35. Pharmacology of eicosanoids. Drugs acting on smooth muscle

Eicosanoids

Synthesis of 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.

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, prostacyclins and thromboxanes are collectively called prostanoids.

Prostanoids (prostacyclins, prostaglandins and thromboxanes)

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 actions” Smooth muscle relaxation	Cardiovascular system Platelets Neurons
TP FP EP1	↑ Ca2+	“Excitatory actions” Smooth muscle contraction	Cardiovascular system Platelets Immune system
EP3 DP2	↓ cAMP	“Inhibitory actions” 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 bronchodilation
  • induce cough
  • causes contraction of uterus in pregnant women
  • causes relaxation and dilatation of cervix in pregnant women
  • decreases acid secretion
  • vasodilate afferent arteriole in kidney
  • increase Na+, K+ and water excretion
  • induce fever by acting on the hypothalamus
  • maintain the ductus arteriosus
• Thromboxanes:
  • cause vasoconstriction
  • promote platelet aggregation

Leukotrienes

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

Leukotriene agonists and antagonists

• Leukotriene agonists
  • None
• Leukotriene antagonists
  • Zafirlukast
  • Montelukast

Indications

Leukotriene agonists have no therapeutic use.

Leukotriene antagonists are used in the maintenance treatment of bronchial asthma. They’re taken orally.

Aspirin asthma

Leukotrienes are involved in the development of NSAID-induced airway obstruction, so-called "aspirin-exacerbated respiratory disease" or “aspirin asthma”. When COX is inhibited, all the arachidonic acid molecules that are produced will be converted into leukotrienes. Leukotrienes cause swelling, increased mucus secretion and bronchoconstriction in the bronchi, causing asthma. Aspirin-exacerbated respiratory disease only occurs in a small percentage of people.

Prostanoid analogues

Compounds

• Alprostadil (= prostaglandin E1)
• Misoprostol (prostaglandin E1 analogue)
• Dinoprostone (= prostaglandin E2)
• Epoprostenol (= prostacyclin I2)
• Carboprost (prostaglandin F2α analogue)
• Latanoprost (prostaglandin F2α analogue)

Indications

• Misoprostol
  • Termination of pregnancy
  • Induction of labour
  • Preventing NSAID-related ulcers
  • Maintaining ductus arteriosus
  • Erectile dysfunction – as an injection into the corpus cavernosum
• Dinoprostone
  • Induction of labour
• Carboprost
  • Postpartum haemorrhage
• Epoprostenol
  • Inhibit platelet aggregation during extracorporeal circulation
  • Primary pulmonary hypertension
• Latanoprost (eye drops)
  • Open-angle glaucoma

Eicosanoids in general have very short half-life, so instead of giving eicosanoids we often give eicosanoid analogues, which are molecules that are similar in structure and have similar effects 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.

Mechanism of action

Prostaglandin E1 and E2 analogues induce contraction of the uterus, thereby causing termination of pregnancy or induction of labour, depending on the concentration used.

Prostaglandin F2α analogues like carboprost induce contraction of the uterus and induce lysis of the corpus luteum, thereby stopping post partum bleeding. Normally, contraction of the uterus during labour compresses the blood vessels and thereby prevents haemorrhage. A lack of uterine contraction, called uterine atony, is the most common cause of post partum haemorrhage and can be treated with carboprost.

Prostaglandin E1 analogues like misoprostol acts on EP3 receptors in the stomach and inhibits HCl secretion and induces gastric mucus secretion, thereby preventing ulcer development.

Prostaglandin E1 is important in maintaining the ductus arteriosus in infants. Alprostadil keeps the ductus arteriosus open, which is beneficial for congenital heart defects that need surgery when the ductus arteriosus is necessary for the survival before the surgery, so-called ductus-dependent congenital heart lesions.

Alprostadil relaxes vascular smooth muscle in the corpus cavernosum when injected into it, thereby inducing erection.

Epoprostenol (prostacyclin I2) induces vasodilation in the pulmonary circulation when given IV. It also inhibits platelet aggregation.

Latanoprost decreases intraocular pressure.

Pharmacokinetics

The only orally active prostanoid analogue is misoprostol. All the others must be given by injection or as eye drops.

Adverse effects

• For all
  • Fever
  • GI symptoms
• Prostaglandin F2α analogues
  • Bronchoconstriction
  • Hypertension
• Prostaglandin E2 analogues
  • Hypotension
• Prostacyclin I2 analogues
  • Hypotension

Drugs that inhibit formation of eicosanoids

NSAIDs inhibit COX-1 and/or COX-2, depending on the type of NSAID.

Glucocorticoids increase the synthesis of lipocortin, a protein which inhibits phospholipase A2.

Drugs which relax smooth muscle

Compounds

• Spasmolytics
  • No clinical use
    • Papaverine
    • Drotaverine
  • Metamizole
  • Butylscopolamine
  • Bencyclane

Many drugs act on smooth muscle, including eicosanoids, however we reserve the name spasmolytic drugs for drugs that prevent spasms of the smooth muscles in the GI tract or genitourinary tract.

Indications

They’re used to treat spasms, often those that occur due to bile stone or kidney stone.

Mechanism of action

There are two types of spasmolytics: the directly-acting ones, that work by influencing ion channels or enzymes, and the indirectly-acting ones, which act on receptors. Papaverine, drotaverine, bencyclane and metamizole are direct spasmolytics. Butylscopolamine is an indirect spasmolytic.

Papaverin is a phosphodiesterase (PDE) 3 and 4 inhibitor, and it also inhibits L-type calcium channels. Drotaverine is similar but is specific for PDE4 and doesn’t act on calcium channels.

Bencyclane acts by inhibiting L-type calcium channels.

Metamizole is an NSAID with additional direct spasmolytic effects.

Butylscopoloamine is a quaternary amine muscarinic receptor antagonist, which gives it indirect spasmolytic effects.

Drugs which contract smooth muscle

Compounds

• Oxytocin
• Prostaglandins (see above)
  • Dinoprostone
  • Misoprostol
  • Carboprost
• Ergot alkaloids
  • Ergometrine
  • Ergotamine

Prostaglandins and oxytocin are essential for contraction of the uterus. Prostaglandins’ role in this was discussed above.

Indications

• Oxytocin
  • Induce labour
  • Postpartum haemorrhage
    • Promote lactation
• Ergot alkaloids
  • Induce abortion
  • Postpartum haemorrhage

Mechanism of action

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 activates phospholipase C. When secreted it evokes 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.

The ergot alkaloids act by unknown mechanisms. They cause a sustained contraction with no periods of relaxation, so if they were used while a live foetus is in the uterus the foetus would die.

Pharmacokinetics

Oxytocin has a short half-life due to rapid elimination by the liver and kidney.

Tocolytics

Tocolytics are drugs which postpone labour by causing uterine smooth muscle to relax. Many drugs can act as tocolytics:

• β2 adrenergic agonists
  • Terbutaline
  • Salbutamol/albuterol
• Calcium channel blockers
  • Nifedipine
• Oxytocin receptor antagonists
  • Atosiban
• NSAIDs
  • Indomethacin