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1. Autacoids & related drugs
Dr. Karun Kumar
Senior Lecturer
Dept. of Pharmacology

2. Autacoids
• This term is derived from Greek  autos—self,
akos—healing substance or remedy
• These are
1. Diverse substances
2. Produced by a wide variety of cells in the body
3. Have intense biological activity
4. Act locally (e.g. within inflammatory pockets) at the
site of synthesis and release

3. • They have also been called ‘local hormones’.
• However, they differ from ‘hormones’ in two
important ways
1. Hormones are produced by specific cells
2. Are transported through circulation to act on
distant target tissues

4. Types of autacoids
1. Amine autacoids  Histamine, 5-
Hydroxytryptamine (Serotonin)
2. Lipid derived autacoids  Prostaglandins,
Leukotrienes, Platelet activating factor
3. Peptide autacoids  Plasma kinins (Bradykinin,
Kallidin), Angiotensin
4. Cytokines (interleukins, TNFα, GM-CSF, etc.) and
several peptides like gastrin, somatostatin,
vasoactive intestinal peptide

5. Histamine
• Histamine, meaning ‘tissue amine’ (histos—tissue) is
almost ubiquitously present in animal tissues and in
certain plants
• Histamine is present mostly within storage granules
of mast cells
• Tissues rich in histamine are skin, gastric and
intestinal mucosa, lungs, liver and placenta
• Nonmast cell histamine occurs in brain, epidermis,
gastric mucosa

7. • Histamine is formed when the amino acid histidine is
decarboxylated in a reaction catalyzed by the enzyme
l–histidine decarboxylase
• Histamine is stored in granules (vesicles) in mast cells
and basophils until it is released
• It is released from mast cells when membrane-bound
immunoglobulin E (IgE) interacts with an IgE antigen
to cause mast cell degranulation

12. Pathophysiological roles
1. Gastric secretion  Histamine mediates secretion
of HCl in the stomach
2. Allergic phenomena  Released from mast cells
following AG : AB reaction
3. As transmitter  Afferent transmitter which
initiates the sensation of itch and pain at sensory
nerve endings.
4. Inflammation  Mediator of vasodilatation

14. Classification
1. Highly sedative
1. Diphenhydramine
2. Dimenhydrinate
3. Promethazine
2. Moderately sedative
1. Pheniramine
2. Meclozine (Meclizine)
3. Cinnarizine

15. 3. Mild sedative
1. Chlorpheniramine
2. Dexchlorpheniramine
3. Triprolidine
4. Second generation antihistaminics
1. Fexofenadine
2. Loratadine
3. Desloratadine
4. Cetirizine
5. Levocetirizine

16. H1 antagonists (1st gen.)
1. Antagonism of histamine  Block histamine
induced bronchoconstriction, contraction of
intestinal and other smooth muscle and triple
response—especially wheal, flare and itch
2. Antiallergic action  Many manifestations of
immediate hypersensitivity (type I reactions) are
suppressed. Urticaria, itching and angioedema are
well controlled
3. CNS  The older antihistamines produce variable
degree of CNS depression

21. 4. Anticholinergic action
5. BP  Most antihistaminics cause a fall in BP on i.v.
injection (not evident on oral administration)

22. Uses
1. Allergic disorders  Antihistaminics do not
suppress AG: AB reaction, but block the effects of
released histamine—are only palliative. They
effectively control certain immediate type of
allergies, e.g. itching, urticaria, seasonal hay fever,
allergic conjunctivitis and angioedema of lips,
eyelids, etc.
• Some skin rashes also respond

23. 2. Other conditions involving histamine  They afford
symptomatic relief in insect bite and ivy poisoning
• Abnormal dermographism is suppressed
• They have prophylactic value in blood/saline infusion
induced rigor.
3. Pruritides  Though relief is often incomplete, older
antihistaminics Chlorpheniramine, Diphenhydramine,
remain the first choice drugs for itching
4. Common cold  Afford symptomatic relief by
anticholinergic (reduce rhinorrhoea) and sedative
actions

