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LOCAL HORMONES
January, 2012
5/3/2017
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Local Hormones
•




Includes:Histamine
serotonin ( 5-HT )
Prostaglandins
vasoactive peptides- platelet activating
factor (PAF), bradykinin, nitric oxide
neuropeptides, cytokines
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HISTAMINE-Synthesis, Storage &
Release
• Is a basic amine formed from amino acid
histidine by histidine decarboxylase.
• It is found in most tissues but is present in high
concentrations in the lungs and the skin, and in
particularly high concentration in the
gastrointestinal tract.
• At cellular level, it is stored in high
concentrations in mast cells.
• But non-mast cell histamine occurs in
‘histaminocytes’ in the stomach and in
histaminergic neurons in the brain.
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HISTAMINE-Synthesis, Storage &
Release….
• In mast cells and basophils, histamine is
complexed in intracellular granules with an
acidic protein and a high-molecular-weight
heparin termed macroheparin
• It is released from mast cells by exocytosis
during inflammatory or allergic reactions
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Histamine-…….
• It is metabolized by amine oxidase
enzymes
• Histaminase and/or by methylating
enzyme imidazole N-methyltransferase
• Excess production of histamine in the
body can be detected by measurement of
imidazole-acetic acid, its major metabolite,
in the urine.
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Histamine…
• Because it is released from mast cells in
response to immunoglobulin E (IgE)mediated ( immediate ) allergic reactions,
this autacoid plays an important
pathophysiologic role in seasonal rhinitis (
hay fever ), urticaria, and angioneurotic
oedema.
• Histamine also plays an important role
in control of acid secretion in the
stomach.
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Histamine Receptors and Effects
• Produces its action by an effect on specific
histamine receptors which are of three
main types:• H1, H2 and H3- receptors, distinguished
by means of selective antagonist drugs.
• H1 and H2 receptors mediate most of the
well-defined peripheral actions
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Histamine Receptors and
Effects…
a) H1 receptor: This receptor is important in
smooth muscle effects, especially those caused
by IgE-mediated responses.
• Causes contractions of the smooth muscles
of (the ileum, the bronchi, bronchioles and
uterus)
• Typical responses include bronchoconstriction
and vasodilation, the latter by release of
endothelium-derived relaxing factor (EDRF).
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Histamine Receptors and
Effects…
• Capillary endothelium, in addition to
releasing endothelium-derived relaxing
factor (EDRF), also contracts, opening
gaps in the permeability barrier and
resulting in the formation of local oedema.
• These effects are manifested in allergic
reactions and in mastocytosis, a rare
neoplasm of mast cells.
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b) H2 receptors: has three actions which are:• mediates gastric acid secretion by parietal
cells in the stomach. Clinically, this is the
most important action of histamine, since
it is implicated in the pathogenesis of
peptic ulcer.
• It also has cardiac stimulant effect.
• A third action is to reduce histamine release
from mast cells:-a –ve feedback effect.
These actions are mediated by activation of
adenylyl cyclase, which increases intracellular
cAMP.
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Histamine Receptors and
Effects…
c) H3 receptor:
• This receptor appears to be involved
mainly in presynaptic modulation of
histaminergic neurotransmission in the
CNS .
• In periphery, it appears to be a presynaptic
heteroceptor with modulatory effects on
the release of other transmitters.
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CLINICAL USE
• Histamine has no therapeutic applications,
but drugs that block histamine’s effects are
very important in clinical medicine
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HISTAMINE H1 ANTAGONISTS
• A wide variety of antihistaminic H1
blockers are available from different
chemical families.
• Diphenhydramine and Chlorpheniramine may
be considered prototypes.
• Because they have been developed for use in
chronic conditions, H1 blockers are all active by
the oral route.
• Most are metabolized extensively in the liver.
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HISTAMINE H1 ANTAGONISTS…
• Half-lives of the older H1-blockers vary
from 4 hours to 12 hours.
• Several newer agents (“ second
generation “ antihistamines, e,g.
