergic,
serotoninergic, GABAergic, and glutamatergic neurons. Both in vitro and in vivo, H3 receptors in the brain exhibit strong
constitutive activity; as a result, inverse agonists with high intrinsic activity will activate these neurons.
ā¢ H3-receptorligands currently are research tools to delineate the functional role ofcerebral histamine and are drug candidates in
neuropsychiatry
34.
35. BRADYKININ, KALLIDIN, AND THEIR ANTAGONISTS
ā¢ Bradykinin and kallidin are produced in the tissues as a result of several circumstances, such as tissue injury, allergic
reactions, viral infections, and other inflammatory processes. As autacoids that act locally to cause pain, vasodilation, and
increased vascular permeability, these peptides contribute to inflammatory responses. The activation of the release of
powerful mediators like prostaglandins, NO, or endothelium-derived hyperpolarizing factor (EDHF) is largely responsible
for their activity.
ā¢ Basic carboxypeptidases produce kinin metabolites that were previously thought to be inert degradation products. These
metabolites operate as agonists for a receptor (B1) that is distinct from the receptor for intact kinins (B2), whose expression
is triggered by tissue damage.
ā¢ Kinins and their des-Arg metabolites produce vasoactive substances as well and may act as mediators of pain and
inflammation. These results may offer up new therapeutic pathways for treating chronic inflammatory conditions.
38. Functions and Pharmacology of Kallikreins and Kinins-
Pain
Inflammation.
Respiratory Disease.
Cardiovascular System
Kidney
Other Effects.
39. ā¢ PAIN
ā¢ When applied to the exposed blister base, the kinins are potent analgesics that produce a severe burning pain. Bradykinin
causes the production of neuropeptides such substance P, neurokinin A, and calcitonin gene-related peptide by stimulating
primary sensory neurons. Despite some overlap, B2 receptors often mediate acute bradykinin algesia, but chronic
inflammation-related pain seems to include more B1 receptors.
ā¢ INFLAMMATION
ā¢ A number of inflammatory illnesses involve kinins. The microcirculation's permeability is raised by plasma kinins. The action,
which is exerted on the small venules and entails separating the connections between endothelial cells, is similar to that of
histamine and serotonin in some animals. Edema is brought on by this and a raised hydrostatic pressure gradient. In humans,
this edema and activation of nerve endings (see below) cause a "wheal and flare" reaction to intradermal injections.In episodes
of swelling, laryngeal edema, and abdominal pain in hereditary angioedema, bradykinin is produced, and the elements of the
kinin cascade are depleted.
ā¢ Interleukin 1 (IL-1) and tumour necrosis factor (TNF-) production can be induced by B1 receptors on inflammatory cells like
macrophages. A number of chronic inflammatory disorders, including rhinitis brought on by antigen inhalation and those
connected to rhinoviral infection, have elevated kinin levels. Gout, disseminated intravascular coagulation, inflammatory
bowel disease, rheumatoid arthritis, and asthma are a few illnesses where kinins may play a key role. The skeletal alterations
found in chronic inflammatory situations may also be influenced by kinins. Through B1 and possibly B2 receptors, as well as
possibly through osteoblast-mediated osteoclast activation, kinins promote bone resorption.
40. Respiratory Disease.
ā¢ . The kinins have been implicated in the pathophysiology of allergic airway disorders such as asthma and rhinitis. Inhalation
or intravenous injection of kinins causes bronchospasm in asthmatic patients but not in normal individuals. This
bradykinin-induced bronchoconstriction is blocked by anticholinergic agents but not by antihistamines or cyclooxygenase
inhibitors. Similarly, nasal challenge with bradykinin is followed by sneezing and serious glandular secretions in patients
with allergic rhinitis. A bradykinin B2-receptor antagonist improved pulmonary function in patients with severe asthma.
ā¢ Cardiovascular System.
ā¢ Urinary kallikrein concentrations are decreased in individuals with high blood pressure. In experimental animals and
humans, infusion of bradykinin causes vasodilation and lowers blood pressure. Hypertensives also excrete less urinary
kallikrein . Bradykinin causes vasodilation by activating its B2 receptor on endothelial cells. The endothelium-dependent
dilation is mediated by NO, prostacyclin, and a hyperpolarizing epoxyeicosatrienoic acid that is a CYP-derived metabolite
of arachidonic acid .
ā¢ The kallikreinākinin system appears to be cardioprotective. Because part of the activity of the widely used ACE inhibitors
is attributed to enhancement of bradykinin effects, much was learned about the function of kinins, such as their
antiproliferative effects. Bradykinin contributes to the beneficial effect of preconditioning the heart against ischemia and
reperfusion injury. In the presence of endothelial cells, bradykinin prevents vascular smooth muscle cell growth and
proliferation. Bradykinin stimulates tissue plasminogen activator (tPA) release from the vascular endothelium . In this way,
bradykinin may contribute to the endogenous defense against cardiovascular events such as myocardial infarction and
stroke. Kinins also may increase sympathetic outflow via central and peripheral nervous mechanisms.
41. ā¢ Kidney.
