Autacoids

Introduction
Definition
• They are substances of diverse nature normally present in the body or
may be formed there.
• The word autacoid is derived from the Greek word autos (self) and
akos (medical agent or remedy).
• Thus the word autacoids was used for substances that act within
restricted, local areas near their site of synthesis.
• But hormones that are produced by specific cells and then transferred
by circulation to distant sites of action.
Introduction cont.
• These substances usually have a brief lifetime.
• Heterogeneous substances have been included as autacoids.
• Substances produced locally by one group of cells that exerts effects
on other types of cells in the same region.
• They regulate many physiological and biological processes occurring
in the body.
• Autacoids can be released by various stimuli and when released they
bring about many physiological changes such as reddening of the
skin, pain, itching, bronchospasm, etc.
Functions of autacoids
They are involved in ;
• Inflammation
• Allergic reactions
• Anaphylactic reactions( not so much)
• Neurotransmission
• Gastric acid secretion
• Neuroendocrine regulation
Function cont.
In the central nervous system, they are responsible for
• Wakefulness
• Decreased Appetite
• Regulation of drinking
• Regulation of temperature
• Secretion of ADH
• Control of blood pressure
• Perception of pain.
Classification of autacoids
Autacoids

Decarboxylated Polypeptides Eicosanoids

amino acid
Kinins
Histamine (angiotensins) Prostaglandins

Serotonin (5-HT) Thromboxane

Leukotrienes
Classification of autacoids
Decarboxylated amino acids/ amine e.g
• Histamine and
• Serotonin (5 HT)
Endogenous peptides e.g.
• Angiotensin and renin-angiotensin-aldosteron system
• Kallikrein–kininogen–kinin system;
• Natriuretic peptide (ANP, BNP, CNP);
Classification cont.
• Vasoactive intestinal peptide (VIP);
• Substance P;
• Neurotensin;
• Endothelins;
• Calcitonin-gene related peptide (CGRP);
• Neuropeptide Y;
• Endorphine-enkephaline system.
Classification cont.
Lipid-derived autacoids (eicosanoids) -
• Products of Cyclooxygenases:
- Prostaglandins: PGA -> PGJ;
- Tromboxanes: TXA, TXB.
• Lipoxygenase products:
- Leukotrienes: LTA ->LTE;
- Lipoxins;
- Hepoxilins.
Classification cont.
• Epoxygenase products:
- Epoxyprostaglandins;
- Dioli.
• Products of other pathways:
- Isoprostanes.
Decarboxylated amino acids/ amine)
Histamine
• a basic amine, „ TISSUE AMINE ‟( Histos- tissue)
• present in all animal tissues and in some plants
• stored in mast cell and basophil granules
• mediators of allergic and inflammatory reactions
• involved in gastric acid secretions
• act as Neurotransmitter and Neuromodulator
• produce effects by acting on H1, H2 or H3 (and possibly H4) receptors
on target cells
Histamine cont.
• Tissues rich in histamine
e.g. skin, gastric mucosa, intestinal mucosa, lungs, liver and placenta
• Non mast cell histamine
e.g. brain, epidermis, gastric mucosa and growing regions
• It can also be found in blood, most of body secretions, venoms,
pathological fluids
Functions of histamine
• histamine 1 receptor (H1) → in smooth muscle, endothelium and to the
brain, they transmit the biological signal post-receptor stimulating the
formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG);
thereby causes;
-vasodilatation
- increased vascular permeability
-contraction of most smooth muscle, except blood vessels
• histamine 2 receptor (H2) → in the gastric mucosa, heart muscle, and brain
to mast cells, they transmit the biological signal post-receptor stimulating
the formation of cAMP;
Functions of histamine cont.
-cardiac stimulation
-stimulation of gastric secretion
• histamine 3 receptor (H3) → in the brain, plexus mesenteric and
other neurons, they decrease the release of histamine from
histaminergic neurons
Action of histamine
Intradermal injection of histamine causes 'triple response'
• reddening (local vasodilatation)
• weal or swollen(direct action on blood vessels)
• flare (from an 'axon' reflex in sensory nerves releasing a peptide
mediator)
Main pathophysiological roles of histamine
• Stimulate gastric acid secretion -(treated with H2-receptor
antagonists)
• Mediate type I hypersensitivity reactions such as urticaria & hay fever
-(treated with H1-receptor antagonists)
 Case Study
A 37 year old woman presented to accident and emergency (A&E) having
consumed yellow-fin tuna. Within 20 minutes she had developed an
urticarial rash on her face, neck, and trunk with chest tightness.
She had no history of hypersensitivity and normally consumed tuna on a
weekly basis. On arrival she was tachycardic and tachypnoeic, had mild
facial angio-oedema but no wheeze.
She was seen immediately by a registrar who diagnosed a hypersensitivity
reaction and administered intramuscular adrenaline (epinephrine),
intravenous hydrocortisone, and chlorpheniramine. The patient’s symptoms
improved within 30 minutes and after a further six hour observation period,
was discharged home on a short course of oral corticosteroids.
Synthesis
• Decarboxylation of amino acid L-histidine catalyzed by pyridoxal PO4-
dependent L-histidine decarboxylase.
• Ingested from food or formed by bacteria in the GIT
SYNTHESIS AND DEGRADATION OF
HISTAMINE
 HISTAMINE RECEPTORS
Released histamine binds with the receptors.
Four classes of receptors (H1, H2, H3, and H4) mediate the action of
histamine.
Histamine receptors belongs to the family of G-Proteins coupled receptors.
Receptors are present at the cell surface of the target tissue .

