9autacoids

Autacoids

Greek : autos = self Akos = medicinal agents or remedy•naturally occurring chemical substances • produced within the body •transported to the other parts of the body where they exert their effects• protect the body from adverse situations.

Classification of autacoids

In the basis of structure autacoids can be divided into three categories:a) Decarboxylated amino-acid

HistamineSerotonin (5-HT)

b) Polypeptides: Angiotensin

Plasma kinins (Bradykinin and kallidin)VasopressinVIP

c) Ecosanoids:ProstaglandinthromboxanesleukotrienesPlatelet activating factor (PAF)

Histamine

• Imidazole ethylamine• Important inflammatory mediator• potent biogenic amine and plays an important

role in inflammation, anaphylaxis, allergies, gastric acid secretion and drug reaction

• Histidine Enzyme histidine decarboxylase Histamine

Sites of histamine release

1) Mast cell site:• Pulmonary tissue (mucosa of bronchial tree)• Skin• GIT(intestinal mucosa)• Conc. Of histamine is particularly high in these

tissues

2) Non-mast cell sites:• CNS (neurons)• Epidermis of skin.• GIT(gastric cells)• Cells in regenerating or rapidly growing tissues • Basophils (in the blood)

Sites of histamine Storage

• Mast cell in most tissues.• Basophils in the blood.• Other storage site includes (non-mast cell

sites):• Epidermis of skin.• Cells in the gastric mucosa• Neurons in the CNS.

Metabolism of histamine

• The bound form of histamine is biologically inactive.• There are two major paths of histamine metabolism in

man. The more important of these involves ring methylation. Alternatively histamine undergoes oxidative deamination.

• The products of metabolism are imidazole acid and its ribosides.

• The metabolites are excreted in urine.• Granules of mast cell contain glycosaminoglycans,

acidic protein in histamine.

Release of histamine

• Antigen-antibody reactions • Mechanical trauma.• Stings and venom.• Fragments of complements (c3a and c5a)• Lysosomal protein (protease)• Proteolytic enzyme(trypsin)• Surface acting antigen (bile salt, lysolecithin)• High molecular weight compound(dextran,

ovomucoid)

• Drugs:a) Chemotherapeutic agents b) Centrally acting drugs c) Spasmolytic drugs d) Sympathomimetic drugs e) Vasodilator drugs f) NM blocking agents g) Anticoagulants

Mechanism of Histamine release

• immunological.• lgE antibody sensitized mast or basophil cells +antigen-

> Fall of intracellular c AMP and an influx of ca++occurs-> degranulation Histamine released

• Histamine held by an acidic protein and heparin within intracellular granules, when granules are extruded by exocytosis, Na+ gets exchanged for histamine

• Substance release during IgG or lgM immunoreactions also release histamine from the mast cells & basophil.

• Chemical and mechanical mast cells injury causes degranulation of cytoplasmic granules & histamine is released.

• Certain amines ( E.g. morphine, d-tubocurarine) accumulate in the mast cells due to affinity for heparin, displace histamine and form a heparin liberator complex. This complex increases the permeability of the mast cell membrane and diffuse histamine.

• Loss of granules from mast cells relapsed histamine by ion exchange. Na+

in the extra-cellular fluid rapidly displace histamine from the complex.

• Compound 48/80 releases histamine from tissue from tissue mast cells by an exocytotic degranulation process requiring energy and ca++

Histamine release inhibitors

• Guanidine, papaverine• Thiamine• Histamine itself• Corticosteroids• β-adrenoceptor agonist• aminophylline• LSD• Monoamine oxidase inhibitors

Histamine receptorsType /location Agonist drugs

H1receptor (H1-R)Bronchus Adrenal medulla skin Blood vessels urinary bladder Gastrointestinal tract CNS(post-synaptic)

Hypothalamus cerebellum

Histamine> 2-thiazolyle-thylamine>2-beta-histine>2-pyridylethyl-amine.

**G-protein coupledPIP2 hydrolysis---increased IP3/DAGRelease of Ca++Protein Kinase C activation

H2receptor (H2-R)Gastric parietal cells HeartUterusCNS (postsynaptic) some blood vessels Mast cells.

Impromadine> Histamine>Dimaprit> 4-methylhistaine > Betazole.

**G- protein coupledH2 – R acts by increase cAMPAdenyl cyclase activation---increase cAMP

H3 receptor (H3 -R )Pre-synaptic ( Brain) myenteric plexus other neurons .

