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Autocoids 2

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Autocoids

Autacoids
• Endogenous compounds;
• Play an important role in the
physiological and pathological
processes;
• have very short t1/2
• have local action.
 Autacoids are the substances released
from the cells in response to various types
of stimulation to elicit normal
physiological responses locally.
 An imbalance in their synthesis, release or
in the transduction system contributes
significantly to pathological conditions
such as inflammation, allergy,
hypersensitivity and ischaemia-
reperfusion.
Classifications:
A. Amine Autocoids:
1. Histamine
2. Serotonin
B. Eicosanoids
1.PGs;
2.Thromboxane
3.Leukotrienes
C. Peptides Autocoids:
1.Kinins
2. Renin
3.Angiotensins etc
1.HISTAMINE
Histamine
 An endogenous substance
synthesized, stored and released
 Mast cells
◦ Basophils

◦ Some neurons in CNS or PNS (as


neurotransmittor)

◦ Enterochromaffin-like cells (stomach)


Storage and release
The stores of histamine in mast cells can be released through several
mechanisms
a. Immunologic Release:
 The most important mechanism for histamine release is in
response to an immunological stimulus.
 Mast cells, if sensitized by surface IgE antibodies,
degranulate when exposed to specific antigen.
 Degranulation means liberation of the contents of the mast
cell granules, including histamine.
 Degranulation is involved in the immediate (type I) allergic
reaction.
Storage and release
 Chemical and mechanical release:

Certain amines (morphine, tubocurarine) can displace


histamine from its bound form with in the cell.
Receptor Distribution Post-receptor
Subtype mechanism

H1 Smooth muscles, Gq
endothelium , brain

H2 Gastric mucosa, Cardiac Gs


muscle, mast cells, brain

H3 Presynaptic autoreceptors Gi
and heteroreceptors, brain,
myenteric plexus, other
neuron
H4 Eosinophils, neutrophils, Gi
CD4 T -cells
Pharmacological / organ system
effects of Histamine
1.Bronchial smooth muscles
◦ bronchoconstriction mediated by H1 receptors

2.GIT
◦ significant increase in gastric acid and gastric pepsin
secretion
◦ promotes intestinal smooth muscle contraction (mediated
by H1 receptors)
Pharmacological / organ system
effects
3.Cardiovascular System
◦ ↓Systolic and diastolic blood pressure- by direct
Vasodilation of arterioles and precapillary
sphincters

◦ ↑ in heart rate involves both stimulatory actions


of histamine on heart & reflex tachycardia

◦ Vasodilation (by small doses)  H1 receptor


activationmediated by NO release from
endothelium
◦ H 2 (at higher doses) cAMP mediated vasodilation
& direct cardiac effect
Pharmacological / organ system
effects
◦ Histamine-associated edema:
Caused by the action of amine on H1 receptor in vessels
of microcirculation (postcapillary vessels)
 Associated with separation of endothelial cellstrasudation of fluid ,
molecules & large proteins in perivascular tissue

◦ Direct cardiac effects:


 increased contractility (positive inotropism)& increased
pacemaker rate (positive chronotropism) mediated
by H2-receptor
Pharmacological / organ system
effects
4.Nervous system
◦ Sensory nerve endings stimulated by
histaminemediate pain and itching.
◦ H1 mediated affects-imp. in urticarial response,
reactions to insects & nettle stings.
◦ H1 & H3 receptors play important role in appetite &
satietywith antipsychotic drugs(weight gain)
◦ Presynaptic H3 receptors  modulating release of
several transmitters
◦ H3 agonist reduce release of ach, amine, &peptide
transmitters
5.Secretory tissue
◦ Histamine  stimulation of release by secretory
tissues
◦ ↑ gastric acid secretion
◦ ↑release of gastric pepsin and Intrinsic factor
production (lesser extent)
◦ histamine interacts with H2 receptors in gastric
parietal cells
6. Metabolic effects:
Absence of H3 receptor  increased food intake ,
decrease energy expenditure & obesity
The “Triple Response”
 Intradermal injection of histamine causes atypical triple
response