H1 receptors H2 receptors
Smooth Muscles, Endothelium, Gastrointestinal, Vascular Smooth Muscle
Tissue
Central Nervous System Tissue
HISTAMINE
RECEPTORS H4 receptors
H3 receptors
(Just discovered in 2000)
Central Nervous System and Some
Bone Marrow,Basophils,Thymus,Small
Peripheral Nervous System
intestine,Spleen,Colon
Effects of histamine receptors
H1 H2 H3
S.M - contraction Gastric gland-acid secretions Brain- inhibition of histamine
release- sedation
B.V – vaso dilation B.V-dilation B.V - vaso dilatation

Afferent nerve ending - stimulation Heart-postive inotropy Skin , gastric, mucosa- decrease
histamine release
Ganglionic cell- stimulation Uterus - relaxation Lungs , spleen – decrease
histamine release

Adrenal medulla-release of
CAs
 Effects of histamine receptors cont.
H1 H2 H3

SELECTIVE AGONISTS 2- methylhistamine, 2- 4-methy histamine, Dimaprit, ἀ-methyl histamine

pyridylethylamine,2- thiazolyl impromidine
ethylamine

SELECTIVE ANTAGONISTS Mepyramine, chlorpheniramine Cimetidine, ranitidine Thioperamide, impromidine

RECEPTOR TYPE G-Protein coupled G-P G-P

EFFECTOR PATHWAY IP3/DAG Ca+ release C-AMP inc Ca+ infulx ,K+ channel activation,
cAMP dec
Receptor Mechanism Location and function Agonists Antagonsits

H1 Gq type IP3/DAG : Smooth muscle (GIT, airway, 2 methyl histamine, Mepyramine,

Release of Ca2+ Pk- uterus)- contraction blood vessels: 2-pyridyl ethylamine, chlorphenaramine,
C activation Endothelium- Vasodilation (R NO)
Smooth muscle - Vasoconstriction
brain – transmitter
Adrenal – release of CAs.
H2 Gs type Increase in Gastric – acid secretion. 4 methyl histamine, Cimentidine,
cAMP. Blood vessels (smooth muscle)- dimaprit, ranitidine, famotidine,
Phosphorylation of dilation. heart: A- +ve chrono and impromidone nizatidine
specific proteins V - +ve ionotropy Brain -
transmitter
H3 G i – autoreceptor. (presynaptic) – inhibition of (R) α methyl Thioperaminde,
Dec in ca influx Dec release – sedation( brain), Ileum – histamine, imetit impromidine,
in c AMP. dec in Ach release Blood vessels – ciproflaxacin
dec in NA release - VD
H4 G I Dec in c AMP Mediate mast cell chemotaxis Thioperamide
Classification (HISTAMINE AGONISTS)
Histamine receptor agonists
- H1 receptors agonists: Histaprodifen
- H2 receptors agonists: Amthamine
- H3 receptors agonists: R-Methylhistamine, imetit, immepip
- H4 receptors agonists: Clobenpropit, imetit, clozapine
Factors that stimulate histamine release: -
physical factors: trauma, burns;
chemical factors (including drugs that release histamine): opiates,
Quinine, Hydralazine,
Histamine agonists
natural and semi-synthetic penicillins, cephalosporins,aminoglycosides,
pachycurares, D-tubocurarine, Atracurium, Pipecuronium,
Pancuronium, Rocuronium, Vecuronium, Gallamine;
barbiturates;
bradykinin;
snake venom, insect bites, allergens from pollens.
H1-receptors are coupled to Gq protein– phospholipase C and mediate the
following effects:
• Contraction of smooth muscle and neuronal actions are due to increases in [Ca2+]i
and activation of protein kinase C .
• Relaxation of vascular smooth muscle involves Ca2+ -induced formation of nitric
oxide (NO).
• Mediate contraction of bronchiolar and intestinal smooth muscle, vasodilation of
small arteries and veins, increased capillary permeability and pruritus.
• The guinea pig bronchi are the most sensitive but the bronchi of rabbit, dog, goat, calf, pig,
horse, and human also contract. I
• n contrast, histamine relaxes respiratory smooth muscle in cats (via H1 and H2) and sheep
(via H2).
• The mechanisms by which H1-receptors mediate brochodilation in cats are not known.
• H2- receptors mediate bronchodilation via an increase in cAMPlevels.
H1-Receptor Mediated Responses
• Contraction of Bronchioles
• Contraction of smooth muscles
• Intestinal Cramp & Diarrhea
• Increase capillary permeability
• Increased contraction of smooth muscles
• Increased nasal and bronchial mucus
• Blocked of sodium channel in excitable membrane
• Asthma
• H2-receptors are coupled to Gs protein-adenylyl cyclase Stimulation
of Gs-coupled H2 receptors activate adenylyl cyclase and increase
tissue cAMP levels.
• This is the mechanism by which vascular smooth muscle relaxes and
gastric acid secretion is stimulated.
• H2-receptor primarily mediates gastric acid secretion and
vasodilatation.
• Agonists include 4-methylhistamine and dimaprit.
• H2-Antihistaminec include: cimetidine, ranitidine, famotidine, and nizatidine.
• Recent evidence suggests, just like H1-antihistamines, these drugs are inverse
agonists..
 COMMON RESPONSES OF
H1 &H2- HISTAMINE RECEPTORS