Terfenadine, Fexofenadine, Astemizole,
Loratadine ) have half lives of 12-24 hours
and decreased CNS penetration.
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MECHANISM AND EFFECTS
• H1 blockers are competitive pharmacologic
antagonists at H1receptor, these drugs
have no effect on histamine release from
storage sites. Because their structure
closely resembles that of muscarinic
blockers and alpha blockers, many of
these agents are also pharmacologic
antagonists at these receptors. A few also
block 5HT receptors. However, they have
negligible effects at H2 receptors.
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MECHANISM AND EFFECTS…
• H1-blocking drugs have sedative and antimotion sickness effects in the CNS. In
periphery, they competitively inhibit the
effect of histamine ( especially if given
before histamine release occurs ).
• Many H1 blockers are potent local
anaesthetics.
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Clinical Use of Histamine H1antagonists
• Have many application in allergies of immediate
type ( i.e. those caused by antigens acting on
IgE antibody-sensitized mast cells ).
• These conditions include hay fever and urticaria.
• The drugs have a broad spectrum of adverse
effects that limit their usefulness but can
sometimes be used to good effect ( e.g. the
sedative effect is used in over-the-counter (OTC)
sleep aids ).
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TOXICITY AND INTERACTIONS
• Sedation is common, with
Diphenhydramine and Promethazine.
• It is less common with newer agents that
do not enter the CNS readily ( e.g.
Terfenadine, Astemizole ).
• Antimuscarinic effects such as dry mouth
and blurred vision occur with some drugs
in some patients.
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TOXICITY AND INTERACTIONS…
• Alpha-blocking actions may cause
orthostatic hypotension.
• Interaction occur between older
antihistamines and other drugs with
sedative effects, e.g. benzodiazepines and
alcohol.
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• Drugs that inhibit hepatic metabolism may result
in dangerously high levels of non sedating
antihistaminic drugs that are taken concurrently .
For e.g. Ketoconazole inhibits metabolism of
astemizole and terfenadine.
• In the presence of this anti-fungal drug, the
plasma concentration of either antihistamine may
increase and precipitate lethal arrhythmias.
• Cardiac arrhythmias are effects of excessive
concentrations of terfenadine and astemizole.
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• Terfenadine is the pro-drug of the active
antihistaminic molecule Fexofenadine.
• It is not subjected to the interaction
described above and has become
available as a prescription drug.
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HISTAMINE H2 ANTAGONISTS
• Cimetidine is the prototype.
• These drugs do not resemble H1 blockers
structurally.
• They are orally active, with half-lives of 1-3
hours.
• Because they are relatively non-toxic, they can
be given in large doses, so that the duration of
action of a single dose may be 12-24 hours.
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HISTAMINE H2 ANTAGONISTS
MECHANISM AND EFFECTS
• These drugs produce a surmountable
pharmacologic blockade of histamine H2
receptors.
• They are relatively selective and have no
significant blocking actions at H1 or
autonomic receptors.
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HISTAMINE H2 ANTAGONISTS
MECHANISM AND EFFECTS…
• The only therapeutic effect of clinical
importance is the reduction of gastric
acid secretion, but this is a very useful
action.
• Blockade of cardiovascular H2 receptormediated effects can be demonstrated but
has no clinical significance.
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HISTAMINE H2 ANTAGONISTS
CLINICAL USE
• In acid-peptic disease, especially
duodenal ulcer, these drugs reduce
symptoms, accelerate healing, and
prevent recurrences.
• Acute ulcer is usually treated with 2 or
more doses per day, while recurrence of
the ulcer can often be prevented with a
single bed-time dose.
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HISTAMINE H2 ANTAGONISTS
TOXICITY
• Cimetidine is a potent inhibitor of hepatic
drug metabolizing enzymes and may
reduce hepatic blood flow.
• It also has significant anti-androgen effects
in many patients.
• Ranitidine has weaker inhibitory effect on
hepatic drug metabolism; neither it nor the
newer H2 blockers appear to have
endocrine effects.
