BP503T-3

Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial
ASBASJSM COLLEGE OF PHARMACY (AN AUTONOMOUS COLLEGE) BELA

COLLEGE OF PHARMACY
(An Autonomous College)
BELA (Ropar) Punjab
Program : B. Pharmacy
Semester : V
Subject /Course : Pharmacology-II
Subject/Course ID : BP503T
Module No. : 03
Module Title : Autocoids and related drugs
Course coordinator : Ritu Kainth
Mobile No. : 8847359620
Email id : ritukainth20@gmail.com
Learning Outcome of Module-3

LO Learning Outcome (LO) Course Outcome
Code
LO1 Classification of autocoids and related drugs BP503.3
LO2 K Know about the various types of drugs acting as autocoids. BP503.3
LO3 Know about the different classes and mechanism of action of BP503.3
various drugs acting as autocoids like histamine, Bradykinin, 5-HT,
prostaglandins, substance P, Angiotensin.
LO4 Know about classifications and MOA of NSAIDS, anti-gout drugs, BP503.3
anti-rehumatic drugs.
The Pioneer Pharmacy Institute of Punjab

Module Content Table

No. Topic
1 Introduction of autocoids and classification.
2 E Histamine, 5-HT and their antagonists
3 Prostaglandins, Thromboxanes and Leukotrienes.

4 Angiotensin, Bradykinin and Substance P.
5 Non-steroidal anti-inflammatory agents.
6 Anti-gout drugs
7 Anti-rehumatic drugs.

AUTOCOIDS AND RELATED DRUGS

The word autacoids come from the Greek "autos" (self) and "acos" (relief; i.e., drug). Autacoids
or "autocoids" are biological factors (molecules) which act like local hormones, have a brief
duration, and act near their site of synthesis. Vasodilator autacoids are releasedduring periods of
exercise.
The effects of autacoids are primarily local, though large quantities can be produced and moved
into circulation. Autacoids may thus have systemic effects by being transported via the
circulation. These regulating molecules are also metabolized locally. In sum, these compounds
typically are produced locally, act locally and are metabolized locally. Autacoids can have a
variety of different biological actions, including modulating the activities of smooth muscles,
glands, nerves, platelets and other tissues.
Some autacoids are chiefly characterized by the effect they have on specific tissues, such as
smooth muscle. With respect to vascular smooth muscle, there exist both vasoconstrictor and
vasodilator autacoids. Vasodilator autacoids are released during periods of exercise. Their main
effect is seen in the skin, where they facilitate heat loss. These are local hormones; they therefore
have a paracrine effect. Some notable autacoids are: eicosanoids, angiotensin, neurotensin, NO
(nitric oxide), kinins, histamine, serotonin, endothelins and palmitoylethanolamide.
Recently, research on autacoids has given rise to the nascent field of "Autacoid
Medicine” particularly since new lipid autacoids have been found to be of utility in the treatment
of chronic disorders, where inflammation plays a role. In 2015, a new definition of autacoids was
proposed, which helps to more specifically describe Autacoid Medicine.
Definition:
These are heterogeneous substances produced by a wide variety of cells having widely different
structures and intense biological activity but generally act locally at the site of its synthesis and
release.
"Autacoids are locally produced modulating factors, influencing locally the function of cells
and/or tissues, which are produced on demand and which subsequently are metabolized in the
same cells and/or tissues".
Classification of Autacoids:
1. Amine Autacoids (Decarboxylated autacoids amines): Hiatamine, 5-hydroxy tryptamine
(Serotonin).

2. Peptide autacoids (Polypeptide): Bradykinin, Kallidin, Vasoactive intestinal pepetides.
3. Lipid derived autacoids (Eicosonoids): Prostaglandins, Thromboxane, Leucotrines,
Platelets activating factors (PAF).
CLASSIFICATION OF AUTACOIDS
Different autacoids are:
• Histamine
• 5 Hydroxytryptamine (5HT)
• Bradykinin and Kallidin
• Cytokines
• Autacoids derived from membrane phospholipid
 Eicosanoids – arachidonic acid
 (PG, PGI, TXA2, LT)
 Modified phospholipids – PAF
HISTAMINE
Synthesis
Histamine is a basic amine formed from histidine by histidine decarboxylase.
Storage: It is found in most tissues but is present in high concentrations in the lungs and the
skin, and in particularly high concentrations in the gastrointestinal tract. At the cellular level, it is
found largely in mast cells but non-mast cell histamine occurs in 'histaminocytes' in the stomach
and in histaminergic neurons in the brain.
In mast cells and basophils, histamine is complexed in intracellular granules with an acidic
protein and a high-molecular-weight heparin termed macroheparin. Stored in granules of mast
cells, basophils and secreted when complement interact with cell membranes or antigen with cell
IgE. Others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing
tissues and body fluids. Produces effects by acting on H1, H2, H3 receptors.
Histamine Release
Histamine is released from mast cells by exocytosis during inflammatory or allergic reactions.
Stimuli include C3a and C5a that interact with specific surface receptors, and thecombination of
antigen with cell-fixed IgE antibodies. In common with many secretory processes, histamine
release is initiated by a rise in cytosolic Ca2+. Various basic drugs, such as morphine and

tubocurarine, release histamine through a non-receptor action. Agents that increase cAMP
formation (e.g. β-adrenoceptor agonists;) inhibit histamine secretion.
Replenishment of secreted histamine by mast cells or basophils is a slow process, which may
take days or weeks, whereas turnover of histamine in the gastric histaminocyte is very rapid.
Histamine is metabolised by histaminase and/or by the methylating enzyme imidazole N-
methyltransferase.
Histamine-Synthesis and Metabolism
MOA:
• Histamine act on H1 (Gq, protein coupled) receptor cause activation of IP3 and DAG and
protein kinase and release NO.
• Histamine acts on H2 (GS protein coupled) receptor and cause activation of cAMP and release
of Ca2+. Activation of H/K+ ATPase pumps and increases HCL secretion.

• Histamine acts on H3 (Gi protein coupled) receptor and inactivate cAMP and decreased influx
of calcium and opening of K+ channels.
Pharmacological Action:
1. CVS: H1 mediated response
Blood vessels:

• Contraction of major blood vessels like artery and veins.
• Dilation of minor blood vessels like capillaries, venules and cranial blood vessels.
• Net effects – vasodilatation.
Blood pressure:
• Moderate dose - Hypotension.
• High dose - Prolonged hypotension.
Heart:
• Increase forced and frequency of ventricular contraction.
• Increased coronary blood flow.
• Large dose - Ventricular arrhythmias.
2. Allergic Reaction: H1 mediated response.
Itching occurs if histamine is injected into the skin or applied to a blister base, because it
stimulates sensory nerve endings by an H1-dependent mechanism. Injected intradermally,
histamine causes the 'triple response':
• Reddening /Flush (local vasodilatation),
• Flare (bright flare, irregular outline extended upto 1-5 mm beyond flush, it is develop from an
'axon' reflex in sensory nerves releasing a peptide mediator) and
• Weal (direct action on blood vessels, developments of localized edema due to escape of fluid
from localized capillaries)
3. Smooth muscle: H1 mediated response.
• Moderate dose - Contraction of smooth muscles of GIT urethral.
• High dose - Abdominal cramps, colic and increase intestinal contraction.
4. Exocrine glands: H2 mediated response. Powerful stimulation of gastric acid and pepsin
secretion. Histamine acts on H2 (Gs protein coupled) receptor and cause activation of cAMP and
release of Ca2+. Activation of H/K+ ATPase pumps and increases HCl secretion.

