AUTACOIDS

GENERAL INFORMATION

•Autos = self Akos = healing substance

- inflammatory and immunological reactions

- transmitters in nervous system.

Types-

• Amines –histamine, serotonin

• Lipids –PG ,LT, PAF

• Peptides –bradykinins, angiotensin

• Others –TNFα ,Gastrin,somatostatin ,intestinal peptide

HISTAMINE TISSUE AMINE

•Mast cells –storage 

           Ex --Skin lungs liver gastric mucosa placenta

• Nonmast cell –

1) brain epidermis gastric mucosa and growing

regions

2) blood ,most body secretions,venoms and

pathological fluids .

• Synthesis – amino acid histidine locally

* Histamine liberation 

Venoms (insect/reptile bites)

Food products (crabs, lobsters, fish)

Trauma due to cold, chemical, thermal, radiant energy

Antigen antibody reactions

Drugs: d-tubocurarine,morphine, pethidine, amphetamine

HISTAMINE RECEPTORS

G Protein coupled -- H1 , H2

• H3 - only in brain

• H4

• By convention antihistaminic drugs = H1 blockers ..

• competitively block histamine receptors

BODY DISTRIBUTION OF H1 AND H2 AND ACTIONS MEDIATED

➡ H1

 1) Smooth muscles of intestine airway,uterus,blood vessels=contraction ---bronchospasm

• Increased secretions –saliva and mucus

2) blood vessels –endothelium = release of EDRF,NO=

vasodilatation ,hypotension,↑ capillary permeability ,oedema

• Histamine dilates arterioles, capillaries and venules

• Triple response reaction—inj intradermally— wheal,flare,

flush

3) afferent nerve endings = stimulation------itch and pain

4) brain =transmitter ---wakefulness and some other

functions

➡H2

1) gastric glands =acid secretion

2)smooth muscles of blood vessels =dilatation

3) heart atria =+ve chronotrophy heart ventricles =+ve ionotrophy

4) uterus = relaxation

5) brain = transmitter

PATHOPHYSIOLOGICAL ROLE

 1) Gastric secretion = H2

 2) allergy =[ H1] AG: AB reaction

                        ↓Mast cell

                histamine

                        ↓

 urticaria , angioedema, bronchoconstriction,anaphylactic shock

 Histamine is not involved in delayed /retarded type of allergy

3)role as transmitter =

 a) at sensory nerve endings –itch and pain

 b) In brain it is involved in maintaining wakefulness (H1) and some other functions

 4) inflammation = vasodilatation

*H1 ANTIHISTAMINICS -MOA

Competitive antagonism of H1 R

Effects seen-- Anti allergic

Anticholinergic

Anti inflammatory

CNS depression

Local anaesthetics

CLASSIFICATION –

1) Conventional/traditional/first generation antihistaminics

a) highly sedative --

b) moderately sedative

c)mild sedative

They have some action on cholinergic alpha adrenergic and

serotonin R –base for some clinical uses

2) second generation antihistaminics –highly selective for H1

H1 blockers

OLDER/CLASSICAL/TRADITIONAL/1st Gen

🔸MOST SEDATIVE and potent: 25-50 mg

Diphenhydramine ( Benadryl)

Dimenhydrinate ( Dramamine)

Promethazine (Phenergan)

(phenothiazine structure-chlorpromazine)

Hydroxyzine Atarax

🔸Moderate sedative, moderate potent

Pheniramine Avil 25-50 mg

Antazoline Antistine 50-100 mg

Cyproheptadine Ciplactin/periactin/peritol

Meclizine Ancolan 25-50 mg

Buclizine Longifene 25-50 mg

🔸Mild sedative, less potent

Chlorpheniramine Zeet/Piriton 2-4 mg

Dimethindone Foristal 1 mg

Mebhydroline Incidal 100 mg

Clemastine Tavist 1-2 mg

2nd generation/newer

Mainly antiallergic/usual uses

Terfenadine Terfed/Terin 30-60mg

Antivertigo, antimigraine (Weak Ca blockers)