 The effect involves three separate cell types


-smooth muscle in microcirculation
-capillary or venular endothelium, and
-sensory nerve endings
Clinical uses

 Pulmonary function testing laboratories


◦ histamine aerosol has been used as a
provocative test of bronchial hyper-
reactivity
Toxicity/Contraindictaions
 Flushing
 Hypotension
 Tachycardia
 Headache
 Bronchoconstriction
 GI disturbances

Contraindications
 Should not be given to asthmatics (except with extreme caution in
pulmonary function testing)
 Should not be given to patients with active ulcer disease or
gastrointestinal hemorrhage
ANTIHISTAMINES/HISTAMINE
ANTAGONIST
 Physiologic antagonists (agents that produce opposing effects,
acting at different receptors)

◦ Epinephrine smooth muscle action opposite to histamine

 Release inhibitors

◦ reduced mast cell degranulation: example: cromolyn and

nedocromil

 Histamine Receptor antagonists

◦ selective blockade of histamine receptors (H1, H2, H3 types)


H1 receptor antagonists-Classification
First-Generation Agents First-Generation Agents Second-Generation Agents
Tricyclic Dibenzoxepins Alkylamines
Piperazines
Doxepin hydrochloride Acrivastine
Hydroxyzine HCl
Ethanolamines Piperazines
Carbinoxamine maleate Hydroxyzine pamoate Cetirizine hydrochloride
Clemastine fumarate Cyclizine HCl Phthalazinones
Diphenhydramine HCl Azelastine hydrochloride
Cyclizine lactate
Dimenhydrinate
Piperidines
Ethylenediamines Meclizine HCl
Levocabastine hydrochloride
Pyrilamine maleate Phenothiazines
Tripelennamine HCl Loratadine
Promethazine HCl
Tripelennamine citrate Desloratadine
Alkylamines Piperidines
Ebastine
Chlorpheniramine maleate Cyproheptadine HCl §
Mizolastine
Brompheniramine maleate Phenindamine tartrate
Fexofenadine
Pharmacological effects
 Histamine H1 Receptor Blockade

Competitive antagonism for H1 receptor sites

◦ Prevent bronchiolar or gastrointestinal smooth muscle


constriction

◦ Do not completely prevent cardiovascular effects (some


of these effects are mediated by H2 receptors)

◦ No affect on increases in gastric acid secretion or mast


cell histamine release because these effects are
H2 receptor site mediated
Pharmacological effects
 Sedation
◦ Common side effect of first-generation H1 antagonists

◦ But used as sleep-aids, i.e. hypnotics

 Anti-emetic/Anti-nausea actions
◦ Some first-generation H1 antagonists prevent motion sickness

◦ should be used as prophylaxis (cyclizine, meclizine)


Pharmacological effects
 Anticholinergic effects
◦ strong anti-muscarinic actions (atropine-like effects,
promethazine, diphenhydramine)

 Alpha adrenergic blocking effects may


cause postural hypotension

 Local Anesthetic effects


◦ Many first-generation H1 antagonists are local anesthetics,
exhibiting sodium channel blockade
Clinical Uses
 Allergic Reactions
◦ Cetrizine, acrivastine

◦ Diphenhydramine

 Motion Sickness
◦ Diphenhydramine and promethazine

◦ Cyclizine and meclizine


Toxicity
 Uncommon toxic effects following systemic demonstration:
◦ excessive excitation and convulsions in children
◦ orthostatic (postural) hypotension
◦ Allergic responses
 Drug allergy -- relatively common topical use of
H1 antagonists
 First-generation overdosage: similar to atropine
overdosage
 Second-generation overdosage: may induce cardiac
arrhythmias
H2 antagonists (e.g Cimetidine, Ranitidine)
Mechanism of action:
 Supress secretory responses to food
stimulation & nocturnal secretion of gastric
acid via their ability to decrease (indirectly)
activity of proton pump

 Also partially antagonize HCl secretion caused


by vagally or gastrin induced release of
histamine from ECL-like cells (GI mast cells)