5. CNS: H3 mediated response. Histamine do not cross BBB its synthesized locally from
histidine. Central physiological role is not clear, intracerabral and intravetebral injection may
cause hypothermia and vomiting.
6. Autonomic ganglion and adrenal medulla:
Histamine at high concentration stimulates both and cause release of Adrenaline.
Metabolism:
• Major pathways: Histamine is metabolised by histaminase and/or by the methylating enzyme
imidazole N-methyltransferase, and converts to N-methly histamine, which is act by MAO, after
oxidation excreted in urine as methyl imidazole acetic acid.
• Deamination: Small intestine, liver, kidney and monocytes. Methylation – small intestine,
liver, skin, kidney, thymus and leukocytes. N-methylimidazole acetic acid − principal urinary
metabolite
Uses:
1. Role in allergic responses – Ag + IgE (bound to mast cells and basophils).
2. Preformed mediators.

3. Most important mechanism of release/controlled by H2 esp. in skin and blood.
4. Release of other autacoids.
5. Release by drugs (morphine, urase, amines), peptides, venoms and other agents.
6. Release by urticarias.
7. Gastric secretagogue.
8. Neurotransmitter increased wakefulness, thermoregulation.
ADR:
• Hypotension, Flushing, Headache, Visuals distribution, Allergic reaction like-Flush, flare and
weal, Anaphylaxis shock.
ANTI HISTAMINE
Definition:
These are the drugs antagonized various actions of histamine that liberate in the body or
exogenously administered.
These drugs are use mainly for symptomatic relief of allergic disorders and peptic ulcer.
These acts in 3 Ways:
• Physiological Antagonist: Adrenaline
• By inhibiting the release of histamine from the sensitive mast cells following:
o Antigen Antibody reaction - Disodium chromoglycote, Nedocromil Sodium,
Calcium channels blockers, Loratidine, Citrizine
• Receptor antagonists - Which prevents histamine to reach at the site of actions.
Competitively inhibits the action of Histamine at Histamine Receptor:
• These are the competitive Antagonists at all the H receptors.
• H1 antagonists: Triprolidine, Chlorpheniramine.
• H2 antagonists: Ranitidine, Famotidine.
• H3 antagonists: Iodophenprofit, Chlobenpropit.
• H4 antagonists: Thioperamide.
Classifications of H1 Antagonists:
1. Potent and Sedative: Diphenhydramine, Promethazine, Dimenhydramine.
2. Potent and non-Sedative: Tripalanamine, Chlorcyclizine, Chlorpheniramine.
3. Less Potent and Less sedative: Pheniramine, Phenindone, Mepyramine.
4. Non sedative:

 First generation: Loratidine, Cetrizine, hydroxyzine.
 Second generation: Astimazole, Acrivastine, Terfenamide, Desloratidine,
Fexofenatidine.
 First generation ones are short/ intermediate acting; more sedating; more anti
muscarinic effect.
 Second generation have longer duration of action, poor permeability to BBB, so less
sedating.
Histamine H2 receptor blocker: Cimetidine, Ranitidine, Famotidine.
MOA:
Antihistamine blocks histamine receptor and antagonize the action produce by histamine.
H1 Receptor Blocking Action:
CNS:
It produced CNS depression that may leads to sedation, hypnosis, drowsiness and sleep. These
drugs also may be used in motion sickness due to various degree of CNS depression.
Smooth Muscles:
It antagonizes contraction of bronchial smooth muscles produced by histamine and relax
bronchial smooth muscles. The relaxation of smooth muscles of intestine, uterus and gall bladder
is lesser extent compare to bronchial smooth muscles. These all action mediated through H1
receptor blocking action.
CVS:
It produces membrane stabilizing action which leads to anti-arrhythmic effects. It also produced
relaxation of vascular smooth muscles.
Anti-Parkinsonism effects:
It produced anti cholinergic effects which may leads to decreased acetyl choline and caused
relief from Parkinsonism.
Local anesthetics action:
Due to its membrane stabilizing action it produces local anaesthesia. General action: It blocks
histamine receptor and cause relief from all allergic reaction including triple response.
H2 Receptor Blocking Action:

ADME: Well absorbed by oral and parenteral routes of administration, 50-60% binds to plasma
proteins, metabolized in liver by hydroxylation and followed by glucuronide conjugation and
excreted in urine.
Therapeutic uses: H1 Blocker:
• Prevents or treats symptoms of allergic rhinitis and urticaria.
• First generation ones cause sedation and are better for itching so used in atopic dermatitis.
• Second generation ones are non sedative, preferred for hay fever.
• Most of them show anti muscarinic effect, though as a side effect.
• So used in motion sickness ( cyclizine, meclizine).
• Used as anti emetics ( hydroxyzine, promethazine).
• Suppressing Parkinsonism Symptoms ( Diphenhydramine, promethazine).
ADR: H1 Blocker:
• Sedation and anti cholinergic actions like dry mouth, urinary retention, constipation.
• Drug allergy with topical agents.
• Tolerance after prolonged use.
• Teratogenic effects by hydroxyzine, cyclizine.
• Toxic doses leads to excitement, hallucinations, convulsions and coma.
• Drowsiness, Euphoria, diplopia, tinnitus, weakness.
• High Dose- Anti cholinergic effects- Gastric distress, Dryness of mouth and throat, Blurred
vision, Lightness of chest, Hypotension.
Therapeutic uses: H2 Blocker:
• In peptic ulcer.

