AUTACOIDS

DR SYED IHTISHAM HAIDER

ASSOCIATE PROFESSOR
 Autacoids
• Autacoid This term is derived from Greek: autos—self, akos—healing
substance or remedy.
• Autacoids are diverse substances produced by a wide variety of cells
in the body, having intense biological activity, but generally act locally
(e.g. within inflammatory pockets) at the site of synthesis and release.
• They have also been called ‘local hormones’
• However, they differ from ‘hormones’ in two important ways
• Hormones are produced by specific cells
• Hormones are transported through circulation to act on distant target tissues.
• Autacoids are involved in a number of physiological and pathological
processes (especially reaction to injury and immunological insult)
• Some autacoids, in addition, serve as transmitters or modulators in
the nervous system, but their role at many sites is not precisely
known. A number of useful drugs act by modifying their action or
metabolism. The classical autacoids are—
• Amine autacoids Histamine, 5­Hydroxytryptamine (Serotonin)
• Lipid derived autacoids Prostaglandins, Leukotrienes, Platelet
activating factor
• Peptide autacoids Plasma kinins (Bradykinin, Kallidin), Angiotensin
• In addition, cytokines (interleukins, TNFα, GM-CSF, etc.) and several
peptides like gastrin, somatostatin, vasoactive intestinal peptide,
endothelins and many others may be considered as autacoids.
 HISTAMINE
• Histamine, meaning ‘tissue amine’ (histos—tissue) is almost
ubiquitously present in animal tissues and in certain plants, e.g.
stinging nettle.
• Histamine is present mostly within storage granules of mast cells
• Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs,
liver and placenta
• Non-mast cell histamine occurs in brain, epidermis, gastric mucosa
and growing regions
• Histamine is also present in blood, most body secretions, venoms and
pathological fluids
 Synthesis, Storage and
Destruction
• Histamine is synthesized locally from the amino acid histidine and
degraded rapidly by oxidation and methylation.
• In mast cells, histamine (positively charged) is held by an acidic
protein and heparin (negatively charged) within intracellular granules
• When the granules are extruded by exocytosis, Na+ ions in
extracellular fluid are exchanged with histamine to release it free
• Increase in intracellular cAMP (caused by β adrenergic agonists and
methylxanthines) inhibits histamine release
• Histamine is inactive orally
 Histamine Receptors
• All four histamine receptor types have been cloned and belong to the
large superfamily of G protein-coupled receptors (GPCR)
• The structures of the H1 and H2 receptors differ significantly and
appear to be more closely related to muscarinic and 5-HT1 receptors,
respectively, than to each other
• The H3 and H4 receptors have about 40% homology but do not seem
to be closely related to any other histamine receptor
• Two receptors for histamine, H1 and H2, mediate most of the
peripheral actions
• The triple response, a classic demonstration of histamine effect, is
mediated mainly by H1 and H2 receptors
• A small red spot at the center of an intradermal injection of histamine
surrounded by an edematous wheal, which is surrounded by a red flare
• H1 receptor—This Gq-coupled receptor is important in smooth
muscle effects, especially those caused by IgE-mediated responses
• Inositol trisphosphate (IP3) and diacylglycerol (DAG) are the second
messengers
• Typical responses include pain and itching in the skin, vasodilation and
bronchoconstriction
• H2 receptor—This Gs-coupled receptor mediates gastric acid
secretion by parietal cells in the stomach
• It also has a cardiac stimulant effect
• A third action is to reduce histamine release from mast cells—a
negative feedback effect
• These actions are mediated by activation of adenylyl cyclase, which increases
intracellular cyclic adenosine monophosphate (cAMP)
• H3 receptor—This Gi-coupled receptor appears to be involved mainly
in presynaptic modulation of histaminergic neurotransmission in the
central nervous system (CNS)
• H4 receptor—The H4 receptor is located on leukocytes (especially
eosinophils) and mast cells and is involved in chemotactic responses
by these cells
• Like H3, it is Gi coupled
 Histamine
Antagonists/Antihistamine
Drugs
• The older members of the first-generation agents, typified by
diphenhydramine, are highly sedating agents with significant
autonomic receptor-blocking effects
• A newer subgroup of first-generation agents is less sedating and has
much less autonomic effect
• Chlorpheniramine and cyclizine may be considered prototypes
• The second-generation H1 blockers, typified by cetirizine,
fexofenadine, and loratadine, are far less lipid soluble than the first-
generation agents and have greatly reduced sedating and autonomic
effects.
