autacoids

Autacoids Autacoids

IntroductionIntroduction

• Autos – selfAutos – self

• Akos – remedyAkos – remedy

• Examples: Histamine, 5HT, Examples: Histamine, 5HT, Bradykinin, Eicosanoids (PGs, Bradykinin, Eicosanoids (PGs, thromboxanes, leukotrienes) and PAFthromboxanes, leukotrienes) and PAF

Histamine Histamine

• Imidazole + amino group Imidazole + amino group

• Chief storage site: Mast cellChief storage site: Mast cell

• Every tissue contains some amountEvery tissue contains some amount

• Synthesis involves de-carboxylation of Synthesis involves de-carboxylation of histidine by a decarboxylase enzyme.histidine by a decarboxylase enzyme.

Note: Mast cell in skin, intestinal and respiratory tract mucosa Note: Mast cell in skin, intestinal and respiratory tract mucosa serve as the major storage site, also Basophils.serve as the major storage site, also Basophils.

HistamineHistamine

• Metabolism involves methylation by Metabolism involves methylation by N-methyl transferase. N-methyl transferase.

• The N – methyl-histamine may be The N – methyl-histamine may be converted to N-methyl indole acetic converted to N-methyl indole acetic acid by MAO. acid by MAO.

• Also histamine may undergo Also histamine may undergo oxidative deamination with the oxidative deamination with the production of imidazole acetic acid production of imidazole acetic acid which is later converted to riboside.which is later converted to riboside.

HistamineHistamine

• Functions of endogenous histamine:Functions of endogenous histamine:

• Hypersensitivity/allergyHypersensitivity/allergy

• Gastric acid secretionGastric acid secretion

• Neurotransmitter.Neurotransmitter.

• Systemic effects: Hypotension, Systemic effects: Hypotension, flushing, headache, Edema,flushing, headache, Edema,

HistamineHistamine

• GIT – Contraction of intestinal smooth GIT – Contraction of intestinal smooth muscle(H1) and gastric acid secretion muscle(H1) and gastric acid secretion (H2).(H2).

• Respiratory system – Broncho-Respiratory system – Broncho-constriction (H1)constriction (H1)

• Uterus – Contraction (H1).Uterus – Contraction (H1).

• Nerve ending – stimulation (H1) Nerve ending – stimulation (H1) producing pain and itching.producing pain and itching.

HistamineHistamine

• Release of histamine is consequent Release of histamine is consequent upon binding of antigen to the Fc upon binding of antigen to the Fc segment of IgE with the increase in segment of IgE with the increase in cytosolic Ca2+ and fusion of histamine cytosolic Ca2+ and fusion of histamine containing vesicles to the plasma containing vesicles to the plasma membrane. membrane.

• It is presumed that Ca 2+ - calmodulin It is presumed that Ca 2+ - calmodulin dependent protein kinase are involved dependent protein kinase are involved in the fusion and exocytosis processes. in the fusion and exocytosis processes.

HistamineHistamine

• Other mediators of histamine Other mediators of histamine release: PAF, Kinins, LTD4.release: PAF, Kinins, LTD4.

• NB: Release of mediators is NB: Release of mediators is enhanced by muscarinic and α- enhanced by muscarinic and α- adrenergic receptor agonists. adrenergic receptor agonists.

• B-adrenergic agonists inhibit B-adrenergic agonists inhibit secretion of the same agents.secretion of the same agents.

HistamineHistamine

• Agents that stimulate release of histamine Agents that stimulate release of histamine (without prior sensitization) include:(without prior sensitization) include:

• amides, amidines, quantenary ammonium amides, amidines, quantenary ammonium compounds, pyridinium, piperidine,compounds, pyridinium, piperidine,

• Alkaloids, Alkaloids, • Other agents: vancomycin, morphine, Other agents: vancomycin, morphine,

radiocontrast, d-Tubocurarine, radiocontrast, d-Tubocurarine, succinylcholine, etc. succinylcholine, etc.

**These histamine liberators do not deplete tissues of non-These histamine liberators do not deplete tissues of non-mast cell histamine. mast cell histamine.

HistamineHistamine

Other releasers of histamine:Other releasers of histamine:

• Cold urticaria, solar urticaria, and Cold urticaria, solar urticaria, and cholinergic urticaria.cholinergic urticaria.

• Receptors are classified as: Receptors are classified as:

• H1, H2 and H3 (H4 also) and all are H1, H2 and H3 (H4 also) and all are G-protein coupled with seven G-protein coupled with seven membrane spanning domains.membrane spanning domains.

HistamineHistamine

• H1 results in increase phospho-H1 results in increase phospho-inostitol hydrolysis.inostitol hydrolysis.