• Dudenal ulcer.
• Zollinger Ellison syndrome.
• Gastro-esophageal reflux.
• Heart burn.
ADR: H2 Blocker:
• Headache, fatigue, myalgia, constipation.
• Mental status change occurs with cimetidine.
• Endocrinial effects with Cimetidine.
• Male impotence.
• Skin rashes, headache, dizziness, gynaecomastia, Impotence, Mental confusion, Hepatotoxicity.
Histamine Release Inhibitors
• Examples are Cromolyn Sodium and Nedocromyl Sodium.
• They prevent degranulation of mast cells hence inhibit histamine release.
• Used as pulmonary inhalants in the treatment of bronchial asthma.
• Nasal and ophthalmic formulations are used to reduce symptoms of allergic rhinitis and
conjunctivitis.
5-HYDROXY TRPTAMINE (5-HT) / SEROTONIN
• In humans, present in GI enterochromaffin cells (90%), platelets and brain.
• Synthesized from tryptophan (in diet) in two steps.
• Platelets do not synthesize but take up from blood (active uptake process in platelets and nerve
terminals).
Distributions
Widely distributed amine (animals + plants). In humans, present in Small intestine-(90%, found
in enterochromaffin cells) platelets, mast cells, lungs, bone marrow, pineal gland and CNS
Sources: Tunicates, mollusks, anthropods, colenterates, fruits, nuts, wasps and scorpions, Cell
storage in granules similar to catecholamines.
Synthesis and metabolism of 5-HT
• Competition at the level of brain and neuronal uptake
• Rate limiting enzyme not saturated usually
• No end-product negative feedback
• 5-OHTr decarboxylase same as DOPA decarboxylase

• 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine.
Receptors:
5HT1 - Subtypes:
5HT1A:
• Located in CNS.
• Inhibitory pre-synaptic receptor.
• Behavioural effects, Sleep, anxiety, thermoregulation, Decreased CAMP.
5HT1B:
• Located in CNS, Vascular smooth muscle.
• Pulmonary contraction, Behavioural effects, Inhibitory pre-synaptic receptor decreased CAMP.
• Act by decreasing IP3 – DAG system.
5HT1D:
• Most parts of the brain, cranial blood vessels.
• Cerebral vasoconstriction.
• Behavioral effects, decreased CAMP.
• Act by decreasing IP3 – DAG system.
5HT2:
• Located mainly CNS, Smooth Muscles and Platelets.
Subtypes:
5HT2A:
• CNS, PNS, Smooth Muscles and Platelets.
• Excitements, Platelets aggregation.

• Behavioral effects, GIT and bronchial smooth muscle contraction.
• Act by Increasing IP3 – DAG system.
5HT2B:
• Located in gastric fundus.
• Contraction.
5HT2C:
• Located in CNS, Choroid plexus and hippocampus.
• CSF secretion.
5HT3:
• Located in PNS and CNS.
• Neuronal excitation, emesis, anxiety and behavioral effects.
• Act by increasing IP3 – DAG system.
5HT4:
• Located in PNS and CNS.
• Neuronal motility and excitation.
• Act by increasing IP3 – DAG system.
5HT5:
• Located in CNS, hippocampus
• Decrease CAMP
• Act by Decreasing IP3 – DAG system
5HT 6:
• CNS, Straitum
• Increased cAMP
• Act by Increasing IP3 – DAG system
5HT7:
• CNS, Hippocampus
• GIT, Blood vessels
• Increased cAMP
• Act by Increasing IP3 – DAG system

Endogenous Function:
• Central neurotransmitter
• Precursor of melatonin
• GI tract: uncertain; motility?
• In carcinoid tumors: large amounts released leading to diarrhea, bronchoconstriction and edema
• Platelets: 5-HT2 receptors → aggregation and vasoconstriction
Pharmacological actions of 5HT:
• Serotonin mediated actions through large number of receptors which posses diverse
characteristics.
• Among these many subtypes receptors lack any specific physiological roles, So common
actions are:
CNS:
• It is very important neurotransmitters in CNS - in brain, brain stem, hypothalamus, raphae
nuclei, limbic system, and pituitary glands.
• 5HT cause regulation of mood, behavior, sleeps, depression, pain, sexual activity,
thermoregulations, Pain perception and Sleep/Wakefulness.
• Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive
behavior, etc.
• Neuroendocrine regulation - controls hypothalamic cells involved in release of several anterior
pituitary hormones.
• Hypothalamic controls release pituitary hormones.
• 5HT in pineal gland is precursor for synthesis of melatonin, a melanocyte stimulating
hormones, which controls/ influences sleep.
CVS:
• 5HT acts on 5HT2 receptor dilates blood vessels of skin, heart, smooth muscles and skeletal
muscles.
• It also produces bradycardia, decreased COP - Overall result is decreased BP/Hypotension,
though there is minor pheripheral vasoconstriction.
Platelets Aggregation:
• It cause released of more 5HT by acting on 5HT2A receptor and also cause release of platelets,
result forms clot and decreased blood shade out of damage organ.

GIT:
• Small intestine very sensitive to serotonin → intense rhythmic contractions due to direct and
indirect (ganglia in wall) effects.
• Increased GI peristalsis partly by acting on 5HT 2 and partly by acting on 5HT 3 and
5HT4.
• Increased gastric acid secretion which result in GIT irritation and nausea, vomiting.
Respiratory system:
• Broncho constriction if asthmatic; stimulation of aortic and carotid chemo receptors→ ↑ RR
and minute vol.
Miscellaneous:
• Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally).
• 5HT cause contraction of Bronchial smooth muscles.
• It produces anorexia.
• It increased pain perception and itching.
ADME: Well absorbed and rapidly degraded
Therapeutic use:
• Useful in various inflammatory responses.
ADR: GIT irritation, vertigo, insomnia, hypotension, edema, nausea and vomiting.
Drugs acting on 5HT Receptors:
Serotonin Agonists:
• Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina.
• Fluoxetine: Selective serotonin uptake inhibitors for depression and other indications.
• Buspirone: 5-HT1A agonist for anxiety.

• Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market
due to fatal arrhythmias).
• LSD: 5HT1A – hallucinogen.
• Ergot alkaloids: 5-HT1 and 2 and other receptors.
Serotonin Antagonists:
• Methysergide and Cyproheptadine: 5HT2 antagonists. In carcinoid, migraine.
• Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive.
• Ondansetron: 5HT3 antagonist for chemotherapy induced nausea and vomiting
• Clozapine: 5HT2A/2C antagonist: for schizophrenia.
5HT Receptor Agonists
Buspirone:
• Newer anti-anxiety drugs, Non Benzodiazapine group.
• Partial agonist of 5HT1 receptor in CNS.
Sumatriptine:
• Selective agonist at 5HT1B and 5HT1D.
• Cerebral vasoconstrictor agents regularly use in migraine attack.
Cisapride and Renzapride:
• 5HT4 receptor agonists, Increased GI motility use to treat gastro esophageal reflux.
5HT Receptor Antagonists:
Ketanserin:
• 5HT2A receptor antagonists also block 5HT2C Receptor.
• Effective antihypertensive agents with mild effects-Dizziness, Lethargy, nausea and
drymouth.
Ritanserin:
• More selective 5HT2A antagonists than Ketanserin.
• Significant α1 blocking action. It inhibits thromboxane formation and platelets aggregation and
increased bleeding time.
Ondansetron, Granisetron, Dolasetron:
• 5HT3 antagonists
• Use in chemotherapy induced emesis.
Risperidone:

