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

•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.

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.

•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.

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

Didimetindene

Embramine

Chlorpyramine

PPromethazineromethazine

Cyproheptadine

(H1&5-HT2)

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

Clemastine (weak sedation)

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 They preventdegranulation and release of histamine and other autacoids from mast cells. They also inhibit leukocyteactivation and chemotaxis.

Indications: prophylactic 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

Buspirone•anxiolytic agent •partial agonist of the 5-HT1A-receptors•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

The agonist of 5-HT1D-receptors

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

•Naratriptan•Rizatriptan•Sumatriptan•Zolmitriptan

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

5-HT3-receptors•Located in enteric neurons and in CNS.

•Effects are excitatory, causing GI motility and vomiting.

Dolasetron

Granisetron

Ondansetron

Tropisetron

Antagonists of 5-HT3-receptors are verypowerful antiemetics:

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)

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 •misoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs); •gemeprost used for terminationof pregnancy.

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)

This has relevance for the mechanism of action of NSAIDs. Most of theminhibit mainly COX-1and can cause peptic ulcer,GI bleeding, bronchial asthma, and nephrotoxicity.

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

SelectiveSelectiveCOX-3COX-3

inhibitorsinhibitors•AntipyreticAntipyretic analgesicsanalgesics

NonselectiveNonselectiveCOX-1/COX-2COX-1/COX-2

inhibitorsinhibitors

ILIL®®ILIL®®

NSAIDsNSAIDs

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.

INFLAMMATION

•alteration

•exudationexudation

•proliferationproliferation

NSAIDs()

Gluco-Gluco-corticoidscorticoids()

()

4. PeptidesEndothelins: ET-1, ET-2, RT-3

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.

55. Cytokines – . 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.

INTERLEUKINES (ILs)

•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 [ recombinant human colony stimulating[ recombinant human colony stimulatingFactors]: Factors]: - Filgrastim, Molgramustim- Filgrastim, Molgramustim, Lenograstim, LenograstimUsed in cancer Used in cancer chemotherapychemotherapy