AUTOCOIDS

BYPROF. A. ALHAIDER

Department of Medical PharmacologyCollege of Medicine

• Definition: Auto = self Coids = Remedy or some times are called Local Hormones

Why are they very important?Because they have a role in physiological and

pathological aspects. (mediators)

• Classifications:A. Amine Autocoids:

1. Histamine 2. Serotonin

B. Eicosanoids (Prostaglandin; Thromboxane ; Leukotrienes)

C. Peptide Autocoids: 1)Kinins

2) Renin; Angiotensin

HISTAMINE• Locations: mediators of allergic and

inflammatory reactions; also involved in gastric acid secretions ; and as a Neurotransmitter & a Neuromodulator.

• Thus, it is located in: a) Mast cells (lung, skin, GIT, Blood vessels..etc) by allergen bind to IgE on M.C b) Basophils, Platelets, Enterochromaffin-like (ECL) cells of the stomach c) Brain

Storage and Release: • Histamine is usually found in storage granules as complex

with sulfated polysaccharides (heparin) and is released locally by:

a) Immunologic Mechanisms (see next slide)

b) Tissue injury mast cell degranulation

c) Chemical and physical conditions ( see table 51-2)

An antigen binds with 2

IgE

Chemical and Physical Agents that Release Histamine

Chemical agentsPhysical agentsMechanical trauma

ChymotrypsinRadiant energy

Compound 48/80, DetergentsThermal energy

Dextran

DMSO (dimethyl- sulfoxide)

Morphine

Pentamidine

Polymyxin B ,

Polyvinyl pyrrolidine

Propamidine

eserpine

Surface active agents

Stilbamidine

Continued

Chemical agentsToxins

Tubocurarinevenoms

Bradykinin

Substance P??

X-ray contrast media

األهم هو خط تحته اللي ان ذكر الدكتور( للتيم( خاص

• Mechanism of Action:Histamine binds to three types of Receptors ,

namely H1 , H2 , H3Receptor sub type

DistributionPost receptor Mechanism

Partially Selecetive Agonists

Partially selective Antagonists

H1

(most important)

Smooth muscle , endothelium , brain(Postsynaptic)

↑IP3 , DAG2-( m-fluorophenyl)-histamine

Mepyramine , triprolidine

H2Gastric mucosa , Cardiac muscle , mast cells , brain.(postsynaptic)

↑cAMPDimaprit, impromidine , amthamine

Ranitidine , tiotidine

H3 Presynaptic: brain, myenetric plexus, other neurons (Presynaptic)

G protein –coupled (decrease Ca)

R- α-Methylhistamine, imetit , immepip

Thioperamide, iodophenpropit ,. clobenpropit

Effects on Organs a) CVS: Systolic and diastolic blood pressure

Heart rate and heart contractility (as a reflex)

b) GIT: Gastric acid secretion (H2) (very important)

Contractility (but less in human)

c) Bronchi: smooth muscle contraction and secretion

What is the significance of this effect?might lead to bronchoconstriction (e,g asthma) d) Nerve endings: Pain & Itching

Toxicity and contraindications:• How does it occur?By action of histamine on the receptors.• Manifestations Flushing, hypotension, tachycardia, headache,

wheals, bronchoconstriction, and gastrointestinal disturbance.

• Treatment1.Epinephrine: a physiological antagonist of

histamine.2.Antihistamine.3.Corticosteroids to inhibit prostaglandins which

are released along with histamine in the body.

Histamine H1 – Receptor Antagonists

Histamine can be antagonized by the following:

• a) Physiological Antagonism by epinephrine

• b) Mast cell release inhibitors (Sodium Chromoglycate)

• C) Histamine Receptors Antagonists (The Most Important Clinical Approach)

Otc: over the counter drug

Used for itching

Better than dramamine

No arrhythmia

Pharmacokinetic of H1-antagonists) ( see Table 16-2)

All are competitive and reversible blockers (1st and 2nd)

Pharmacodynamics:• They block H1 receptors and they may block muscarinic, α

adrenorceptors, serotonin , and local anesthetic receptor sites.

• a) Antagonize Histamine Actions (e.g. Edema resulting from ↑capillary permeability; vascular response; effects on smooth muscle)

Used in allergy

• b) Sedation (First Gen.) used as sleep aids.

• c) Antinausea & Antiemetic Actions I( First Gen.)

• d) Anticholinergic (First. Gen) may be useful in nonallergic rhinorrhea.

• e) Strong serotonin blockade (Cyproheptadine)

• f) ↓ Bronchial and nasal secretion

• G) Local anesthetics

Clinical Uses:• a) Allergic Reactions (e.g.: Allergic

Rhinitis ; Urticarea , atopic dermatitis.