• Potent 5HT2A and D2 receptor antagonists. Use as antipsychotic agents
Methiserzide:
• Ergot group of alkaloids
• Potent 5HT2A-2C antagonists.
• Prophylaxis of Migraine and post gastrectomy.
Cyproheptidine:
• Potent 5HT2 receptor antagonists.
• Also having antihistaminic and anticholinergic action.
• Possesses significant CNS depression action.
• Reduced allergic reactions.
• Stimulate appetite probably by acting on hypothalamus, increased weight gain from first week
of therapy and decreased once its stops.
• It decreases Aldosterone production.
• It also controls secretion of ACTH secretion by hypothalamus.
Therapeutic uses:
• Relief from pruritis, urticaria, dermatitis, itching, skin disease, rashes, patches.
• Treatment of Gastrectomy.
ADR:
• Dryness of mouth, Ataxia, Mental confusion, Headache, Visual hallucination,
Migraine
Clinical Presentations:
• Often accompanied by brief aura (visual scotomas, hemianopia).
• Severe, throbbing, usually unilateral headache (few hours to a few days in duration).
Migraine Pathophysiology:
• Vasomotor mechanism -- inferred from:
 increased temporal artery pulsation magnitude.
 pain relief (by ergotamine) occurs with decreased artery pulsations.
• Migraine attack associated with (based on histological studies):
 sterile neurogenic perivascular edema.
 inflammation (clinically effective antimigraine medication reduce perivascular
inflammation).

Migraine: Drug Treatment:
Ergotamine: best results when drug administered prior to the attack (prodromal phase) −less
effective as attack progresses.
• Combined with caffeine: better absorption
• Potentially severe long-lasting Vasoconstriction.
Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine.
Nonsteroidal Antiinflammatory Drugs (NSAIDs):
Sumatriptan: Alternative to ergotamine for acute migraine treatment; not recommended for
patients with coronary vascular disease risk.
• Formulations: subcutaneous injection, oral, nasal spray.
• Selective serotonin-receptor agonist (short duration of action).
• Probably more effective than ergotamine for management of acute migraine attacks (relief: 10
to 15 minutes following nasal spray).
Migraine: Prophylaxis:
Methysergide
• Effective in about 60% of patients.
• NOT effective in treating an active migraine attack or even preventing an impending attack.
• Methysergide toxicity: retroperitoneal fibroplasia, subendocardial fibrosis.
Recommend 3-4 week drug holiday every six months.
Propranolol:
• Most common for continuous prophylaxis
• Best established drug for migraine attack prevention.
Amitriptyline (TCA):
• Most frequently used among the tricyclic antidepressants.
Valproic acid (Antiepileptic)
• Effective in decreasing migraine frequency.
Nonsteroidal antiinflammatory drugs (NSAIDs)
• Used for attack prevention and aborting acute attack.
PLATELET-ACTIVATING FACTOR (PAF)
• Platelet-activating factor, also known as PAF, it is a potent phospholipid activator and
mediator of many leukocyte functions, platelet aggregation and degranulation, inflammation, and

anaphylaxis. It is also involved in changes to vascular permeability, the oxidative burst,
chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in
phagocytes. PAF is produced by a variety of cells, but especially those involved in host defense,
such as platelets, endothelial cells, neutrophils, monocytes and macrophages. PAF is
continuously produced by these cells but in low quantities and production is controlled by the
activity of PAF acetyl-hydrolases. It is produced in larger quantities by inflammatory cells in
response to specific stimuli.
• Platelets are involved primarily in coagulation and thrombotic phenomena but also play a part
in inflammation. They have low-affinity receptors for IgE, and are believed to contribute to the
first phase of asthma. In addition to generating thromboxane (TX) A2 and PAF, they can
generate free radicals and proinflammatory cationic proteins. Platelet-derived growth factor
contributes to the repair processes that follow inflammatory responses or damage to blood
vessels.
PAF is biosynthesized from acyl-PAF in a two-step process. The action of PLA2 on acyl- PAF
produces lyso-PAF, which is then acetylated to give PAF. PAF, in turn, can be deacetylated to
the inactive lyso-PAF.
Sources of platelet-activating factor:
Platelets stimulated with thrombin and most inflammatory cells can release PAF under the right
circumstances.
Pharmacological action:
• PAF receptor is a G-protein coupled receptor. Activate IP3-DAG system

Increased Ca2++ release
• By acting on specific receptors, PAF is capable of producing many of the signs and symptoms
of inflammation.
• Chemotactic to neutrophil and esinophils.
• Activate leucocytes.
• Activate platelets aggregation.
• It produces vasodilatation (and thus erythema), increased vascular permeability and weal
formation.
Higher doses produce hyperalgesia. It is a potent chemotaxin for neutrophils and monocytes, and
recruits eosinophils into the bronchial mucosa in the late phase of asthma.
• It can activate PLA2 and initiates eicosanoid synthesis.
• On platelets, PAF triggers arachidonate turnover and TXA2 generation, producing shape
change and the release of the granule contents. This is important in haemostasis and thrombosis.
• PAF has spasmogenic effects on both bronchial and ileal smooth muscle.
• The anti-inflammatory actions of the glucocorticoids may be caused, at least in part, by
inhibition of PAF synthesis.
• Competitive antagonists of PAF and/or specific inhibitors of lyso-PAF acetyltransferase could
well be useful anti-inflammatory drugs and/or antiasthmatic agents.
• The PAF antagonist lexipafant is in clinical trial in the treatment of acute pancreatitis.
Leukotriene
• Any of a group of biologically active compounds, originally isolated from leucocytes.
• Leuko - because they are made by white cells, and trienes because they contain conjugated a
triene system of double bonds.
• Synthesized from arachidonic acid by lipoxygenase catalysed pathways.
• Mainly found in lung, platelets, mast cells and white blood cells.
• Leukotrienes together with prostaglandins and other related compounds are derived from 20
carbon fatty acids that contain double carbon. Hence this group is called Eicosanoids.
• It produced along with histamine, unlike histamine they are more potent and have longer
duration and called as Slow Reacting Substances (SRS).
• Main enzyme in this group is 5-lipoxygenase.

