Pharmacology lecture 1
Dr. Sameer AlRekabi
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 ANTI-HISTAMINES
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 degranulation 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 de-granulation.
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.
2- Gastric acid secretion:
histamine is a potent stimulator of
gastric acid secretion , and to lesser
extent pepsin and intrinsic factor.
3- Effect on smooth muscles: 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 genitorurinary tract and eyes.
4- Gland secretion : has no significant
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.
3- Pheochromocytoma.
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- α- 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 ,desloratidine , ketotifen,………
2- 2nd generation H1 blockers :
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.
nd
2
generation H1 blockers includes
:
Astimazole ,
Terfenadine ,
Fexofenadine, Cetrizine.
Clinical indications :
1- Angio-noretic oedema .,
2- Allergic dermatosis ,
3- Urticaria , 4- Hay fever ,
5- Motion sickness , 6- insect bite
, 7- anaphylactic shock, 8- blood
transfusion allergic reactions.
Side effects of H1-blockers
Sedation , dizziness ,
insomnia , blurred vision,
tinnitus , parasthesia .
Drug interactions :
1- Non- specific CNS
depressants like Alcohol ,
Barbiturates .
2- Anti-cholinergic drugs.
3- α- adrenoceptor blockers.
Contraindications of H1 blockers :
1- Hypersensitivity to the drugs.
2- Sever bronchial asthma.
3- Prostatic hyperplasia.
4- Closed angle glaucoma.
5- Bladder neck obstruction .
6- breast feeding.
Serotonin and anti-serotonin
Serotonin is a bioactive amine that
can be synthesized by hydroxylation
of amino acid tryptophan to 5hydroxy 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 anti-hypertensive
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 G-protein
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.
2- Respiratory system: 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.
3- GIT: serotonin has a potent
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 .
4- CNS : Stimulation of sensory
nerve endings leads to pain and
itching.
5- Glandular secretion: Serotonin
has little inhibitory effects on
exocrine glands.
6- Uterus: Large dose of 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.
Treatment is supportive.
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 α-blocker . It was
used in the treatment of hypertension .
3- Ritanserin : It is 5-HT2 blocker and has no αblocking effect.
4- Ondansetron , Granisetron ,Tropisetron 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- α 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 extracranial 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 antiemetic , sedative.
2- prophylactic treatment : many
drugs are used with different outcome
like calcium channel blockers
( Verapamil), B-blockers (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 , PGF1α ,
PGF2α,……..
NOTE : Other types of PGs are derived from the
above compounds.
2- The arachidonic acid and by the 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 PGF2α cause
contraction of the longitudinal
muscle of the gut while PGI2 and
PGF2α cause contraction of the
circular muscle of the gut.PGE2
relaxes the circular muscles. In
general , large dose of PGs inhibits
gastric acid secretion.
2- vascular smooth
muscles : PGE2 and PGI2
cause vasodilatation ,
while PGF2α and TX
cause vasoconstriction .
3- platelets : PGE1 and
PGI2 inhibit platelets
aggregation while TX
induces platelets
aggregation.
4- Respiratory system:
PGE1 , PGE2 and PGI2 cause
bronchi dilatation while
PGF2α and TX cause bronchi
constriction.
5- Renal system: PGE1, PGE2 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.
6- Reproductive system:
PGE2 and PGF2α causes
contraction of uterus , PGI2
increases penile erection.
NOTE: Seminal fluid containing
less than 400 ug/ml of PG is
considered an infertile man
7- CNS:
-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 postganglionic sympathetic nerve endings.
- Neuro-endocrine: PG compounds promote
the secretion of prolactine , GH, TSH, ACTH,
FSH and LH.
8- Bone : PGD2
increases bone turnover
(bone formation and
resorption) .
PG is involved in bone
loss in post-menopausal
women.
9- Eyes: PGF2α
decreases intra-ocular
pressure .
Clinical indications of PG preparations :
1- Reproductive indications:
PGE2 and PGF2α 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 pre-eclampsia ,
cardiac and renal diseases .
b- PGs unlike Oxytocin, having no anti-diuretic effect.
PGE2 and PGF2α are involved in primary dysmenorrhia.
PGE1 is used in sexual dysfunction , injection of PGE1 in cavernosa
is important in management of impotence in man.
2-CVS indications :
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.
3- Blood: PGI2 is
very effective in
preventing platelets
aggregation .
4- Respiratory
indications: PGE2 is
used as aerosol to
relieve bronchiospasm.
5- GIT indications :
PGE1 analogue
(Misoprostol)is
cytoprotective and used
for treatment of gastric
ulcer.
6- Immune indications: PGE2 and PGI2
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 .
7- Eyes : PGF2α analogue is 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 = PGF2α
Dinoprostone = PGE2
Alprostadil = PGE1
Epoprostenol = Prostacyclin = PGI2
Misoprostol = PGE1 analogue
Latanoprost = PGF2α ( 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.
2- GIT : LTB4 : are
implicated with
inflammatory bowel
disease and their amount
is largely increased by
epithelial cells of colon.
3- Respiratory system: LTC4 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
4- Blood : LTB4 is a
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
causation of many pathologies .
1- vaso-dilator amines and peptides:
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).
Biologic Synthesis
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 L-arginine as a substrate
Nitric oxide generation. Activation of
NOS by the influx of extracellular
calcium and binding of calmodulin
Inhibitors of Nitric Oxide
Drugs may inhibit the uptake of Larginine 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 endothelium-dependent
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 .
Septic Shock
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 low-density
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.