AUTACOIDS (LOCAL AUTACOIDS (LOCAL HORMONES) HORMONES) ANDTHEIR PHARMACOLO-GICAL MODULATION

(Summary)

•endogenious compounds; •play an important role

in the physiological and

pathological processes;

• have very short t1/2;

• have local action.

AutacoidsAutacoids

a) Histaminea) Histamine

1. Monoamines1. Monoamines1. Monoamines1. Monoamines

The synthesis and breakdown of histamine

•Histamine is presented in high concentration in the skin, and in the mucous layer of the lung and GIT as an autacoid.

•At cellular level, it is found largely in mast cells and basophiles.

•Non-mast-cell histamine occurs as a neurotransmitter in CNS.

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In mast cells and basophiles histamineis located in intracellular granulestogether with heparin.

− distributionHistamine

Histamine is released from mastcells by a secretory process duringinflammatory or allergic reactions(Ag-Ab reactions).

The secretory process is initiated by a raise in intracellular Ca2+.

Histamine is released from mast cells during burns too.

Some drugs (mainly alkaloids atropine, morphine, reserpine,tubocurarine in high doses)release histamine by non-receptor action and can cause bronchoconstriction, arterial hypotension, and otherunwanted effects.

Folia UrticaeNaja naja (Leaves of Nettle)

Spoilt (putrid) fish contains histidine!

•contains potent allergens: can be potentially dangerous.•remains allergenic despite cooking.

FISH

Agents which increase cAMP(adrenaline, salbutamol, and others) inhibit histamine secretion and produce bronchodilation(antiasthmatic effect).

•Histamine produces effects by acting on H1, H2, H3, H4, and H5-receptors.•Histamine’s receptors are G-protein coupled.

Stimulation of H1-receptors•contraction of endothelium, increasing of vascular permeability and producing type I hypersensitivity reactions (urticaria and hay fever);•contraction of smooth muscle of bronchi, GIT, uterus;•excitement of CNS.

Histamine andantagonists ofH1-receptors(H1-blockers)

NH N

CH2 CH2 NH2

H1-blockers•Used mainly for the treatment of urticaria and hay fever.•Some of them (embramine, promethazine) have antiemetic effect too.

Dimetindene

Embramine

Chloropyramine

PromethazinePromethazine

Cyproheptadine

(H1&5-HT2)

H1-blockers from1st generation(with sedative andM-cholinolytic effects)

Clemastine (weak sedation)

Hydroxyzine is an H1-blockerwith anxyolitic, antiemetic,antimuscarinic, and spasmolyticeffects. It is effectivein pruritus and urticaria.

Astemizole

CetirizineLoratadineTerfenadine

H1-blockers from 2nd generation(without sedative and M-cholinolytic effects)

prolongation of QT interval prolongation of QT interval and hypokalemiaand hypokalemia

H1-blockers from 33…rd……rd… generation

•Desloratadine (Aerius® – film-tab. 5 mg; t1/2 27 h)•Levocitirizine

•cardiac stimulation•stimulation of gastric acid secretion

Activation of H2-receptors:

•Cimetidine (? …)•Famotidine •Nizatidine•Ranitidine •Roxatidine

Antagonist of H2-receptors(H2-blockers) – for the treatmentof peptic ulcer:

Cromoglycate – per inh. (Cromolyn – USAN)Ketotifen (p.o.)Nedocromil – per inh.

Mast cell stabilizers prevent transmembrane influxof calcium ions, provoked by antigen-IgE antibodyreaction on the mast cell membrane. They preventdegranulation and release of histamine and other autacoids from mast cells.

Indications: treatment of asthma.