• On cell activation, this enzyme translocates to the nuclear membrane, where it associates with a
crucial accessory protein, affectionately termed FLAP (five-lipoxygenase activating protein.
• The 5-lipoxygenase incorporates a hydroperoxy group at C5 in arachidonic to form
5-hydroperoxytetraenoic acid (5-HPETE) leading to production of unstable acid
leukotriene(LTA4) which is enzymatically converted to LTB4.
• LTB4, utilising a separate the glutathione, to with conjugation involving pathway cysteinyl-
containing leukotrienes LTC 4, LTD4, LTE4 and LTF4
(sulfidopeptide leukotrienes by mainly )which are produced eosinophils, mast cells, basophils
macrophages.
• LTB4 is produced mainly by neutrophils.
• Lipoxins and other active products, some of which have anti inflammatory properties, are also
produced from arachidonate.
Receptors and Actions:
• Receptors are termed BLT if the ligand is LTB4, CysLT for the cysteinyl leukotrienes.
• Receptors couple with Gq protein and function through the IP3/DAG transducer mechanism.
• BLT receptors are chemotactic and primarily expressed in leucocytes and spleen. BLT1
receptor has high, while BLT2 receptor has lower affinity for LTB4.
Leukotrienes B4 Receptors (BLT):
Includes:
1. BLTR1
2. BLTR2
• G Protein coupled receptors associated with Gq, activated upon binding of cells.
• Gq stimulates the membrane bound phospholipase C which then cleaves PIP2 into two second
messengers IP3 and DAG.
• DAG remains bound to the membrane and IP3 is released.
• IP3 binds to IP3 receptors within cells particularly Calcium channels in endoplasmic reticulum
and cause increase in release of Ca.
Cysteinyl Leukotrienes: They include
1. LTC4
2. LTD4
3. LTE4

• Signaling pathway is similar to LTB receptors.
• Mainly expressed in bronchial and intestinal muscle and has higher affinity for LTD4 than for
LTC4.
• The primary location of cysLT2 receptor is leucocytes and spleen, and it shows no preference
for LTD4 over LTC4.
• Cysteinyl leukotrienes may mediate the cardiovascular changes of acute anaphylaxis.
• Agents that inhibit 5-lipoxygenase are therefore obvious candidates for antiasthmatic and anti-
inflammatory agents.
• All Leukotrienes acts through IP3 DAG system.
The respiratory system:
• Cysteinyl leukotrienes are potent spasmogens contraction of human , causing dose-related
muscle in vitro bronchiolar
• LTE4 is less potent than LTC4 and LTD4, mucus secretion in lasting. All cause an increase but
its effect is much longer.
The cardiovascular system:
• Small amounts of LTC4 or LTD4 given pressure, and rapid, short lived fall in blood
intravenously cause a constriction of small coronary resistance vessels.
The role in inflammation:
• LTB4 is a potent chemotactic agent for neutrophils and macrophages.
• Regulates membrane adhesion molecule expression on neutrophils, and increases the
production of toxic oxygen products and the release of granule enzymes.
On macrophages and lymphocytes:
• It release and stimulates proliferation and cytokine control and regulation.
Membrane Phospholipids:
• Control and regulation is dependent on factors like availability and amount of integral fatty
acids.
• Alpha linoleic acid-present in the plasma membrane.
• Fatty acids are broken down to arachidonic by lipoxygenase for the leukotriene synthesis.
Metabolism:

• LTB4 is metabolized by a unique membrane-bound cytochrome P450 enzyme in neutrophils
and then further oxidised to 20-carboxy-LTB4
• LTC4 and LTD4 are metabolized to LTE4, which is excreted in the urine
Therapeutic Uses:
• Abortion
• Induction of labour
• Post partum haemorrhage
• Cervical ripening
• Peptic ulcer
• Glaucoma
• To avoid platelet damage
ADR:
• Nausea
• Vomiting
• Diarrhoea
• Uterine cramps• Forceful uterine contractions
• Flushing
• Shivering
• Fever
• Fall in BP
• Tachycardia
• Chest pain.
BRADYKININ
Bradykinin and lysyl bradykinin (kallidin) are active peptides formed by proteolytic cleavage of
circulating proteins termed kininogens through a protease cascade pathway.
Source and Formation of Bradykinin
• An outline of the formation of bradykinin from high-molecular-weight kininogen in plasma by
the serine protease kallikrein.
• Kininogen is a plasma α-globulin that exists in both high and low molecular weight forms.
Kallikrein is derived from the inactive precursor prekallikrein by the action of Hageman factor
(factor XII).

• Hageman factor is activated by contact with negatively charged surfaces such as collagen,
basement membrane, bacterial lipopolysaccharides, urate crystals and so on.
• Hageman factor, prekallikrein and the kininogens leak out of the vessels during inflammation
because of increased vascular permeability, and exposure to negatively charged surfaces
promotes the interaction of Hageman factor with prekallikrein.
• The activated enzyme then 'clips' bradykinin from its kininogen precursor.
• Kallikrein can also activate the complement system and can convert plasminogen to plasmin.
• In addition to plasma kallikrein, there are other kinin-generating isoenzymes found in pancreas,
salivary glands, colon and skin. These tissue kallikreins act on both highand low-molecular-
weight kininogens and generate mainly kallidin, a peptide with actions similar to those of
bradykinin.
Metabolism and Inactivation of Bradykinin
• Specific enzymes that inactivate bradykinin and related kinins are called kininases.
• One of these, kininase II, is a peptidyl dipeptidase that inactivates kinins by removing the two
C-terminal amino acids.
• This enzyme, which is bound to the luminal surface of endothelial cells, is identical to
angiotensin-converting enzyme which cleaves the two C-terminal residues from the inactive
peptide angiotensin I, converting it to the active vasoconstrictor peptide angiotensin II.
• Thus kininase II inactivates a vasodilator and activates a vasoconstrictor.
• Potentiation of bradykinin actions by ACE inhibitors may contribute to some side effects of
these drugs (e.g. cough).
• Kinins are also metabolised by various less specific peptidases, including a serum
carboxypeptidase that removes the C-terminal arginine, generating des-Arg9- bradykinin, a
specific agonist at one of the two main classes of bradykinin receptor.
Bradykinin Receptors
• There are two bradykinin receptors, designated B1 and B2.
• Both are G-protein-coupled receptors and mediate very similar effects.
• B1 receptors are normally expressed at very low levels but are strongly induced in inflamed or
damaged tissues by cytokines such as IL-1.
• B1 receptors respond to des-Arg9-bradykinin but not to bradykinin itself. A number of
selective peptide antagonists are known.

• It is likely that B1 receptors play a significant role in inflammation and hyperalgesia, and there
is recent interest in developing antagonists for use in cough and neurological disorders.
• B2 receptors are constitutively present in many normal cells and are activated by bradykinin
and kallidin, but not by des-Arg9-bradykinin.
• Peptide and non-peptide antagonists have been developed, the best known being icatibant.
None are yet available for clinical use.
Actions and Role of Bradykinin in Inflammation
• Bradykinin causes vasodilatation and increased vascular permeability.
• Its vasodilator action is partly a result of generation of PGI2 and release of NO.
• It is a potent pain-producing agent, and its action is potentiated by the prostaglandins. It
stimulates pain nerve endings.
• Bradykinin also has spasmogenic actions on intestinal, uterine and bronchial smooth muscle (in
some species).
• The contraction is slow and sustained in comparison with that produced by histamine (hence
brady, which means 'slow').
• Although bradykinin reproduces many inflammatory signs and symptoms, its role in
inflammation and allergy has not been clearly defined, partly because its effects are often part of
a complex cascade of events triggered by other mediators.
• However, excessive bradykinin production contributes to the diarrhoea of gastrointestinal
disorders, and in allergic rhinitis it stimulates nasopharyngeal secretion.
• Bradykinin also contributes to the clinical picture in pancreatitis
Physiologically, the release of bradykinin by tissue kallikrein may regulate blood flow to certain
exocrine glands, and influence secretions.
• It also stimulates ion transport and fluid secretion by some epithelia, including intestine,
airways and gall bladder.
EICOSANOIDS
• Unlike histamine, eicosanoids are not preformed in cells but are generated from
phospholipid precursors on demand.
• They are implicated in the control of many physiological processes, and are among the most
important mediators and modulators of the inflammatory reaction.

