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Autacoids pharmacology

Reading time: 12 minutes, 6 seconds
Autacoids are also known as local hormones. They are a collective term for various endogenous peptides, prostaglandins, leukotrienes, and cytokines. In other word autacoids are substances with biologic activity that are synthesized at the site of action and exert primarily localized effects.

They are not stored and released from neither gland, nor do they need to circulate to the site of action like "classical" hormones.

They play important roles in physiologic processes and also have several pharmacological significances.

Pathophysiology of Inflammation

❖The initial inflammation phase consists of three subphases:

1. acute,
2. subacute, and
3. chronic (or proliferative).

❖The acute phase typically lasts 1–3 days and is characterized by the five classic clinical signs: heat, redness, swelling, pain, and loss of function.

❖The subacute phase may last from 3–4 days to ~1 mo and corresponds to a cleaning phase required before the repair phase.

❖If the subacute phase is not resolved within ~1 mo, then inflammation is said to become chronic and can last for several months. Tissue can degenerate and, in the locomotor system, chronic inflammation may lead to tearing and rupture.

❖Alternatively, after the subacute inflammatory phase, tissue can repair and be strengthened during the remodeling phase.

In the acute response to tissue injury occurs in the microcirculation at the site of injury.

Initially, there is a transient constriction of arterioles; however, within several minutes, chemical mediators released at the site relax arteriolar smooth muscle, leading to vasodilation and increased capillary permeability.

Protein-rich fluid then exudes from capillaries into the interstitial space. This fluid contains many of the components of plasma including albumin, fibrinogen, kinins, complement, and immunoglobulins that mediate the inflammatory response.

The subacute phase is characterized by movement of phagocytic cells to the site of injury. In response to adhesion, molecules released from activated endothelial cells, leukocytes, platelets, and erythrocytes in injured vessels become sticky and adhere to the endothelial cell surfaces.

Polymorphonuclear leukocytes such as neutrophils are the first cells to infiltrate the site of injury.

Basophils and eosinophils are more prevalent in allergic reactions or parasitic infections. As inflammation continues, macrophages predominate, actively removing damaged cells or tissue. If the cause of injury is eliminated, the subacute phase of inflammation may be followed by a period of tissue repair.

Blood clots are removed by fibrinolysis, and damaged tissues are regenerated or replaced with fibroblasts, collagen, or endothelial cells.

During the remodeling phase, the new collagen laid down during the repair phase (mainly type III) is progressively replaced by type I collagen to adapt to the original tissue.

However, if inflammation becomes chronic, further tissue destruction and/or fibrosis occurs.

Factors involved in the inflammatory response

A. Increased blood flow and vascular permeability

It produces redness, heat and swelling at the site of inflammation

B. Production of Chemical Mediators

1) Vasoactive amines - produce an immediate response to tissue damage - histamine and serotonin

2) The kinnin system - bradykinnin - the most potent vasodilator; increases permeability of veinoules, increases sensitivity to pain

There are two types of receptors B1 and B2 receptors; B1 are induced by inflammation.

3) Arachadonic acid derivatives - products of cyclooxygenase and lipoxygenase pathways: prostaglandins, prostacyclin, throboxane, leukotienes

4) The Complement system - complement can be directly involved in cell/tissue damage.

C. Leukocyte chemotaxis/phagocytosis

1) migration of large numbers of white blood cells to the site of the injury

2) Release of lysosomal enzymes

D. Nitric Oxide (NO) is produced by the conversion of arginine to citrulline by nitric oxide synthase (NOS)

- NO produced from endothelial cells causes vasodilation
- NO may protect against inflammation by scavenging free radicals
-NO may mimic the cytoprotective effects of prostaglandins in the gastric mucosa
- NO that increases inflammatory cytokines
- NO released during airway inflammation

E. Immune Response

1) Humoral - antigens produced to host tissues.
2) Cellular - Tissue toxicity from cytolytic T cells. - Delayed hypersenstivity reactions

1. Histamine

It is a potent tissue amine widely distributed in plant and animal tissues and in the venoms of bees.
In man, it is formed by decarboxylation of histidine and major portion is stored in mast cells and basophils.