α- methyl-histamine

**G protein coupled Decrease Ca++ influxK+ channel activationDecrease cAMP

Physiologic role of Histamine

• Play an important role in gastric HCl secretion by stimulating H2 receptor.

• Endogenous histamine plays a central role in the immediate hypersensitivity and allergic reaction.

• In regulation of microcirculation through its vasoactive properties. • Histamine acts as a neurotransmitter in the CNS.• Inflammation• Tissue growth and repair• Headache• Histamine helps in implantation of fertilized ovum by increasing

blood supply to the myometrium.

Role of Histamine in Inflammation

• Histamine induces action of prostaglandin as well as bradykinin to produce pain.

• Histamine helps in the release of proteolytic & hydrolytic enzymes from the lysosomes.

• Histamine causes vasodilation and increases capillary permeability. So,

• Increase exudation of serum & plasma to surrounding area (oedema).

• Increase migration of polymorph leucocyte to the traumatic area.

• Increase migration of inflammatory cell to other places.• All the processes are in the favour of inflammation

Indications of Histamine

• Diagnostic use:• Diagnosis of pernicious anaemia (vit-B12 deficiency).• Pernicious anaemia -> Achlorohydria (no HCI) -

>Histamine administered -> if no HCI(diagnostic)• Diagnosis of phaechromocytoma:

phaechromocytoma ->histamine administered -> excessive adrenaline release from adrenal medulla-> hypertensive crisis.

• Diagnosis of integrity of reflex arc.

• Therapeutic use• Meniere's disease.( non suppurative disease of labyrinth ) ---

betahistine• Various vascular headache.

Contraindication of histamine

• Bronchial asthma. • Patient with active peptic ulcer disease .• Gastrointestinal bleeding.• Angina with hypotension.

Adverse effect of Histamine

• Dyspnoea due to bronchospasm.• Hypotension (histaminic shock)• Headache.• Itching and pain• Flushing• Abdominal cramps.• Diarrhea.• Visual disturbance• Metallic test

Histaminic Shock

Histamine Antagonists

• Actions of histamine opposed in 3 ways :i) Adrenaline type ii) Release inhibition– Adrenal steroids– Sodium cromoglycate

iii) Direct histamine receptor antagonists

H1-receptor blockers :

Chlorpheniramine , promethazine, Diphenhydramine, citirizine, Terfenadine, Loratadine, Desloratadine.

H2-receptor blocker:

Cimetidine RanitidineFamotidineNizatidine

H3-receptor blockers:

ThioperamideImpromidine

Individual H1 receptor antagonist classification

1) Sedative (first generation) antihistamines: Highly lipid soluble and easily enters into the CNS:

a) Potent and marked sedative:• Promethazine (phenergan) :widely used• Diphenhydramine• Dimenhydrinateb) Potent and moderate sedative:• Chloryclizine• Chlorpheniramine• Tetrahydeoxy carbolinec) Less potent and less sedative:• Mepyramine• Pheniramine(avil)

2) Non-sedative (second generation ) antihistamines: Less lipid soluble therefore cannot enter into the CNS:

• Cetrizine• Terfenadine• Astemizole• Loratadine• Ketotifen• Cyclizine

3) Antihistamines having anti-cholinergic action a) Anti-emetic and anti-motion sickness.

Promethazine Diphenhydramineb) Anti-parkinsonism:

Orphenadrine Phenindamine

Central action: anti- emetic, anti-motion sickness and anti- parkinsonism.

Peripheral action: Atropine like side effects.4) Anti-histamines having anti-serotonin actionCyproheptadine -5-HT antagonist action.5) Antihistamine having local anaesthetic property: Promethazine

Diphenhydramine

:

Pharmacological action of H1blocker

• H1 receptor blockade action• Action not caused by histamine receptor blockade:– Sedation– Anti nausea and anti emetic – Anti parkinsonism – Anti cholinergic – Alpha adrenoceptor block( orthostatic hypotension)– Anti serotonin – Local anesthetic action

2nd generation anti histamines (newer antihistamines )

• Fexofenadine• Loratadine• Cetrizine• Azelastine, mizolastine• Mequitazone• Terfenadine • astemizol• ebastine