• Decreased BP by reducing PVR

• Dilation and increased permeability of capillaries result in Leakage of
proteins and fluid and skin show Triple Response.
• Wheal formation
• Redness
• Flare/Flash
• H3-receptors are coupled to Gi/o protein.
• Inhibition of the release of histamine and other neurotransmitters
involves inhibition of cAMP synthesis, opening of K + channels to
increase K+ efflux, and closure of Ca2+ channels to block Ca2+ entry
into the nerve.
• H3-receptors are located presynaptically on neurons and inhibit
neurotransmitter release.
• H4-receptors are coupled to Gi/o protein and activate phospholipase C-β
by Gβγ.
• These receptors are selectively expressed in mast cells, basophils, and
eosinophils.
• Activation of H4-receptors mediates histamine-induced mast cell
chemotaxis and leukotriene B4 production via activation of phospholipase
C-β.
• H4-receptors may play a role in early events of inflammation, edema, and
thermal hyperalgesia.
• H4-receptor antagonists are being developed as anti-inflammatory drugs
that involve mast cells and eosinophils.
TRIPPLE RESPONSE OF HISTAMINE
 Physiologic and pathologic roles
Gastric acid secretion
• Histamine is the most important regulator of gastric acid secretion and it stimulates secretion via
H2 receptors
Allergic reactions and anaphylactic shock
• The binding of antigenic substances to IgE molecules on mast cells causes the release of
histamine.
• Biologically active substances such as prostaglandin D2 and leukotrines (LTC4 and LTD4) are also
released.
Inflammation
• Histamine may be involved in the vasodilation observed in the inflammatory process.
Neurotransmission
• Histamine is a neurotransmitter in various brain areas and is involved in activating sensory nerves
resulting in pain and itch sensations.
Microcirculation
• Histamine relaxes arterioles and increases capillary permeability
Pharmacologic effects
 Pharmacologic effects
Cardiovascular system
• Histamine dilates arterioles, capillaries, and venules, increases cardiac
contractility and heart rate by activating both H1– and H2-receptors.
• There is a decrease in peripheral resistance (vasodilatation), resulting
in hypotension.
• The stimulation of cardiac activity involves a direct action and reflex activation of
the sympathetic nervous system, which is activated by the low blood pressure.
• There is an increase in capillary permeability brought about by contracting the
endothelial cells, which exposes the basement membrane. Fluid and protein pass
across the basement membrane to produce edema.
Respiratory system
• Respiratory smooth muscle is contracted in most species via H1-receptors.
• There is also stimulation of glandular secretion and prostaglandin formation.
• Asthmatics are generally more sensitive to histamine than normal animals.
Glandular tissue.
Histamine can stimulate glandular tissues to increase secretion. A most important action of
histamine is its ability to increase gastric acid and pepsin secretion from the gastric mucosa via
H2-receptors.
• Regulation of gastric acid production is quite complex. Acid secretion by parietal cells is
regulated by histamine, acetylcholine (ACh), gastrin, and prostaglandin E2 (PGE2).
• Sight and smell of food activate the vagus via the CNS to release ACh on parietal cells (M3-
muscarinic receptor) and on enterochromaffin-like (ECL) paracrine cells (M1-muscarinic
receptor).
• The presence of food and an increase in antral pH initiate the release of gastrin. Gastrin acts
on cholecystokinin (CCK2) receptors of the parietal and ECL cells. Histamine is released from
ECL cells that are close by, and activate parietal H2-receptors.
• ACh has both a direct and indirect action on gastric acid production. Activation of M3-
receptors directly activates the parietal cell, whereas activation of the M1-receptor on the
ECL cells releases histamine which in turn activates H2-receptors on the parietal cell.
• Gastrin has both a direct and indirect action.
• Gastrin directly activates CCK2-receptors on parietal cells to increase gastric acid secretion and
indirectly increases gastric acid secretion by activating the release of histamine from ECL cells,
which again in turn activates H2-receptors on the parietal cells. Thus, histamine release is a major
factor in the stimulation of acid production by both ACh and gastrin.
• Activation of H2-receptors enhances the gastric acid secretion by ACh and gastrin on
parietal cells.
• Upon H2-receptor stimulation, intracellular cAMP is increased. Activation of PKA by cAMP
translocates H+, K+-ATPase in tuberovesicles to canalicular membrane, which subsequently releases
H+ into the lumen. Upon stimulation of M3-receptors and gastrin (CCK2) receptors, calmodulin
kinase is activated to translocate the H+, K+-ATPase to canalicular membrane as well. Chloride is
released into lumen by K+ and Cl− carrier, evoking next increase in HCl level in the lumen.
• H2-antihistamines inhibit not only HCl secretion by histamine but secretion stimulated
by gastrin, ACh (vagus), and food.
• This explains why H2-antihistamines are effective therapy for peptic ulcers. Proton pump inhibitors
(e.g., omeprazole) block the H+, K+-ATPase in canalicular membrane. PGE2 act as a negative
regulator of gastric acid secretion as PGE2 activates Gi/o-coupled EP3 receptors on parietal cells.
• Histamine can increase the release of catecholamines from the adrenal medulla and
stimulate salivary secretion
Intradermal tissue.
• Intradermal injection of histamine produces a triple response (of
Lewis). Insect and plant stings mimic many of these responses.
• A reddening at the site of injection is due to dilation of the small arterioles.
• Dilation of arterioles extends beyond injection site (Flare). The flare involves
an axon reflex since cutting the cholinergic nerves abolishes the reflex.
• Swelling (Wheal) occurs at the injection site due to separation of the
endothelial cells and edema caused by the increased capillary permeability,
which is due to H1-receptor-mediated contraction of endothelial cells.
• The intradermal injection of histamine causes pain and itching by
stimulation of H1-receptors on sensory nerve endings
Therapeutic uses of histamine agonists
• Histamine phosphate can be used for diagnostic purposes for testing
of gastric acid secretion and pheochromocytoma. However, its
profound side effects limit its use.
• Betazole is an analog of histamine, which is an H2-receptor agonist.
Betazole has a 10-fold selectivity for stimulation of gastric acid
production over vasodilation.
• Pentagastrin is also used for this purpose.
HISTAMINE ANTAGONISTS
Physiologic antagonists: Adrenaline, Noradrenaline (NA)