Mechanisms of Action:

Histamine acts on 2 major types of receptors

a. Stimulation of H1 receptors results in smooth muscle contraction, increased vascular permeability, and mucus production.
These effects are blocked competitively by H1 antagonists.

b.Activation of H2 receptors increases gastric acid production, and this effect is blocked by H2 blockers such as cimetidine.
Both types of receptors are involved in vascular dilatation and edema formation.

Pharmacological Actions:

1. Cardiovascular system
Histamine produces dilatation of capillaries and venules accompanied by a fall in blood pressure. The mechanism is direct relaxation of the smooth muscles of blood vessels.This effect cannot be adequately reversed by antihistaminic agents but by adrenaline.
It also has positive inotropic and chronotropic actions on the heart, impairs AV conduction, and increases coronary blood flow.

2. Smooth Muscles:
Histamine directly stimulates the smooth muscles of various tissues including the bronchi and uterus. Histamine-induced bronchospasm is effectively antagonized by adrenaline.

3. Exocrine Glands:

It is a powerful stimulant of HCl secretion by the gastric mucosa.

4. CNS:

Histamine is formed locally in the brain and is believed to be a “waking amine”, acting by “increasing the sensitivity of large cerebral areas to excitation inputs”

5. Miscellaneous actions include induction of itching and pain.
Histamine has no valid therapeutic use currently. But it plays very important role in anaphylaxis and other forms of allergic reactions.
Its release may be induced by various agents including certain venoms, drugs, trauma (thermal, chemical, radiation), and antigenantibody reactions.

Pathophysiological roles

1. Gastric secretions. Mediates secretion of HCL in the stomach.

2. Allergic phenomenon. Mediates hypersensitivity reactions.

However othe mediators are also involved. Causes urticaria, angioedema, bronchoconstriction and anaphylactic shock. H1 antagonists can effectively control these except asthma and hypotension.

3. As transmitter- It is the afferent transmitter which initiates the sensation of itching and pain at sensory nerve endings.
Non mast cells in the brain contain Histamine and is involved in maintaining wakefulness. H1 antagonists block this function and hence the sedative effect. Histamin also is a transmitter that regulates body temperature, cardiovascular function, thirst etc

4. Inflammation. Mediator of vasodilation and other changes that occur during inflammation.

5. Tissue growth and repair. Growing and regenerating tissues contain high levels of histamine and may play a role in the process of growth and repair.

6. Headache. Implicated in certain vascular headaches.

Pathophysiological roles

Histamine releasers: variety of mechanical, chemical and immunological stimuli cause release of histamine from mast cells.

1. Tissue damage- stings, venoms, trauma
2. Antigens
3. Polymers eg Dextran, PVP
4. Some basic drugs eg Tubocurarine, morphine,
5. Surface acting agents eg Tween 80.

Betahistine;

Orally active H1 selective histamine analogue.
Used in treatment of Meniere’s disease caused by vasodilation in inner ear.

Treatment of Anaphylaxis

1. Exposure to the offending agent should be terminated.

2. Adrenaline has actions opposite to those of histamine and thus acts as a physiological antagonist. It may be given by SC or IM route.

3. Hypotension should be corrected with the infusion of intravenous fluids.

4. Corticosteroids are occasionally used.

5. Other supportive measures include administration of oxygen and artificial respiration if necessary.

N.B. Antihistaminic drugs are not able to counteract the hypotension and brochospasm characteristic of anaphylactic shock.

Qualitatively, all H1 antihistaminics have similar actions, but there are quantitative differences esp in the sedative property.

These drugs competitively block histamine receptors and are of two types:

1. H1 receptor antagonists

2. H2 receptor antagonists (used in the treatment of acid-peptic disease)

H1 Receptor Antagonists

Classification of H1 receptor antagonists:

1. Potent and sedative: such as diphenhydramine and promethazine.
2. Potent but less sedative: such as cyclizine and chlorpheniramine
3. Less potent and less sedative: such as pheniramine
4. Non-sedative: such as terfenadine, loratadine, and cetrizine.