Properties of newer antihistamine

• They are highly selective for H1 receptors• Less lipid soluble; hence no or poor penetration into CNS.• They are devoid of significant anti-cholinergic actions like

older antihistamines.• They are usually active orally.• Their metabolites are also active H1 antagonist• Astemizole are extensively plasma protein bound(t1/2:20hrs)• These drugs are able to suppress the wheal and flare

response to histamine or allergen for more than 12hours • Low incidence of side effects

Indication of H1 blockers

1)Dermatitis of all types.2)Allergic reaction :Urticaria,Rhinitis,Conjunctivitis and3)Anaphylactic shock4)Anti-motion sickness: diphenhydramine5)Anti-emetic:Cyclizine,Meclizine,Doxylamine (in pregnancy)6) Anti-parkinsonism: Diphenhydramine is used.7) Preanesthetic medication8) As sedative agent: Promethazine9)Cough depressant.10)Otitis media.11)common cold.

Adverse effect of H1 blockers

CNS : sedationDrowsinessFatigueIrritability IncoordinationNervousnessTinnitus

Ocular :disturbance of ocular accommodation anti-muscarinic action.Dryness of mouth Blurring of vision.Constipation.Urinary retention

GIT : gastrointestinal upset.Teratogenicity : Cyclizine (teratogenic)

Doxylamine (no teratogenicity)Others : Dermatitis, skin rashes

Agranulocytosis

5-HYDROXYTRYPTAMINE (SEROTONIN):

– regulator of smooth muscle in the cardiovascular system and the gastrointestinal tract, an enhancer of platelet aggregation, and a neurotransmitter in the CNS

– 5-HT is found in high concentrations in enterochromaffin cells throughout the gastrointestinal tract, in storage granules in platelets, and broadly throughout the CNS

– widely distributed in the animal and plant kingdoms– It occurs in vertebrates; mollusks, arthropods, and

coelenterates; and in fruits and nuts. It also is present in venoms, including those of the common stinging nettle and of wasps and scorpions

Synthesis and metabolism of serotonin

• essential amino acid tryptophan• 2 steps• Tryptophan hydroxylase, a mixed-function oxidase converts

tryptophan to 5-hydroxytryptophan.• aromatic L-amino acid decarboxylase converts to 5-

hydroxytryptamine• Released by exocytosis from the serotonergic neurons • metabolism of 5-HT involves oxidative deamination by

monoamine oxidase (MAO), forming an acetaldehyde intermediate and then to 5-hydroxyindole acetic acid (5-HIAA) by a ubiquitous enzyme, aldehyde dehydrogenase

Serotonin receptors

• The 5-HT1, 5-HT2, and 5-HT4-7 receptor families are members of the superfamily of GPCRs. The 5-HT3 receptor, on the other hand, is a ligand-gated ion channel that gates Na+ and K+ similar to nicotinic receptors.

• 5-HT1 Receptors. All 5 members of the 5-HT1-receptor subfamily inhibit adenylyl cyclase.decrease cAMP, autoreceptors, inhibit serotonergic receptors

• 5-HT2 Receptors. The 3 subtypes of 5-HT2 receptors are linked to phospholipase C with the generation of two second messengers, diacylglycerol (a cofactor in the activation of protein kinase C) and inositol trisphosphate (which mobilizes intracellular stores of Ca2+).

• 5-HT3 receptor- corresponding to M type receptor gating cation channel , present in somatic and autonomic nerve endings, nerve endings in myenteric plexus, and area postrema.

• 5-HT4 receptor is thought to evoke secretion in the alimentary tract and to facilitate the peristaltic reflex. 5-HT4 receptors couple to Gs to activate adenylyl cyclase, leading to a rise in intracellular levels of cyclic AMP (cAMP)

Sites of 5-HT Action

• 1) Enterochromaffin Cells: gi mucosa , highest density in duodenum, synthesize 5-HT from tryptophan and store 5-HT and other autacoids. Basal release of enteric 5-HT is augmented by mechanical stretching.

