AUTACOIDS

• The term derived from Greek word

Autos= Self

Akoid (Akos)= Medicinal agent or

Remedy

• Produced by wide variety of cells in the body and released locally

• Act at site or near the site of their release

so called as local hormones

Classical autacoids are• Amine autacoids:-

• Histamine (H),• 5- Hydroxy tryptamine (Serotonin, 5HT)

• Lipid derived autacoids:- • Prostaglandins (PG) , • Leuckotrines (LT), • Platelet activating factors (PAF)

• Peptide hormones :-• Plasmakinin (Bradykinin,Kalliidin),• Angiotensin (AT).Others:- VIP

GastrinSomatostatinCytokines

HISTAMINE

• Histamine tissue amine (Histo=Tissue), also called as biogenic amine

• It was identified in 1907• Pharmacology studied by Dales 20th

century.

N N

NH2

H

1

2

3

45

Histamine

Heterocyclic amine

• Naturally occurring imidazole derivative (ß-imidazole ethylamine)

• synthesized locally & Storage granules of mast cells.

• Tissues rich in histamine are

skin, Intestinal mucosa, Lungs,

Liver and placenta• Non mast cell histamine occurs in brain,

epidermis, gastric mucosa.

L-Histidine

Synthesis

Histamine

Histidine de carbosylase

α Fluromethyl hisitidine

+Gastrin, Nicotine, stress

L-A.A decarboxylase

Stored in mast cells

N- Methyl histamine

Imidazole N- methyl transferees Di amine oxidase

Imidazole acetic acid

MAO-B Ribose

N- Methyl imidazole acetic acid Imidazole acetic acid riboside

Storage• In mast cell histamine (+ve) and get ionically

complexed with acidic –ve protein and heparin high molecular weight.

• Bounded form is biologically inactive

• Non mast cells stored in histaminocytes in the stomach and histaminergic neuron in brain.

Histamine

Heparin/protein

Release

• The stored histamine from the mast cells released by 2 ways mechanisms.

– Immunological release (anaphylactic)

– Chemical mediators (anaphylactoid)

Immunological release

Allergen enter (Forgein body)

Immunological reaction (AG:AB Complex formation)

Circulation in blood

Basophiles, Neutrophilis engulf

Cause neutralizationContd.,

Whenever same allergen re-exposed

Activation of AG:AB complex

Reacts with mast cells (Degranulation of mast cells)

Spasmogens release(Like Histamine,5HT,PGs,LT4, Cytokines)

Mast CellDegranulation

Chemical Release • Chemical mediators:

Chemical injures mast cell

(Granules exposed)

Drugs or chemicals release histamine • Morphine Hydralazine

• d-TC Dextran

• Pentamidine Bilesalts

• Trimethophan Detergents

• Tolazoline Substance –P

• Polymyxin –B Bradykinin

• SCh, component

48/80

• Polyvinylprolidone (PVP)

• Drugs decrease release of Histamine:-

– ß-Agonists

– Mast cell stabilizers

– Negative feed back control on mast cells.

Histamine receptor classification

• Histamine receptor were classified by Asch and Schild (1966) into H1, H2.

• H3 receptor was postulated by Schwartz 1983, confirmed by Arang in 1987.

• H4 receptors also present , but clinical less important.

Receptor Distribution Post receptor mechanism

H1

Post synaptic

a)Smooth muscle ( Intestine, bronchi, Uterus)b) Blood vesselsc) CNSd) Sensory nerve ending e) Adrenal medulla

Gq IP3, DAG

Release Ca+ PKC activation

H2

Post synaptic

a) Gastric glandb) Blood vesselsc) Heart d) Brain

Gq IP3, DAG

Release Ca+ PKC activation

H3

Pre synaptic

a) Brain presynaptic b) Lung, Spleen, Gastric mucosa c )Blood vessels

Gi

CAMP, Ca+2 influx , opening K+ channels

H4 a) Eosinophils b) Neutrophils CD4T Cells.

Gi

CAMP, Ca+2 influx , opening K+ channels

Pharmacological actions

H1 mediated pharmacological actions:- Sensory nerve endings:- Powerful stimulant on sensory nerve endings especially those mediating pain and itching.

H1 mediated effect is an important component of utricarial response to insect bites and stings.

Smooth muscle:-Bronchial:- Histamine cause broncho constriction.

• GIT:-cause contraction of intestinal smooth muscle result in intestinal cramps and diarrhoea.

• Uterus:- spasmodic contractions of uterus and ileum

• Glands:-Increases secretions of endocrine glands in bronchioles, pancreas, salivary and lacrimal glands.

