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Pharmacology lecture 1

Dr. Sameer Al- Rekabi

Autacoids = local
hormones

DEFINITION
These are heterogeneous group of
chemical substances with wide spectrum
of biological effects , synthesized by
different tissues and exerting local effect
with no or very minute serum level.
Autacoids' include histamine , serotonin ,
prostaglandins , leukotriens , vaso-active
intestinal polypeptides (VIPs), kinins,
Angiotensin , Nitric oxide (NO),
endothelin,etc.

HISTAMINE and ANTIHISTAMINES


Histamine : is a bioactive amine ,
widely distributed in animal and
plant tissues.
In human body, histamine present
in skin , GIT , lungs , CNS , CVS,
basophiles. It is stored in
granules in mast cell, it is
released in response to many
physical and chemical agents
that lead to de-granulation of the
mast cells.

:Synthesis
Histamine is synthesized by 2
enzymes:
1- Histidine de-carboxylase that
converts histidine to histamine.
This enzyme is inhibited by
methyl histidine.
2- Aromatic amino acid decarboxylase which is non
specific enzyme and inhibited by
methyl-dopamine .

:Release
Histamine is released by the process of degranulation in response to:
1- Immunological reactions : Ag-Ab
complex stimulates mast cell degranulation.

2- Chemical and mechanical reactions like


histamine release by drugs like morphine
codeine , Vancomycin , polymexin,.etc.
Mechanical reaction like in triple response
of Lewis.

: Metabolism
By 2 routs
1- By histaminase or di-amine
oxidase.
2- By histamine methylating
enzymes.

:Mechanism of action of histamine

Histamine acts by
binding to 4
subclasses of
receptors [ H1 , H2 ,
H3 , H4] which
distributed in different
tissues.

:Physiological role of histamine


1- neurotransmitter in CNS.
2- Micro-circulatory regulation.
3- control sleep and alertness .
4- correlates with fetal development .
5- wounds healing.
6- Has a role in thermal and body
weight regulation.
7- WBC chemotaxis.
8- Gastric acid secretion.

:Pharmacological action of histamine

1- CVS : in systolic and


diastolic blood pressure.
On heart : -ve inotropic
effect through H1 receptor .
+ve inotropic and
chronotrpic effect through
H2 receptor.

Gastric acid secretion:- 2


histamine is a potent
stimulator of gastric acid
secretion , and to lesser
extent pepsin and intrinsic
.factor

Effect on smooth muscles:- 3


It has a stimulatory action , it
causes profound
bronchiospasm in patient with
bronchial asthma .It increases
intestinal motility and may
causes diarrhea in large dose.
Histamine has no significant
action on smooth muscle of
.genitor-urinary tract and eyes

Gland secretion : has no significant- 4


action.
5- Suprarenal medulla : stimulates the
release of adrenalin and noradrenalin in
normal subject. It causes massive
secretion of catecholamines in patients
with pheochromocytoma.
6- On nerve endings: It stimulates the
sensory nerve endings causing pain and
.itching

:Triple response of Lewis


Injection of small dose of histamine (10
micrograms) intradermally causes the
triple response of Lewis which includes:
1- Local redness due to local
vasodilatation .
2- Wheal (oedema) due to increase in the
permeability of blood capillaries.
3- Diffused redness ( flare) due to
general vasodilatation related to neural
mechanism ( axonal reflex).

:Clinical indication of histamine

Histamine has no therapeutic


roles but can be used
clinically in:
1- Diagnosis of pernicious
anemia.
2- Measurement of gastric
acid secretion .
3- Diagnosis of
pheochromocytoma.

:Side effects of histamine

Headache , flushing ,
hypotension ,
tachycardia ,
bronchiospasm , GI
upset.

:Contraindications

1- Bronchial asthma .
2- Active peptic
ulcer.
3Pheochromocytoma
.

:Histamine agonists
1- Betazole : Isomer of histamine and acts
on H2 receptor . It is used for diagnosis of
gastric acid secretion but it is
contraindicated in case of bronchial
asthma.
2- Betahistine : It is analogue of histamine
and acts on H1 receptor , it is used in the
treatment of Meneire,s disease . IT should
be used cautiously in patients with
bronchial asthma and pheochromocytoma.