• H2 acts by: increasing cAMP and is H2 acts by: increasing cAMP and is involved in gastric acid secretion.involved in gastric acid secretion.

• H3 – located at the pre-synaptic and H3 – located at the pre-synaptic and provides feed back inhibition of provides feed back inhibition of histamine, Ach, norepinephine, and histamine, Ach, norepinephine, and 5HT.5HT.

HistamineHistamine

Histamine receptor agonists:Histamine receptor agonists:

• H1: 2 - methyl histamine, 2 Pyridyl- H1: 2 - methyl histamine, 2 Pyridyl- ethylamine, 2 thiazolylethylamineethylamine, 2 thiazolylethylamine

• H2: 4, 5 methyl-histamine, H2: 4, 5 methyl-histamine, ImpromidineImpromidine

• H3: α –methyl-histamineH3: α –methyl-histamine

Histamine AntagonismHistamine Antagonism

Histamine antagonism:Histamine antagonism:

• Physiological – Epinephrine.Physiological – Epinephrine.

• Membrane stabilizers (prevent Membrane stabilizers (prevent release) – Na chromoglycaterelease) – Na chromoglycate

• Receptor antagonists:Receptor antagonists:

HistamineHistamine

• H1 antagonists grouped as follows:H1 antagonists grouped as follows:– Ethanolamines e.g. diphenhydramineEthanolamines e.g. diphenhydramine– Ethylenediamines e.g. pyrilamineEthylenediamines e.g. pyrilamine– Piperazine (e.g. cyclizine)Piperazine (e.g. cyclizine)– Alkylamines e.g. chlorpheniramineAlkylamines e.g. chlorpheniramine– Phenothiazines e.g. promethazinePhenothiazines e.g. promethazine

AntihistamineAntihistamine

– Piperidines e.g. *Astemizole, *TerfenadinePiperidines e.g. *Astemizole, *Terfenadine– Miscellaneous e.g. cyproheptadine, Miscellaneous e.g. cyproheptadine,

loratidine*loratidine*

• *Lack sedating effects and are referred *Lack sedating effects and are referred to as 2nd generation.to as 2nd generation.

• Terfenadine and Astemizole are pro-Terfenadine and Astemizole are pro-drugs. drugs.

• Low lipid solubility and longer half lives Low lipid solubility and longer half lives in 12-24 hours.in 12-24 hours.


• H1 blockers are competitive antagonists.H1 blockers are competitive antagonists.

Other effects: Other effects:

• sedation (H1) sedation (H1)

• antiemesis (antimuscarinic), antiemesis (antimuscarinic), antiparkinsonism (antimuscarinic).antiparkinsonism (antimuscarinic).

• Blurred vision and urinary retention (anti M),Blurred vision and urinary retention (anti M),

• Hypotension (α-adrenoceptor blocking Hypotension (α-adrenoceptor blocking action).action).


Uses:Uses:

• Anti allergy – allergic rhinitis, Anti allergy – allergic rhinitis, urticarial, angioedemaurticarial, angioedema

• Motion sicknessMotion sickness

• Nausea and vomitingNausea and vomiting


Acute toxicity of antihistamine:Acute toxicity of antihistamine:• HallucinationHallucination ))• ExcitementExcitement ))• Inco-ordinationInco-ordination ))• AthetosisAthetosis• ConvulsionConvulsion ))• Fixed dilated pupil) Similar to atropine poisoningFixed dilated pupil) Similar to atropine poisoning• Urinary retentionUrinary retention ))• Dry mouth, feverDry mouth, fever• TachycardiaTachycardia ))• Cardiovascular collapse may lead to death eventually.Cardiovascular collapse may lead to death eventually.


Other ADR – sedation/Excitation in childrenOther ADR – sedation/Excitation in children

• Dizziness, tinnitus, inco-ordination Dizziness, tinnitus, inco-ordination

• Drug allergyDrug allergy

• Postural hypotension, leukopeniaPostural hypotension, leukopenia

• Teratogenesis ?? AgranulocytosisTeratogenesis ?? Agranulocytosis

• Q-T prolongation, especially with newer Q-T prolongation, especially with newer generationgeneration

• Anorexia, diarrhea/constipation, dysuria Anorexia, diarrhea/constipation, dysuria


ChlorpheniramineChlorpheniramine

• An alkylamine, An alkylamine,

• high bioavailability (= 50%)high bioavailability (= 50%)

• Duration of action = 4-6 hrsDuration of action = 4-6 hrs

• Peak plasma concentration = 2-3 hrsPeak plasma concentration = 2-3 hrs

• Plasma protein binding = 70%Plasma protein binding = 70%

AntihistaminesAntihistamines

• H2 antagonists:H2 antagonists:• Nizatidine Rantidine, CimetidineNizatidine Rantidine, Cimetidine• Selective H3 antagonist: Thioperamide, Selective H3 antagonist: Thioperamide,

impromidine and burimamide ( H2 agonist impromidine and burimamide ( H2 agonist as well).as well).