 No effect on gastric emptying time


H2 antagonist
Uses
 PUD
 GERD(gastro esophageal reflex disease
 Zollinger-Ellison syndrome

Side effects
 GI distress
 Diziness, somnolence, slured speech, & delirium

 Cimeidine is a major inhibitor of P450 isoforms


increase effect of quinidine, phenytoin, TCA’s,
warfarin
Serotonin
 Serotonin is an important
neurotransmitter
 a local hormone in the gut
 a component of the platelet clotting
process
 Is thought to play a role in migraine
headache and several other clinical
conditions, including carcinoid syndrome
.
Functions of Serotonin in the body
 Brain serotonergic neurons are involved
in numerous diffuse functions such as
 mood
 sleep
 appetite
 temperature regulation
 perception of pain
 regulation of blood pressure
 vomiting
Functions of Serotonin in the body
 Serotonin also appears to be involved in
clinical conditions such as
 Depression
 Anxiety
 Migraine.
 Serotonergic neurons are also found in
the
 enteric nervous system of the GIT
 around blood vessels.
Synthesis and Metabolism of Serotonin
Serotonin
 5-hydroxytryptamine (5-HT)
 An important neurotransmitter
 A local hormone in the gut
 A component of the platelet clotting
process
 An autocoid
Pharmacodynamics

 Effects mediated through serotonin

receptors:

 seven major 5 HT subtypes identified

◦ Six through G protein coupled

◦ One ligand-gated channel


Receptors
Receptor
Distribution Post-receptor mechanism
Subtype
5-HT 1 Brain Gi; ↓cAMP

5-HT2 Smooth muscle, platelets Gq; ↑ IP3, DAG

Area postrema (CNS), sensory Ligand-gated cation channel


5-HT3 and enteric nerves

Presynaptic nerve terminals in Gs; ↑ cAMP


5-HT4 the enteric nervous system

5-HT5 Brain ↓ cAMP

5-HT6,7 Brain Gs; ↑ cAMP


Tissue and Organ System Effects
Cardiovascular system
 Serotonin directly causes the contraction of vascular smooth muscle,
mainly through 5-HT 2 receptors.
 In humans, serotonin is a powerful vasoconstrictor except in skeletal
muscle and the heart, where it dilates blood vessels.
 5-HT-induced vasodilation requires the presence of vascular
endothelial cells.
 When the endothelium is damaged, coronary vessels are constricted by
5-HT.
 A tri-phasic blood pressure response is often seen following injection
of serotonin in experimental animals.
◦ Initially, there is a decrease in heart rate, cardiac output, and blood pressure
caused by the chemoreceptor response.
◦ After this decrease, blood pressure increases as a result of vasoconstriction.
◦ The third phase is again a decrease in blood pressure attributed to
vasodilation in vessels supplying skeletal muscle. Pulmonary and renal
vessels seem especially sensitive to the vasoconstrictor action of serotonin.
Tissue and Organ System Effects
Gastrointestinal tract
 Serotonin :contraction of gastrointestinal
smooth muscle
◦ increased tone, increased peristalsis

◦ 5-HT2 receptor mediated:

 direct effect on smooth muscle receptors

 stimulation of enteric ganglia cells

◦ Serotonin  activation of 5-HT4 receptor

 increased acetylcholine release (increased motility, prokinetic)


Tissue and Organ System Effects
Nervous System
 Serotonin stimulates itch and pain sensory nerve endings
 Serotoninactivates chemosensitive nerve endings in coronary
vessels

 5-HT3 receptor activation on these chemosensitive vagal nerve

endings causes chemoreceptor reflex also called as Bezold-Jarisch

reflex.

 This reflex response is associated with Bradycardia and hypotension

 bradycardia  vagal mediated


Tissue and Organ System Effects

Respiratory system
 Serotonin has a small direct stimulant effect on
bronchiolar smooth muscle in normal humans,
probably via 5-HT 2A receptors.