:Histamine antagonists
The action of histamine can be
antagonized by :
1- Physiological antagonist : By
adrenalin .
2- Competitive pharmacological
antagonists : we have H1 and H2
blockers .
3- Mast cells stabilizers (drugs that
prevent mast cell de-granulation )
like chromolyin and nedochromil.

Anti-histamines (H1 blockers)


These are heterogeneous
group of drugs that antagonize
the effect of histamine on H1
receptor , rapidly absorbed
from GIT , extensively
metabolized by liver , excreted
by kidney , also secreted into
milk of lactating woman.

:Pharmacological actions of H1 blockers


1- they produce CNS depression in therapeutic doses
BUT may produce CNS stimulation , convulsion and
hyperthermia when they are given in large doses
especially in children.
2- they have anti-nausea and anti-vomiting effects.
3- Anti-cholinergic effect (dry mouth, constipation ,
urine retention , glaucoma ,.)
4- Local anesthetic effect.
5- Anti- parkinsonism effect.
6- Antiserotoninergic effect
7- - adrenoceptor blocking effects.
8- they inhibit P-glycoprotein (P-glycoprotein
responsible for cytotoxic drugs efflux outside of tumor
cells).

: Classification of H1-blockers

1- 1st generation H1-blockers


General properties include :
a- Great CNS depression .
b- relatively of short duration of
action.
c- relatively of little dangerous
drug interaction with macrolides
antibiotics and antifungal drugs.

1st generation H1 blockers includes

:
1- Ethanolamine group : like Diphenhydramine (allermin)
.
2- Ethylenediamine group : like Antazoline.
3- Alkylamine group: like chlorpheneramine (Histadine).
4- Piperazin group: like Hydroxyzine , cyclizine.
5- Phenothiazines group: like promethazine.
6- Miscellaneous group : like cyproheptadine (periactin)
which used as appetite stimulant especially in children , in
carcinoid syndrome (it has antiserotoninergic effect), in hay
fever , in dumping syndrome after gasterectomy, as
prophylactic in migraine .
Other drugs like acrivastin , clemastin , loratidine ,des, loratidine , ketotifen

:2nd generation H1 blockers- 2


General properties includes:
a- Low or no CNS depression.
b- relatively of long duration of action.
c- relatively of dangerous drug interaction
with macrolides antibiotics(erythromycin
and Clarithromycin) and anti-fungal
(Ketocanazole) drugs that may lead to
prolonged QT interval and ventricular
arrhythmias.

2nd generation H1 blockers


:includes

Astimazole ,
Terfenadine ,
Fexofenadine,
Cetrizine.

:Clinical indications

Angio-noretic oedema ., - 1
2- Allergic dermatosis ,
3- Urticaria , 4Hay fever ,
5- Motion
sickness , 6- insect bite , 7anaphylactic shock, 8blood transfusion allergic
.reactions

Side effects of H1blockers

Sedation , dizziness ,
insomnia , blurred
vision, tinnitus ,
.parasthesia

:Drug interactions

1- Non- specific CNS


depressants like
Alcohol , Barbiturates .
2- Anti-cholinergic drugs.
3- - adrenoceptor
blockers.

:Contraindications of H1 blockers
123456-

Hypersensitivity to the drugs.


Sever bronchial asthma.
Prostatic hyperplasia.
Closed angle glaucoma.
Bladder neck obstruction .
breast feeding.

Serotonin and anti-serotonin

Serotonin is a bioactive amine


that can be synthesized by
hydroxylation of amino acid
tryptophan to 5-hydroxy
tryptophan ( by enzyme =
tryptophan hydroxylase) then by
enzyme aromatic amino acid
decarboxylase to 5-hydroxy
tryptamine= serotonin.

Serotonin is one of most important


autacoid , has many physiological roles
and serotonin agonists and antagonists
have many clinical applications .

Serotonin is widely distributed in plants


and animal tissues. In human , about
90% of total body serotonin present in
enterochromaffin tissues , 8% in
platelets and 2% in CNS .