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SEROTONIN
( 5-Hydroxytryptamine, 5-HT )
Revision:
• Discuss the distribution, biosynthesis,
storage, release, re-uptake and
degradation of 5-HT
• What are the actions and functions of
5-HT?
• Classify the main 5-HT receptor subtypes;
in each state the location, main effects,
agonists and antagonists
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5-HT-Revision…
• What are the important drugs that act on
5-HT receptors in the periphery?
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SEROTONIN ( 5-Hydroxytryptamine,
5-HT ) and Related Agonists
• Serotonin is produced from tryptophan and
stored in the enterochromaffin cells of the
gut and in the CNS.
• Degradation of 5-HT occurs mainly
through oxidative deamination, catalysed
by monoamine oxidase (MAO), followed
by oxidation to 5-hydroxy-indoleacetic acid
(5-HIAA), which is excreted in urine.
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• Excess production of serotonin in the
body can be detected by measuring its
major metabolite, 5-hydroxyindoleacetic acid ( 5-HIAA ), in the
urine.
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Serotonin (5-HT)…
• 5-HT appears to play a physiologic enteric role
as a neurotransmitter in both the CNS and the
nervous system and perhaps as a local hormone
that modulates gastrointestinal tract activity.
• 5-HT is also stored ( but synthesized to only a
minimal extent ) in platelets.
• Only one drug is in use for its 5-HT agonist
effects i.e. specific agonist. (Revision-What is
it? Its use??)
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Serotonin (5-HT)…
• Answer: The drug is Sumatriptan, a 5HT1D receptor agonist used to treat
migraine.
• Others include: Buspirone used in anxiety;
5-HT4 receptor agonist metoclopramide
used to stimulate gastric emptying.
Ergotamine is a partial agonist
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Serotonin (5-HT)…
• Several drugs are in use or under
investigation as 5-HT antagonists.
(Revision- E.g??? Use???
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5-HT Receptor Antagonists
Revision
• 5-HT3-receptor antagonists (e.g.
ondansetron, granisetron; tropisetron)
used as anti-emetic drugs particularly for
controlling the severe nausea and
vomiting that occurs with many forms of
cancer chemotherapy.
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5-HT Receptor Antagonists
Revision…
• 5-HT2-receptor antagonists (e.g.
dihydroergotamine, methysergide,
cyproheptadine, kentanserin, ketotifen,
pizotifen). These ‘classical’ 5-HT
antagonists act mainly on the 5-HT2receptors. They are, however nonselective, and act also on targets, such as
alpha-adrenoceptors and histamine
receptors.
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5-HT Receptor Antagonists
Revision…
• Dihydrergotamine and methysergide
belong to the ergot family and are used
mainly for migraine prophylaxis. Ketotifen
is sometimes used to treat asthma but
the role of 5-HT receptors in this
condition is unclear. Other 5-HT2
antagonists are used to control the
symptoms of carcinoid tumours.
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RECEPTORS AND EFFECTS
• 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.
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• 5HT2 receptors: Are important in both brain
and peripheral tissues.
• These receptors mediate synaptic excitation in
the CNS and smooth muscle contraction ( gut,
bronchi, uterus, vessels ) or dilation ( vessels).
• The mechanism involves ( in different tissues )
decreased potassium conductance, decreased
cAMP, and increased inositol triphosphate
(IP3).
• In carcinoid tumor, this receptor probably
mediates some of the flushing, diarrhoea, and
bronchoconstriction characteristic of the
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disease.
• 5HT3 receptors: Are found in the CNS,
especially in the chemoreceptive area and
vomiting centre, in peripheral sensory and
enteric nerves.
• These receptors mediate excitation via a 5-HTgated cation channel ( i.e, the mechanism of
serotonin at the 5-HT3 receptors resembles that
of Ach at nicotinic cholinergic cation channels ).
• Antagonists acting at this receptor have proved
to be of useful anti-emetic drugs.
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CLINICAL USE
• Serotonin has no clinical applications.