• b) Motion Sickness & Vestibular disturbances (Cyclizine; Meclizine)

• c) Nausea & Vomiting of Pregnancy (Doxylamine (BendectinR)

• Local anesthesia: first generation (Diphenhyramine and promethazine)

Why Antihistamines are not used for Asthma?. Because they are not strong bronchodilators.

In cough syrup we use 1st generation together with pseudoephidrine to relieve nasal congestion and ↓ secretion

• Side Effects: sedation and antimuscarinic action.Less common side effects: excitation, convulsion, postural hypotension and allergic

responses

• Receptors selectivity: 1st generation antihistamines are of poor H1 receptor selectivity. They block other receptors leading to adverse effects:

• Cholinergic R blockade: dry mouth, urinary retention, & tachycardia -adrenergic R blockade, by promethazine, leading to hypotension, tachycardia &

dizziness• Serotonin R blockade leading to increased appetite (Cyproheptadine)• Cyproheptadine:Used for skin allergies, cold urticaria Counteract the sexual side effects

of serotonin-specific reuptake inhibitor (SSRI)

• Drug Interactions: • Liver microsomal enzyme inhibitors increase the arrythmogenic action of piperidine second

generation (Astemazole and Terfenadine). . Sedative actions of antihistamine increase if given with alcohol or any sedative drugs

FIRST – GENERATION ANTIHISTAMINESDrugsAnt-chol.

activityComments

Triprolidine (ActiveR)+Marked sedation used for cough preparation (e,g

Actived)

Drugs Anti-chol. activity

comments

PiperidinesAstemizole (Hismanal)

_Slow onset of action ( withdrawn))Arrhythmia(

Terfenadine (Seldane)_Prompt onset of action (arrhythmia)

2nd generation

Serotonin• Definition and Location: It is a neurotransmitter found in enterochromaffin

cells in GIT (90%) , and in plateletes and in raphe nuclei of brain stem.

• Mechanism of action : Interacts with 12 receptor subtypes (see next slide)

• Why does the 5-HT3 receptor differ from other 5- HT receptors?

Because it is linked to ion channel.

Pharmacological actions of Serotonin• CVS: 1) Blood vessels:

potent vasoconstrictor (via 5- HT2 ) EXCEPT : skeletal muscles and coronary blood vessels.

• Note : 5- HT can give rise to triple action:1. Decrease BP due to chemoreceptor response2. Increase BP due to Vasoconstriction (5-HT2)3. Decrease BP due to skeletal muscle vasodilation.

2) Platelet: Increase platelet aggregation via 5-HT2

• GIT:• 1) Increases contraction of smooth muscles (via 5-

HT4 by stimulating the release of Ach).

2) Nausea and vomiting (via 5-HT3).

• Respiration : 5-HT may produce weak bronchoconstriction.

• CNS: very important.(Appetite; depression and mania??; Pain; Anxiety; Schizophrenia).

• Clinical Uses of Serotonergic Drugs:

• Note 1: Unlike NE or DA, serotonin itself has no clinical uses (because it is non-selective). However, its agonists and antagonists have very important therapeutic applications.

• Note 2: Unlike histamine where its antagonists are used only, serotonin’s agonists and antagonists can be used.

Clin. Uses of Serotonergic Agonists:1 (Buspirone: 5-HT1A agonists are used as anxiolytic agents.

2 (Sumatriptan: 5-HT1D agonist for migraine (Treatment

and prophylactic.(3 (Metoclopromide (Plasil):it act as :5-HT4 agonist and 5-HT3

antagonist.• Used as prokinetic agent for treatment of gastroesophageal reflex (by

release Ach).• Used as treatment for nausea and vomiting by antagonizing 5-HT3

4 (Dexfenfuramine: Acts by stimulating the release of serotonin as well as inhibiting its reuptake .

Used as an anorexic (appetite suppressant) agent.

Clinical Uses of Serotonergic Antagonists:

1) Ondansetron & Granisetron: 5-HT3 antagonists are commonly used for Rx of N/V induced by cytotoxic (chemotherapy) drugs.

2) Cyproheptadine: Is an antagoinst of H1, 5-HT1,2, cholinergic receptors.

• used in case of carcinoid tumors (carcinoid tumors produce serotonin and cyproheptadine antagonize the action of serotonin).

• Used to ↑ appetite.

3) Ketanserin: 5-HT2 and 5-HT1c antagonist and 1-adrenergic blocker.(used as antihypertensive agent)

4) Methysergide: This is an ergot alkaloid acts as 5-HT1,2 antagonist used for Rx of migraine.