• 2) platelets: not synthesized in platelets, but is taken up from the circulation and stored in secretory granules by active transport, regulates thrombosis and hemostasis (5-HT2a)

• 3) Cardiovascular System: The classical response of blood vessels to 5-HT is contraction, particularly in the splanchnic, renal, pulmonary, and cerebral vasculatures,

• Contraction – large vessels• Relaxation( due to release of EDRF)• Bradycardia- activation of coronary chemoreflex• Hypotension and apnoea• positive inotropic and chronotropic actions• 4) Central Nervous System. A multitude of brain functions are influenced by 5-HT,

including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion.( but injected serotonin doenot have CNS effects)

• A) sleep and wake cycles• B) anxiety and depression• C) Aggression and Impulsivity

Pathophysiological roles• Neurotransmitter-sleep, temperature regulation, thought, cognitive

function, behaviour and mood, vomiting and pain perception• Precursor of melatonin• Neuroendocrine function• Nausea and vomiting• Migraine-methysergide, sumatriptan• Haemostasis• Raynaud’s disease-ketanserin• Variant angina• Hypertension-ketanserin• Intestinal motility• Carcinoid syndrome

Serotonin agonists• 5-HT1A receptor

Azapirones such as buspirone, gepirone, and tandospirone are 5-HT1A agonists marketed primarily as anxiolytics, but also recently as antidepressants, 8-OH DPAT( hydroxydipropylaminotetraline)

• 5-HT1B receptor

Triptans such as sumatriptan, rizatriptan, and naratriptan, are 5-HT1B receptor agonists that are used to abort migraine and cluster headache attacks.

• 5-HT1D receptor

In addition to being 5-HT1B agonists, triptans are also agonists at the 5-HT1D receptor, which contributes to their antimigraine effect.

• 5-HT1F receptor.

Lasmiditan has successfully completed Phase II clinical trials in early 2010.

• 5-HT2A receptor

Psychedelic drugs such as LSD, mescaline, psilocin, , act as 5-HT2A agonists. Their action at this receptor is responsible for their hallucinogenic effects.It is now known that many of these drugs act as agonists at many other 5HT receptors in addition to the 5-HT2A including the 5-HT2C and others.

• 5-HT2C receptor

Lorcaserin is a thermogenic and anorectic weight-loss drug which acts as a selective 5-HT2C agonist.

• 5-HT4 receptor

Cisapride is a 5-HT4 partial receptor agonist that has been used to treat disorders of gastrointestinal motility. Prucalopride is a highly selective 5-HT4 receptor agonist that can be used to treat certain disorders of gastrointestinal motility

other drugs affecting 5-HT system

1) 5-HT precursor- tryptophan2) synthesis inhibitors- p-chlorophenylalanine3) uptake inhibitors: TCA, SSRIs4) storage inhibitors- reserpine5) degradation inhibitors – tranylcypromine, clorgyline6) neuronal degeneration- 5,6-dihydroxytryptamine

5-HT-Receptor Antagonists

• 5-HT1 antagonist:• 5-HT2 antagonist:metergoline, Ketanserin(2C)

Clozapine, Cyproheptadine, Methysergide,.• 5-HT3 antagonist:Ondansetron, dolasetron,

and granisetron

• 'Ketanserine' blocks 5 HT2A,5 HT2C and alpha 1 receptors. • 'Ondansetron,Dolansetron,Granisetron' are 5 HT3 receptor

antagonist.they are efficacious in treating chemotherapy induced emesis. ‘

• Clozapine' blocks 5 HT2A,5 HT2C,D4 receptors.• Quetiapine' blocks 5 HT2A,5 HT1A,D1-2,HI,alpha 1 receptors.• Methsergide' is 5 HT2A-2C antagonist and nonselective 5 HT 1

receptor blocker.it causes retrperitoneal fibrosis and mediastinal fibrosis.

• Cyproheptadine' blocks 5 HT2A, HI and it is a mild anticholinergic.• Pizotifen' is a 5 HT2A-2C , H1 blocker and anticholinergic used for

migraine prophylaxis

Cyproheptadine

• 5-HT2a, H1 antagonist• Allergy, pruritus• Increase appetite in children• Weight gain• Carcinoid• Postgastrectomy dumping syndromes• Antagonise priapism and orgasmic delays

caused by SSRIs

Clozapine

• Clozapine , a 5-HT2A/2C-receptor antagonist, represents a class of atypical antipsychotic drugs

• reduced incidence of extrapyramidal side effects compared to the classical neuroleptics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia

• Also has a high affinity for subtypes of dopamine receptors.

Ondansetron

• Selective serotonin (5-HT3) receptor antagonist that inhibits serotonin receptors in GI tract or chemoreceptor trigger zone.