• Interest in eicosanoids arose in the 1930s after reports that semen contained a lipid substance
that contracted uterine smooth muscle.
• The substance was believed to originate in the prostate, and was saddled with the misnomer
prostaglandin.
• Later, it became clear that prostaglandin was not a single substance but a whole family of
compounds that could be generated from 20-carbon unsaturated fatty acids by virtually all cells.
Structure and biosynthesis
• In mammals, the main eicosanoid precursor is arachidonic acid (5,8,11,14-
eicosatetraenoicacid), a 20-carbon unsaturated fatty acid containing four double bonds (hence
eicosa, referring to the 20 carbon atoms, and tetraenoic, referring to the four double bonds).
• In most cell types, arachidonic acid is esterified in the phospholipid pool, and the concentration
of the free acid is low.
• The principal eicosanoids are the prostaglandins, the thromboxanes and the leukotrienes,
although other derivatives of arachidonate, for example the lipoxins, are also produced.
• (The term prostanoid will be used here to encompass both prostaglandins and thromboxanes.)
• In most instances, the initial and rate-limiting step in eicosanoid synthesis is the liberation of
arachidonate, either in a one-step process or a two-step process from phospholipids by the
enzyme phospholipase A2 (PLA2).
• Several species exist, but the most important is probably the highly regulated cytosolic PLA2.
This enzyme generates not only arachidonic acid (and thus eicosanoids) but also lysoglyceryl-
phosphorylcholine (lyso-PAF), the precursor of platelet activating factor, another inflammatory
mediator.
• Cytosolic PLA2 is activated (and hence arachidonic acid liberated) by phosphorylation.
• This occurs in response to signal transduction events triggered by many stimuli, such as
thrombin action on platelets, C5a on neutrophils, bradykinin on fibroblasts, and antigen-antibody
reactions on mast cells.
Metabolism:
• General cell damage also triggers the activation process. The free arachidonic acid is
metabolised by several pathways, including the following.
• Fatty acid cyclo-oxygenase (COX). Two main isoform forms, COX-1 and COX-2, transform
arachidonic acid to prostaglandins and thromboxanes.

• Lipoxygenases: Several subtypes synthesise leukotrienes, lipoxins or other compounds.
PROSTANOIDS
• The term prostanoids encompasses the prostaglandins and the thromboxanes.
• Cyclo-oxygenases (COXs) oxidise arachidonate, producing the unstable intermediates
prostaglandin (PG) G2 and PGH2.
• There are two main COX isoforms: COX-1, a constitutive enzyme, and COX-2, which is often
induced by inflammatory stimuli.
• Cyclo-oxygenase-1 is present in most cells as a constitutive enzyme that produces prostanoids
that act as homeostatic regulators (e.g. modulating vascular responses), whereas COX-2 is not
normally present but it is strongly induced by inflammatory stimuli and therefore believed to be
more relevant to inflammation therapy (see next chapter for a full discussion of this point).
• Both enzymes catalyse the incorporation of two molecules of oxygen into every arachidonate
molecule, forming the highly unstable endoperoxides PGG2 and PGH2.
• These are rapidly transformed by isomerase or synthase enzymes to PGE2, PGI2, PGD2,
PGF2α and TXA2, which are the principal bioactive end products of this reaction.
• The mix of eicosanoids thus produced varies between cell types depending on the particular
endoperoxide isomerases or synthases present. In platelets, for example, TXA2 predominates,
whereas in vascular endothelium PGI2 is the main product.
• Macrophages, neutrophils and mast cells synthesise a mixture of products. If eicosatrienoic
acid (three double bonds) rather than arachidonic acid is the substrate, the resulting prostanoids
have only a single double bond, for example PGE1, while eicosapentaenoic acid, which contains
five double bonds, yields PGE3.
• The latter substrate is significant because it is present in abundance in some fish oils and may,
if present in sufficient amounts in the diet, come to represent a significant fraction of cellular
fatty acids.
• When this occurs, the production of the proinflammatory PGE2 is diminished and, more
significantly, the generation of TXA2 as well.
• This may underlie the beneficial anti-inflammatory and cardiovascular actions that are ascribed
to diets rich in this type of marine product.
Catabolism of the prostanoids

• This is a multistep process. After carrier-mediated uptake, most prostaglandins are rapidly
inactivated by 'prostaglandin-specific' enzymes, and the inactive products are further degraded
by general fatty acid-oxidising enzymes.
• The prostaglandin-specific enzymes are present in high concentration in the lung, and 95% of
infused PGE2, PGE1 or PGF2α is inactivated on first passage. The half-life of most
prostaglandins in the circulation is less than 1 minute.
• Prostaglandin I2 and TXA2 are slightly different. Both are inherently unstable and decay
rapidly (5 minutes and 30 seconds, respectively) in biological fluids into inactive 6-keto-PGF1α
and TXB2.
Prostanoid receptors
• There are five main classes of prostanoid receptors, all of which are typical G-protein-coupled
receptors.
• They are termed DP, FP, IP, EP and TP receptors, respectively, depending on whether their
ligands are PGD2, PGF2α, PGI2, PGE2 or TXA2.
• Some have further subtypes; for example, the EP receptors are subdivided into three subgroups.
• Act by IP3/DAG system.
Pharmacological Actions of the prostanoids
The prostanoids affect most tissues and exert a variety of effects.
• PGD2 causes vasodilatation, inhibition of platelet aggregation, relaxation of gastrointestinal
and uterine muscle, and modification of release of hypothalamic/pituitary hormones. It has a
bronchoconstrictor effect through an action on TP receptors.
• PGF2α causes myometrial contraction in humans, luteolysis in some species (e.g. cattle) and
bronchoconstriction in other species (cats and dogs).
• PGI2 causes vasodilatation, inhibition of platelet aggregation, renin release and natriuresis
through effects on tubular reabsorption of Na+.
• TXA2 causes vasoconstriction, platelet aggregation and bronchoconstriction (more marked in
guinea pig than in humans).
• PGE2 is prominent in inflammatory responses and is a mediator of fever. Main effects are:
o EP1 receptors: contraction of bronchial and gastrointestinal tract (GIT) smooth muscle
o EP2 receptors: relaxation of bronchial, vascular and GIT smooth muscle