NB
• Clinical conditions in which 5-HT plays a
role: there are two situations in which the
peripheral actions of 5-HT are believed to
be important, are migraine and carcinoid
syndrome
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OTHER SEROTONIN AGONISTS
• Sumatriptan, a receptor agonist: It is a 5HT1D agonist.
• Effective in the treatment of acute
migraine and cluster headache attacks- an
observation that supports the association
of 5-HT abnormalities with these
headache syndromes.
• It is available for oral, nasal, or parenteral
administration.
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SEROTONIN RE-UPTAKE
INHIBITORS
• Used for treatment of depression.
• Dexfenfluramine, a reuptake inhibitor with
other effects, was used exclusively for its
appetite-reducing effect. While effective as
an anorexiant, it is toxic: cardiac disease
in patients and neurological damage in
animals were reported.
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5-HT-ANTAGONISTS
• Ketanserin is a 5HT2 and alphaadrenoceptor blocker.
• Phenoxybenzamine- an alphaadrenoceptor blocker and Cyproheptadine
a H1-blocker are also good 5-HT2 blockers.
• Ondansetron is a 5-HT3 blocker.
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MECHANISMS AND EFFECTS of
5-HT-ANTAGONISTS
• Ketanserin and Cyproheptadine are
competitive pharmacological antagonists.
• Phenoxybenzamine is an irreversible
blocker.
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CLINICAL USE
• Used in the treatment of carcinoid tumour,
a neoplasm that secrete large amount of
5-HT ( and peptides ) and causes
diarrhoea, bronchoconstriction, flushing.
• Ondansetrone is extremely useful in the
control of post-operative vomiting
associated with cancer chemotherapy.
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TOXICITY
• Adverse effects of Ketanserin are those of
alpha blockade and H1 blockade. (H/W
what are they?)
• The toxicity of Ondansetron include
diarrhoea and headache.
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ERGOT ALKALOIDS
• The ergot alkaloids are partial agonists at
alpha adrenoceptors and 5-HT receptors.
• The balance of agonist-versus-antagonist
effect varies from compound to compound.
• Some are also agonists at the dopamine
receptor.
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CLASSIFICATION AND
PROTOTYPES
• The ergot alkaloids may be subdivided into
3 major groups on the basis of the organ
or tissue in which they have their primary
effects.
• This division is not absolute, since most of
the alkaloids have some effects on several
tissues.
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•The brain is a target organ for several
natural ergot alkaloids that cause the
hallucinations and chemical psychoses
associated with epidermics of ergotism.
• The most important derivatives acting in
the CNS are the semisynthetic drugs
lysergic acid diethylamide-LSD and
Bromocriptine.
• The uterus is very sensitive to ergot
alkaloids as term pregnancy nears but less
so at other times.
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• Ergonovine is a prototypical oxytocic ergot
alkaloid.
• Blood vessels are sensitive to ergonovine
and other ergot drugs ergotamine is a
prototype
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EFFECTS
• VESSELS: Ergot alkaloids can produce
marked and prolonged alpha receptormediated vasoconstriction.
• An overdose can cause ischaemia and
gangrene of the limbs.
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EFFECTS
• UTERUS: A powerful contraction occurs in
this tissue near term. This is sufficient to
cause abortion or miscarriage.
• After delivery of the placenta, ergonovine
or ergotamine can produce a useful
contraction of the uterus that reduces
blood loss.
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• BRAIN: Hallucinations may be prominent with
the naturally occurring ergots and with
lysergic acid diethylamide (LSD) but less
common with therapeutic ergots.
• Although LSD is potent 5-HT2 blocker in
peripheral tissues, its CNS effects may be
due to actions at dopamine receptors.
• In pituitary, some ergot alkaloids are potent
dopamine-like inhibitors of prolactin secretion.
• Bromocriptine and Pergolide are among the
most potent of the semisynthetic derivatives
at these dopamine D2 receptors and at similar
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receptors
in the basal ganglia.
CLINICAL USES
• Ergotamine is a mainstay of treatment of
acute attacks of migraine.
• Methysergide and ergonovine are used
prophylactically.