• Ergot Alkaloids• Produced from a fungus and they act on -

adrenoceptors, dopamine, and 5-HT.

• Mechanism of action: Acts on several types of receptors either agonist, partial agonist, or antagonists.

• CNS:– Stimulation of 5-HT2 receptors leads to hallucinogenic

action (e.g.: by LSD)– Stimulation of dopaminergic receptors in the pituitary

gland decreases prolactin release and relieves the symptoms of parkinsonism (e.g: Bromocriptine)

صورة فيذا 6 -16حط

• CVS:– Vasoconstriction via -adrenoceptors and 5-HT2 receptors

(Ergotamine act via 1 and increase NE)Uterine Smooth Muscle:Why are they more effective in pregnancy? Because they

stimulate α receptors which contract uterine muscles(e.g.: Ergonovine)

Clinical Uses of Ergot Alkaloids– Migraine (Ergotamine (with caffeine) or

dihydroergotamine during the attack while methysergide for prophylaxis)

– Hyperprolactinemia (Bromocriptine)– Parkinsonism (Bromocriptine)– Post partum hemorrhage (Ergonovine) to induce

uterine vasoconstriction.– Diagnosis of variant angina (Ergonovine) by

producing vasoconstriction during coronary angiography.Toxicity:

GIT as diarrhea; N/V; Prolongs vasospasm (ergotamine and ergonovine) may progress to gangrene.

Eicosanoids• Definition: Products of plolyunsaturated

long-chain fatty acids.

• Classifications; (check figures 18-1; 18-2 ;18-3)

• a ) Cyclooxygenase derivatives (prostaglandins and thromboxane)

• b) Lipoxygenase products (leukotrienes)

Synthesis of eicosanoids and sites of inhibitory effects of anti-inflammatory drugs

Membrane lipidCorticosteroids

Arachidonic acid

NSAIDs

Hydroperoxides Endoperoxides (HPETES) (PGG, PGH)

Leukotrienes Prostacyclin Thromoxane(LTB, LTC ,LTD, LTE) (PGI) (TXA)

Prostaglandins(PGE, PGF)

-

-

Phospholipase A2

LipoxygenaseCycloxygenase

zileuton

-

Physiological and Pharmacological Actions of Eicosanoids

Mechanism and Receptors: Act on cell surface receptors.All coupled to G-protein.PGI and PGE increase adenylyl cyclase (decrease intracellular calcium) while TXA2 increases IP3 (increases intracellular calcium)

Pharmacological & Physiological Effects: (also check next slide).

A. Uterine ToneB. Blood pressure regulation (Dilatation and constriction)C. Inflammation D. Gastric Secretion and motility.E. Platelet aggregationF. Bronchial toneG. Effect on kidney H. CNS (Fever; Pain; Sleep)J. Eye

Table 1: Effects of some eicosanoids

EffectPGE2PGF2αPGI2 TXA2LTB4LTC4LTD4

Vascular tone

↓↑↓↓↑↑↑?,↑↓,↑↓

Bronchial tone

↓↓↑↓↑↑↑?↑↑↑↑↑↑↑↑

Uterine tone↑↑↑↑↑↓????

Platelete aggration

↑or ↓?↓↓↓↑↑↑???

Leukocyte chemotaxis

????↑↑↑↑??

↑= slight increase, ↑↑= moderate, ↑↑↑=high, ↑↑↑↑=very high, ↓= slight decrease, ↓↓= moderate and, ↓↓↓= marked; ?= unknown effects

Clinical Uses of Eicosanoids and Inhibitors:•

• A. Uses of Eicosanoids:

– Oxytocis agents(inducer of labor): (e.g.: Dinoprostone PGE2) vaginally or Misoprostol (p.o)??

• _ - Impotance: Alprostadil PGE2• _ -Glaucoma: Latanoprost PGF2

– Pulmonary Hypertension ( PGI2 or prostacyclin, Epoprostenol)– Peptic Ulcer (PGE1 Misoprostol (cytoprotective: protective effect against

peptic ulcer) by bicarbonate and blood perfusion and acid secretion• B- uses of Eicosanoids blockers:

– Asthma: Leukotriene antagonists (Zafirleukast; Montelukast); or Lipoxegenase inhibitor e.g. Zileuton

•– Anti-inflammatory and rheumatoid arthtritis (NSAIDs)

– Antiplatelet action (Aspirin) because it is selective for thromboxan.