EP3 receptors: inhibition of gastric acid secretion, increased gastric mucus secretion, contraction
of pregnant uterus and of GIT smooth muscle, inhibition of lipolysis and of autonomic
neurotransmitter release.
• PGF2α acts on FP receptors, found in uterine (and other) smooth muscle, and corpus luteum,
producing contraction of the uterus and luteolysis (in some species).
• PGD2 is derived particularly from mast cells and acts on DP receptors, causing vasodilatation
and inhibition of platelet aggregation.
• In their own right, PGE2, PGI2 and PGD2 are powerful vasodilators and synergise with other
inflammatory vasodilators such as histamine and bradykinin.
• It is this combined dilator action on precapillary arterioles that contributes to the redness and
increased blood flow in areas of acute inflammation.
• Prostanoids do not directly increase the permeability of the postcapillary venules, but potentiate
this effect of histamine and bradykinin.
• Similarly, they do not themselves produce pain, but potentiate the effect of bradykinin by
sensitising afferent C fibres to the effects of other noxious stimuli.
• The anti-inflammatory effects of the NSAIDs stem largely from their ability to block these
actions of the prostaglandins.
• Prostaglandins of the E series are also pyrogenic (i.e. they induce fever). High concentrations
are found in cerebrospinal fluid during infection, and there is evidence that the increase in
temperature (attributed to cytokines) is actually finally mediated by the release of PGE2.
NSAIDs exert antipyretic actions by inhibiting PGE2 synthesis in the hypothalamus.
• However, some prostaglandins have anti-inflammatory effects under some circumstances. For
example, PGE2 decreases lysosomal enzyme release and the generation of toxic oxygen
metabolites from neutrophils, as well as the release of histamine from mast cells. Several
prostanoids are available for clinical use.
The role of the prostanoids in inflammation
Mediators derived from phospholipids:
• The main phospholipid-derived mediators are the eicosanoids (prostanoids and leukotrienes)
and platelet-activating factor (PAF).
• The eicosanoids are synthesised from arachidonic acid released directly from phospholipids by
phospholipase A2, or by a two-step process involving phospholipase C and diacylglycerol lipase.

• Arachidonate is metabolised by cyclo-oxygenase (COX)-1 or COX-2 to prostanoids, or by 5-
lipoxygenase to leukotrienes.
• PGI2 (prostacyclin), predominantly from vascular endothelium, acts on IP receptors, producing
vasodilatation and inhibition of platelet aggregation.
• Thromboxane (TX) A2, predominantly from platelets, acts on TP receptors, causing platelet
aggregation and vasoconstriction. PAF is derived from phospholipid precursors by
phospholipase A2, giving rise to lyso- PAF, which is then acetylated to give PAF. The
inflammatory response is inevitably accompanied by the release of prostanoids. PGE2
predominates, although PGI2 is also important. In areas of acute inflammation, PGE2 and PGI2
are generated by the local tissues and blood vessels, while mast cells release mainly PGD2. In
chronic inflammation, cells of the monocyte/macrophage series also release PGE2 and TXA2.
Together, the prostanoids exert a sort of yin-yang effect in inflammation, stimulating some
responses and decreasing others. The most striking effects are as follow.
Therapeutic uses of Prostanoids:
• Gynaecological and Obstetric:
o termination of pregnancy: gemeprost or misoprostol (a metabolically stable
prostaglandin (PG) E analogue)
o induction of labour: dinoprostone or misoprostol
o postpartum haemorrhage: carboprost.
• Gastrointestina:
 to prevent ulcers associated with non-steroidal anti-inflammatory drug use:
misoprostol
• Cardiovascular:
 to maintain the patency of the ductus arteriosus until surgical correction of the defect in
babies with certain congenital heart malformations: alprostadil (PGE1)
 to inhibit platelet aggregation (e.g. during haemodialysis): epoprostenol (PGI2),
 especially if heparin is contraindicated
 primary pulmonary hypertension: epoprostenol
• Ophthalmic
open-angle glaucoma: latanoprost eye drops.
ANGIOTENSIN

• The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is
a hormone system that regulates blood pressure and fluid and electrolyte balance, as well as
systemic vascular resistance.
• When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor
prorenin (already present in the blood) into rennin and secrete it directly into circulation.
• Plasma renin then carries out the conversion of angiotensinogen, released by the liver, to
angiotensin I. Angiotensin I is subsequently converted to angiotensin II by the angiotensin-
converting enzyme (ACE) found on the surface of vascular endothelial cells, predominantly
those of the lungs.
• Angiotensin II is a potent vasoconstrictive peptide that causes blood vessels to narrow,
resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone
aldosterone from the adrenal cortex.
• Aldosterone causes the renal tubules to increase the reabsorption of sodium and water into the
blood, while at the same time causing the excretion of potassium (to maintain electrolyte
balance). This increases the volume of extracellular fluid in the body, which also increases blood
pressure.
• If the RAS is abnormally active, blood pressure will be too high. There are many drugs that
interrupt different steps in this system to lower blood pressure.
• These drugs are one of the primary ways to control high blood pressure, heart failure, kidney
failure, and harmful effects of diabetes.
• The system can be activated when there is a loss of blood volume or a drop in blood pressure
(such as in hemorrhage or dehydration). This loss of pressure is interpreted by baro receptors in
the carotid sinus.
• It can also be activated by a decrease in the filtrate sodium chloride (NaCl) concentration or a
decreased filtrate flow rate that will stimulate the macula densa to signal the juxtaglomerular
cells to release renin.
1. If the perfusion of the juxtaglomerular apparatus in the kidney's macula densa decreases, then
the juxtaglomerular cells (granular cells, modified pericytes in the
glomerular capillary) release the enzyme rennin.
2. Renin cleaves a decapeptide from angiotensinogen, a globular protein. The decapeptide is
known as angiotensin I.

3. Angiotensin I is then converted to an octapeptide, angiotensin II by angiotensinconverting
enzyme (ACE), which is thought to be found mainly in endothelial cells of the capillaries
throughout the body, within the lungs and the epithelial cells of the kidneys. One study in 1992
found ACE in all blood vessel endothelial cells.
4. Angiotensin II is the major bioactive product of the renin–angiotensin system, binding to
receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood
vessels surrounding them and causing the release of aldosterone from the zona glomerulosa in
the adrenal cortex. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine
hormone.
Cardiovascular Effects:
It is believed that angiotensin I may have some minor activity, but angiotensin II is the major
bio-active product. Angiotensin II has a variety of effects on the body:
• Throughout the body, angiotensin II is a potent vasoconstrictor of arterioles.
• In the kidneys, angiotensin II constricts glomerular arterioles, having a greater effect on
efferent arterioles than afferent.
• As with most other capillary beds in the body, the constriction of afferent arterioles increases
the arteriolar resistance, raising systemic arterial blood pressure and decreasing the blood flow.
• However, the kidneys must continue to filter enough blood despite this drop in blood flow,
necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II
constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing

glomerular pressure. The glomerular filtration rate (GFR) is thus maintained, and blood filtration
can continue despite lowered overall kidney blood flow.
Cardiovascular Effects:
It is believed that angiotensin I may have some minor activity, but angiotensin II is the major
bio-active product. Angiotensin II has a variety of effects on the body:
• Throughout the body, angiotensin II is a potent vasoconstrictor of arterioles.
• In the kidneys, angiotensin II constricts glomerular arterioles, having a greater effect on
efferent arterioles than afferent.
• As with most other capillary beds in the body, the constriction of afferent arterioles increases
the arteriolar resistance, raising systemic arterial blood pressure and decreasing the blood flow.
• However, the kidneys must continue to filter enough blood despite this drop in blood flow,
necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II
constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing
glomerular pressure. The glomerular filtration rate (GFR) is thus maintained, and blood filtration
can continue despite lowered overall kidney blood flow.