:Serotonin metabolism
By mono-amino oxidase enzyme to form 5hydroxy indol acetic acid which is excreted in
the urine in amount of about 3-10 mg /day.

The excretion of 5-hydroxy indol acetic acid


in the following conditions :
1- Carcinoid syndrome ( tumor of
enterochromaffin cells).
2- in case of using some of old antihypertensive drugs (reserpine).
3- ingestion of banana.

:Physiological roles of serotonin


1- It acts as a neurotransmitter in the brain.
2- Regulation of temperature.
3- Pain perception .
4- In pathogenesis of migraine.
5- In pathogenesis of depression.
6- In pathogenesis of anxiety.
7- Involved in intestinal motility .
8- Control of vomiting.
9- Control of appetite.
10- Pathogenesis of carcinoid syndrome.

:Mechanism of action of serotonin

Serotonin exerts its action by


binding to 7 subtypes of receptor
[ 6 of them are G-protein coupled
and one of them "5-HT3" is ionic
channels coupled.
The second messenger of Gprotein coupled receptors is
either cyclic AMP or IP3 and DAG.


:Pharmacological action of serotonin

1- CVS: - On heart : serotonin has small +ve


inotropic and +ve chronotropic effect on the heart.
Elevated plasma level of serotonin in carcinoid
syndrome lead to pathogenic endocardial changes.
- On blood vessels : serotonin produces
triphasic response which includes:
1- early depressor phase due to heart rate
and cardiac output due to chemoreceptor reflex.
2- Presser effect due to peripheral vascular
resistance and cardiac output.
3- Late depressor phase : related to
vasodilatation in skeletal muscle.

Respiratory system:- 2
Serotonin produces a small
direct stimulation to bronchial
smooth muscle in normal
person but produce a
bronchiospasm in patients with
carcinoid syndrome. Serotonin
produces hyperventilation due
to stimulation of bronchial
.sensory nerve endings

GIT: serotonin has a potent- 3


stimulation on the smooth
muscle of the gut which
increases the tone and facilitate
peristalsis that related to the
action of serotonin on 5HT
receptor in smooth muscle and
ganglionic stimulation of the
.enteric plexus

CNS : Stimulation of- 4


sensory nerve endings leads
.to pain and itching

Glandular secretion:- 5
Serotonin has little inhibitory
.effects on exocrine glands

Uterus: Large dose of- 6


serotonin impairs placental
blood supply and may lead to
.fetal distress

:Serotonin syndrome
It is related to the interactions of
serotonin re-uptake inhibitors
with mono-amino oxidase
inhibitors (MAOIs) or interactions
of serotonin agonists with MAOIs.
It is a clinical emergency with
high mortality rate and
characterized by rigidity ,
hyperthermia , myoclonus ,
mental changes, tachycardia.

:Serotonin agonists
1- Buspirone : acts on 5-HT1A receptor .It is an anxiolytic
drug ( non benzodiazepines non barbiturates anxiolytic).
2- Dexfenfluramine : Suppresses appetite and used to
body weight.

3- Sumatriptan ,Amlotriptan , Eletriptan ,


Naratriptan , Rizatriptan , Zolmitryptan : They act on
5-HT 1 B and D receptors and used in treatment of acute
migraine.

4- Cisapride : It is used in the management of reflux


esophagitis but now rarely used because it causes serious
ventricular arrhythmias .It acts on 5-HT4 receptors .Other
5-HT4 receptor agonists are: Tagaserol and metaclopromide
.

:Serotonin antagonists
1- Cyproheptadine (periactin): It is H1
and 5-HT2 blocker , used mainly as
appetite stimulant. Other uses include :
Allergic rhinitis , cold urticaria ,
prophylaxis of migraine , in Dumping
syndrome after gasterectomy and in
carcinoid syndrome.
2- Ketanserin: It is 5-HT 2 and -blocker .
It was used in the treatment of
hypertension .

Ondansetron , Granisetron ,Tropisetron - 4


and
Alosetron:
Acts on 5-HT3 receptor as antagonists and used
mainly in cytotoxic induced nausea and vomiting.

