Lipid derived autacoids

The 3 main groups of Lipid derived autacoids or arachidonic acid metabolites are:

1. Prostaglandins (PG)
2. Leukotrienes (LT)
3. Platelet activating factor (PAF)

• An essential fatty acid is one that cannot be formed in body. It must be obtained from the diet. the essential fatty acids required are:
  • Eicosatrienoic acid – 3
  • Eicosatetraenoic acid – 4
  • Eicosapentaenoic acid – 5

Arachidonic acid is not a circulating compound, nor does it have any intrinsic biological activity. Arachidonic acid is incorporated into phospholipids, which make up the membranes of all cells. Hence, arachidonic acid is present in all cells of the body.

The first step in the metabolism of arachidonic acid is the removal of it from the phospholipid. This step is done by phospholipase A₂ or C.

Eicosanoids

Eicosanoids and modified phospholipids like platelet activating factor are two distinct families of lipid derived, autacoids. This group includes prostaglandins, prostacyclin, thromboxane A₂ and leukotrienes. They are called as eicosanoids because they are derived from 20 carbon essential fatty acids that contain three, four or five double bonds.

Biosynthesis of eicosanoids

Prostaglandins may be considered as derivatives of prostanoic acid, though prostanoic acid does not naturally occur in the body. Leukotrienes are named so because they were first obtained from leukocytes.

Eicosanoids are the most universally distributed autacoids in the body. Practically every cell and tissue is capable of synthesizing one or more types of prostaglandins or leukotrienes.

There are no preformed stores of prostaglandins and leukotrienes. They are synthesized locally at rates governed by the release of arachidonic acid from membrane lipids in response to appropriate stimuli.

These stimuli activate hydrolases including phospholipase A₂, probably through increased intracellular Ca^++.

The cycloxygenase (COX) pathway generates eicosanoids with a ring structure (PGs, TXs, prostacyclin) and lipoxygenase (LOX) produce open chain compounds (LTs).

All tissues have COX – can form cyclic endoperoxides PGG₂ and PGH_2, which are unstable compounds. PGE₂ and PGF_2α are the primary prostaglandins. PGs A, B and C are not found in the body.

They are artifacts formed during extraction procedures. Lung and spleen can synthesize the whole range of cycloxygenase products. Platelets primarily synthesize TXA₂  which is  chemically unstable, spontaneously changes to TXB₂.

Vessel wall mainly generates prostacyclin (PGI₂), also chemically unstable. Cycloxygenase exists in two forms – COX₁ and COX₂.

Eicosanoids produced by COX₁ participate in physiological functions such as secretion of mucus for protection of gastric mucosa, homeostasis and maintenance of renal functions, while those produced by COX₂ lead to inflammatory and other pathological changes. 

COX₁ is a constitutive form found in the mast cells. It is continuously forming prostaglandins in small amounts. COX₂ is induced in inflammatory cells in response to inflammatory stimulus. Its formation is induced by signals (mainly inflammatory).

It produces very high levels of prostaglandins in a short amount of time (compared to COX₁ which produces small amounts over a prolonged time). The prostaglandins produced are only released during pathological conditions.

Aspirin is selelctive COX₁ inhibitor and nabumetone, meloxicam and nimesulide are selective COX₂ inhibitors. Lipoxygenase pathway appears to operate mainly in the lung, WBC and platelets.

Its most important products are leukotrienes, particularly LTB₄ (potent chemotactic) and LTC₄, LTD_4, which together constitute the slow reacting substance of anaphylaxis (SRS-A).

Inhibition of synthesis of eicosanoids

Synthesis of cycloxygenase products can be inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). Aspirin acetylates COX and causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors. Most NSAIDs are non-selective COX₁ and COX₂ inhibitors, but some newer agents like nimesulide, nabumetone and meloxicam are relatively selective for COX₂.

Degradation of eicosanoids

Degradation of arachidonates occurs rapidly in most tissues. The fastest degradation occurs in the lungs. The plasma half life of most of these agents range from a few seconds to a few minutes.

Actions and pathophysiological roles

The cyclic eicosanoids produce a variety of actions depending upon the particular prostaglandin, species on which tested, hormonal status and other factors. The same prostaglandin may have opposite effects under different circumstances.

Side effects of prostaglandins

Side effects are common with prostaglandins. But, their intensity varies with the prostaglandin, the dose and the route of administration. They include- nausea, vomiting, watery diarrhoea, uterine cramps,  forceful uterine contractions, flushing, shivering, fever, fall in blood pressure and tachycardia.

Clinical uses of prostaglandins

Prostaglandins and their analogues are used infrequently because of their high cost-

1. Abortion
   • Prostaglandins (PGF_2α )have a role to play in midterm abortion, though delayed and erratic action may be a problem – luteolysis. This activity of PGF_{2α ^{is used for}}  oestrous synchronization in cattle.
   • They convert oxytocin resistant midterm uterus to oxytocin responsive uterus.
   • There are many side effects. Eg: cramps, diarrhea, incomplete abortion so surgery must still be performed to remove residual tissue.
   • If the foetus is near term, these prostaglandins are used to induce labour. 
2. Induction of parturition
   • Prostaglandins do not offer any advantage over oxytocin for induction of labour at term.
   • They are less reliable and show wider individual variation in action.
3. Post partum haemorrhage 
   •  15-methylPGF_2α can be used in cases not responding to ergometrine or oxytocin.
4. Peptic ulcer 
   • Stable analogues of PGE₁ and PGE₂ can be used for healing peptic ulcer especially when continuous use of NSAIDs is required. Eg: Misoprostal
   • Long term use of NSAIDs (e.g. aspirin) will cause reduced prostaglandin levels (since COX has been inhibited).
   • PG’s are required to maintain the viability of the gastric mucosal barrier.
5. To avoid platelet damage
   • In cardiac surgery blood going into the heart lung bypass tends to clot, because platelets become activated as a result of the abnormal surface.
   • If PGI₂ is infused in the patient, the platelets will not aggregate because PGI₂ is anti-aggregatory.
   • After surgery, risk of bleeding is minimal because of the relatively short half life of PGI₂. However, the vasodilator effects of PGI₂ may cause an unwanted drop in blood pressure, which would cause a reflex tachycardia, which is undesirable especially after cardiac surgery.
6. Patency of PDA
   • Prostaglandins can keep the ductus arteriosus open in newborn children who have a congenital abnormality of the aorta.
   • If the ductus arteriosus were to close in these babies, death would occur very quickly