Histamine release inhibitors: Cromolyn (Disodium cromoglycate),
Nedocromil
others: Amlexanox; Lodoxamide; Pemirolast; Reprinast;
Methylxantine; Flavonoids.
Histamine receptor antagonists: -
H1 receptor antagonists:
Histamine antagonists cont.
1st generation (cross the blood-brain barrier):
- Alkylamines: Chlorpheniramine, Brompheniramine;
- Phenothiazines: Promethazine, Prochlorperazine, Thiethylperazine,
Alimemazine;
- Tricyclic dibenzoxepins: Doxepin
- Ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine, Dimenhydrinate;
- Imidazolines: Antazoline;
- Ethylaminediamines: Pyrilamine, Tripelenamine;
- Ethylendiamines: Chloropiramine;
- Piperazines: Hydroxyzine, Cyclizine, Meclizine;
- Miscellaneous: Cyproheptadine (also a 5-HT antagonist), Phenindamine,
Clemastine, Clorfenoxamine, Dimetinden, Bamipine, Ketotifen;
Histamine antagonists cont.
2nd generation (do not cross the blood-brain barrier):
- Piperidines: Loratadine, Desloratadine, Fexofenadine,
- withdrawn from market: Astemizol, Terfenadine;
- Piperazines: Cetirizine, Levocetirizine, Mequitazine;
- Miscellaneous: Ebastine, Levocabastine, Azelastine, Mizolastine,
Acrivastine.
- H2 receptor antagonists: Cimetidine, Ranitidine, Nizatidine, Famotidine.
- H3 receptor antagonists: Thioperamide, Clobenpropit
- H4 receptor antagonists: Thioperamide.
HISTAMINE antagonists cont.
Cromolyn (Disodium cromoglycate)
Mechanism of action:
- inhibition of the release of histamine and leukotrienes from
sensitized mast cells;
-block the transmembrane calcium influx caused by the interaction of
immunoglobulin E to the antigen on the surface of mast cells;
- inhibition of phosphodiesterase;
- alteration of channel function of chlorine channels in cell membranes;
- interference effects of platelet factor.
Histamine antagonists cont.
Indications: (prophylaxis only):
- bronchial asthma;
- allergic rhinitis;
- allergic conjunctivitis;
- food allergies.
Adverse effects
- dermatitis, urticaria (rarely);
- myositis; -
- pulmonary infiltrates with eosinophilia; -
- arthralgia;
- dysuria, nausea, bad taste;
- transient bronchospasm, coughing, wheezing (rarely).
- Nedocromil: effects similar to Cromolyn (Disodium cromoglycate), in
addition, it inhibits the cough.
HISTAMINE ANTAGONISTS H1 receptor
antagonists
Pharmacodynamic effects:
- anti-allergic effects;
- sedative effects
anti-H1 1st generation
- phenothiazines: Promethazine, Prochlorperazine, Thiethylperazine,
Alimemazine,
- piperazine derivatives: Hydroxyzine, Cyclizine, Meclizine,
- ethylenediamines: Chloropiramine,
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
Uses of H1 antagonists
antiemetic effects:
- phenothiazines: Promethazine, Prochlorperazine, Tiethylperazine,
Alimemazine,
- piperazine derivatives: Hydroxyzine, Cyclizine, Meclizine,
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate anticholinergic effects:
- phenothiazines: Promethazine, Prochlorperazine, Thiethylperazine,
Alimemazine,
- ethylenediamines: Chloropiramine, -
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
- alkylamines: Chlorpheniramine, Brompheniramine;
Uses of H1 antagonists
antiparkinsonian effects
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
- ethylenediamines: Chloropiramine,
- α1 adrenergic receptor blockade (especially phenothiazines,
alkylamines);
- phenothiazines: Promethazine, Prochlorperazine, Tiethylperazine,
Alimemazine,
- alkylamines: Chlorpheniramine, Brompheniramine;
antiserotoninergic effects (Cyproheptadine);
Uses of H1 antagonists
the local anesthetic (piperidine derivatives, ethanolamines,
ethylenediamines);
anti-inflammatory effect
-anti-H1 2nd generation
- Hydroxyzine: inhibits release of substance P, serotonin,
prostaglandins.
Indications
• prevention and treatment of allergic reactions (bronchial asthma, allergic rhinitis,
allergic conjunctivitis, allergic dermatitis);
• as antiemetics and for the treatment of motion sickness (phenothiazines,
ethanolamines, piperazines);
• nausea and vomiting (Doxylamine);
• Meniere’s disease (Prochlorperazine);
• anxiolytics, sedative-hypnotics (ethanolamines, ethylenediamine, phenothiazines,
piperazines);
• as antipsychotics (Chlorpromazine);
• stimulation of appetite (Cyproheptadine);
• Parkinson’s disease (ethanolamines);
• interstitial cystitis syndrome (Hydroxyzine).
Adverse effects
• sedative effects: in children determine paradoxical excitement,
nervousness, euphoria;
• anticholinergic effects;
• stimulation of appetite and weight gain (Cyproheptadine);
• lethal tachyarrhythmias (torsades de pointes) when aadminsiterred
with grapefruit juice: Terfenadine, Astemizol.
H2 RECEPTOR BLOCKERS
H2 receptor antagonists
Mechanism of action:
- antagonism on H2 receptors;
- Nizatidine: also it is acetylcholinesterase inhibitor.
Pharmacodynamic effects:
-inhibition of basal gastric secretion of HCl.
Pharmacokinetics:
- Cimetidine: is inhibitor of drug metabolism.
Indications
• peptic ulcer;
• Zollinger-Ellison syndrome;
• gastroesophageal reflux;
• non-ulcer dyspepsia;
• prevention of gastritis induced by stress;
• hypersecretory conditions (systemic mastocytosis, leukemia,
basophilia).
Adverse effects
• Cimetidine:
- in the CNS: confusional states, hallucinations, delusions, agitation;
- endocrine effects: gynecomastia, galactorrhea, decreased
spermatogenesis, libido;
- hematological effects: granulocytopenia, aplastic anemia;
- effects on the liver: the elevation of transaminases, cholestatic jaundice, acute
hepatitis;
- Ranitidine: elevation of transaminases, cholestatic jaundice, acute hepatitis;
- Famotidine: headache, transient elevation of transaminases;
- Nizatidine: headache; transient elevation of transaminases, prokinetic effect,
reduction in heart rate, reducing the force of contraction of the heart.
Serotonin (5HT)
• It is also called 5-Hydroxytreptamine (Serotonin)
• It is widely distributed in plants and animals.
• Highest concentration in mammals is found in the pineal gland, acting
as a precursor for melatonin.
• It is synthesized from the amino acid tryptophan and acts on several
types of receptors.
Serotonin
• It also stimulates smooth muscles, especially of the intestines.
• Serotonin is widely distributed in the CNS, serving as a
neurotransmitter.
• Altered functions may be responsible for disturbances in sleep, mood,
sexual behavior, motor activity, pain perception, migraine,
temperature regulation, endocrine control, psychiatric disorders and
extra-pyramidal activity.
Synthesis
• It is 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.
Metabolism
By mono-amino oxidase enzyme to form 5- hydroxy 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 increase in the following