NH

OH CH2 CH2 NH2

b) Serotoninb) Serotonin (5-Hydroxytryptamine: (5-Hydroxytryptamine: 5-HT)5-HT)

Indol derivative

Rang et al. Pharmacology– 5st Ed. (2003)

Rang et al. Pharmacology– 5st Ed. (2003)

Structures rich in 5-HT

• GIT (chromaffin cells and enteric neurons)• platelets• CNS

Important actions of 5-HT•increased GI motility •increased platelet aggregation•increased microvascular permeability•stimulation of nociceptive nerve endings

•control of appetite, sleep, mood, hallucinations, stereotyped behavior, pain perception, and vomiting

Clinical conditions in which5-HT plays a role include:

• migraine• mood disorders (depressive illnesses)• anxiety• vomiting• carcinoid syndromecarcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)

5-HT1-receptors:

•5-HT1A − 5-HT1F

•All subtypes occur in CNS and cause neural inhibition•Act by inhibiting adenylate cyclase

BuspironeBuspirone is a selective partial agonsist of presynaptic 5-HT1A-receptors. It is an anxyolitic agent, used in anxiety.

5-HT1D-receptors are found in some blood vessels (a. carotis externa et interna, meningeal vessels). They produce vasoconstriction. pathophysiology of migraine

Pathogenesis of migraine and drug treatment

Rang et al. Pharmacology– 5st Ed. (2003)

Rang et al. Pharmacology– 5st Ed. (2003)

The agonist of 5-HT1D-receptors

are highly effective, but expensive,in acute attacks of migraine:

•Naratriptan•Rizatriptan•Sumatriptan•Zolmitriptan

Activation of5-HT2-receptors•in CNS produces excitement•in blood vessels - contraction and platelet aggregation •act through phospholipase C/ inositol phosphate pathway

Antagonists of 5-HT2-receptors are used:

•for prophylaxis of migraine - cyproheptadine- iprazochrome- methysergide- pizotifen

•as a peripheral vasodilator- Naftidrofuryl (Dusodril®)

Adverse effectsof methysergide:•retroperitoneal fibrosis•renal failure

SSRIs (selective serotonin SSRIs (selective serotonin reuptake inhibitors): reuptake inhibitors): Fluvoxamine,Fluvoxamine, Citalopram, Fluoxetine,Citalopram, Fluoxetine,Paroxetine,Paroxetine,Sertraline Sertraline are used inare used inhumans humans to treat:to treat:•chronic anxietychronic anxiety•Depression, Depression, bulimiabulimia

Monoamine Reuptake InhibitorsMonoamine Reuptake Inhibitors αα22-adrenergic -adrenergic blockersblockers

EnzimeEnzimeinhibitorsinhibitors

Mainly NA-ergicDesipramineNortriptyline

Mainly 5-HT-ergicAmitriptyline

ClomipramineImipramine

Selective NARIsReboxetine

Selective 5-HTRIsCitalopram, Fluoxetine

Escitalopram, FluvoxamineParoxetine, Sertraline

Mianserine**MirtazapineTrazodone

Tricyclic antidepressants

MAO-AIsMoclobemide

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

DA&NARIsBupropion

5-HT3-receptors•Located in enteric neurons and in CNS.•Act by stimulating adenylate cyclase.•Effects are excitatory, causing GI motility and vomiting.

Dolasetron

Granisetron

Ondansetron

Tropisetron

Antagonists of 5-HT3-receptors are verypowerful antiemetics:

Agonists of 5-HT4-receptors

•Tegaserod (Zelmac®) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion. Indication: colon irritable syndrome

2. EICOSANOIDS2. EICOSANOIDS(20 carbon atoms!) (20 carbon atoms!) 2. EICOSANOIDS2. EICOSANOIDS(20 carbon atoms!) (20 carbon atoms!)

•prostanoids

− prostaglandins (PGs)

− thromboxanes (Txs)

•leucotrienes (LTs)

•lipoxins

(eic

osi =

20)

•The eicоsanoids are important mediators of inflammation and allergy.

•The main source of eicosanoids is arachidonic acid. It is a 20-carbon unsaturated fatty acid.