– Dysmenorrhea الطمث (NSAIDs) آالم

Pulmonary Hypertension

C. Vasoactive Peptides

• A. Vasoconstrictors: Angiotensin II, vasopressin, endothelins, and neuropeptide Y

• B. Vasodilators: Bradykinin and related Kinins, Natriuretic Peptides, Vasoactive Intestinal Peptide, substance P, and

neurotensin

Kinins : (e.g. : Bradykinin & kallidin)• Polypeptides present in plasma and several tissues including

kidneys, pancreas, intestine, salivary and sweat glands.• The active B1, B2, B3 receptors are linked to

phospholipase C and A2.

ACTIONS : CVS : Very potent vasodilator directly via B2 and by

increasing EDRF(NO). Also, increases the body capillary permeability. Indirect & direct tachycardia & increase in cardiac output. Produces coronary vasodilation.

• Bronchioles : Contraction of bronchial smooth muscles leading to cough.

• Inflammation (B2) : Kinins can produce all the symptoms of inflammation (pain and edema when injected into tissue).

• Pain : Intradermal injection of kinins elicit potent pain (Stimulate nociceptive nerve afferent fibers)

• DOES BRADYKININ PLAY A ROLE IN THE MECHANISM OF ACEI’S ACTION?

See next slide

ACEI result in

↑bradykinin

•Bradykinin has a cardiac anti-ischemic effect, which is inhibited by B2 antagonists (NO & PI2 dependent) .•Kinins produce bronchoconstriction and itching in the respiratory system (aspirin inhibit prostaglandins so it antagonizes the action of kinins)

•Aprotinin (Trasylolol), a kallikrein inhibitor, used in treatment of acute pancreatitis, carcinoid syndrome, and hyperfibrinolysis

Natriuretic peptides:Location: Atrial (ANP) and Brain (BNP) (Found in the ventricle as well).Clinical significance: (increase in heart failure, renal failure, SIADH)Action: Decrease the secretion of renin, aldosterone and vasopressin; decrease blood pressure and increase sodium excretion. Act via activation of guanylyl cyclase.

Calcitonin: Is the most potent vasodilator in the body.

Vasoactive-intestinal peptides:• Distributed in the CNS, GIT, PNS, heart, lung, kidney.• Vasodilator and exerts +ve inotropic and chronotropic effect.• Effects are mediated by G protein coupled receptor.

The Natriuretic Peptide Family• Include atrial natriuretic peptide (ANP),

brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP)

• ANP derived from a 126-amino acid prohormone which is secreted prima-rily from cardiac atria.

• BNP was found initially in the brain, yet it is secreted from atria & ventricles.

• CNP identified in brain & in vascular endothelial cells

• Stretch receptors in the atria and ventricles detect changes in cardiac chamber volume related to increased cardiac filling pressure resulting in the release of both ANP and BNP but not CNP.

The Natriuretic Peptide Family

• The actions of the natriuretic peptides are mediated by natriuretic peptide receptors (NPRs), NPR-A/B/C

• NPR-A & NPR-B are coupled to membrane-bound Guanylyl Cyclase.

• NPRs are localized in vascular SM, endothelium, platelets, the adrenal glomerulosa, & the kidney.

• ANP & BNP increase urine volume & sodium excretion, decrease vascular resistance, and inhibit release of renin and secretion of aldosterone & vasopressin.

• Neutral endopeptidases (NEPs) inactivate NPs.

Substnace P: •Is an arteriolar vasodilator also a pain-mediating neurotransmitter

•causes venoconstriction and bronchoconstriction.

•Capsiasin (from chili peppers) releases substance P from nerve endings. Thus, used for arthritic joints and post-therapeutic neuralgia.

ADH (vasopressin)

•Peptide hormone released from posterior pituitary gland.•Stimulus : rising plasma tonicity or falling blood pressure•It acts on 2 receptors:1.V1 in vascular smooth muscles vasoconstriction2.V2 receptors in renal tubule cells increase water reabsorption

2. Vasoconstrictor peptides:

Angiotensin IIYou should know its synthesis (See slide 41)Actions:

1. The most potent vasoactive agent in the body (direct and via NE)

2. Stimulate release of aldosterone and rennin as well.

3. In the CNS it stimulates thirst receptors and increases the secretion of vasopressin and ACTH.

Endothelins:• Widely distributed in the body (in the endothelium)• ACTION: Dose-dependent Vasoconstriction in most vascular beds, Thus:

– Decrease GFR – Increase aldosterone, vasopressin and ANP– Potent bronchoconstriction

Endothelin Antagonists: Endothelin-converting enzyme inhibitors:(Bosentan) (for pulmonary hypertension).