25. 5. Motion sickness  Promethazine, Diphenhydramine,
Dimenhydrinate and Meclizine have prophylactic value
in milder types of motion sickness; should be taken one
hour before starting journey
• Promethazine can also be used in morning sickness,
drug induced and postoperative vomiting
6. Vertigo  Cinnarizine inhibits vestibular sensory
nuclei in the inner ear, possibly by reducing stimulated
influx of Ca2+ from endolymph into the vestibular
sensory cells
• Dimenhydrinate is also used

26. 7. Preanaesthetic medication  Promethazine has
been used for its anticholinergic and sedative
properties
8. Cough  Antihistaminics like Chlorpheniramine,
diphenhydramine and promethazine are constituents
of many popular cough remedies
9. Parkinsonism  Promethazine and some others
afford mild symptomatic relief in early cases—based on
anticholinergic and sedative property

27. 10. Acute muscle dystonia  Caused by antiemetic-
antipsychotic drugs is promptly relieved by parenteral
promethazine, diphenhydramine or hydroxyzine
11. As sedative, hypnotic, anxiolytic  Antihistamines
with CNS depressant action have been used as sedative
and to induce sleep. Promethazine has produced
serious respiratory depression in young children; it is
contraindicated in children aged 2 years or less

28. Side effects
1. Most common  Sedation, diminished alertness
and concentration, light headedness, motor
incoordination, fatigue and tendency to fall asleep
are the most common, impairment of psychomotor
performance
• Patients should be cautioned not to operate motor
vehicles or machinery requiring constant attention
2. Dryness of mouth, alteration of bowel movement,
urinary hesitancy and blurring of vision 
anticholinergic property
3. Epigastric distress and headache may be felt
• Local application can cause contact dermatitis

30. Second generation antihistaminics
1. Absence of CNS depressant property.
2. Higher H1 selectivitiy: no anticholinergic side
effects.
3. Additional antiallergic mechanisms apart from
histamine blockade
• They have poor antipruritic, antiemetic and
antitussive actions

31. Indications
1. Allergic rhinitis and conjunctivitis, hay fever,
pollinosis—control sneezing, runny but not blocked
nose, and red, watering, itchy eyes
2. Urticaria, dermographism, atopic eczema
3. Acute allergic reactions to drugs and foods

33. 5-Hydroxytryptamine
• Serotonin was the name given to the vasoconstrictor
substance which appeared in the serum when blood
clotted and was shown to be 5-hydroxytryptamine
(5-HT)
• About 90% of body’s content of 5-HT is localized in
the intestines; most of the rest is in platelets and
brain

36. Actions
1. Constriction of larger arteries and veins but
dilatation of arterioles
2. Enhanced peristalsis and secretion in gut causing
diarrhoea
3. Inhibition of gastric acid and pepsin secretion
(ulceroprotective)
4. Proaggregatory action on platelets
5. Activation of afferent nerve endings 
Tingling/Pricking sensation, pain

37. Pathophysiological roles
1. Neurotransmitter in brain; involved in sleep,
temperature regulation, cognitive function,
behaviour and mood, vomiting and pain perception
2. Regulation of gut peristalsis
3. Precursor of melatonin in pineal gland (Regulation
of biological clock)
4. Control of anterior pituitary hormones function by
hypothalamus
5. Nausea and vomiting (Cancer chemo/radiotherapy)

38. 6. Migraine  Involved in initiating constriction of
cranial vessels
7. Haemostasis  By promoting platelet aggregation
and blood vessel retraction
8. Vasospastic disorders like Raynaud’s phenomenon
and variant angina
9. Carcinoid syndrome  5-HT mediated bowel
hypermotility and bronchoconstriction

39. Lipid derived autacoids
• Prostaglandins (PGs) and Leukotrienes (LTs) are
biologically active derivatives of 20 carbon atom
polyunsaturated essential fatty acids that are
released from cell membrane phospholipids
(Eicosanoids)