• Obstetric bleeding: Ergonovine and
ergotamine are effective agents for
reduction of postpartum bleeding
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• Hyperprolactinemia and Parkinsonism:
Bromocripine and Pergolide are used to reduce
prolactin secretion ( dopamine is the
physiologic prolactin release inhibitor ).
• Bromocriptine also reduce the size of pituitary
tumours of prolactin-secreting cells. This drug is
also useful in the treatment of Parkinson’s
disease.
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OTHER USES
• Methysergide has been used in
carcinoid tumour.
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TOXICITY
• VASCULAR EFFECTS Severe prolonged
vasoconstriction can result in ischemia
and gangrene.
• The only consistently effective antagonist
is Nitroprusside
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• Methysergide produces an unusual
hyperplasia of connective tissue.
• Similar lesions are found in some patients
with characinoid, suggesting that this
action is probably mediated by agonist
effects at serotonin receptors.
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GASTROINTESTINAL EFFECTS: They
cause nausea, vomiting, diarrhoea in
many individuals.
UTERINE EFFECTS; Marked uterine
contractions may be produced.
• Although abortion due use of ergot for
migraine is rare, most obstetricians
recommend avoidance.
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CNS EFFECTS
• Hallucination resembling psychosis are
common with LSD but less common with
other ergot alkaloids.
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VASOACTIVE PEPTIDES
• Include angiotensin, bradykinin, atrial
natriuretic peptide, vasoactive intestinal
peptide, substance P, calcitonin generelated peptide, vasopressin, glucagons,
and several opioid peptides
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MECHANISMS
• These agents probably all act on cell
surface receptors.
• Most act via G protein-coupled receptors
and cause the production of second
messengers; a few may open ion
channels.
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ANGIOTENSIN AND ITS
ANTAGONISTS
SOURCE AND DISPOSITION;
• Angiotensin I is produced from
angiotensinogen by renin, a proteolytic
enzyme released from the juxtaglomerular
apparatus of the kidney.
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• An inactive decapeptide, angiotensin I is
converted into angiotensin II, an octapeptide, by
angiotensin-converting enzyme (ACE), also
known as peptidyl dipeptidase or kinisase II.
• Angiotensin II, the active form of peptide, is
rapidly degraded by peptidases
(angiotensinases ).
• H/W- Read on Renin-Angiotensin system
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EFFECTS
• Angiotensin II is potent arteriolar
vasoconstrictor and stimulant of
aldosterone release.
• A-II directly increases peripheral vascular
resistance and, through aldosterone,
causes renal sodium retention.
• A-II also facilitates the release of noradrenaline from adrenergic nerve endings
via pre-synaptic hetero-receptor action.
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CLINICAL ROLE
• In the past it was used to control bleeding
by intra-arterial in sites difficult to access.
• Its major clinical significance is as a
pathophysiologic mediator in some cases
of hypertension ( high-renin hypertension )
and in congestive heart failure.
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ANTAGONISTS
• Two types of antagonists are available.
• Angiotensin II receptor-blockers ( e,g,
losartan, valsartan ) are orally active
non-peptide inhibitors at the angiotensin II
AT1 receptor.
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• Saralasin, a peptide a partial agonist at
this receptor, is not used clinically.
• Angiotensin-converting enzyme
inhibitors (e.g, captopril, enalapril ) are
important agents for the treatment of
hypertension and heart failure.
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• Blocking the effects of angiotensin by
either of these drug types is often
accompanied by a compensatory increase
in renin and angiotensin I.
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BRADYKININ
SOURCE AND DISPOSITION:
• Is one of several vasodilator kinins
produced from kininogen by a family of
enzymes, the kallikreins.
• Bradykinin is rapidly degraded by various
peptidases, including angiotensinconverting enzymes.
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EFFECTS
• Bradykinin is one of the most potent
vasodilator known. The peptide is thought
to be inyolved in inflammation and cause
oedema and pain when released or
injected into tissue.
• Bradykinin can be found in saliva and may
play a role in stimulating its secretion.