ā¢ Renal kinins act in a paracrine manner to regulate urine volume and composition Kallikrein is synthesized and secreted by
the connecting cells of the distal nephron. Tissue kininogen and kinin receptors are present in the cells of the collecting
duct. Like other vasodilators, kinins increase renal blood flow. Bradykinin also causes natriuresis by inhibiting sodium
reabsorption at the cortical collecting duct. Renal kallikreins are increased by treatment with mineralocorticoids, ACE
inhibitors, and neutral endopeptidase (neprilysin) inhibitors Kallikrein is synthesized and secreted by the connecting cells
of the distal nephron. Tissue kininogen and kinin receptors are present in the cells of the collecting duct. Like other
vasodilators, kinins increase renal blood flow. Bradykinin also causes natriuresis by inhibiting sodium reabsorption at the
cortical collecting duct. Renal kallikreins are increased by treatment with mineralocorticoids, ACE inhibitors, and neutral
endopeptidase (neprilysin) inhibitors.
ā¢ Other Effects. The rat uterus in estrus is especially sensitive to contraction by kinins through the B2 receptor. Kinins
promote dilation of the fetal pulmonary artery, closure of the ductus arteriosus, and constriction of the umbilical vessels, all
of which occur in the transition from fetal to neonatal circulation.
ā¢ The kinins also affect the CNS, in addition to their ability to disrupt the bloodābrain barrier and allow increased CNS
penetration. A bradykinin analog (RMP7) that is resistant to degradation by carboxypeptidase N and M and ACE has been
tested in the laboratory and clinically to enhance the penetration of drugs to brain tumors through the bloodābrain barrier
44. ā¢ Aprotinin (TRASYLOL) is a natural proteinase inhibitor obtained for commercial purposes from bovine lung, but it is
identical with Kunitzās pancreatic trypsin inhibitor .
ā¢ Aprotinin inhibits mediators of the inflammatory response, fibrinolysis, and thrombin generation following
cardiopulmonary bypass surgery, including kallikrein and plasmin. In several placebo-controlled, double-blind studies,
administration of aprotinin reduced requirements for blood products in patients undergoing coronary artery bypass grafting.
Depending on patient risk factors, aprotinin is given as a loading dose of either 1 or 2 million kallikrein inhibitor units
(KIU)
ā¢ followed by continuous infusion of 250,000 or 500,000 KIU/h during surgery. Hypersensitivity reactions may occur with
aprotinin, including anaphylactic or anaphylactoid reactions. The rate of such reactions is less than 1% in patients who have
not been exposed previously to aprotinin and higher (1% to 9%) ) in patients who have been exposed to aprotinin. A test
dose of aprotinin (10,000 KIU) should be given prior to full dosing; however,
ā¢ this test is not risk-free. Aprotinin can interfere with an activated clotting time used to determine the effectiveness of
heparin anticoagulation (see Chapter 54). For this reason, alternate methods must be used in patients treated with aprotinin.
In one multicenter study, there was an increased closure rate of saphenous vein grafts in patients treated with aprotinin
compared with placebo; there were no differences in rates rates of myocardial infarction or death .
47. Bradykinin Antagonists.
ā¢ The development of orally active nonpeptide-receptor antagonists promises to make bradykinin antagonism therapeutically
feasible in the treatment of inflammatory disease. The first of these, WIN64338, suffered from having muscarinic
cholinergic activity. More recently, the nonpeptide antagonist FR173657 has been shown to decrease bradykinin-induced
edema and hypotension in animal models. On the other hand, synthetic B2- receptor agonists (such as FR190997) may be
cardioprotective. Synthetic small-molecule bradykinin agonists or antagonists will not necessarily bind to the same
extracellular domains of the B2 receptor as the peptide but may interact with the hydrophobic transmembrane portion .
48. CLINICAL SUMMARY
ā¢ Aprotinin (TRASYLOL), the potent inhibitor of kallikrein and other serine proteases, is employed clinically to reduce
blood loss in patients undergoing coronary artery bypass surgery.
ā¢ ACE inhibitors are widely used drugs in the treatment of hypertension, congestive heart failure, and diabetic nephropathy,
and they reduce mortality in patients with a variety of cardiovascular risk factors . One effect of ACE inhibitors is to
prevent the degradation of bradykinin.
ā¢ A major problem for such applications is to establish a safe therapeutic window between potentially protecting the heart
and avoiding proinflammatory stimulation.
49. LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR
ā¢ Membrane lipids supply the substrate for the synthesis of eicosanoids and platelet-activating factor. Eicosanoidsā arachidonate
metabolites, including prostaglandins, prostacyclin, thromboxane A2, leukotrienes, lipoxins and hepoxylinsāare not stored but are
produced by most cells when a variety of physical, chemical, and hormonal stimuli activate acyl hydrolases that make arachidonate
available.