41. Cyclooxygenase (COX) - 1
• Constitutive enzyme in most cells
• “House keeping” enzyme
1. Secretion of mucus for protection of gastric mucosa
2. Haemostasis
3. Maintenance of renal function

42. Cyclooxygenase (COX) - 2
• “Inducible” by
1. Cytokines,
2. Growth factors, and
3. Other stimuli during inflammatory response
• Participates in inflammation
• Constitutively present in kidney and brain

43. Lipoxygenase (LOX)
• Pathway
operates in
1. Lung
2. Leucocytes
(WBCs)
3. Blood
(Platelets)

44. Biosynthesis of PGs and LTs
Annexins

45. Inhibition of synthesis
• Synthesis of COX products can be inhibited by
nonsteroidal anti inflammatory drugs (NSAIDs)
• Aspirin acetylates COX and causes irreversible
inhibition while other NSAIDs are competitive and
reversible inhibitors
• Most NSAIDs are nonselective COX-1 and COX-2
inhibitors, but some later ones like Celecoxib,
Etoricoxib are selective for COX-2

46. Degradation
• Biotransformation of arachidonates occurs rapidly in
most tissues (fastest in the lungs)
• Most PGs, TXA2 and prostacyclin have plasma t½ of a
few seconds to a few minutes
• A specific carrier mediated uptake into cells occurs,
side chains are oxidized & double bonds are reduced
in a stepwise manner to yield inactive metabolites
• Metabolites are excreted in urine
• PGI2 is catabolized mainly in the kidney

47. Pathophysiological roles
1. PGI2  Regulation of local vascular tone (dilator)
2. PGE2  Continuously produced in the ductus
arteriosus during fetal life (keeps it patent). At birth,
their synthesis stops and closure occurs. Aspirin and
indomethacin have been found to induce closure
3. PGs along with LTs and other autacoids may
mediate vasodilatation and exudation at the site of
inflammation
4. TXA2 and PGI2 constitute a mutually antag. system

48. Importance of PGs & LTs
PGE2

49. Aspirin
• NSAID with analgesic, antipyretic, & anti-
inflammatory effects
• Inhibits platelet aggregation & used to prevent
and treat arterial thromboembolic disorders
• Prostacyclin (PGI2)  Vasc. Endoth. & inh. P.a.
• TXA2  Platelets & promotes platelet aggreg.
• Low doses of aspirin  Sel. Inh. TXA2 synth.
• Higher doses  Inhibit the synthesis of both

51. Aspirin
• TXA2 produced by platelet COX-1 amplifies platelet
aggregation
• Aspirin is an irreversible inhibitor of COX and
decreases the synthesis of both TXA2 and PGI2
• After some time, endothelial cells produce new COX
enzyme (contains nucleus) whereas platelets due to
lack of nucleus cannot produce TXA2  Net effect is
platelet anti aggregatory activity
• Aspirin is only NSAID in MI prophylaxis

54. Why low dose Aspirin ?
• At low dose, Aspirin selectively inhibits COX-1 in
platelets in the portal circulation (by acetylation)
• The compound which leaves the portal circulation is
salicylic acid which is unable to inhibit COX enzyme in
endothelium
• If a high dose is given, the compound leaving the
portal circulation may contain active acetyl salicylic
acid which can interfere with anti-platelet action by
inhibiting PGI2 synthesis in endothelium

56. 5. PGs produced by fetal tissues at term mediate
initiation and progression of labour. Aspirin has been
found to delay the initiation of labour.
6. Dysmenorrhoea in many women is due to uterine
cramps and ischemia induced by ↑ PG synthesis in
endometrium (NSAIDs help in relieving it)
7. PGs may be involved in mediating toxin induced ↑
fluid movement in secretory diarrhoeas. PGs appear to
play a role in growth of colonic polyps and cancer.
Regular intake of low dose Aspirin lowers incidence of
colon cancer.