conditions :
- Carcinoid syndrome ( tumor of enterochromaffin cells).
- in case of using some of old anti-hypertensive drugs (reserpine).
- ingestion of banana
Role of serotonin
• It acts as a neurotransmitter in the brain.
• Regulation of temperature.
• Pain perception .
• In pathogenesis of migraine.
• In pathogenesis of depression.
• In pathogenesis of anxiety.
• Involved in intestinal motility .
• Control of vomiting.
• Control of appetite.
• Pathogenesis of carcinoid syndrome.
Mechanism of action
• Serotonin exerts its action by binding to 7 subtypes of receptor ( 6 are
G-protein coupled and "5-HT3" is ion channels coupled.
• The second messenger of G-protein coupled receptors is either cyclic
AMP or IP3 and DAG.
Pharmacological Actions
• 5-HT causes constriction of renal, splanchnic, meningeal, and
pulmonary arteries and veins and venules, but dilatation of the blood
vessels of skeletal muscles, coronaries, and skin capillaries.
• It has weak direct +ve inotropic and +ve chronotropic effect
myocardium.
• Elevated plasma level of serotonin in carcinoid syndrome lead to
pathogenic endocardial changes.
On blood vessels : serotonin produces triphasic response which
includes:
Pharmacological Actions cont.
early depressor phase due to decrease heart rate and cardiac output
due to chemoreceptor reflex.
Presser effect due to increase peripheral vascular resistance and cardiac
output.
Late depressor phase : related to vasodilatation in skeletal muscle.
Respiratory system:
• It produces a small direct stimulation to bronchial smooth muscle in
normal person but produce a bronchiospasm in patients with carcinoid
syndrome.
• It also produces hyperventilation due to stimulation of bronchial sensory
nerve endings.
Pharmacological Actions cont.
GIT:
• It stimulates the smooth muscle of the gut which increases the tone
and facilitate peristalsis that is related to the action of serotonin on
5HT receptor in smooth muscle and ganglionic stimulation of the
enteric plexus .
CNS:
• Stimulation of sensory nerve endings leads to pain and itching.
Glandular secretion:
• Serotonin has little inhibitory effects on exocrine glands
Pharmacological Actions cont.
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
Buspirone :
• acts on 5-HT1A receptor .
• It is an anxiolytic drug ( non benzodiazepines non barbiturates anxiolytic).
Dexfenfluramine :
• Suppresses appetite and used to decrease body weight.
Amlotriptan , Eletriptan , Naratriptan , Rizatriptan , Zolmitryptan :
They act on 5-HT 1 B and D receptors and used in treatment of acute
migraine.
Serotonin Agonists cont.
Sumatriptan
• It is highly effective in treating acute attacks of migraine, but is not
useful in the prevention.
• It relieves the nausea and vomiting, but the headache may recur,
necessitating repeated administrations.
• It is administered orally or by the subcutaneous route.
• The bioavailability of oral dose is only 14 %; thus, the oral dose is
several times larger than the subcutaneous dose.
Adverse effects of Sumatriptan
• flushing and heat at the injection site,
• neck pain,
• dizziness, and
• tingling of the hands.
• The drug is contraindicated with symptomatic ischemic heart
diseases, angina, and hypertension as it may cause coronary
vasoconstriction.
Serotonin Agonists cont.
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
Cyproheptadine (periactin):
• It is H1 and 5-HT2 blocker
• It is used mainly as appetite stimulant.
• Other uses include : Allergic rhinitis , cold urticaria , prophylaxis of
migraine, in Dumping syndrome after gasterectomy and in carcinoid
syndrome.
Ketanserin:
• It is 5-HT 2 and α-blocker .
• It was used in the treatment of hypertension .
Ritanserin :
• It is 5-HT2 blocker and has no α- blocking effect.
Serotonin Antagonists cont.
Ondansetron , Granisetron ,Tropisetron and Alosetron:
• They act on 5-HT3 receptor as antagonists
• They are used mainly in cytotoxic induced nausea and vomiting.
Ergot Alkaloids :
• They are produced by fungus that infects grain .
• Ergots act on the following receptors:
-Serotonin receptor.
- α adrenoceptor.
- Dopamine receptor.
Ergots act as agonist , partial agonist or antagonist.
Serotonin Antagonists cont.
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.
Serotonin Antagonists cont.
Ergot alkaloid drugs and their clinical uses:
• Bromocriptine: used in acromegaly and hyperprolactinaemia.
• Ergotamine : used in acute migraine .
• Ergonovine: used in post-partum hemorrhage and diagnosis of Varian
angina .
• Lysergic acid diethylamide (LSD) :It is a hallucinogenic agent.
• Methysergide: used in migraine prophylaxis.
• Dihydroergotoxin : Used in cerebral insufficiency.
Serotonin Antagonists cont.
Side effects of Ergot Alkaloids:
• Nausea , vomiting , abdominal pain , drowsiness , hallucination ,
confusion , abortion, retro-peritoneal fibrosis, gangrene.
Methysergide
• It blocks the actions of 5-HT on a variety of smooth muscles.
• It also has a weak direct vasoconstrictor effect.
• It is an effective prophylactic agent for migrainous headaches.
• But has no effect in treating acute attacks, even may worsen the
condition.
Adverse reactions include gastrointestinal irritation, drowsiness,
vertigo, and psychic disturbances.
Cyproheptadine
• It is a potent antagonist of 5-HT and to a smaller extent of histamine
and acetylcholine.
• It stimulates appetite probably by acting directly on the
hypothalamus.
• It can block the release of hydrocortisone, and the production of
aldosterone.
• It is mainly used to relieve the itching associated with skin disorders
such as allergic dermatitis.
• The common adverse reaction is drowsiness.
Ondansetron
• It is a specific 5-HT3 receptor antagonist.
• Given orally or intravenously,
• it is useful in the management of nausea and vomiting associated
with cytotoxic therapy.
Adverse reactions include headache, constipation, and allergic
reactions.
Prochlorperazine and haloperidol
• They have anti-5-HT activity and are sometimes used for resistant
acute attacks
Case study
• A 70-year-old woman was brought in by her husband due to 2 weeks