• Prevention of nausea and vomiting with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin;

• prevention of postoperative nausea or vomiting

Eicosanoids

• Eicosanoids are 20-carbon fatty acid derivatives

• Consist of prostaglandins, related thromoboxanes and leukotrienes

• derived from the oxidative metabolism of arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid)

• arachidonic acid cascade

Nomenclature

• Eicosanoids---eicosa( 20C fatty acid)• Prostate gland derived----prostaglandin• PGA, PGB---ring structure• 1, 2, 3--no of double bonds• Leukocyte and 3 double bonds- leukotrienes

Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases):

• PGG2, and PGH2• 2 enzymes: • COX-1 – constitutive, levels always same • COX-2---normally insignificant but induced by cytokines,

and growth factors• COX-1 inhibitors:• COX-2 inhibitors:• The prostaglandins, thromboxane, and prostacyclin,

collectively termed the prostanoids, are generated from PGH2 through the action of isomerases and synthases

Products of Lipoxygenase

• Lungs, WBC, and platelets• hydroperoxyeicosatetraenoic acids (HPETEs), which

rapidly convert to hydroxy derivatives (HETEs) and leukotrienes

• FLAP (5-lipo-oxygenase activating protein)• associated with asthma, anaphylactic shock, and

cardiovascular disease.• LTA4, the primary product of 5-LOX, can be converted

via 12-LOX in platelets to the lipoxins LXA4 and LXB4

• Lipo-oxygenase inhibitor: zileuton

Epoxygenase Products (cytp450 enzymes)

• four epoxyeicosatrienoic acids (EETs)• The epoxygenase products are synthesized in

endothelial cells, and cause vasodilation in a number of vascular beds by activating the smooth muscle large conductance Ca2+-activated K+ channels

Isoprostanes

• Prostaglandin isomers

• Degradation of eicosanoids:• Fastest in lungs • Oxidation of side chains and reduction of double

bonds• Metabolites excreted in urine

Prostaglandin synthesis inhibitors

• Nonsteroidal anti-inflammatory drugs NSAIDS , block enzymes that convert arachidonic acid to prostaglandins.

• Corticosteroids: by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. inhibit phospholipase A2 activity, probably by interfering with phospholipid binding and thus preventing the release of arachidonic acid.

Prostaglandins

• Basic structural unit is referred to as a prostanoic or prostenoic acid.

• Each PG differs from the others in the substitution pattern in the cyclopentane ring and the sidechains

• Prostaglandins are broadly classified as PGA, PGB,PGC, PGD, PGE, PGF, PGG, and PGH based on their cyclopentane/pentene ring substitution pattern

• subclassified based on the degree of unsaturation (i.e. PGE1, PGE2)

Physiologic actions of prostaglandins

• inflammation, • pain,• pyrexia, • cardiovascular disease, • renal disease, • cancer,

• glaucoma, • allergic rhinitis, • asthma• preterm labor, • male sexual dysfunction• osteoporosis.

Prostaglandin receptors

• eight prostanoid receptors have been cloned and characterized.

• receptors are coupled to either phospholipase C (PLC) or adenylate cyclase

• in the case of adenylate cyclase, the action of the PGs may be stimulatory or inhibitory.

Prostaglandin receptors

Pharmacologic actions

• powerful vasodilators; especially PGI2 and PGE2, promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium,

• In kidney: increased excretion of salt in the urine. • inhibit the action of vasopressin on the kidney tubules,• mediate the control of GnRH over LH secretion, modulate

ovulation, and stimulate uterine muscle contraction and facilitate fertilization

• dysmenorrhoea• inducing labor in pregnant• Administration of either PGE2 or PGF2 results in colicky cramps

• Low concentrations of PGE2 enhance, whereas higher concentrations inhibit, platelet aggregation. Both PGD2 and PGI2 inhibit aggregation

• PGE2 promotes the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH.

• increase bone turnover, ie, stimulation of bone resorption and formation

• PGE and PGF derivatives lower intraocular pressure• Mediate fever and malaise

Prostaglandin agonists1) Alprostadil (PGE1)• produces vasodilation,• inhibits platelet aggregation and stimulates intestinal and uterine smooth muscle.• ductus arteriosus• erectile dysfunctionAdverse Reactions:

♦ Cardiovascular: Flushing, bradycardia, hypotension, tachycardia, edema , lesscommonly more severe effects such as cardiac arrest, congestive heart failure, second degree heart block, shock, supraventricular tachycardia and ventricular fibrillation.

♦ CNS: Fever, seizures, cerebral bleeding, hyperextension of the neck, hyperirritability, hypothermia,lethargy and stiffness .