• Because the filtration fraction has increased, there is less plasma fluid in the downstream peri
tubular capillaries. This in turn leads to a decreased hydrostatic pressure and increased oncotic
pressure (due to unfiltered plasma proteins) in the peri tubular capillaries.
• The effect of decreased hydrostatic pressure and increased oncotic pressure in the peri tubular
capillaries will facilitate increased reabsorption of tubular fluid.
• Angiotensin II decreases medullary blood flow through the vasa recta. This decreases the
washout of NaCl and urea in the kidney medullary space.
• Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of
tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive
reabsorption of sodium along the thick ascending limb of the Loop of Henle.
• Angiotensin II stimulates Na+/H+ exchangers located on the apical membranes (faces the
tubular lumen) of cells in the proximal tubule and thick ascending limb of the loop of Henle in
addition to Na+ channels in the collecting ducts. This will ultimately lead to increased sodium
reabsorption.
• Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium
reabsorption.
• In the adrenal cortex, angiotensin II acts to cause the release of aldosterone. Aldosterone acts
on the tubules (e.g., the distal convoluted tubules and the cortical collecting ducts) in the
kidneys, causing them to reabsorb more sodium and water from the urine.
• This increases blood volume and, therefore, increases blood pressure. In exchange for the
reabsorbing of sodium to blood, potassium is secreted into the tubules, becomes part of urine and
is excreted.
• Angiotensin II causes the release of anti-diuretic hormone (ADH), also called vasopressin –
ADH is made in the hypothalamus and released from the posterior pituitary gland. As its name
suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate
reabsorption of water in the kidneys.
• ADH also acts on the central nervous system to increase an individual's appetite for salt, and to
stimulate the sensation of thirst.
• These effects directly act together to increase blood pressure and are opposed by atrial
natriuretic peptide (ANP).
Local Renin–angiotensin Systems:

• Locally expressed renin–angiotensin systems have been found in a number of tissues, including
the kidneys, adrenal glands, the heart, vasculature and nervous system, and have a variety of
functions, including local cardiovascular regulation, in association or independently of the
systemic renin–angiotensin system, as well as non-cardiovascular functions.
• Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted
locally in some tissues; its precursor pro renin is highly expressed in tissues and more than half
of circulating prorenin is of extra renal origin, but its physiological role besides serving as
precursor to renin is still unclear.
• Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in
some tissues; with renin they form angiotensin I, and locally expressed angiotensin-converting
enzyme, chymase or other enzymes can transform it into angiotensin II. This process can be
intracellular or interstitial.
• In the adrenal glands, it is likely involved in the paracrine regulation of aldosterone secretion;
in the heart and vasculature, it may be involved in remodeling or vascular tone; and in the brain,
where it is largely independent of the circulatory RAS, it may be involved in local blood pressure
regulation. In addition, both the central and peripheral nervous systems can use angiotensin for
sympathetic neurotransmission.
• Other places of expression include the reproductive system, the skin and digestive organs.
Medications aimed at the systemic system may affect the expression of those local systems,
beneficially or adversely.
Fetal Renin–angiotensin System:
• In the fetus, the renin–angiotensin system is predominantly a sodium-losing system, as
angiotensin II has little or no effect on aldosterone levels. Renin levels are high in the fetus,
while angiotensin II levels are significantly lower; this is due to the limited pulmonary blood
flow, preventing ACE (found predominantly in the pulmonary circulation) from having its
maximum effect.
Clinical Significance:
• ACE inhibitors–inhibitors of angiotensin-converting enzyme are often used to reduce the
formation of the more potent angiotensin II. Captopril is an example of an ACE inhibitor. ACE
cleaves a number of other peptides, and in this capacity is an important regulator of the kinin–
kallikrein system, as such blocking ACE can lead to side effects.

• Angiotensin II receptor antagonists, also known as angiotensin receptor blockers, can be used
to prevent angiotensin II from acting on its receptors.
• Direct renin inhibitors can also be used for hypertension. The drugs that inhibit rennin are
aliskiren and the investigational remikiren.
• Vaccines against angiotensin II, for example CYT006-AngQb, have been investigated.

IMPORTANT QUESTIONS
Very Short Answer Type Questions
1. What are analgesics?
2. What are anti-pyretics?
3. What are anti-inflammatory drugs?
4. Define histamine.
5. What are anti-histaminic drugs?
6. What is serotonin?
7. Explain the effect of prostaglandin.
8. Define thromboxane.
9. What is leukotriene?
10. What is angiotensin?
11. What is bradykinin?
12. Define substance P.
Short Answer Type Questions
1. Classify and describe the functions of autocoids.
2. Explain the synthesis, metabolism and degradation of histamine.
3. Discuss anti-histaminic drugs, write the pharmacology of cetirizine.
4. Explain leukotrienes and its receptors. Write the pharmacology of leukotrienes.
5. Explain the pharmacology of bradykinin.
6. Classify anti-gout drugs. Explain the pharmacology of allopurinol.
Long answer type questions
1. Write a note on autocoids and classification.
2. Classify antihistamine with examples.
3. Write the mechanism of action and therapeutic uses of Prostaglandins, Thromboxanes and
Leukotrienes.
4. Discuss the pharmacology of Angiotensin, Bradykinin and Substance P.
5. Write a note on pharmacology of anti-rheumatic drugs.

BP503T-3

Uploaded by

Copyright:

Available Formats

BP503T-3

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

BP503T-3

Uploaded by

Copyright:

Available Formats

Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial

ASBASJSM COLLEGE OF PHARMACY (AN AUTONOMOUS COLLEGE) BELA

Learning Outcome of Module-3

LO1 Classification of autocoids and related drugs BP503.3

The Pioneer Pharmacy Institute of Punjab

Module Content Table

2 E Histamine, 5-HT and their antagonists

3 Prostaglandins, Thromboxanes and Leukotrienes.

The Pioneer Pharmacy Institute of Punjab

AUTOCOIDS AND RELATED DRUGS

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

The Pioneer Pharmacy Institute of Punjab

You might also like