ā¢ Membrane glycerophosphocholine derivatives can be modified enzymatically to produce platelet-activating factor (PAF). PAF is formed
by a smaller number of cell types, principally leukocytes, platelets, and endothelial cells. Eicosanoids and PAF lipids contribute to
inflammation, smooth muscle tone, hemostasis, thrombosis, parturition, and gastrointestinal secretion. Several classes of drugs, most
notably aspirin, the traditional nonsteroidal antiinflammatory agents (tNSAIDs), and the specific inhibitors of cyclooxygenase-2 (COX-
2), such as the coxibs, owe their principal therapeutic effects to blockade of eicosanoid formation. In order to understand the therapeutic
potential of selective inhibitors of eicosanoid synthesis and action, it is enlightening to first review the synthesis, metabolism, and
mechanism of action of eicosanoids and PAF.
52. Inhibitors of Eicosanoid Biosynthesis.
ā¢ Inhibition of phospholipase A2 decreases the release of the precursor fatty acid and thus the synthesis of all its metabolites.
ā¢ Glucocorticoids also inhibit phospholipase A2, but they appear to do so indirectly by inducing the synthesis of a group of
proteins termed annexins (formerly lipocortins) that modulate phospholipase A2 activity . Glucocorticoids also down-
regulate induced expression of COX-2 but not of COX-1 . Aspirin and tNSAIDs were found originally to prevent the
synthesis of prostaglandins from AA in tissue homogenates . It now is known that these drugs inhibit the COX but not the
HOX moieties of the prostaglandin G/H synthases and thus the formation of their downstream prostanoid products. These
drugs do not inhibit LOXs and may result in increased formation of LTs by shunting of substrate to the lipoxygenase
pathway. Dual inhibitors of the COX and 5-LOX pathways are under investigation.
53. Pharmacological Properties of Eicosanoids
ā¢ . Cardiovascular System. In most vascular beds, PGE2 elicits vasodilation and a drop in blood pressure ), although
vasoconstrictor effects have been reported, depending on which PGE2 receptor is activated (see below). Infusion of PGD2
in humans results in flushing, nasal stuffiness, and hypotension; subsequent formation of F-ring metabolites may result in
hypertension. Responses to PGF2Ī± vary with species and vascular bed; it is a potent constrictor of both pulmonary arteries
and veins in humans. Blood pressure is increased by PGF2Ī± in some experimental animals owing to venoconstriction;
however, in humans, PGF2Ī± does not alter blood pressure.
ā¢ Platelets. Low concentrations of PGE2 enhance and higher concentrations inhibit platelet aggregation (Fabre et al., 2001).
Both PGI2 and PGD2 inhibit the aggregation of human platelets in vitro.
ā¢ Inflammation and Immunity. Eicosanoids play a major role in the inflammatory and immune responses, as reflected by
the clinical usefulness of the NSAIDs. While LTs generally are proinflammatory and lipoxins antiinflammatory,
prostanoids can exert both kinds of activity.
54. ā¢ Smooth Muscle. Prostaglandins contract or relax many smooth muscles besides those of the vasculature. The LTs contract
most smooth muscles.
ā¢ Bronchial and Tracheal Muscle.
ā¢ Uterus.
ā¢ Gastrointestinal Muscle.
ā¢ Gastric and Intestinal Secretions.
ā¢ Kidney and Urine Formation. PGs influence renal salt and water excretion by alterations in renal blood flow and by
direct effects on renal tubules (Cheng and Harris, 2004). PGE2 and PGI2 infused directly into the renal arteries of dogs
increase renal blood flow and provoke diuresis, natriuresis, and kaliuresis, with little change in glomerular filtration rate.
TxA2 decreases renal blood flow, decreases the rate of glomerular filtration.
Eye. Although PGF2Ī± induces constriction of the iris sphincter muscle, its overall effect in the eye is to decrease intraocular
pressure (IOP) by increasing the aqueous humor outflow of the eye via the uveoscleral and trabecular meshwork pathway
55. ā¢ Central Nervous System. While effects have been reported following injection of several PGs into discrete brain areas, the
best established biologically active mediators are PGE2 and PGD2. The induction of fever by a range of endogenous and
exogenous pyrogens appears to be mediated by PGE2 (Smyth and FitzGerald, 2003). Exogenous PGF2Ī± and PGI2 induce
fever but do not contribute to the pyretic response.
ā¢ Endocrine System. A number of endocrine tissues respond to PGs. In a number of species, the systemic administration of
PGE2 increases circulating concentrations of adrenocorticotropic hormone (ACTH), growth hormone, prolactin, and
gonadotropins. Other effects include stimulation of steroid production by the adrenals, stimulation of insulin release, Drug
Therapy of Inflammation thyrotropin-like effects on the thyroid.
ā¢ Bone. PGs are strong modulators of bone metabolism. PGE2 stimulates bone formation and resorption through osteoblastic
and osteoclastic activities affecting bone strength and composition
56. Endogenous Prostaglandins, Thromboxanes, and Leukotrienes: Functions inPhysiologicalandPathological Processe
Platelets
Reproduction and
Parturition
Vasculature
Lung.
KIDNEY
Inflammatory and
Immune Responses.
Cancer.
57. Therapeutic Uses -
Inhibitors and Antagonists.
Therapeutic Abortion.
Gastric Cytoprotection.
Maintenance of Patent
Ductus Arteriosus
PUMONARY HYPOTENSION
THERAPEUTIC USES