The newer generation agents are relatively free of central depressant effects.

Pharmacological Actions:

1. Antihistaminic Actions:-they block histamine effects at various sites.

2. Other Effects: are independent of the antihistaminic effects and vary widely according to the drug used.

Most of them produce CNS depression resulting in sedation, drowsiness, inability to concentrate, and disturbances of coordination.

But very few agents such as phenindamine may produce stimulation.

Anti-motion sickness effects are exhibited by promethazine, diphenhydramine, and dimenhydinate.

Promethazine and mepyramine have significant local anesthetic effect.

Majority possess atropine-like effects.

Some have central antimuscarinic actions which is useful in the treatment of Parkinsonism.

Pharmacokinetics:

They are well-absorbed following oral and parenteral administration.

And are mainly metabolized by the liver; degradation products are removed in the urine.

Therapeutic Uses:

1. Allergic Disorders:-Including urticaria, seasonal hay fever, atopic and contact dermatitis, mild blood transfusion reactions.
N.B. Their topical use is not recommended because of the risk of sensitization and a high tendency to cause eczematous reactions.
They are not effective in bronchial asthma and common cold.

2. Other uses:
Diphehydramine and promethazine are used as hypnotics.
Diphenhydramine and orphenadrine are effective in the treatment of Parkinsonism .

Dimehydrinate and promethazine are employed in the prevention and treatment of motion sickness, other vomiting disorders associated with labyrinthine dysfunction as well as nausea and vomiting associated with pregnancy.

Diphenhydramine is frequently used in the treatment of cough as combination preparation with other agents.

Adverse Effects:

-Are usually mild.
-Most common is sedation.
-The most common anticholinergic adverse effect is dryness of the mouth.
-They may themselves occasionally cause allergic reactions.

Second generation antihistamines Properties:

Higher H1 selectivity

Absence of CNS depressant property

Additional antiallergic mechanisms apart from histamine blockade

Indications

Allergic rhinitis, conjuctivitis, hay fever

Urticaria, atopic eczema

Acute allergic reactions to drugs and food.

They have poor antitussive, antiemetic and antipruritic activities.

They include:

Fexofenadine, Loratadine, Desloratadine, Cetirizine, levocetirizine, azelasine, Ebastine,Rupatadine.

Inhibitors of mast cell degranulation and histamine release

Cromolyn sodium - prophylaxis for asthma believed to inhibit calcium influx

Nedocromil - mechanism similar to cromolyn
Lodoxamide tromethamide - prevents antigen-induced calcium influx into mast cells that causes histamine release. Used topically for inflammatory diseases of the eye.

5-Hydroxytreptamine (Serotonin)

It is widely distributed in plants and animals. It is found in wasp and scorpion sting. Highest concentration in mammals is found in the pineal gland, acting as a precursor for melatonin.

Synthesis, Storage and destruction

It is synthesized from the amino acid tryptophan and acts on several types of receptors.
Degraded by MOA primarily and a dehydogenase to a smaller extent.

5-HT is actively taken up by an amine pump into platelets and at serotonergic nerve endings..

This is inhibited by selective serotonin reuptake inhibitors and tricyclic antidepressants. It is stored within vesicles.

Pharmacological Actions:
5-HT causes constriction of renal, splanchnic, meningeal, and pulmonary arteries and veins and venules, but dilatation of the blood vessels of skeletal musles, coronaries, and skin capillaries.

It has weak direct iono-chronotropic effect on the myocardium.

It also stimulates smooth muscles, especially of the intestines.

Serotonin is widely distributed in the CNS, serving as a Neurotransmitter.

Altered functions may be responsible for disturbances in sleep, mood, sexual behavior, motor activity, pain perception, migraine, temperature regulation, endocrine control, psychiatric disorders and extra-pyramidal activity.

Inhibits gastric secretion but increases mucus production.