 It also appears to facilitate acetylcholine release


bronchial vagal nerve
Serotonin agonists
 Triptans (class of drugs) → 5-HT1D/1B agonists
◦ Sumatriptan
◦ Zolmitriptan Used in
◦ Almotriptan migraine
◦ Frovatriptan
◦ Rizatriptan
-Cisapride → 5-HT4 agonist

 Tegaserod → 5-HT4 partial agonist


Serotonin receptor antagonists

Ketanserin
◦ 5-HT2 receptors blocker

◦ blocks vascular α1 adrenoceptors

Ritanserin
◦ 5-HT2 antagonist
Serotonin receptor antagonists

 5-HT3 antagonists
◦ Ondansetron

◦ Granisetron

◦ Dolasetron

◦ Tropisetron
Treatment of Migraine
2. EICOSANOIDS
(20 carbon atoms)
(eicosi = 20)

•Prostanoids
- Prostaglandins (PG’s)
- Thromboxane's (TX’s)
•Leukotriene's (LT’s)
•Lipoxins
PGs
Prostanoids Synthesis
Clinical importance of product of
arachidonate series
 Alprostadil (PGE 1 ) may be used
 for its smooth muscle relaxing effects to
maintain the ductus arteriosus patent in
some neonates awaiting cardiac surgery and
 in the t/m of impotence.
 Misoprostol
 a PGE 1 derivative is a cytoprotective
prostaglandin
 used in preventing peptic ulcer
 in combination with mifepristone (RU-486)
as abortifacient.
Clinical importance of product of
arachidonate series
 PGE 2 and PGF 2 are used in obstetrics
to induce labor

 Latanoprost and several similar


compounds are topically active PGF 2α
derivatives used in ophthalmology to
treat open-angle glaucoma.
Clinical importance of product of
arachidonate series cont’d….
Prostacyclin
 (PGI 2 , epoprostenol)
 synthesized mainly by the vascular
endothelium
 powerful vasodilator and
 inhibitor of platelet aggregation
 used clinically to treat pulmonary hypertension
and portopulmonary hypertension.
Clinical importance of product
of arachidonate series cont’d….

Thromboxane (TXA 2 )
 has undesirable properties (aggregation of
platelets, vasoconstriction).
 TXA 2 –receptor antagonists and synthesis
inhibitors have been developed for
cardiovascular indications
Leukotrienes biosynthesis
Lipoxins biosynthesis
Eicosanoids Antagonists
3.Peptide Autacoids
RENIN
 synthesized as a preprohormone
(prorenin)
 synthesized and stored in the
juxtaglomerular apparatus of the nephron
 An important modulator of angiotensin
production
ANGIOTENSIN II
 Plays a key role in the regulation of

◦ fluid and electrolyte balance

◦ arterial blood pressure

 Excessive activity can result in

◦ hypertension

◦ disorders of fluid and electrolyte homeostasis


Actions
 Increase BP
 Adrenal Cortex-stimulate aldosterone synthesis

 Kidney

◦ increase proximal tubular sodium reabsorption

◦ inhibit the secretion of renin


Actions
 Central Nervous System

◦ increase secretion of vasopressin

◦ increase secretion of ACTH


 Cell Growth

◦ mitogenic for vascular and cardiac muscle


cells
Receptors
 AT1 receptor → Gq-coupled receptor
 AT2 receptor → nitric oxide mediated
Drugs
 Angiotensin-Converting Enzyme Inhibitors

◦ Captopril, enalapril

 Angiotensin Receptor Blockers

◦ Losartan, valsartan, irbesartan, candesartan,


olmesartan, telmisartan

 Renin Inhibitors

◦ Aliskiren → Inhibits catalytic activity of renin


SUBSTANCE P
 CNS → neurotransmitter

 GIT → transmitter in ENS and as a local hormone

 Involved in behavior, anxiety, depression, nausea, and emesis

 a potent arteriolar vasodilator

 causes contraction of venous, intestinal, and bronchial


smooth muscle

 stimulates secretion by the salivary glands

 causes diuresis and natriuresis by the kidneys


Assignment # 2
Topic :
DRUGS ACTING ON GENITOURINARY
SYSTEM
Oxytoxic drugs
Ergot alkaloids
Uterine relaxants

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