5- Ergot Alkaloids : They are produced by fungus


that infects grain . Ergots act on the following
receptors:
a- Serotonin receptor.
b- adrenoceptor.
c- Dopamine receptor.

.Ergots act as agonist , partial agonist or antagonist

Ergotism: It is the clinical


manifestation of ergot alkaloid
poisoning and characterized by
nausea , vomiting , abdominal
pain , abortion of pregnant
woman , gangrene ,
hallucination , confusion and
.convulsion

Ergot alkaloid drugs and their clinical uses:


1- Bromocriptine: used in acromegaly and
hyperprolactinaemia.
2- Ergotamine : used in acute migraine .
3- Ergonovine: used in post-partum
hemorrhage and diagnosis of Varian angina .
4- Lysergic acid diethylamide (LSD) :It is a
hallucinogenic agent.
5- Methysergide: used in migraine
prophylaxis.
6- Dihydroergotoxin : Used in cerebral
.insufficiency

Side effects of Ergot


Alkaloids:
Nausea , vomiting ,
abdominal pain , drowsiness ,
hallucination , confusion ,
abortion, retro-peritoneal
.fibrosis, gangrene

:Migraine Syndrome

It is a syndrome of
recurrent throbbing
unilateral headache with
or without aura ( visual
halos) with nausea ,
vomiting , phonophobia
and photophobia.

:Aetiology
It is poorly understood , it is
precipitated by stress , anger ,
fatigue , diet , rich in chocolate and
cheese , alcohol , menses in female or
using contraceptive , hypoglycemia.
Changes in vascularity between intra
and extra- cranial blood vessels and
stimulation of trigeminal nerve by
calcitonin genes related peptides are
the most popular concept concerning
Aetiology of migraine.

:Treatment of migraine

1- Treatment of acute attack


: by using Paracetamol ,
NSAIDs (aspirin), serotonin
agonists like Sumatriptan ,
..other serotonin agonists
or by ergot alkaloid derivatives
like ergotamine.
Other supportive treatment like
anti-emetic , sedative.

prophylactic treatment : many- 2


drugs are used with different
outcome like calcium channel
blockers
( Verapamil), Bblockers (propranolol ) , ergot
alkaloid ( Methysergide) , clonidine,
tricyclic anti-depressant
(imipramine), anti-serotonin
.
( cyproheptadine and pizotifen)

:Eicosanoids

prostaglandins "PGs" ,
leukotriens "LTs" ,
thromboxanes "TXs" ,
lipoxines "LXs",
isoprostanes, epoxides.

They are the oxidation


products of poly
unsaturated long chain
fatty acid. They are short
lived , highly potent
compounds with broad
spectrum of biologic
activity. They act in
autocrine or paracrine
.fashion

:Synthesis of eicosanoids
1-Arachidonic acid is the source of eicosanoids .
Arachidonic acid is formed by the action of
phospholipase A2 which converts phospholipids in
cell membrane into arachidonic acid.
Arachidonic acid is converted to PGs
endoperoxides by the help of 2 enzymes :
a- Cyclo-oxygenase I "COX I " [ PGH
synthase I] which is widely distributed in body
tissues and has gastro-cytoprotection.]
b-Cyclo-oxygenase II " COX II" [ PGH
synthase II] which is inducible by inflammatory
reactions and concerns with development of renal
function.

NOTE : Non-steroidal anti-inflammatory


drugs [NSAIDs] exert their effects through
inhibition of COX I and II.
COX I and II produce both PGs and TXs.

PGs are widely distributed in brain , lung ,


liver, kidney , adrenals , uterus , testis ,
and prostate .
We have PGE1, PGE2 , PGE3 , PGF1 ,
PGF2,..

NOTE : Other types of PGs are derived


.from the above compounds

The arachidonic acid and by the- 2


action of lipo-oxygenase enzyme
produces LTs and LXs . LTs are
biologically active compounds but lipoxines
with no clear biological activity.

3- Epoxides : unstable compounds and


have effects on smooth muscle that may
concern with renal function.