57. 8. PGs (esp. PGI2) may be functioning as natural ulcer
protectives by enhancing gastric mucus and
bicarbonate production as well as by improving
mucosal circulation. The ulcerogenic action of NSAIDs
may be due to loss of this protective influence.
9. NSAIDs tend to retain salt and water (Blunt action of
Furosemide)
10. PGE2 mediate bacterial or other pyrogen induced
fever. Aspirin and other NSAIDs (antipyretic)

58. 11. PGs (esp. PGE2 and PGI2) sensitize afferent nerve
endings to pain inducing chemical and mechanical
stimuli
12. PGF2α lowers i.o.t. by enhancing uveoscleral and
trabecular outflow of aqueous humor. Latanoprost is 1st
line drug for open angle glaucoma

60. Leukotrienes
• LTB4  neutrophils; LTC4 and LTD4  macrophages
1. CVS and blood  LTC4 and LTD4 injected i.v. evoke a
brief ↑ in BP followed by ↓
• LTB4  Chemotactic for T-lymphocytes, neutrophils
& monocytes
• LTC4 and LTD4  Chemotactic for eosinophils
• Role  Mediators of inflammation, greater role in
chronic inflammatory states

61. 2. Visceral smooth muscle  LTC4 & D4 contract most
smooth muscles
• Bronchoconstrictors & induce spastic contraction of
g.i.t. at low conc.
• ↑ mucus secretion in airways
• Role  The cysteinyl LTs (C4 and D4) are the most
important mediators of human allergic asthma LTs
• Also responsible for abdominal colics during systemic
anaphylaxis

62. 3. Afferent nerves  Like PGE2 and I2 , LTB4 also
sensitizes afferents carrying pain impulses
↓
Pain and tenderness of inflammation

63. Prostanoid receptors
• 5 prostanoid receptors have been designated, each
after the natural PG for which it has the greatest
affinity
• DP (for PGD2), EP (for PGE2) FP (for PGF2α), IP (for
prostacyclin or PGI2) and TP (for TXA2)
• All prostanoid receptors are GPCRs which utilize the
IP3/DAG or cAMP transducer mechanisms.

64. 1. ‘Excitatory’ group (EP1, FP, TP)  Smooth muscle
contraction, platelet aggregation, etc
2. ‘Relaxant’ group (DP1, EP2, EP4, IP)  Smooth
muscle relaxation, inhibition of platelet aggregation
3. ‘Inhibitory’ group (EP3)  Inhibits lipolysis

65. 3
i

66. LEUKOTRIENE RECEPTORS
• Function through the IP3/DAG transducer
mechanism
• The cys LT1 receptor is expressed in bronchial and
intestinal muscle
• cys LT1 receptor antagonists (Montelukast,
Zafirlukast)  Bronchial asthma

67. LTR antagonists

68. Classification of PGs
1. Natural
1. Dinoprostone (PGE2) 2. Gemeprost
3. Dinoprost (PGF2α) 4. Alprostadil (PGE1)
5. Prostacyclin (PGI2)
2. PG analogues
1. Carboprost
2. Misoprostol
3. Latanoprost
4. Bimatoprost

69. Uses of PGs
1. Abortion  Single oral dose of Misoprostol after 2
days of Mifepristone (antiprogestin) priming is used
to terminate pregnancy of upto 7 weeks duration.
Extra or intra amniotic injection of PGE2 or PGF2α
can be used for 2nd trimester abortion
2. Induction/augmentation of labour  Intravaginal
PGE2 or PGF2α are alternatives to i.v. Oxytocin but
less reliable

70. 3. Cervical priming (ripening)  Low doses of PGE2
applied in cervical canal/vagina make the cervix soft
and more compliant for delivery/abortion
4. Postpartum haemorrhage (PPH)  Carboprost (15-
methyl PGF2α) i.v. is an alternative drug to Ergometrine
or Oxytocin
5. Peptic ulcer  Misoprostol (PGE1 analogue) can be
used for healing NSAID associated peptic ulcer
6. Glaucoma  Topical PGF2α analogues like
Latanoprost, Travoprost, Bimatoprost are the first
choice drugs in wide angle glaucoma