♦ GI: Diarrhea, gastric regurgitation and hyperbilirubinemia. Hematologic: Disseminated intravascular coagulation, anemia, bleeding, thrombocytopenia

♦ Renal: Anuria and hematuria ♦ Respiratory: Apnea, bradypnea, bronchial wheezing, hypercapnia, respiratory

depression, respiratory distress and tachypnea

2) Prostaglandin E2 (Dinoprostone)• PGE2 stimulates the production of PGF2α which in turn

sensitizes the myometrium to endogenous or exogenously administered oxytocin.

Indications : • 1)initiation or continuation of cervical ripening in pregnant

women at or near term with a medical or obstetrical need for labor induction (cervical ripening)

• 2) the management of missed abortion or intrauterine fetal death up to 28 weeks gestational age and,

• 3) management of nonmetastatic gestational trophoblastic disease (benign hydatidiform mole).

3) Misoprostol, Enprostil- for peptic ulcer as anti secretory and cytoprotective agents)

• Antisecretory Actions: decreased HCl and pepsin secretion( basal or stimulus)

• Cytoprotective Activities: increased gastric blood flow, increased mucous and bicarbonate protection

• Immunologic Actions: inhibit basophilhistamine release, thus it has a potential role as immunotherapy designed to reduce early-phase and late-phase allergic inflammation

• Reproductive Effects: Misoprostol produces uterine contractions that may endanger pregnancy

• 4) Prostaglandins for Treatment of Pulmonary Hypertension: Epoprostenol, Treprostinil and Beraprost

CLINICAL PHARMACOLOGY OF EICOSANOIDS

1) Female reproductive system:a) Abortion—mifepristone pretreatment

misoprostol +methotrexateb) Post partum hemorrhage– carboprost,

dinoprostine, gemeprost c) Facilitation of labour --d) Dysmenorrhoea e) Menstruation inducing contraceptive--

2) Male reproductive system:erectile dysfunction-- alprostadil

3) Pulmonary hypertension4) Patent ductus arteriosus5) Peripheral vascular diseases6) Blood platelet aggregation7) GIT8 ) Immune system

a) Cell-mediated organ transplant rejectionb) Inflammationc) Rheumatoid arthritis

9) Glaucoma10) Bronchial asthma

Thromboxanes

• process of clot formation begins with an aggregation of blood platelets (TXA2). This process is strongly stimulated by thromboxanes and inhibited by prostacyclin.

• Prostacyclin--- vasodilation and lowers BP

Leukotrienes

• LTB4- neutrophils• LTC4 and LTD4- macrophages • LTC4 and LTD4 are potent bronchoconstrictors

and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis

Effects of leukotrienes :

1) CVS and blood: brief rise in BP followed by a prolonged fall, due to coronary constriction induced decrease in cardiac output and reduction in circulating volume due to increased capillary permeability

2) Inflammation = redness (rubor), heat (calor), pain (dolor), swelling (tumor),

migration of neutrophils to the inflammatory site promoted by LTB4

3) Smooth muscle- contraction, potent bronchoconstrictors, and also increase bronchial secretions

4) Afferent nerves- sensitizes afferent neurons carrying pain impulses

Leukotriene receptors

• All function through IP3/DAG transducer mechanism.

Leukotriene receptor antagonists

• Monteleukast• Zafirleukast• Adverse effectsCNS: Headache; dizziness. GI: Nausea; diarrhea;

dyspepsia; abdominal pain; vomiting. HEPATIC: Elevation in transaminase levels. OTHER: Infection; fever; asthenia; generalized pain; myalgia; back pain

Leukotriene synthesis inhibitor

• Nedocromil Sodium

Vasoactive peptides 1)vasoconstrictors

– angiotensin II,– vasopressin,– endothelins,– neuropeptide Y, and– urotensin

2) vasodilators – bradykinin and related kinins, – natriuretic peptides, – vasoactive intestinal peptide, – substance P, – neurotensin, – calcitonin gene-related peptide(CGRP), and – adrenomedullin.