• H4 receptor are found on the eosinophils H4 receptor are found on the eosinophils and and

• An agonist of H4 is Clozapine An agonist of H4 is Clozapine (another e.g (another e.g clobenpropit)clobenpropit). .

• Thioperamide is an antagonist of H3 and H4 Thioperamide is an antagonist of H3 and H4 receptors. receptors.

KININSKININS

KININSKININS

Two major isoforms: Two major isoforms:

• BradykininBradykinin

• Lysyl-bradykinin.Lysyl-bradykinin.

• Source: kininogen from the liverSource: kininogen from the liver

• Kininogenase cleaves nonapeptide Kininogenase cleaves nonapeptide bradykinin from kininogen*bradykinin from kininogen*

*Plasma HMWK or tissue LMWK*Plasma HMWK or tissue LMWK

Synthesis of BradykininSynthesis of Bradykinin

HMWKHMWK

↓↓ ↓ ↓Hageman factor* Hageman factor*

↓↓Kallikrein** ~ ~ PrekallikreinKallikrein** ~ ~ Prekallikrein

BradykininBradykinin

*Hageman factor is activated by exposure to damaged *Hageman factor is activated by exposure to damaged tissue(inhibited by C1 inhibitor)tissue(inhibited by C1 inhibitor)

**Kallikrein is inhibited by C1 inhibitor and **Kallikrein is inhibited by C1 inhibitor and αα2 2 macroglobulinmacroglobulin

KININSKININS

• Formed from circulating kininogen by Formed from circulating kininogen by Kallekrein* (a protease). Kallekrein* (a protease).

• Metabolism involves kininase I & II**Metabolism involves kininase I & II**• T ½ ~ 15 seconds.T ½ ~ 15 seconds.

Both agents circulate as pre~ HMWK & prekallikrein to Both agents circulate as pre~ HMWK & prekallikrein to protect from effects of kinin. Hageman factor sets up protect from effects of kinin. Hageman factor sets up the cascade ff its activation by tissue injurythe cascade ff its activation by tissue injury

** The carboxyl terminal Arginine is removed by ** The carboxyl terminal Arginine is removed by Carboxypeptidase thus inactivating itCarboxypeptidase thus inactivating it

KININSKININS

Receptors: B1 & B2 Receptors: B1 & B2 • B2 is constitutive in all normal tissuesB2 is constitutive in all normal tissues• B1 is up-regulated in reaction to injury. B1 is up-regulated in reaction to injury. • B2 is G-protein coupled and activates B2 is G-protein coupled and activates

PLA2 and PLC. PLA2 and PLC. • The stimulated PLA2, librates The stimulated PLA2, librates

arachidionic acid from membrane bond arachidionic acid from membrane bond phospholipids phospholipids which in turn may be metabolized to which in turn may be metabolized to other potent mediators of inflammation.other potent mediators of inflammation.

KININSKININS

Effects:Effects:• -Vasodilation* directly -Vasodilation* directly and through release of and through release of

EDRF and synthesis of PGE2 and PGI2.EDRF and synthesis of PGE2 and PGI2.

• -Venocostriction and contraction of -Venocostriction and contraction of endothelial cell resulting in EDEMA.endothelial cell resulting in EDEMA.

• -Release of mediators of Inflammation-Release of mediators of Inflammation

• broncho-spasmbroncho-spasm* x10 histamine* x10 histamine

KININSKININS

• Other effects: Pain (B1), Other effects: Pain (B1),

• bone re-absorption (B1) bone re-absorption (B1)

• Asthma, Asthma,

• RBF, RBF,

• Destruction of blood-brain barrier.Destruction of blood-brain barrier.

Serotonin (5HT)Serotonin (5HT)


High concentrations in entero-High concentrations in entero-chromaffin cells of:chromaffin cells of:

• GI, GI,

• Platelets* and Platelets* and

• CNS.CNS.

• (*Lacks synthetic ability) (*Lacks synthetic ability)


Biosynthesis – Tryptophan

↓ (Tryptophan lydroxylase) (oxygen, pteridine)

Hydroxytryptophan ↓

↓(decarboxylase) 5HT


• Metabolism:Metabolism:

• MAO and aldehyde dehydrogenaseMAO and aldehyde dehydrogenase

• To form 5-HIAA.To form 5-HIAA.