of progressive behavior changes, gait disturbance, and generalized
weakness that had worsened over the previous 3 days. Her home
health aide had noted increased lethargy and a diffuse tremor during
the week prior to presentation. She was minimally verbal at baseline
but could typically perform activities of daily living without difficulty.
Her husband and aide denied any recent illness, fever, trauma,
shortness of breath, urinary symptoms, diarrhea, or skin changes.
• Her past medical history was significant for hypertension,
hyperlipidemia, depression, and dementia, and her past surgical
history was significant for thyroidectomy.
• Her family history was non-contributory, and she had no known drug
allergies. Her home medications included lisinopril, quetiapine,
paroxetine, and atorvastatin.
• Her vital signs were: rectal temperature 39.3°C; blood pressure
109/80 mm of mercury (mmHg); heart rate 104 beats per minute;
respiratory rate 25 breaths per minute; and oxygen saturation 93% on
room air.
• A physical examination was notable for a patient in moderate distress
who exhibited a resting tremor in all 4 extremities. Her neck was
contracted to the left but had full passive range of motion without
meningismus. Her pupils were equal, round, and reactive to light and
accommodation, and extraocular movements were intact.
Hyperreflexia and 6 beats of inducible clonus were noted.
• The results of cardiopulmonary, abdominal, and skin examinations
were all unremarkable. Chemistries, blood cultures, and urine studies
were collected, and the patient was given acetaminophen,
vancomycin, ceftriaxone, acyclovir, ampicillin, diazepam, and 2 L of
lactated Ringer’s solution.
• The hemoglobin/hematocrit, platelets, antinuclear antibody (ANA),
complement 3 and 4 levels (C3, C4), procalcitonin, vitamin B12, and
thyroid function were all within normal limits.
• Tests for human immunodeficiency virus (HIV), syphilis, and
coronavirus disease-19 (COVID-19) were non-reactive. Alcohol,
salicylates, and acetaminophen were not detected.
• Lumbar puncture showed normal opening pressure and cerebrospinal
fluid chemistries, as well as a negative meningitis-encephalitis
polymerase chain reaction panel for all tested pathogens (Escherichia
coli, Haemophilus influenza, Streptococcus agalactiae and
pneumoniae, Cytomegalovirus, Enterovirus, Herpes simplex virus,
Human herpes virus 6, Human parechovirus, Varicella zoster virus,
and Cryptococcus neoformans). Blood, urine, and cerebrospinal
cultures yielded no growth.
• Electrocardiography showed sinus tachycardia with narrow QRS
complexes, normal QTc intervals, and no ischemic changes. A chest X-
ray revealed no acute pulmonary pathology. Computed tomography
(CT) of the head was negative for acute intracranial pathology. The
patient was admitted to the Medicine Department for
encephalopathy secondary to a suspected toxidrome and metabolic
derangements.
• Cyproheptadine was given every 2 h, with improvement in clonus.
The elevations in white blood cell count, transaminases, troponin,
creatinine, and creatine kinase all resolved.
• Video electroencephalography (EEG) was performed and showed
mild-to-moderate generalized slowing as well as focal slowing in the
right temporal lobes with sharp waves that were non-epileptiform;
these findings were consistent with non-specific, diffuse cerebral
dysfunction and focal dysfunction in the right temporal region.
Vancomycin, ceftriaxone, ampicillin, and acyclovir were discontinued.
A gradual return to baseline followed and the patient was discharged
to hospice care
Natriuretic peptide
Natriuretic peptide (ANP, BNP, CNP):
• Natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic
peptide (BNP), and C-type natriuretic peptide (CNP)
• They are a family of endogenous polypeptide mediators mainly of
cardiac origin with natriuretic and vasodilator effects,
• inhibition of renin secretion, angiotensin II and aldosterone and
sympatholytic effect.
• They act on specific natriuretic peptide receptors.
Therapeutic application:
-synthetic derivative of BNP e.g. Nesiritide
Indications:
congestive heart failure acutely decompensated (iv).
Adverse effects:
- hypotension, ventricular tachycardia, ventricular extrasystoles, angina
pectoris.
- headache, insomnia, dizziness, anxiety
- abdominal pain, nausea, vomiting.
- increases in serum creatinine.
Endothelins
• They are polypeptides found in vascular endothelium (which explains
their denomination)
• It can alsobe found in brain, kidney, intestine, adrenal gland.
• There are three endothelins, endothelin I (ET-1), endothelin II (ET-2)
and endothelin III (ET-3), different only by some amino acids.
• Endothelin I is considered as the most active and determines
vasoactive effects, proarrhythmia, stimulation of the proliferation of
vascular smooth muscle cells, proinflammatory effects, pro-platelet
effects.
• Endothelin II determines vasoactive effects.
• These act on endotheline receptors called ETA and ETB.
• Endothelins, by activating ETA and ETB receptors, determine a general
vasoconstriction.
Therapeutic application:
-antagonist of endothelin ETA and ETB receptors e.g. Bosentan
Mechanism of action:
• inhibits vasoconstriction.
Indications:
pulmonary hypertension (oral administration).
Adverse effects:
- increases in aminotransferases and in total bilirubin.
Contraindications:
- liver impairment
- pregnancy.
Prostaglandins
• Prostaglandins are produced by all nucleated cells except
lymphocytes.
• They are autocrine and paracrine lipid mediators that act upon
platelets, endothelium, uterine and mast cells.
• They are rapidly metabolized to inactive products at the site of action.
(short half-life)
Synthesis
• primary precursor – Arachidonic acid
• They are synthesized via the cyclooxygenase pathway.
i) COX-1 - physiologic production
ii) COX-2 – produces prostaglandins through stimulation
- Inflammation - oxidative stress
- injury - ischemia
- seizures - neurodegenerative diseases
The actions of prostaglandins are mediated by their binding to variety of cell
membrane receptors.