• Autonomic ganglia:- Stimulates, cause release adrenaline.

• CNS:- Histamine does not penetrate BBB. No central effect.

• Intra cerebroventricular administration produces BP, cardiac stimulation, behavioral arousal, hypothermia, vomiting and ADH release.

• H1 mediate the maintenance of wakefulness.

H2 mediated action:-• powerful stimulant of gastric acid on

activation of H2 receptors on gastric cells. • It associated with cAMP & intracellular

Ca+2 concentration

H3 mediated action:- CNS and ANS , presynaptic H3 receptors act as feed back inhibitor for the release of histamine, NE and Ach.

• H3 receptor activation by histamine, it inhibits gastric acid release and block inflammatory process.

H1 and H2 actions:- • Stimulation of both receptor cause dilatation

of arterioles and post capillary venules. Result remarkable fall in BP.

• Vasodilation is mediated by the release of Endothelium Derived Relaxing Factor (EDRF).

• Dilatation of post capillary venules cause headache due to stretching of sensory nerve fibers around the cranial arteries.

• Histamine inj intradermally, atypical triple response is produced

• It characterized by an immediate redding of skin (Flush) , formation of edematous patch (Wheal) and a red irregular halo surround the wheal (Flare)

Flare

Wheal

Flush

• Flush:- Due to vasodilatation

• Wheal:-Exudation of fluid from capillaries and venules due to inc. permeability

• Flare: Consequence of axon reflex causing vasodilatation through the release of vasodilatory neuromediators.

CVS:- + ve chronotrophic (H2) and positive inotropic effect (H1+ H2) on heart

• These effect occurs reflexly due to fall in BP.

Receptor Distribution Function

H1

Post

synaptic

a)Smooth muscle ( Intestine, bronchi, Uterus)b) Blood vesselsc) CNSd) Sensory nerve ending e) Adrenal medulla

ContractionDilatationNTStimulation( Pain) Release catecholamines

H2

Post

synaptic

a) Gastric glandb) Blood vesselsc) Heart

d) Brain

Inc. acid secretion DilatationAtria +ve chronctrophicVentricle +ve inotrophicNT

H3

Pre synaptic

a) Brain presynaptic b) Lung, Spleen, Gastric mucosa c )Blood vessels

Inhibitor dec.Ach, NE, H, releaseDilatation

H4 a) Eosinophils b) Neutrophils CD4T Cells.

Histamine antagonists

• Histamine released in the body reduced by 3ways.

• Release inhibitors:-Disodium cromoglycate, Nedocromic sodium prevent the degranulation of mast cell.

• Prevent the release of histamine & other inflammatory mediators from mast cells.

• Iodoxasmide, Tromethamine are newer mast cell stabilizers.

• Ketotifen fumarate H1 blcoker + Mast cell stabilizer

Physiological antagonists:- Ex:- Epinephrine

It have smooth muscle action opp. to histamine; but they acts at different receptors.

Histamine receptor antagonists: These are antagonize the effect of histamine by competitively blocking the receptors.

H1 antagonists• Called as conventional anti histamines.

(Old)

• These are introduced at 1930s.

• These are conveniently divided into 1st & 2nd generations

• These group are distinguished by the relatively strong side effects most 1st generations.

1st generation 2nd generations

• Short to intermediate action

• BBB cross• Sedative action• Produce anti muscurnic

side effects • Also block auonomic

receptors • Cheap

• Long acting

• Poor penetration • No • No

• No

• Relatively expensive

Name Adult dose Oral

in mg

Duration of action

(hr)

Anti cholinergic

activity

Uses

Highly sedative DimenhydrinateDiphenhydramineDoxylamineHydroxyzinePromethazine

25-5025-5015-2525-5010-25

4-64-6

4-64-6

++++++++

++++++

Anti motion sickness activityAnti motion sickness activitySleep aidAntiemeticAntiemetic

Moderate sedativePyralamineTripelennamineCyproheptadineCarbinoxamine(Clistin)

Clemastine

25-5025-50

44-82-6

4-64-64-64-612

++

++++++++

Sleep aid-Anti serotonin effects--

Mild sedativesCyclizineMeclizineChlorphenaramineDexchlorphenaramineTriprolidine

25-5025-50

4-84-6

2.5-65

4-612-20

4-64-64-6

+++++++

---Anti motion sickness activity

-

Pharmacological actions• Antagonism of histamine:- Blocks

• Histamine induced broncho constriction

• Contraction of intestinal other smooth muscle

• Triple response.