• Action in the CNS is terminated by an Action in the CNS is terminated by an uptake process.uptake process.


5HT plays a role in: 5HT plays a role in:

• mood, headache, sleep, mood, headache, sleep,

• temperature regulation temperature regulation

• pain perception, pain perception,

• blood pressure regulation and blood pressure regulation and

• platelet function.platelet function.


Receptors:Receptors:

• 5HT5HT1-71-7

• 5HT1: (A, B, D, E, F)5HT1: (A, B, D, E, F)

• 5HT2: (A, B, C)5HT2: (A, B, C)

• 5HT5: (A, B)5HT5: (A, B)


• Some are G-protein coupled: Some are G-protein coupled:

• Gi/Go (1A,. 2A,)Gi/Go (1A,. 2A,)

• Gq (2A)Gq (2A)

• Gs (4,6,7)Gs (4,6,7)


Effects:Effects:• Vasoconstriction (2A)Vasoconstriction (2A)• Release of EDRF and vasodilation: (5HT). Release of EDRF and vasodilation: (5HT). • Hypotension and bradycardia (5HT3) Hypotension and bradycardia (5HT3) • Smooth muscle contraction (2A, C, 4) Smooth muscle contraction (2A, C, 4) • Vascular muscle relaxation (5HT7) Vascular muscle relaxation (5HT7) • Bronchoconstiction.Bronchoconstiction.• Emesis (5HT3, Area postrema). Emesis (5HT3, Area postrema). • Behaviour (aggression, anxiety, Behaviour (aggression, anxiety,

depression).depression).


SSRI:SSRI:

• E.g’s fluoxetineE.g’s fluoxetine

• Prevent 5HT re-uptake and used for Prevent 5HT re-uptake and used for depression.depression.

• 5HT agonists: 5HT agonists:

• LSD (Lysergic Acid Diethylamide), LSD (Lysergic Acid Diethylamide),

• Buspirone, sumatriptan, cisapride (5HT4 Buspirone, sumatriptan, cisapride (5HT4 to stimulate, GI motility).to stimulate, GI motility).


Antagonists:Antagonists:

• Ondansetron (5HT3), Ondansetron (5HT3),

• Clozapine (5HT2 and5HT7) Clozapine (5HT2 and5HT7)

• Methylsergide(5HT2A/2C), Methylsergide(5HT2A/2C),

• Cyproheptadine (5HT2A)Cyproheptadine (5HT2A)

OndansetronOndansetron

• A selective 5HT3 receptor antagonist.A selective 5HT3 receptor antagonist.

• Uses include:Uses include:

• Treatment and prophylaxis of Treatment and prophylaxis of emesis/nausea of cancer emesis/nausea of cancer chemotherapychemotherapy

• Treatment and prophylaxis of Treatment and prophylaxis of emesis/nausea post-operativelyemesis/nausea post-operatively


• Preparations: Ondansetron HCl exists Preparations: Ondansetron HCl exists as white powder as white powder

• usually mixed with Dextrose or usually mixed with Dextrose or N/saline and N/saline and

• Available as oral, IV or IMAvailable as oral, IV or IM


Mechanism*: Antagonist at the 5HT Mechanism*: Antagonist at the 5HT receptor:receptor:

• -Chemorecptor trigger zone or -Chemorecptor trigger zone or

• -Area Postrema in the brain.-Area Postrema in the brain.

• Both Dopamine and 5HT receptors Both Dopamine and 5HT receptors are found hereare found here

*It is not known for certain whether action is central or *It is not known for certain whether action is central or peripheral or bothperipheral or both


PHK:PHK:• Plasma binding is about 75-80%Plasma binding is about 75-80%• Extensively metabolized (95%) in the liver Extensively metabolized (95%) in the liver

by hydroxylation* by hydroxylation* • Followed by: sulphation and glucuronidationFollowed by: sulphation and glucuronidation• T1/2 averages 5.5 hours and prolonged in T1/2 averages 5.5 hours and prolonged in

hepatic diseases. (> 12hours)hepatic diseases. (> 12hours)• Renal excretion of parent drug is about 5%Renal excretion of parent drug is about 5%• * Major enzyme is CYP3A4, others include: CYP2D6, CYP1A2.* Major enzyme is CYP3A4, others include: CYP2D6, CYP1A2.

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Unwanted effects:Unwanted effects:

• HeadacheHeadache

• ConstipationConstipation

• FlushingFlushing

• ArrhythmiasArrhythmias

• BradycardiaBradycardia

• HypotensionHypotension

• seizuresseizures

autacoids

Documents

gastric acid

mast cell

c1 inhibitor

area postrema

protein coupled

histamine

histamine

effects