Therefore they have variety of effects depending on the tissues.
For examples:
i) Constriction or dilation in vascular smooth muscle cells
ii) Aggregation of platelets
iii) Sensitize spinal neurons to pain
iv) Decrease intraocular pressure
v) Regulate inflammatory mediation
vi) Stimulate contractility of uterine and other smooth muscle
vii) Regulate acid secretion of stomach
Therapeutic uses:
1) Abortion – e.g. misoprostol (synthetic prostaglandins E1 analog)
- It is administered vaginally
- Common complications – infection, hemorrhage, retained tissue
2) Peptic ulcers – e.g. misoprostol
- It inhibits secretion of HCl and pepsin, and enhances mucosal
resistance.
- Useful in patients with gastric ulcer who chronically take aspirin.
3) Treatment of glaucoma
4) In pulmonary hypertension
5) As a vasodilator in severe Raynaud’s phenomenon or ischemia of a limb
Leukotriene
• “Leuko” = white blood cells
• “trienes”=three conjugated double bond
• Family of eicosanoid inflammatory mediators produced in leukocytes,
mast cells, macrophages and others
• Collections of oxygen derivative of 20 essential fatty acid
• Consists of family of the 5-lipo oxygenase pathway of arachidonic acid
metabolism.
• They are derived from 20 carbon (Eicosa) FA with double bonds
(Eicosanoids)
• They are immunological stimuli
• They are produced along with histamine but unlike histamine they are
four folds more potent &have longer duration ( Slow Reacting
Substance)
• Like hormone produced in low concentration and rapid metabolic
turn over. Unlike hormones they are not produced in acentral organ
but locally produced.
• Examples inc: LTA4, LTB4, LTC4, LTD4, LTE4
• They are potent lipid mediators formed from arachidonic acid
through multiple enzymatic steps/rxn
 • Cysteinyl LT (cysLTs): LTC4, LTD4, LTE4
• LTB4
• Importance in clinical course & physiologic changes of asthma.
 Leukotriene synthesis
• Phospholipid enzymatically metabolized by phospholipases to arachidonic
acid (AA).
• AA metabolized
• Cyclooxygenase pathway
• Lipooxygenase pathway (5-LO pathway)
• Initiated by 5-lipoxygenase (5-LO) in concert with 5-LO activating protein
(FLAP)
• Production of an unstable intermediate known as LTA4
• LTA4 LTB4 by LTA4 hydrolase
• LTA4 LTC4 by LTC4 synthase
• LTC4 LTD4 LTE4
• LTC4 synthase
• Metabolizes LTA4 to LTC4 through a glutathione transferase.
• Found on chromosome 5q a region associated with many other genes linked
with asthma and atopy.
• LTC4 is then rapidly metabolized to LTD4 and LTE4 through enzymes ϒ-
glutamyltranspeptidase and dipeptidase
• LTC4 are produced 10ly by mast cells, basophil and eosinophils
• LTB4 produced 10ly by neutrophils and monocytes/macrophages.
Receptors of LT
There are two types
• Leukotriene B4 receptor (BLT) receptors (BLTR1 &BLTR2)
• CLT receptors
• BLT
Signalling pathway
• G-protein coupled receptors associated with Gq upon binding of cells
with receptors, activated Gq protein
• Gq stimulates the membrane bowel phospholipase C (Cleave
Phospholipids) which cleaves PIP2 into two second messangers IP3 &
DAG.
• DAG remain bound to the membrane while IP3 is released as soluble
structure, into cytosol, IP3 binds to IP3 receptors within cell
particularly calcium channels in ER and causes increase Ca and
release mediators.
Location of BLT
• Spleen, Blood leukocytes, ovary, pancreas, heart, prostate gland,
testes, kidney, colon, muscles, plancenta.
• BLT1 has limited expression mainly circulating blood leukocytes and
lymphocytes.
Functions
• Acts as chemo attractant
• Involved in condition which inflammation is dependent on
neutrophils eg cystic fibrosis inflammatory bowel disease & psoriasis
• Casuse adhension of granulocytes to the vascular endothelium by
activating receptors on surface of granulocytes
• It damages & increases vascular permeability by
• Release of lysosomal enzymes &production oxygen radicals
• Increase the synthesis of interleukin
 Cysteinyl L
• Effects
• LCT4, LTD4 & LTE4 • Stimulate pro-inflammatory activities like
• They are like LTB receptor constrictn of airway smooth muscles,
• The signaling pathway is the same increased vascular permeability, edema,
as LTB receptor Gq associated. increase mucus secretion, decrease
mucocilliary clearance, mucus
Functions hypersecretion, chemokine production by
• Involved in pathophysiology of mast cells and endothelial cell adherence.
bronchial asthma, rhinitis, atopic • CYSLTR1 is activated by LTD4
dermatitis, urticarial, CVS disorder
& tumor • CYSLTR2 is activated by LTC4, LTD4 & LTE4
Effects of organs/muscles
Smooth muscle
• Order of potency: LTD4> LTC4> LTE4
• Causes contraction of smooth muscle
• Airways
• Causes bronchoconstriction
• LTC4 and LTD4 are potent constrictor while LTE4 is less potent.
• LTB4 is also a potent constrictor and lead to tachyphylaxis
Secretion of mucus
• LTs are not potent agonists of mucus secretion but may be one of
other mediators which influence secretion of mucin into inflamed
airways i.e. synergism may occur with other agonists such as PGs in
allergic conditions of airways.
Microvasculature
• In human skin, LTC4 & LTD4 are potent vasodilators and produce
wheal and flare responses at low conc.
Leukotriene
Leukotriene antagonists:
• 5-lipoxigenase inhibitors: Zileuton;
• LTD4 antagonists: Montelukast, Zafirlukast, Pranlukast.
Mechanism of action:
- Zileuton: inhibition of 5-lipoxygenase
-inhibit the production of LTC4 and LTD4 (which determine
bronchospasm),
-LTB4 (which has role in chemotactic effects and leukocyte activation
in the bronchial mucosa);
Leukotriene cont.
Montelukast, Zafirlukast, Pranlukast:
- antagonists on leukotriene LTD4 receptors.
Indications:
- long-term treatment of bronchial asthma, including asthma induced
by aspirin, bronchial asthma induced by effort or bronchial asthma
induced by antigens.
- Zafirlukast is also indicated for asthma with concomittant allergic
rhinitis.
Leukotriene receptor antagonists
• The leukotriene receptor antagonists are selective and competitive
antagonists of cysteinyl leukotriene (CysLT1) receptor.
• They antagonize the contractile actions of LTC4, LTD4 and LTE4 in
