Actions and Pathophysiological Roles

ACTIONS AND PATHOPHYSIOLOGICAL ROLES

Prostaglandins, Thromboxanes And Prostacyclin

The cyclic eicosanoids produce a wide variety of actions depending upon the particular PG (or TX or PGI), species on which tested, tissue, hormonal status and other factors. PGs differ in their potency to produce a given action and different PGs sometimes have opposite effects. Even the same PG may have opposite effects under different circumstances. The actions of PGs and TXA₂ are summarized in Table 13.1. Since virtually all cells and tissues are capable of forming PGs, they have been implicated as mediators or modulators of a number of physiological processes and pathological states.

CVS

PGE₂ and PGF_2α cause vasodilatation in most, but not all, vascular beds. In isolated preparations, they are more potent vasodilators than ACh or histamine. PGF_2α constricts many larger veins including pulmonary vein and artery. Fall in BP occurs when PGE₂ is injected i.v., but PGF_2α has little effect on BP.

1.     PGI₂ is uniformly vasodilatory and is more potent hypotensive than PGE₂.

2.     TXA₂ consistently produces vasoconstriction.

3.     PG endoperoxides (G₂ and H₂) are inherently vasoconstrictor, but often produce vasodilatation or a biphasic response due to rapid conversion to other PGs, especially PGI₂ in the blood vessels themselves.

4.     PGE₂ and F_2α stimulate heart by weak direct but more prominent reflex action due to fall in BP. The cardiac output increases.

Role

a.    PGI₂ is probably involved in the regulation of local vascular tone as a dilator.

b.     PGE₂ and PGI₂ are believed to be continuously produced locally in the ductus arteriosus during foetal life—keep it patent; at birth their synthesis is inhibited and closure occurs. Aspirin and indomethacin induce closure when it fails to occur spontaneously. These PGs may also be important in maintaining placental blood flow.

c.        PGs, along with LTs and other autacoids may mediate vasodilatation and exudation at the site of inflammation.

Platelets

TXA₂, which can be produced locally by platelets, is a potent inducer of aggregation and release reaction. The endoperoxides PGG₂ and PGH₂ are also proaggregatory. On the other hand PGI₂ (generated by vascular endothelium) is a potent inhibitor of platelet aggregation. PGD₂ has antiaggregatory action, but much less potent than PGI₂. PGE₂ has inconsistent effects.

Role

TXA₂ produced by platelets and PGI₂ produced by vascular endothelium probably constitute a mutually antagonistic system: preventing aggregation of platelets while in circulation and inducing aggregation on injury, when plugging and thrombosis are needed.

Aspirin interferes with haemostasis by inhibiting platelet aggregation which is due toTXA₂ production. Before it is deacetylated in liver, aspirin acetylates COX in platelets while they are in portal circulation. Further, platelets are unable to regenerate fresh COX (lack nucleus: do not synthesize protein), while vessel wall is able to do so (fresh enzyme is synthesized within hours). Thus, in low doses, aspirin selectively inhibits TXA₂ production and has antithrombotic effect lasting > 3 days.

Uterus

PGE₂ and PGF_2α uniformly contract human uterus, pregnant as well as nonpregnant in vivo. The sensitivity is higher during pregnancy and there is a further modest increase with progress of pregnancy. However, even during early stages uterus is quite sensitive to PGs though not to oxytocin. PGs increase tone as well as amplitude of uterine contractions.

When tested in vitro, PGF_2α consistently produces contraction while PGE₂ relaxes nonpregnant but contracts pregnant human uterine strips.

At term, PGs at low doses soften the cervix and make it more compliant.

Role

1.     Foetal tissues produce PGs and at term PGF_2α has been detected in maternal blood. It has been postulated that PGs mediate initiation and progression of labour. Aspirin has been found to delay the initiation of labour and also prolongs its duration.

2.     Because PGs are present in high concentration in semen and can be rapidly absorbed when lodged in the vagina at coitus, it is believed that they so coordinate movements of the female genital tract that transport of sperms and fertilization is facilitated.

3.     Dysmenorrhoea in many women is associated with increased PG synthesis by the endometrium. This apparently induces uncoordinated uterine contractions which compress blood vessels → uterine ischaemia → pain. Aspirin group of drugs are highly effective in relieving dysmenorrhoea in most women.

Bronchial Muscle

PGF_2α, PGD₂ and TXA₂ are potent bronchoconstrictors (more potent than histamine) while PGE₂ is a powerful bronchodilator. PGI₂ produces mild dilatation. Asthmatics are more sensitive to constrictor as well as dilator effects of PGs. PGE₂ and PGI₂ also inhibit histamine release and are effective by aerosol—but produce irritation of the respiratory tract and have a brief action.

Role

Asthma may be due to an imbalance between constrictor PGs (F _2α, PGD₂, TXA₂) and LTs on one hand and dilator ones (PGE₂, PGI₂) on the other. In few individuals aspirinlike drugs consistently induce asthma, possibly by diverting arachidonic acid to produce excess LTC₄ and D₄. This sensitivity is not shared by selective COX2 inhibitors, indicating that suppression of COX1 at the pulmonary site is responsible for the reaction. In allergic human asthma, LTs are more important and COX inhibitors are without any effect in most patients.