4- Isoprostanes : They are considered as


PGs isomers and they are concerned in the
pathogenesis of hepato-renal syndrome
. [ complication of liver cirrhosis]

Mechanism of action of PGs:


They bind to G-protein coupled
receptor --------- cAMP
Mechanism of action of
thromboxane A2:
They bind to G-protein coupled
receptor------------ IP3 and DAG

Pharmacological actions of PGs and


:TX

1- GIT: PGE2 and PGF2


cause contraction of the
longitudinal muscle of the gut
while PGI2 and PGF2 cause
contraction of the circular
muscle of the gut.PGE2
relaxes the circular muscles.
In general , large dose of PGs
inhibits gastric acid secretion.

vascular smooth- 2
muscles : PGE2 and
PGI2 cause
vasodilatation , while
PGF2 and TX cause
.vasoconstriction

platelets : PGE1- 3
and PGI2 inhibit
platelets
aggregation while TX
induces platelets
.aggregation

Respiratory- 4
system: PGE1 , PGE2
and PGI2 cause bronchi
dilatation while PGF2
and TX cause bronchi
.constriction

Renal system: PGE1, PGE2- 5


and PGI2 increase GFR
(vasodilating effect ) and
increase the Na excretion , also
enhance the release of rennin.
PGE2 is involved in renal
phosphate excretion.
TX reduces renal function and
.GFR

Reproductive- 6
system: PGE2 and PGF2
causes contraction of
uterus , PGI2 increases
penile erection.
NOTE: Seminal fluid
containing less than 400
ug/ml of PG is considered
an infertile man

CNS: - 7
-Fever : PGE1 and PGE2 when are
injected into cerebral ventricles , they
increase the body temperature.
PGD2 when infused into cerebral
ventricles produces sleepiness .
- Neurotransmission: PG compounds
inhibit the release of Nor-adrenalin from
post-ganglionic sympathetic nerve
endings.
- Neuro-endocrine: PG compounds
promote the secretion of prolactine , GH,
.TSH, ACTH, FSH and LH

Bone : PGD2- 8
increases bone
turnover (bone
formation and
resorption) .
PG is involved in
bone loss in post.menopausal women

Eyes: PGF2- 9
decreases intra.ocular pressure

Clinical indications of PG
:preparations
1- Reproductive indications:
PGE2 and PGF2 when used in early pregnancy , they
will cause abortion , they terminate pregnancy at any
stage , facilitates labor if given at time of labor.
Advantages of PG over Oxytocin [ which also used in
labor] :
a- PGs are more safe in pregnant women with preeclampsia , cardiac and renal diseases .
b- PGs unlike Oxytocin, having no anti-diuretic effect.

PGE2 and PGF2 are involved in primary


dysmenorrhia.

PGE1 is used in sexual dysfunction , injection of PGE1


in cavernosa is important in management of

CVS indications :-2


PG compounds have antihypertensive effect due to
their vasodilating and
natriuretic effects.
PGI2 is used in pulmonary
hypertension.

PGE1 and PGI2 are used in


.Ryanaud disease

Blood: PGI2 is- 3


very effective in
preventing
platelets
.aggregation

Respiratory- 4
indications: PGE2
is used as aerosol
to relieve
. bronchiospasm

GIT indications :- 5
PGE1 analogue
(Misoprostol)is
cytoprotective and
used for treatment
.of gastric ulcer

Immune indications: PGE2 and PGI2- 6


inhibit T-cell proliferation and clonal
expansion by inhibiting interleukin I and
II.

While TX and platelet activating factor


(PAF)stimulate T-cell proliferation and
clonal expansion by stimulating IL-I and
II.

NOTE: PGs in general decrease incidence


.of organ transplantation rejection

Eyes : PGF2 analogue is- 7


used in treatment of
glaucoma .
Side effects of PGs :
GIT upset , headache ,
dizziness , bronchiospasm ,
allergic reactions , syncope ,
hypo or hypertension ,
. uterine laceration

:Some PGs preparations

Dinoprost = PGF2
Dinoprostone = PGE2
Alprostadil = PGE1
Epoprostenol = Prostacyclin =
PGI2
Misoprostol = PGE1 analogue
Latanoprost = PGF2 ( eye
preparation)

Leukotriens
Potent biologically active
compounds are synthesized from
arachidonic acid with the help of
5-lipo-oxygenase in neutrophiles ,
monocytes , macrophages and
keratinocytes.
LTs present in brain , heart , lung
and spleen . The slow reacting
substance A released as result of
immunological reactions contains
LTC4 , LTD4 and LTE4

:Pharmacological effects of LTs

1- CVS : These
agents reduce
myocardial
contractility and
coronary blood flow.