Precusor of melatonin in pineal gland- regulates the circadian rhythm

Nausea and vomiting esp evoked by cytotoxics or radiotherapy is mediated by release of 5HT

Serotonin Agonists:

Sumatriptan is a selective agonist of 5-HT1 receptors and is highly effective in treating acute attacks of migraine, but is not useful in the prevention.

It relieves the nausea and vomiting, but the headache may recur, necessitating repeated administrations.

It is administered orally or by the subcutaneous route.

The bioavailability of oral dose is only 14%; thus, the oral dose is several times larger than the subcutaneous dose.

Adverse effects include flushing and heat at the injection site, neck pain, dizziness, and tingling of the hands.

The drug is contraindicated in symptomatic ischemic heart diseases, angina, and hypertension as it may cause coronary vasoconstriction.

Rizatriptan is a derivative of sumatriptan. It is more potent, has a higher bioavailability with faster onset of action.

Buspirone, another serotonin agonist, is a useful effective anxiolytic agent.

Serotonin Antagonists:

a. Methysergide: blocks the actions of 5-HT on a variety of smooth muscles. It also has a weak direct vasoconstrictor effect.

It is an effective prophylactic agent for migrainous headaches. But has no effect in treating acute attacks, even may worsen the condition.
Adverse reactions include gastrointestinal irritation, drowsiness, vertigo, and psychic disturbances.

b. Cyproheptadine: is a potent antagonist of 5-HT and to a smaller extent of histamine and acetylcholine. It stimulates appetite probably by acting directly on the hypothalamus. It can block the release of hydrocortisone, and the production of aldosterone. It is mainly used to relieve the itching associated with skin disorders such as allergic dermatitis. The common adverse reaction is drowsiness.

c. Ondansetron: is specific 5-HT3 receptor antagonist.

Given orally or intravenously, it is useful in the management of nausea and vomiting associated with cytotoxic therapy.
Adverse reactions include headache, constipation, and allergic reactions.

d. Prochlorperazine and haloperidol have anti-5-HT activity and are sometimes used for resistant acute attacks.

3. Prostaglandins:

Biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids released from membrane phospholipids.

They were named so because of their presumed origin from the prostate gland. Human seminal fluid is the richest known source, but they are also present in various tissues.

The prostaglandins are synthesized from polyunsaturated fatty acids at their sites of action.

PG E2 and PG F2 are the two main prostaglandins.
They are released in the body by mechanical, chemical, and infectious insults.

They play an important role in the development of the inflammatory response in association with other mediators.

Pharmacological Actions:

a. Smooth muscle:
Most stimulate myometrium and are known to be important in the initiation and maintenance of labor.
Prostaglandin E has bronchodilator action.

b. GIT:

They increase intestinal motility. PG E inhibits gastric acid secretion and has cytoprotective action on the gastroduodenal mucosa. Both PG E and F produce contraction of the longitudinal muscle of the gut.
They also stimulate intestinal fluid secretion, resulting in diarrhea.

c. CVS:
PGE is peripheral vasodilator and powerful natriuretic.
PGF constricts arterioles and veins.

d. Platelets:
Thromoboxane causes platelet aggregation and vasoconstriction. PG I (prostacycline) is found in the vascular endothelium and is a potent inhibitor of platelet aggregation and is a vasodilator.

e. Miscellaneous:
Prostaglandins are important in pain generation and perception. PGE and PGI produce hyperalgesia associated with inflammation. In addition, PG E is a potent pyrogenic substance

Natural prostaglandins have no therapeutic application because of short duration of action, but their derivatives such as carboprost, dinoprostone and misoprostol find clinical application.

Therapeutic uses include cervical ripening and labor induction, control of postpartum hemorrhage, induction of abortion, and prophylaxis of NSAID-induced peptic ulcers. They are also finding several other uses more recently such as erectile dysfunction, glaucoma, etc.
Adverse Effects include fever, diarrhea, abdominal cramps, headache, nausea, and vomiting.


Post References

  • Atlas of pharmacology, Lange textbook of basic and clinical pharmacology, NCBI, PubMed

  • Revised on: 2021-07-03 13:56:43