Phospholipase APhospholipase A22PhospholipidsPhospholipids

Arachidonic acidArachidonic acid

5-lipoxygenase5-lipoxygenase

LeucotrienesLeucotrienes

Cyclooxygenase (CoxCyclooxygenase (Cox))

EndoperoxidesEndoperoxides

PGsPGs TxATxA22

15-lipoxygenase15-lipoxygenase

LipoxinsLipoxins

Inflammatory stimulusInflammatory stimulus

PGI2 (prostacyclin) is located

predominantly in vascular endothelium. Main effects:

•vasodilatation•inhibition of platelet aggregation

TxA2 is found in the platelets.

Main effects:•platelet aggregation•vasoconstriction

PROSTANOIDS (PGs & Txs)PROSTANOIDS (PGs & Txs)

Several thromboxaneA2-receptor antagonists

may be able to restrict further infiltration of inflammatory cells

in atherosclerotic vessels, thus stabilizing vulnerable plaques

in the related cardiovasculardiseases.

PGEPGE11

•alprostadil (prodrug – used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects, and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis); •misoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs); •gemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for terminationof pregnancy.

PGEPGE22 causes:•contraction of pregnant uterus•inhibition of gastric acid secretion•contraction of GI smooth muscles

PGFPGF22αα – main effects:•contraction of bronchi•contraction of myometrium

PGFPGF2α2α (dinoprost)(dinoprost)

PGEPGE22 (dinoprostone)(dinoprostone)

areare given for:given for:•induction of labourinduction of labour•termination of pregnancytermination of pregnancy

PGEPGE11 (gemeprost)(gemeprost)

Dorland’s IllustratedDorland’s IllustratedMedical DictionaryMedical Dictionary

(2003, 2004)(2003, 2004)

Dorland’s IllustratedDorland’s IllustratedMedical DictionaryMedical Dictionary

(2003, 2004)(2003, 2004)

Mainactionsof the

eicosanoids

Lüllmann, Color Atlasof Pharmacology – 2nd Ed. (2000)

Lüllmann, Color Atlasof Pharmacology – 2nd Ed. (2000)

CyclooxygenaseCyclooxygenase (COX) (COX) is found bound to the endoplasmaticreticulum. COX exists in3 isoforms:•COX-1COX-1 (constitutive) acts in physiological conditions.•COX-2COX-2 (inducible) is induced in inflammatory cells by pathological stimulus.•COX-3COX-3 (in brain)

Aspirin-like drugsAspirin-like drugsinhibit mainly COX-1and can cause peptic ulcer,GI bleeding, bronchial asthma, and nephrotoxicity.

Inhibiting activity rateInhibiting activity rate(COX-2/COX-1)(COX-2/COX-1)

•AspirinAspirin•IndometacinIndometacin•MeloxicamMeloxicam

155155 6060 0,80,8

((Preferential COX-2 inhibitorPreferential COX-2 inhibitor))

ClassicalClassicalNSAIDsNSAIDs

Arachidonic acidArachidonic acid

Cyclooxygenase (Cox)Cyclooxygenase (Cox)

EndoperoxidesEndoperoxides

PGsPGs TxATxA22

((−− ))

AspirinAspirin

Thromboxane AThromboxane A22 synthase synthase ((−− )) 100 mg/24 h100 mg/24 h

>1 g/24 h>1 g/24 h

COX-2COX-2inhibitorsinhibitors • Selective (coxibs)Selective (coxibs)• PreferentialPreferential

SelectiveSelectiveCOX-3COX-3

inhibitorsinhibitors•AntipyreticAntipyretic analgesicsanalgesics

NonselectiveNonselective(Aspirin-like)(Aspirin-like)COX-1/COX-2COX-1/COX-2

inhibitorsinhibitorsNSAIDsNSAIDs

COX INHIBITORSCOX INHIBITORS

Coxibs are selective COX-2 inhibitors. They exertanti-inflammatory, analgesic and antipyretic actionwith low ulcerogenic potential. Coxibs can causeinfertility. They have prothrombotic cardiovascularrisk. The ulcerogenic potential of preferential COX-2 inhibitors Meloxicam, Nabumetone, andNimesulide (Aulin®) is significant.