GIT : LTB4 : are- 2


implicated with
inflammatory bowel
disease and their
amount is largely
increased by epithelial
.cells of colon

Respiratory system: LTC4- 3


and LTD4 are bronchio-constrictor
, they increase the intravascular
permeability and plasma
exudates and also increase
mucus secretion.
Drugs that block leukotriens
receptors like Zafirleukast and
Monteleukast and are highly
effective in management in
bronchial asthma

Blood : LTB4 is a- 4
potent chemo
attractant of
neutrophiles , LTC4
and LTD4 are chemo
attractant of
.eosinophiles

: Lipoxins

Act on specific
receptor on PMN
cells , inhibits NK
cells.

PAF:

Has role in
Pathophysiology of
asthma and shock.
Lexipafant is PAF
antagonist and used in
management of acute
. pancreatitis

Vaso-active amines and


:peptides
These are heterogeneous
group of peptides that act in
autocrine and paracrine
fashion and include
vasodilators and
vasoconstrictors and play a
major roles in pathogenesis of
many diseases with
increasable understanding in

vaso-dilator amines and peptides:- 1

a- Nitric oxide [NO]:


Nitric Oxide, Donors, & Inhibitors:
Nitric oxide (NO) is a gaseous signaling molecule that
readily diffuses across cell membranes and regulates
a wide range of physiologic and patho-physiologic
processes including cardiovascular, inflammation,
immune and neuronal functions.
The endothelium released a short-lived vasodilator,
which unlike endothelium-derived prostacyclin was not
blocked by cyclo-oxygenase inhibitors. They named
this vasodilator endothelium-derived relaxing
. factor (EDRF)

It is synthesized by a family of
enzymes that are collectively
called nitric oxide synthase,
NOS Three isoforms of NOS
have been identified.(NOS-1,
NOS-2, NOS-3). These isoforms
are heme-containing
flavoproteins employing Larginine as a substrate Nitric
oxide generation. Activation of
NOS by the influx of
extracellular calcium and

Inhibitors of Nitric Oxide


Drugs may inhibit the uptake
of L-arginine into cells, thus
depriving the
NOS isoforms
of substrate. Other methods
include deprivation of the
cofactors and calmodulin
antagonists, inhibitors of NOS
synthesis, inhibitors of binding
of arginine to NOS, and
scavengers of nitric oxide

Role of Nitric Oxide


Nitric oxide has major
effects that are mediated
by activation of
cytoplasmic soluble
guanylyl cyclase and
stimulated production of
cGMP, an important
second messenger.

Vascular Effects
Nitric oxide., it is released by
acetylcholine and other endotheliumdependent vasodilators. Infusion of NOS
inhibitors increases vascular tone and
elevates mean arterial pressure.
Vasodilatation mediated of cGMP
synthesis results in smooth muscle
relaxation. Also it a potent inhibitor of
neutrophiles adhesion to the vascular
endothelium.

Respiratory Disorders

Pulmonary artery
hypertension: NO is approved
for this indication, and acute
respiratory distress syndrome,
use for defective gas
exchange in the newborn .

Increased urinary
excretion of nitrate, is
reported in gramnegative bacterial
infection, resulting in
exaggerated
hypotension, This
hypotension is reversed
by NOS inhibitors.

Atherosclerosis
In vitro, NO carriers and donors
and cGMP analogs inhibit smooth
muscle cell proliferation. In addition,
it may blocks the oxidation of lowdensity lipoproteins (LDL) and thus
preventing the formation of foam
cells in the vascular wall.

Platelets
Nitric oxide is a potent
inhibitor of platelet
adhesion and aggregation.
NO affects blood
coagulation by enhancing
fibrinolysis via an effect on
plasminogen.