airway smooth muscle.
• These drugs are selective for CysLT1 receptors and do not bind with
significant affinity to prostanoid, cholinergic or beta-adrenergic
receptors found in respiratory tissues.
• They inhibit bronchoconstriction and attenuate the early- and late-
phase reaction caused by several kinds of inhalational challenges in
asthma patients including sulfur dioxide, cold air antigens such as
grass, cat dander, ragweed and mixed antigens.
• They also attenuate the increase in bronchial hyperresponsiveness to
inhaled histamine that followed inhaled allergen challenge.
• Zafirulast: Prophylaxis and chronic treatment of asthma in adults and
children ≥ 5 years of age.
• Montelukast: Prophylaxis and chronic treatment of asthma in adults
and pediatric patients ≥ 2 years of age.
 Pharmacokinetics
Absorption
• Both drugs are rapidly absorbed (60-80%) following oral administration,
giving peak plasma levels in 3-4 hours.
• Administration of zafirlukast with food reduced the mean bioavailability by
» 40%.
• The oral bioavailability and Cmax of montelukast are not significantly
influenced by a standard meal.
Distribution:
• Both drugs are highly (>99%) bound to plasma proteins (predominantly
albumin).
• Zafirlukast has a substantially larger volume of distribution (70 L) than
montelukast (8-11 L).
• Metabolism
• Both drugs are extensively metabolized.
• The most common metabolic products of zafirlukast are hydroxylated
metabolites, formed through the cytochrome P450 2C9 (CYP2C9)
enzyme pathway.
• The metabolites of zafirlukast found in plasma are at least 90 times
less potent as LTD4 receptor antagonists than zafirlukast in a standard
in vitro test of activity.
• Zafirlukast inhibits the CYP3A4 and CYP2C9 isoenzymes at
concentrations close to the clinically achieved plasma concentrations.
• Based on this clearance profile, the Cmax and AUC of of these drugs
are significantly increased in patients with moderate to severe hepatic
impairment. Therefore,Doses need not be adjusted in renal
impairment.
• Cytochromes P450 3A4 and 2C9 are involved in the metabolism of
montelukast. Forming a diacid, sulfoxide, multiple hydroxy
metabolites (positions 21, 25 and 36) and the acyl glucuronide.
Excretion:
• Both drugs and their metabolites are excreted almost completely in
the bile (biliary excretion).
• The mean plasma half-life of zafirlukast is 8-16 hours.
• The mean plasma half-life of montelukast ranges from 2.7 to 5.5
hours
Adverse Reactions and Warnings:
• CNS: Headache, dizziness
• GI: Nausea, diarrhea, abdominal pain, vomiting, dyspepsia
• Infection: An increased proportion of patients > 55 years of age receiving
these drugs experience mild or moderate respiratory tract infections.
• Hypersensitivity reactions, including urticaria, angioedema and rashes,
with or without blistering have been reported in association with these
drugs.
• Concomitant warfarin therapy with zafirlukast
• Hepatic function impairment: The clearance of these drugs is reduced in
patients with cirrhosis.
• Acute asthma attacks: These drugs are not indicated for use in the
reversal of bronchospasm in acute asthma attacks, including status
asthmaticus.
• Churg-Strauss Syndrome, a rare and sometimes fatal reaction, has
been reported with zafirlukast, usually when patients are reducing
their oral steroid dose.
Drug Interactions
• Because of zafirlukast's inhibition of cytochrome P450 2C9 and 3A4
isoenzymes, use caution with coadministration of drugs known to be
metabolized by these isoenzymes.
• Potent cytochrome P450 enzyme inducers, such as phenobarbital or
rifampin, are coadministered with montelukast may reduce drug
levels
Zileuton
• Zileuton is a specific inhibitor of 5–lipoxygenase and thus inhibits the
formation of leukotrienes LTB1, LTC1, LTD1 and LTE1.
• Both the R(+) and S(-) enantiomers of this drug are active as 5–
lipoxygenase inhibitors.
• Zileuton also inhibits leukotriene-dependent smooth muscle
contractions.
• Pretreatment with zileuton attenuates bronchoconstriction caused by
a variety of stimuli in patients with asthma
Pharmacokinetics:
Absorption
• Zileuton is rapidly absorbed upon oral administration with a time to
peak plasma concentration (Tmax) of 1.7 hours and a mean peak level
(Cmax) of 4.98 mcg/ml.
• The absolute bioavailability of zileuton is unknown.
• Administration of zileuton with food results in a small but statistically
significant increase (27%) in zileuton Cmax without significant
changes in the extent of absorption (AUC) or Tmax. Therefore,
zileuton can be administered with or without food.
Distribution
• The apparent volume of distribution of zileuton is about 1.2 L/kg and
the drug is 93% bound to plasma proteins, primarily to albumin, with
minor binding to alpha-acid glycoprotein.
Metabolism
• Zileuton is converted to a number of metabolites including the
diastereomeric Oglucuronide conjugates (major metabolites) and an
N-dehydroxylated (reduced) metabolite of zileuton.
• The urinary excretion of the inactive N-dehydroxylated metabolite
and unchanged zileuton each accounted for less than 0.5% of the
dose.
• Zileuton and its N-dehydroxylated metabolite can be oxidatively
metabolized by the cytochrome P450 isoenzymes including CYP1A2,
CYP2C9 and CYP3A4. Based on this clearance profile zileuton is
contraindicated in patients with active liver disease. Also, dose
adjustment in renal dysfunction or hemodialysis is not necessary.
Excretion
• Clearance of zileuton is mainly via metabolism with a terminal half-life
of 2.5 hours.
 Adverse Reactions and Warnings
• Hepatotoxicity: Elevations of one or more liver function tests
(asymptomatic elevations of serum aminotransferase)
• Acute asthma attacks: Zileuton is not indicated for use in the reversal of
bronchospasm in acute asthma attacks, including status asthmaticus.
• Hematologic: Transient reductions in white blood cell count
• Hepatic function impairment: Caution!
Common ADRs:
• GI and Headache Drug Interactions:
• Caution when using zileuton with other drugs that inhibit any of the
P450 isoenzymes 1A2, 2C9 and 3A4.