PfizerPfizer$2.3 $2.3 billionsbillionspenaltypenalty

Inflammatory stimulusInflammatory stimulus

(+)(+)

Phospholipase APhospholipase A22PhospholipidsPhospholipids

Arachidonic acidArachidonic acid

((−− ))

LipocortinLipocortin

GlucocorticoidsGlucocorticoids(+)(+)

INFLAMMATION

•alteration

•exudationexudation

•proliferationproliferation

NSAIDs(−)

Gluco-Gluco-corticoidscorticoids

(−)

(−)

Arachidonic acidArachidonic acid

5-Lipoxygenase5-Lipoxygenase

Leukotrienes (LTs)Leukotrienes (LTs)

LTCLTC44--receptorreceptor

LTDLTD44--receptorreceptor

LTELTE44--receptorreceptor

Montelukast, ZafirlukastMontelukast, Zafirlukast(-)(-)(-)(-)

3. Platelet activating 3. Platelet activating factor (PAF)factor (PAF)

3. Platelet activating 3. Platelet activating factor (PAF)factor (PAF)

•PLAPLA22 releases PAF in inflammation. releases PAF in inflammation.•PAF causes vasodilatation, PAF causes vasodilatation, increases vascular permeability,increases vascular permeability, activates platelet aggregation.activates platelet aggregation.

3. Peptidesa) Vasoconstroctors

Endothelins (ET-1, -2, -3)

Blockers of ET-1 receptorsBlockers of ET-1 receptors are areindicated for the treatment of PAHindicated for the treatment of PAH(pulmunary arterial hypertension): (pulmunary arterial hypertension):

AMBRISENTANAMBRISENTANBOSENTANBOSENTAN

MACITENTANMACITENTAN

ANPANPCGRPCGRPSPSP

NPY (with NA)NPY (with NA)VIP (with ACh)VIP (with ACh)Kinins Kinins (kallikrein, (kallikrein, bradykininbradykinin

Cholecystokinin (CCK) Cholecystokinin (CCK)

b) Vasodilators:

c) Neuripeptide involved in c) Neuripeptide involved in pathogenesis of panic reactionspathogenesis of panic reactions

soluble proteins and glycoproteinssoluble proteins and glycoproteinsthat interact with specific cellularthat interact with specific cellularreceptors. Cytokines are involvedreceptors. Cytokines are involvedin inflammatory and immunein inflammatory and immuneresponse.response.

5. Cytokines – 5. Cytokines –

Cytokines act together (“as a team”) on:endothelium, leucocytes,mastocytes, fibroblasts, stem cellsand osteoclasts.Cytokines control their proliferation,differentiation and/or activation byreceptor mechanism.

IL-1IL-1 participates in the pathogenesisof rheumatoid arthritis.Glucocorticosteroids andglucosamine depress the synthesisof IL–1.IL-2:IL-2: used i.v. in renalcarcinoma but has ADRs!IL-11IL-11 stimulates thrombocytopoesis.

INTERLEUKINES (ILs)

IL-18:•Upregulated INF production•Enhenced NK cell cytotoxicityIL-23:•Anti-viral activity•Stimulates T-cell, macrophage, and•NK cell activity.•Direct anti-tumor effects•Used therapeuticaly in viral and autoimmune conditions

•Interferon alpha-2bInterferon alpha-2b (Intron©): - in chronic hepatitis B and C

- lymphomas, melanomas, etc.

•Interferon beta-1bInterferon beta-1b (Betaferon©) s.c. in multiple sclerosis.•Interferon gammaInterferon gamma – in the regulation of the immune system.

INTERFERONS (INFs)

•Colony-stimulating factorsColony-stimulating factors (rHuCSFs): (rHuCSFs): - Filgrastim, Molgramustim, Lenograstim- Filgrastim, Molgramustim, Lenograstim(to treat agronulocytosis and leukopenia)(to treat agronulocytosis and leukopenia)•TNF-alTNF-alphpha (ala (alffa)a)•TNF-betaTNF-beta•VEGFVEGF•PDGF,PDGF,•EGF, etc.EGF, etc.

Cetuximab

(–)

Colorectal cancerColorectal cancer