RENIN AND ANGIOTENSIN

• pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy

• Circulating renin angiotensin system• Tissue (local) renin-angiotensin system

• Extrinsic local RAS- blood vessels • Intrinsic local RAS- heart , blood vessels, brain, kidneys,

adrenal glands

Angiotensinogen

• Synthesized in liver • Glycoprotein with a molecular weight 57, 000• Synthesis increased by:

a) corticosteroids b) estrogens c) thyroid hormones d) angiotensin II

Elevated during pregnancy and in women taking OCP

• Components of RENIN-ANGIOTENSIN SYSTEM1) Angiotensinogen2) Renin 3) Angiotensin I 4) Angiotensin coverting enzyme5) Angiotensin II6) angiotensinase

Renin aspartyl proteasewithin kidney synthesized by JG cells

Renin secretion controlled by:a) Renal vascular receptor: decreased stretch =increased reninb) Macula densa: sensitive to Na+ and Cl- delivery to distal tubule, signal transmission by:

adenosine( inhibits renin) , prostaglandins ( stimulates renin) and nitric oxide. Decrease= increased renin

c) Sympathetic nervous system: increased nerve activity= increased renin beta1 receptors (renal)

etrarenal beta receptorsd) angiotensin: Angiotensin II inhibits renin secretione) Pharmacologic alteration of renin release: stimulated by : vasodilators

beta agonists Alpha antagonists Phosphodiesterase enzyme inhibitors ( theophylline, milrinone, amrinone)

Angiotensin I

No biologic activity Must be converted to angiotensin II

Angiotensin converting enzyme

• Peptidyl dipeptidase ( PDP)• ACE• Kininase II• Carboxypeptidase • Substrates: angiotensin I

bradykininalso cleaves enkephalins and substance P

• Distributed widely in body , mostly on luminal surface of vascular endothelial cells

Angiotensin II

• Potent pressor agent• 40 times more potent than norepinephrine• Pressor response due toa) Direct contraction of vascular smooth muscleb) Reset baroreceptor reflex controlc) Stimulates autonomic ganglia d) Facilitate sympathetic transmission e) Direct positive inotropic action on heart

• In adrenal cortex: acts on zona glomerulosa to stimulate

aldosterone biosynthesis, also glucocorticoid biosynthesis

• In Kidney:renal vasoconstrictionincrease proximal tubular reabsorptioninhibit secretion of renin

• CNS: stimulate drinking (dypsogenic )

increased secretion of vasopressin and ACTH• Cell Growth:

mitogeniccauses cardiovascular hypertrophy

Angiotensin receptors

AT1 • high affinity for losartan and low for PD123177,

predominant in vascular smooth muscle ,• GPCR • activation of phospholipase C and IP3/DAG-

smooth muscle contraction• Vascular and cardiac growth mediated by

tyrosine kinases and increased transcription of specific genes

AT2• Fetal tissue development• Inhibition of growth and proliferation • Cell differentiation• Apoptosis • vasodilation

Angiotensinogenase

• Angiotensin II having very short half life• Most vascular beds ( except lungs)• Metabolites biologically inactive • aminopeptidases, endopeptidases, and

carboxypeptidases.

Drugs acting on renin angiotensin system

1) Drugs blocking renin secretion: clonidine , propranolol

2) Direct renin inhibitors: remikiren, enalkiren3) ACE inhibitors captopril, enalapril4) Angiotensin antagonists :

a) peptide: saralasinb) non peptide: losartan , valsartan, erposartan, irbesartan, candensartan, telmesartan

KININS

• potent vasodilator peptides• formed enzymatically by the action of

enzymes known as kallikreins or kininogenases acting on protein substrates called kininogens.

• metabolised by nonspecific exopeptidases or endopeptidases, commonly referred to as kininases

Kallikreins• present in plasma and in several tissues, including the kidneys, pancreas,

intestine, sweat glands, and salivary glands. • Plasma prekallikrein can be activated to kallikrein by trypsin, Hageman

factor, and possibly kallikrein itself.• Kallikreins can convert prorenin to active renin

Kininogens• precursors of kinins and substrates of kallikreins• present in plasma, lymph, and interstitial fluid. • Two kininogens are known to be present in plasma: • A) low-molecular-weight form (LMW kininogen)- crosses capillary walls and

serves as the substrate for tissue kallikreins• B) high-molecular-weight form (HMW kininogen)(15–20% of the total plasma

kininogen). confined to the bloodstream and serves as the substrate for plasma kallikrein.

• Three kinins have been identified in mammals: bradykinin, lysylbradykinin (also known as kallidin), and methionyl-lysylbradykinin

• Bradykinin is released by plasma kallikrein, lysylbradykinin by tissue kallikrein, and methionyl-lysylbradykinin by pepsin and pepsin-like enzymes

Actions of kinins Effects on the Cardiovascular System• marked vasodilation• direct inhibitory effect of kinins on arteriolar smooth muscle • mediated by the release of nitric oxide or vasodilator prostaglandins

such as PGE2 and PGI2

Venous constriction• direct stimulation of venous smooth muscle or from the release of

venoconstrictor prostaglandins such as PGF2

Dual action• Bradykinin also increases blood pressure when injected into the central

nervous system• water and solutes pass from the blood to the extracellular fluid, lymph flow

increases, and edema may result.