GIT

(i) In isolated preparations, the longitudinal muscle of gut is contracted by PGE₂ and PGF_2α while the circular muscle is either contracted (usually by PGF_2α) or relaxed (usually by PGE₂). Propulsive activity is enhanced in man, especially by PGE₂ → colic and watery diarrhoea are important side effects. PGE₂ acts directly on the intestinal mucosa and increases water, electrolyte and mucus secretion. PGI₂ does not produce diarrhoea and infact opposes PGE₂ and toxin induced fluid movement.

Role

PGs may be involved in mediating toxin induced increased fluid movement in secretory diarrhoeas. In certain diarrhoeas, aspirin can reduce stool volume, but is not uniformly effective. PGs appear to play a role in the growth of colonic polyps and cancer. Association of low incidence of colon cancer with regular intake of aspirin is now established. NSAIDs afford relief in familial colonic polyposis by reducing polyp formation.

PGE₂ markedly reduces acid secretion in the stomaArticle No. Volume of juice and pepsin content are also decreased. It inhibits fasting as well as stimulated secretion (by feeding, histamine, gastrin). The gastric pH may rise upto 7.0. PGI₂ also inhibits gastric secretion, but is less potent. Secretion of mucus in stomach and mucosal blood flow are increased; PGs are antiulcerogenic.

Role

PGs (especially PGI₂) appear to be involved in the regulation of gastric mucosal blood flow. They may be functioning as natural ulcer protectives by enhancing gastric mucus production. The ulcerogenic action of NSAIDs may be due to loss of this protective influence.

Normally, gastric mucosal PGs are produced by COX1. Selective COX2 inhibitors are less ulcerogenic. However, COX2 gets induced during ulcer healing, and COX2 inhibitors have the potential to delay healing.

Kidney

PGE₂ and PGI₂ increase water, Na⁺ and K+ excretion and have a diuretic effect. PGE₂ has been shown to have a furosemide like inhibitory effect on Cl¯ reabsorption as well. They cause renal vasodilatation and inhibit tubular reabsorption. PGE₂ antagonizes ADH action, and this adds to the diuretic effect. In contrast, TXA₂ causes renal vasoconstriction. PGI₂, PGE₂ and PGD₂ evoke release of renin.

Role

1.     PGs appear to function as intrarenal regulators of blood flow as well as tubular reabsorption in kidney. The NSAIDs tend to retain salt and water. The diuretic action of furosemide is blunted by indomethacin— indicating a facilitatory role of PGs by increasing renal blood flow and/or augmenting inhibition of tubular reabsorption.

2.     Renin release in response to sympathetic stimulation and other influences may be facilitated by PGs.

3.     Bartter’s syndrome, characterized by decreased sensitivity to angiotensin II is associated with increased PG production; many of the manifestations are improved by prolonged use of NSAIDs.

CNS

PGs injected i.v. penetrate brain poorly and central effects are not prominent. However, injected intracerebroventricularly PGE₂ produces a variety of effects—sedation, rigidity, behavioral changes and marked rise in body temperature. PGI₂ also induces fever, but TXA₂ is not pyrogenic.

Role

1.     PGE₂ may mediate pyrogen induced fever and malaise. Aspirin and other inhibitors of PG synthesis are antipyretic. Pyrogens, including cytokines released during bacterial infection, trigger synthesis of PGE₂ in the hypothalamus, which resets the thermostat to cause fever. COX2 is the major isoenzyme involved; selective COX2 inhibitors are equally efficacious antipyretics. A role of COX3 has also been proposed.

2.     PGs may be functioning as neuromodulators in the brain by regulating neuronal excitability. A role in pain perception, sleep and some other functions has been suggested.

ANS

Depending on the PG, species and tissue, both inhibition as well as augmentation of NA release from adrenergic nerve endings has been observed.

Role

PGs may modulate sympathetic neurotransmission in the periphery.

Peripheral Nerves

PGs (especially E₂ and I₂) sensitize afferent nerve endings to pain inducing chemical and mechanical stimuli (Fig.7.2). They irritate mucous membranes and produce long lasting dull pain on intradermal injection.

Role

PGs appear to serve as algesic agents during inflammation. They cause tenderness and amplify the action of other algesics. Inhibition of PG synthesis is a major anti-inflammatory mechanism. Aspirin injected locally decreases pain produced by injection of bradykinin at the same site.

Eye:

PGF_2α induces ocular inflammation and lowers i.o.t by enhancing uveoscleral outflow.

Non irritating congeners like latanoprost are now first line drugs in wide angle glaucoma.

Role

Locally produced PGs appear to facilitate aqueous humor drainage, since COX2 expression in the ciliary body has been found to be deficient in wide angle glaucoma patients.

Endocrine System

PGE₂ facilitates the release of anterior pituitary hormones—growth hormone, prolactin, ACTH, FSH and LH as well as that of insulin and adrenal steroids. It has a TSH like effect on thyroid.

PGF_2α causes luteolysis and terminates early pregnancy in many mammals, but this effect is not significant in humans. Though PGs can terminate early pregnancy in women, this is not associated with fall in progesterone levels.

Metabolism

PGEs are antilipolytic, exert an insulin like effect on carbohydrate metabolism and mobilize Ca2+ from bone: may mediate hypercalcaemia due to bony metastasis.