23. Pharmacology of eicosanoids. Drugs acting on smooth muscle

Last updated on January 7, 2019 at 13:35

Eicosanoids

You already know these bad boys, prostaglandins, thromboxanes and leukotrienes. They’re synthesized from membrane phospholipids, which are first converted into arachidonic acid by phospholipase A2.

Synthesis of eicosanoids.

These molecules are very short-lived, meaning that they’re rapidly broken down in plasma after they’re produced. Their half-life is only 1 minute! They’re called eicosanoids because they are 20 carbons long fatty acids, and the Greek word for 20 is είκοσι, or eikosi. Prostaglandins and thromboxanes are collectively called prostanoids.

Cyclooxygenase (COX), which produces prostanoids, has two isoforms: COX-1 and COX-2. COX-1 is constantly expressed and produces prostanoids that have physiological, homeostatic functions.

COX-2 on the other hand is inducible, so it’s only activated when needed. It’s activated in response to pathological stimuli like inflammation or injury. These prostanoids play a role in inflammation, pain and fever.

Prostanoids act on G-protein coupled receptors. Here are some of them. This isn’t important to know, just illustrative.

Receptor Second messenger Effect Distribution
IP

DP1

EP2

EP4

↑ cAMP “Inhibitory”

Smooth muscle relaxation

Cardiovascular system

Platelets

Neurons

TP

FP

EP1

↑ Ca2+ “Excitatory”

Smooth muscle contraction

Cardiovascular system

Platelets

Immune system

EP3

DP2

↓ cAMP “Inhibitory”

Smooth muscle relaxation

Throughout the body

Here are some of the physiological functions of prostanoids:

  • Prostaglandins:
    • cause vasodilation
    • enhances capillary permeability with histamine and bradykinin
    • increases sensitivity of nociceptors
    • inhibit platelet aggregation
    • cause bronchodilatation
    • induce cough
    • causes contraction of uterus in pregnant women
    • causes relaxation and dilatation of cervix in pregnant women (you probably see where this is going)
    • decreases acid secretion
    • vasodilate afferent arteriole in kidney
    • increase Na+, K+ and water retention
    • induce fever by acting on the hypothalamus
    • maintain patent ductus arteriosus
  • Thromboxanes:
    • cause vasoconstriction
    • promote platelet aggregation

Leukotrienes act on BLT1, BLT2, CysLT1 and CysLT2 receptors. They mostly work by activating and stimulating immune cells, but also:

  • Increase sensitivity of nociceptors
  • Bronchoconstrict
  • Cause swelling of bronchi
  • Increase mucus secretion in bronchi
  • Vasodilate
  • Increase capillary permeability
Eicosanoids medically

Leukotrienes have no therapeutic use however they are involved in the development of NSAID-induced airway obstruction, so-called “aspirin asthma”. NSAIDs work by inhibiting COX. When COX is inhibited will all the arachidonic acid molecules that are produced by converted into leukotrienes, meaning that the leukotriene levels increase. Leukotrienes cause swelling, increased mucus secretion and bronchoconstriction in the bronchi, which is basically what asthma is.

Eicosanoids in general have very short half-life, so instead of giving eicosanoids we often give eicosanoid analogues, which are molecules that mimic their effect but have longer half-life. However, many of the drugs mentioned are just drug names for endogenous eicosanoids. Dinoprostone is the exact same molecule as prostaglandin E2, for example.

Prostanoid analogues are used in gynaecology to interrupt pregnancy, induce labour and reduce post-partum uterine bleeding. Drugs used for this include dinoprostone, dinoprost, sulprostone, carboprost, mifepristone, misoprostol and gemeprost.

Misoprostol is also used to prevent gastric damage when NSAIDs are administered. Lubiprostone is used as a laxative.

Alprostadil and epoprostenol are given to maintain an open ductus arteriosus in cases where the heart is so messed up that only a patent ductus arteriosus keeps the heart open.

Epoprostenol is also used to treat pulmonary hypertension.

Alprostadil is also used to treat erectile dysfunction by injecting it into corpus cavernosum (ow).

Alprostadil, eprostenol and iloprost are used to inhibit platelet aggregation during dialysis or cardiopulmonary bypass, or when platelets are stored before transfusion.

Latanaprost, bimatoprost, travoprost and unoprostone are used to reduce intraocular pressure in glaucoma.

I wouldn’t bother memorizing these names. They all have “prost” in their name anyway. Probably just remember what prostanoid analogues can be used for. Unless you’re fourth year maybe.

Drugs that inhibit formation or action of eicosanoids

  • NSAIDs inhibit COX-1 and/or COX-2, depending on the type
  • Glucocorticoids inhibit COX-2
  • Zafirlukast, montelukast and pranlukast are leukotriene receptor antagonists used to treat bronchial asthma and allergic rhinoconjuctivitis
Drugs acting on smooth muscle

Many drugs act on smooth muscle, including eicosanoids, however we reserve the name spasmolytic drugs for drugs that relax the smooth muscles in the GI tract or genitourinary tract. They’re used to treat spasms, often those that occur due to bile stone or kidney stone.

Spasmolytics are not effective in reducing menstruation-related uterine pain, however COX inhibitors (NSAIDs) are.

There are two types of spasmolytics: the directly-acting ones, that work by inhibiting ion channels or acting as enzymes, and the indirectly-acting ones, that are receptor agonists or antagonists.

The directly-acting spasmolytics papaverine, drotaverine and bencyclane exist but they have no clinical use that I could find.

Metamizole and butylscopolamine are drugs that have indirect spasmolytic effect in addition to their main effects. Metamizole is an NSAID. Butylscolopamine has direct spasmolytic effect through unknown mechanism (in addition to its indirect spasmolytic effect by being a muscarinic antagonist).

Prostaglandins and oxytocin are essential for contraction of the uterus. Prostaglandin’s role in this was discussed above, so we’ll examine oxytocin’s role.

Oxytocin is a peptide hormone formed in the hypothalamus but released from the posterior pituitary. It acts through a Gq-coupled receptor, meaning that it acts through phospholipase C. When secreted does it evoke rhythmic contractions of the uterus and cause milk ejection in the breasts. Between the contractions are periods of complete relaxation so that foetal asphyxiation doesn’t occur.

Oxytocin is given clinically to induce labour, promote breast feeding and reduce postpartum bleeding. It has a short half-life due to elimination by the liver and kidney.

Ergometrine, methylergometrine and ergotamine are all drugs that can be used to contract the uterus. They act by unknown mechanisms. However, they cause a sustained contraction with no periods of relaxation, so if they were used while a live foetus is in the uterus would the foetus die. They’re instead used to induce abortion, stimulate expulsion of the placenta or to stop postpartum bleeding.

Sometimes do we want to stop labour, like if the foetus is premature or there are complications. Drugs that do this are called tocolytics. In these cases do we give β2 adrenergic agonists, which causes the uterine smooth muscle to relax. Drugs used for this are: terbutaline, salbutamol and ritodrine. Atosiban is a competitive oxytocin antagonist, which is used in the same cases as the β2 adrenergic agonists.

Other tocolytics include:

  • Magnesium ion, given as magnesium sulphate or magnesium gluconate
  • 17-OH-progesterone caproate
  • NSAIDs
  • Nifedipine

Ethanol inhibits oxytocin release and is therefore able to stop delivery, however it obviously shouldn’t be used due to serious toxic effects on the foetus.


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22. Histamine, antihistaminic drugs

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24. Drugs used to treat bronchial asthma

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