Effects on Endocrine & Exocrine Glands• prekallikreins and kallikreins are present in several glands,

including the pancreas, kidney, intestine, salivary glands, and sweat glands

• Local modulators of blood flow• modulate the tone of salivary and pancreatic ducts and help

regulate gastrointestinal motility• influence the transepithelial transport of water, electrolytes,

glucose,and amino acids, and may regulate the transport of these substances in the gastrointestinal tract and kidney

• physiologic activation of various prohormones, including proinsulin and prorenin

• Role in Inflammation Kallikreins and kinins can produce redness,

local heat, swelling, and pain• Effects on Sensory Nerves

elicit pain by stimulating nociceptive afferents in the skin and viscera.

KININ RECEPTORS & MECHANISMS OF ACTION

• B1 and B2

• B2

– widespread distribution – G protein–coupled and agonist binding sets in motion multiple

signal transduction events, including calcium mobilization, chloride transport, formation of nitric oxide, and activation of phospholipase C, phospholipase A2, and adenylyl cyclase

• B1

– Limited distribution

– important in long-lasting kinin effects such as collagen synthesis and cell multiplication.

DRUGS AFFECTING THE KALLIKREIN-KININ SYSTEM

• anti-inflammatory and antinociceptive agents.• Peptides-• Icatibant is a second-generation B2 receptor

antagonist• third generation of B2-receptor antagonists

was developed; examples are FR 173657, FR 172357, and NPC 18884

• the kallikrein inhibitor aprotinin

Pentagastrin

• a synthetic polypeptide that has effects like gastrin when given parenterally.

• stimulates the secretion of gastric acid, pepsin, and intrinsic factor,

• used as a diagnostic aid in the pentagastrin-stimulated calcitonin test.

• binds to the cholecystokinin-B receptor, which is expressed widely in the brain. Activation of these receptors activates the phospholipase C second messenger system.

• When given intravenously it causes panic attacks.

Cholecystokinin

• is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein.

• Also called pancreozymin• CCK also causes the increased production of hepatic bile,

and stimulates the contraction of the gall bladder and the relaxation of the Sphincter of Oddi, resulting in the delivery of bile into the duodenal part of the small intestine.

• CCK administration causes nausea and anxiety, and induces a satiating effect

CCK receptors

• influence neurotransmission in the brain, regulating anxiety, feeding, and locomotion.

• regulation of dopamine activity in the brain. CCK-B activation appears to possess a general inhibitory action on dopamine activity in the brain, opposing the dopamine-enhancing effects of CCK-A.

• Activation enhances GABA release• CCK-B receptors modulate dopamine release, and influence the

development of tolerance to opioids• CCK-B activation decreases amphetamine-induced DA release,

and contributes to individual variability in response to amphetamine.

• Cholecystokinin agonists: cholecystokiningastrin pentagastrin

• Cholecystokinin antagonist: proglumide

Substance P• belongs to the tachykinin family of peptides, Other members of this

family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and B are decapeptides.

• present in the central nervous system, where it is a neurotransmitter, and in the gastrointestinal tract, where it may play a role as a transmitter in the enteric nervous system and as a local hormone .

• Effects in behavior, anxiety, depression, nausea, and emesis.• It is a potent arteriolar vasodilator, producing marked hypotension . The

vasodilation is mediated by release of nitric oxide from the endothelium. • substance P causes contraction of venous, intestinal, and bronchial

smooth muscle.• It also stimulates secretion of the salivary glands and causes diuresis

and natriuresis by the kidneys.

• The actions of substance P and neurokinins A and B are mediated by three G protein-coupled tachykinin receptors designated NK1, NK2, and NK3.

• Substance P is the preferred ligand for the NK1 receptor, the predominant tachykinin receptor in the human brain.

• neurokinins A and B also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NK1 receptors.

• Several nonpeptide NK1 receptor antagonists have been developed. These compounds are highly selective and orally active, and enter the brain.

• these antagonists may be useful in treating depression and other disorders and in preventing chemotherapy-induced emesis. Eg. aprepitant.