Organ Transplantation

High concentrations of NO may


be detrimental during acute
organ rejection due to upregulation of inducible NOS by
cytokines.

The Central Nervous System


It has a major role in the central nervous
system as a neurotransmitter, as a
modulator of ligand-gated receptors, plays a
role in neuronal degeneration in some
conditions. cellular targets include
presynaptic and postsynaptic nerve
terminals, it act to yield cGMP and thus
facilitate transmitter release. It also causes
destruction of photoreceptor cells in the
retina.

The Peripheral Nervous System


Non-adrenergic, noncholinergic
(NANC) neurons are widely distributed
in peripheral tissues, especially the
gastrointestinal and reproductive
tracts , some NANC neurons appear to
release NO and cause penile erection,
it promotes relaxation in the corpora
cavernosa.

Inflammation:
NO promotes edema and vascular
permeability, dietary L- arginine
supplementation exacerbates arthritis.
Psoriasis lesions, airway epithelium in asthma,
and inflammatory bowel lesions in humans all
demonstrate elevated levels of NO. Also it
stimulates the synthesis of inflammatory
prostaglandins by activating cyclo-oxygenase
isoenzyme II (COX-2).

Hypertension associated
with pregnancy.
Manifestation of pre- eclampsia
result from inadequate
physiological response of
pregnancy and combined with
deficiency of NO and
prostacyclin. enhancement of
NO level through nutritional
supplement of L- arginine may
be effective.

b- Kinins
(bradykinin):
It is a well known
vasodilator , it is 10
times more
vasodilator than
histamine

In addition to their CV effects , they


have an effects on endocrine ,
exocrine glands, inflammatory
response and sensory nerve
endings
Note : Kininase are ACE and
inhibition of ACE by ACEIs like
Captopril cause high persistent level
of bradykinin causing dry cough in
about 10-15% of patients taking
ACEIs.

c- Natriuretic peptides which include :


Atrial natriuretic peptide(ANP)and Brain type
natriuretic peptide (BNP).

They are increased by atrial and blood vessel


stretching by blood volume. They cause
vasodilatation , GFR and Na+ excretion .
they act on different receptors [A , B, C]
receptors and metabolized by
endopeptidase. Their levels are increased in
HF and used as diagnostic and prognostic
markers in HF.

NOTE: Nesiritide is BNP analogue and can be used in


HF.

Other vasodilators:
Substance P (also plays role
in pain perception),
Neurotensin ,
PGI2,vasoactive intestinal
peptide (VIP), calcitonin
gene related peptide which
is the strongest vasodilator
discovered yet.

2- vaso-constrictor amines and peptides:


a- Angiotensin : It is a well known
vasoconstrictor. It is formed by Renin
Angiotensin Aldosterone [ RAA] system. It
acts on 2 types of receptor [ AT1 ] which the
most important one and [AT2] which is less
well understood .

Renin is a glycoprotein , synthesized , stored


and released from juxta-glomerular apparatus
of the kidney in response to renal perfusion.

Physiological role of Angiotensin:


It is a potent vasoconstrictor.
It stimulates adrenal cortex to secrete
Aldosterone.
It stimulate thirst
It inhibits Renin release ( -ve feedback)

NOTE: Blockage of Angiotensin


synthesis ( ACEIs) or Angiotensin
receptors (ARBs) are widely used drugs
in medicine (HF , HT , IHD , diabetic
nephropathy)

b- Vasopressin [ ADH]: It acts through 2


types of receptors V1 and V2
V1 is divided into 2 subtypes V1a and V1b.
V1a = Vasoconstriction .
V1b = ACTH

V2 = Anti-diuretic effect.

Vasopressin and its analogues are


indicated in treatment of portal
hypertension
Desmopressin is indicated in treatment
of Hemophilia

c- Endothelin : It is a potent vasoconstrictor . It


acts through 2 types of receptor
(ET1 and ET2
)
Endothelin receptor blocker (Bosentan) is a
new drug that proved for treatment of HF ,
HT , IHD

NOTE: Other vasoconstrictors : Neuropeptide Y


and Urotensin.

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