 Mechanism of Action
• H1 blockers are competitive pharmacologic antagonists or inverse
agonists at the H1 receptor
• These drugs have no effect on histamine release from storage sites
• They are more effective if given before histamine release occurs
• Because their structure closely resembles that of muscarinic
blockers and α-adrenoceptor blockers, many of the first-generation
agents are potent pharmacologic antagonists at these autonomic
receptors
• A few also block serotonin receptors
• Most older first-generation agents are sedating
• First-generation agents have anti-motion sickness effects
• Many H1 blockers are potent local anesthetics
• H1-blocking drugs have negligible effects at H2 receptors
 Clinical Uses
• H1 blockers have major applications in allergies of the immediate
type (ie, those caused by antigens acting on IgE antibody-sensitized mast
cells)
• These conditions include hay fever and urticaria
• Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine
are used as anti-motion sickness drugs
• Diphenhydramine is also used for management of chemotherapy-induced
vomiting
• Doxylamine, in combination with pyridoxine, is promoted for the
prevention of morning sickness in pregnancy
• Adverse effects of the first-generation H1 blockers are sometimes exploited
therapeutically (eg, in their use as hypnotics in over-the-counter sleep aids)
 Toxicity/Adverse Effects
• Sedation is common, especially with diphenhydramine and
promethazine and these drugs should not be consumed before
operating machinery
• It is much less common with second-generation agents, which do not
enter the CNS readily
• Antimuscarinic effects such as dry mouth and blurred vision occur
with some first generation drugs in some patients
• Alpha-adrenoceptor blockade, which is significant with phenothiazine
derivatives such as promethazine, may cause orthostatic hypotension
• Interactions occur between older antihistamines and other drugs with
sedative effects (eg, benzodiazepines and alcohol)
• Drugs that inhibit hepatic metabolism may result in dangerously
high levels of certain antihistaminic drugs that are taken concurrently
 Serotonin Agonists/Antagonists
• Serotonin is produced from tryptophan
• It is stored in vesicles in the enterochromaffin cells of the gut, neurons
of the CNS and enteric nervous system
• After release, it is metabolized by monoamine oxidase
• After release from neurons, it is partially taken back up into the nerve
ending by a serotonin reuptake transporter (SERT)
• Serotonin is also stored (but synthesized to only a minimal extent) in
platelets
 Serotonin Receptors
• 5-HT1 receptors—5-HT1 receptors are most important in
the brain and mediate synaptic inhibition via increased potassium
conductance
• Peripheral 5-HT1 receptors mediate both excitatory and inhibitory
effects in various smooth muscle tissues
• 5-HT1 receptors are Gi-protein-coupled
• 5-HT2 receptors—5-HT2 receptors are important in both
brain and peripheral tissues
• These receptors mediate synaptic excitation in the CNS and smooth
muscle contraction (gut, bronchi, uterus, some vessels) or relaxation
(other vessels)
• Several mechanisms are involved, including (in different tissues)
increased IP3, decreased potassium conductance, and decreased
cAMP
• This receptor probably mediates some of the vasodilation, diarrhea,
and bronchoconstriction that occur as symptoms of carcinoid tumor,
a neoplasm that releases serotonin and other substances
• In the CNS, 5-HT2C receptors mediate a reduction in appetite that has
been used in the treatment of obesity
• 5-HT3 receptors—5-HT3 receptors are found in the CNS,
especially in the chemoreceptive area and vomiting center
• They are also found in peripheral sensory and enteric nerves
• These receptors mediate excitation via a 5-HT-gated cation channel
• Antagonists acting at this receptor are extremely useful antiemetic
drugs
• 5-HT4 receptors—5-HT4 receptors are found in the gastrointestinal
tract and play an important role in intestinal motility
 Clinical Uses of Serotonin
Agonists
• 5-HT1D/1B agonists—Sumatriptan is the prototype
• Naratriptan and other “-triptans” are similar to Sumatriptan
• They are the first-line treatment for acute migraine and cluster
headache attacks
• These drugs are active orally
• Sumatriptan is also available for nasal and parenteral administration
• Ergot alkaloids are partial agonists at some 5-HT receptors
• 5-HT2C agonists—Lorcaserin has recently been approved for the
treatment of obesity
• It activates receptors in the CNS and appears to moderately reduce
appetite
• Older drugs, fenfluramine and dexfenfluramine, appear to act directly
and by releasing neuronal 5-HT
• They also inhibit SERT thereby activating central 5-HT2C receptors
• They were withdrawn in the USA because their use was associated
with damage to cardiac valves
• Dexfenfluramine was combined with phentermine, an amphetamine-
like anorexiant, in a weight-loss product known as “dex-phen”
• Because of toxicity, this combination product is also banned in the
USA
• 5-HT4 Partial agonist—Tegaserod is a newer drug that acts
as an agonist in the colon
• It was approved and briefly marketed for use in chronic constipation
• Because of cardiovascular toxicity, its use is now restricted
• Selective serotonin reuptake inhibitors (SSRI)—A number of
important antidepressant drugs act to increase activity at
central serotonergic synapses by inhibiting the serotonin reuptake
transporter, SERT
 Hyperthermic Syndromes
• Serotonin and drugs with 5-HT agonist effects are sometimes
associated with drug reactions with;
• High fever
• Skeletal muscle effects
• Cardiovascular abnormalities that can be life-threatening
• These syndromes involve
• Serotonin Syndrome
• Neuroleptic Syndrome
• Malignant Hyperthermia
 Serotonin Antagonists
• Ketanserin, phenoxybenzamine, and cyproheptadine are effective 5-
HT2 blockers
• Ondansetron, granisetron, dolasetron, and
alosetron are 5-HT3 blockers
• The ergot alkaloids are partial agonists (and therefore have some
antagonist effects) at 5-HT and other receptors
 Clinical Uses of Serotonin
Antagonists
• Ketanserin is used as an antihypertensive drug outside the United
States
• Ketanserin, cyproheptadine, and phenoxybenzamine may
be of value (separately or in combination) in the treatment of
carcinoid tumor
• A neoplasm that secretes large amounts of serotonin (and peptides) and causes
diarrhea, bronchoconstriction, and flushing
• Ondansetron and its congeners are extremely useful in the control of
vomiting associated with cancer chemotherapy and postoperative
vomiting
• Alosetron is used in the treatment of women with irritable bowel
syndrome associated with diarrhea
 Toxicity of Serotonin
Antagonists
• Adverse effects of ketanserin are those of α blockade and H1 blockade
• The toxicities of ondansetron, granisetron, and dolasetron include
diarrhea and headache
• Dolasetron has been associated with QRS and QTc prolongation in the
ECG and should not be used in patients with heart disease
• Alosetron causes significant constipation in some patients and has
been associated with fatal bowel complications