• Fall in BP is blocked, but H2 antagonists are required.

• Release of Adr form adrenal medulla in response to histamine is abolished.

Anti allergic action:-– Immediate hypersensitivity (type I) are suppressed. – Itching, angioedema are controlled.– Rhinitis, common cold

CNS:- 1st generation anti histamines produce variable degree of CNS depression.– Dec. alertness– Inc. reaction time

- 2nd generation antihistamine are poor penetration to BBB so no sedative action.

• Motion sickness:-– Some antihistamine drugs acts Labyrinthine (H1) and

decrease motion sickness (Dimenhydrinate, Diphenhydramine)

• Chlorpromazine (2-5mg ), Diphenhydramine(15-25mg) and promethazine(15-25mg) are added to antitussive agents.

• Doxylamine is used to prevent nausea and vomiting due to pregnancy.

Pharmacokinetics :- • Well absorbed by oral and parental routes.• Metabolized in liver by microsomal system• Wide distribution and enter brain• Repeated use induce their own metabolism

Side effects:- Sedation, diminished alteration and concentration, light headache, motor in coordination, fatigue, tendency to fall sleep are most common.

• Acute overdose produce central excitation, tremors, convolutions, flushing, hypotension and fever.

• Death is due to respiratory CVS failure.

2nd generation (1980)Name Adult dose

Oral in mgDuration of action

(hr)

Anti cholinergic

activity

Remarks

AstemizoleFexofenadineCetrizineLoratadineDesloratadineLevocetrizineEbastine

10mg OD120-180mg10mg OD10mg OD5mg OD5mg OD

10mg

2412

12-24242424-

- -----

Anti inflammatory action

• Cetrizine is an active metabolite of hydroxyzine (1st G)• Levo cetrizine is L-isomer of cetrizine more potent less

sedative .

• Cetrizine:- poorly penetrate to BBB• Inhibits release of histamine and cytotoxic mediators from

platelets and eosinophil chemotaxis during 2nd phase of allergic response

• Once daily , Elimination t1/2 7-10hr • It is indicated for upper respiratory tract.

Fexofenadine • dose not cross BBB • free anti cholinergic side effect.• Rapidly absorbed, excreted in urine and bile.• t1/2 11-16hr, duration of action is 24hr.

Astemizole:-• 97% plasma protein bound• t1/2 20hr. Its metabolite t1/2 is 12-19days

• Excretion in faeces.• Used for maintenance therapy.

Uses• Allergic reactions:- effectively control

– immediately type of allergies like itching, urticaria,– Allergic conjunctivitis– Angioedema (DOC glucocorti). – lay fever (2nd G), – symptomatic relief in insect bite

• Pruritides:- first choice of drugs for idopathic pruritides.

• Common cold:- produce symptomatic relief by sedative and anticholinergic actions

Motion sickness:- Promethazine, Dimenhydrinate useful for prophylaxis.

• Used in morning sickness, drug induced and post operative vomiting.

Preanaesthetic medication• promethazine used for its anticholinergic and sedative

action (specially in childrens)

Cough• Chlorpromazine , Diphenhydramine and promethazine are

added to antitussive agents.

Motion Vomiting centre M,H1

Vestibular apparatusM,H1

Cerebellum

Anti cholinergic activity

• Parkinsonism• promethazine used due to anticholinergic activity

and sedative action.

• Acute muscle dystonia• parentral promethazine or hydroxyzine.

• As a sedative, hypnotic, anxiolytic• CNS depressant action

• Vertigo• Cinnarizine widely used

• used to control mild blood transfusion and saline infusion reactions like rigors and chills and adjunct in anaphylaxis.

H2 antagonists

These are over the counter drugs OTC• Mechanism of action:- competitively inhibit H2

receptors cells and suppress basal and food stimulated acid secretions.

• They block the actions of histamine released from ECL

• They inhibit stimulation of parietal cells.• Reduced cAMP levels

Clinical uses:• Peptic ulcer:-

– H2 blockers are one of the commonly used drugs is peptic ulcer.

– H2 blockers produce sympathetic relief within days and ulcer healing with in weeks.

• Zollinger Ellison syndrome: – PPIs are drug of choice, H2 blockers are used to

control hypersecretions.

• GERD:– PPIs are used. H2 blcokers also effective.

• Stress ulcers:- H2 blockers or PPIs are used

• Expect astemazole all are competitive blcokers

• Antihistamines absorbed from gut.• Metabolised by liver• Metabolites are long half life