CINNARIZINE Stugeron 25-50mg

FLUNNARIZINE Flunarine/Simentil/Sibelium 5-10mg

Marketed after 1980

properties –

1) absence of CNS depressant property /less sedating –

Psychomotor performance is NoT affected

Less subjective effect on sleep

Don’t potentiate alcohol or benzodiazepine drugs

BBB XX

2) higher H1 selectivity -no

anticholinergic side effects -dryness of mouth ,

blurring of vision

Flip side –narrow spectrum of therapeutic use

3) additional anti allergic mechanisms

• Mainly used in allergic conditions including food and drug allergy

• low antipruritic antiemetic and antitussive action

CLINICAL USES

--due to their

1) ability to block effects of endogenously released histamine

2) sedative property

3) anticholinergic property

Anti hitaminics are ineffective in bronchial asthma

• Because

• Low concentration of antihistaminics in bronchi

insufficient to block histamine released locally

• Leukotrienes and PAF are more important mediators than histamine

USES

1. Allergic disorders –symptomatic relief in acute allergy such as itching skin rash urticaria seasonal hay fever allergic conjunctivitis angioedema of lips and eyelids.

symptomatic relief in insect bite and ivy poisoning.

Prophylactic value in infusion induced rigor Idiopathic pruritis : gen 1

2 ) Common cold : relief by anticholinergic and sedative action . Anticholinergic property reduces nasal secretion : Gen 2 less effective

3.Motion Sickness : Promethazine etc. Should be taken

1 hr before for prophylaxis. Promethazine – morning sickness, drug induced vomiting, post operative vomiting

4.Vertigo : cinnarizine ( vertigon). Cinnarizine has additional anticholinergic, anti 5HT, sedative, vasodilator properties. It inhibits vestibular sensory nuclei in inner ear

5. Pre Anaesthetic medication : Promethazine -anticholinergic, sedative property especially in children

6. Cough : gen 1 gr 1. anticholinergic, sedative property . 

They have no selective cough suppressant action

• As sedative, hypnotic, anxiolytic

• Pre-anesthetic medication-promethazine- postop

vomiting

• Drug-induced dystonia, PARKINSONISM –

• Promethazine orphenadrine

• Most are atropine substitutes:Benzhexol,

benztropine, cycrimine, procyclidine, biperiden, diphenhydramine

• Vertigo-migraine- CINNARIZINE, FLUNNARIZINE

• Lytic cocktail (To produce hypothermia during

surgery) (promethazine, chlorpromazine, pethidine)

Uses – newer/2nd generation

• Anti-allergic – for allergic conditions like-

• Rhinitis conjunctivitis hay fever pollinosis

• Atopic eczema,urticaria –cetrizine drug of choice

• Drug allergy food allergy

• -fexofenadine–loratadine-desloratadine-levocetrizine

• Anti-vertigo, anti-migraine

• (also anti-5HT action)

• (weak ca channel blocking action) - flunarizine, cinnarizine

• Vertigo, Migraine, Ménière's disease

Adverse effects

 ONLY SEEN WITH OLDER /first gen– cross BBB

 Sedation, decreased alertness and conc, motor

incoordination, psychomotor performance impairment

 Regular use of conventional group is NOT advisable in children as CNS depressant property may affect learning

 Skillful acts – drivers/machine operators

 Long term – increased appetite, weight gain (also 5HT

blockade)

 SYNERGISM with CNS depressants (alcohol, sedative hypnotics)—additive toxicity

 Hypotension-alpha blockade

 These are MINIMAL WITH NEWER agents

 ( X BBB)

 Anti Cholinergic adverse effects- dryness, urinary

hesitancy, retention, constipation, blurring vision

 Acute overdose leads to features like belladona poisoning– tremors, convulsions, fall in blood pressure,fever , hallucinations

Management – PHYSOSTIGMINE –crosses blood brain barrier

Sodium bicarbonate – Intravenous