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CLINICAL ROLE
• Although it has no therapeutic application,
bradykinin may play a role in the antihypertensive action of angiotensinconverting inhibitors.
• There are no clinically important
bradykinin antagonists.
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ATRIAL NATRIURETIC
PEPTIDE:[ ANP ]
SOURCE AND DISPOSITION
• ANP also known as atrial natriuretic factor
is synthesized and stored in the cardiac
atria of mammals.
• ANP is released from the atria in response
to distention of the chambers.
( Revision-release of ANP occurs during
volume overload in response to
stretching of the atria)
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EFFECTS of ANP
• ANP activates guanlyl cyclase in many
tissues.
• It is a vasodilator as well as natriuretic
(sodium excretion-enhancing ) agent.
• Its renal action includes increased
glomerular filtration, decreased proximal
tubular sodium reabsorption, and inhibitory
effects on renin secretion.
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EFFECTS of ANP
• The peptide also inhibits the action of
angiotensin II and aldosterone.
• Although it lacks positive inotropic action,
atrial natriuretic peptide may play an
important compensatory role in
congestive cardiac failure by limiting
sodium retention.
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CLINICAL ROLE
• ANP has been studied for possible use in
the treatment of congestive cardiac failure.
• There are no clinically important products
that act as agonist or antagonist at ANP
receptors.
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ENDOTHELIN
• Are peptide vasoconstrictors formed and
released by endothilin cells in blood vessels.
• Endothelins are believed to function as
paracrine hormones in vasculature.
• Three different endothelin peptides [ ET-1, ET-2,
and ET-3 ] with minor variations in amino acid
sequence have been identified, both of which
are G protein-coupled.
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• Endothelin are much more potent than NA as
vasoconstrictors and have a relatively longlasting effect.
• The peptide stimulates the heart, increase atrial
natriuretic peptide release, and activate smooth
muscle proliferation.
• The peptides may be involved in some form of
hypertensions and other cardiovascular
disorders.
• Antagonists have recently become available for
research use.
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VASOACTIVE INTESTINAL PEPTIDE,
SUBSTANCE P, CALCITONIN GENE-RELATED
PEPTIDE AND NEUROPEPTIDE Y
Vasoactive intestinal peptide
• VIP is an extremely potent vasodilator but
probably is physiologically more important
as a transmitter.
• It is found in the central and peripheral
nervous systems and in the G.I.T.
• No clinical application has been found for
this peptide.
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Substance P
• Substance P is another neuro-transmitter
peptide with potent vasodilator action on
arterioles.
• However, substance P is a potent
stimulant of veins and of intestinal and
airway smooth muscle.
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Substance P…
• The peptide may also function as a local
hormone in the G.I.T.
• Highest concentrations of substance P are
found in those parts of the nervous system
that contain neurons subserving pain.
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Substance P…
• At the present time, there are no clinical
applications for substance P or its
antagonists.
• However, capsaicin, the ‘hot’ component
of chilli peppers, release substance P from
its stores in nerve endings and depletes
the peptide.
• Capsaicin has been approved for topical
use on arthritic joints.
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Calcitonin Gene Related Peptide
• Calcitonin gene-related peptide ( CGRP )
is found in high concentrations in the
thyroid and is also present in most smooth
muscle tissues.
• The presence of CGRP in smooth muscle
suggests a function as a co-transmitter in
autonomic nerve endings.
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Calcitonin Gene Related Peptide
• CGRP is the most potent hypotensive
agent discovered to date and cause reflex
tachycardia.
• There is no clinical application for this
peptide at present.
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Neuropeptide Y
• Unlike the three peptides described above,
(i.e. VIP, Substance P, CGRP),
neuropeptide Y ( NPY ) is a potent
vasoconstrictor that stimulate the heart.
• NPY is found in both the CNS and the
peripheral nerves.
• In the periphery, NPY is most commonly
localized as a co transmitter in adrenergic
nerve endings.
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Further reading on:
• Prostaglandins
• Platelet activating factor
• Nitric oxide (revision)
• neuropeptides
• Cytokines
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