Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs) part 2

 

Effects of Eicosanoids
Blood vessels	- PGF2a is a vasoconstrictor. - TXA2 is a potent vasoconstrictor, and it also has a smooth muscle mitogenic   effects. - PGI2 & PGE2. promote vasodilatation by ↑ cAMP and by intracellular Ca². - PGI2 inhibits proliferation of smooth muscle cells.  - PGD, also has a vasodilator effects, is aldominant mediator of flushing induced by niacin (lipid-lowering drug).
GIT	- Most of the PGs and TXs activate gastrointestinal smooth muscle. - PGE2 & PGF2α à Longitudinal muscle contraction. - PGF2α (Strong) & PGI2 (weak) à Circular muscle contraction. - PGE2 à Circular muscle relaxation. - LTs à also have powerful contraction effects.
LUNG	- PGI2 & PGE2 Bronchial smooth muscle relaxation. - PGF2α, TXA2 & PGD2 à Bronchial smooth muscle contraction. - Cysteinyl LTs (LTC4, LTD4 and LTE4) à  Bronchial smooth muscle contraction.            - Being about 1000 times more potent than histamine.            - Stimulate bronchial mucus secretion and cause mucosal edema.            - Bronchospasm occur bout 10% of people taking NSAIDS, because of a shift in              arachidonic acid from COX to 5-LOX.
Platelet	- Low concentration of PGE2 à enhance platelet aggregation. - High concentration of PGE2à inhibit platelet aggregation. - PGF2α & PGD2 à inhibit platelet aggregation. - TXA2 à Induce platelet aggregation.               TXA2 is the major products of COX-1 isoform enzyme.               Platelet COX-1-derived TXA2 biosynthesis is increased during platelet               activation and aggregation and is irreversibly inhibited by chronic               administration of aspirin at low doses.
	- PGs play important roles in maintaining blood pressure & regulating renal function - COX-1-derived products promote salt excretion in the collecting ducts.
Uterine	- PGF2α & TXA2  à uterine smooth muscle contraction. - PGF2α together with oxytocin is essential for the onset of parturition.
Male sex organ	-  Smooth muscle-relaxing PGs such as PGE1 à enhance penile erection by relaxing smooth muscle of the corpora cavernosa.
BRAIN	Fever:             - PGE2 à increases body temperature.             - Endogenous pyrogens release interleukin-1 (IL-1), which in turn promotes               synthesis and release of PGE2.             - PGE2 synthesis is blocked by aspirin and other antipyretic compounds. Sleep:            - PGD2 induces natural sleep, while PGE2 cause wakefulness. Neurotransmission:             - PGE2 may inhibits NE release from postganglionic sympathetic nerve                 ending.  Inflammation: PGE2 & PGI2 are the predominant prostanoids associated with inflammation, markedly enhance edema formation and leukocyte infiltration by promoting blood flow in the inflamed region.
EYE	PGE and PGF derivatives lower intraocular pressure (IOP), by increase aqueous humour outflow (the mechanism is unclear).
Other	Bone Metabolism:           - PGs increase bone turnover by stimulating bone resorption and             formation Cancer:          - COX-2 derived PGE2 can promote tumour growth by binding its            receptors and activating signalling pathways which control cell            proliferation, migration, apoptosis, and/or angiogenesis. However,            the prolonged use of high dosages of COX-2 selective inhibitors is            associated with unacceptable CV side effects.          - Large studies and clinical trials indicate that long term use of NSAIDS,            can decrease the incidence of certain malignancies, including            colorectal. oesophageal, breast, lung, and bladder cancers.

 

Prostaglandin Analogues

Synthetic prostaglandin analogues are molecules which are manufactured to bind to a PG receptors.

Prostaglandin E1 Analogues

- PGE, effects Vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle.

Alprostadil (Caverject®)

- Alprostadil is a PGE1 analogue. - Uses: 1) Maintaining a patent ductus arteriosus in newborns (Firstly; see N.B. below):                      - In certain types of congenital heart disease, it is important to maintain the potency of                        the neonate's ductus arteriosus until corrective surgery can be carried out.                        This can be achieved with Alprostadil.        - Route of administration: because of rapid pulmonary clearance, it must be continuous IV                                                        infusion into a large vein.        - Dose: initial rate: 0.05-0.1 mcg/kg/min, may be increased to 0.4 mcg/kg/min,                                           prolonged infusion has been associated with ductal rupture.               2) Impotence (Erectile Dysfunction; ED): - Dosage form: urethral suppositories and in injectable form.                           - Penile suppository inserted into the urethra.                           - Injected by syringe directly into the corpus cavernosum of the penis, avoid injection                             in midline. - Onset of action: 5 to 10 minutes. - Duration of action: Injectionà  1 to 3 hours, supp.--> 30 to 60 minutes. - Most common side effects: pain at place of injection or pain of urethra (suppository only) and   painful erection. - N.B:       - The ductus arteriosus, is a normal part of a baby's circulatory system before birth that usually         closes shortly after birth. If it remains open, it's called a patent ductus arteriosus.       - Patent ductus arteriosus (PDA); is a persistent opening between two major blood vessels         leading from the heart.       - Large patent ductus arteriosus left untreated can allow poorly oxygenated blood to flow in the         wrong direction, weakening the heart muscle and causing heart failure and other         complications.       - PGE1 & PGE2 are responsible for keeping the ductus patent, NSAIDS such as indomethacin or         ibuprofen (as IV) may been used to help close a PDA.       - NSAIDS during pregnancy in third trimester, increase the risk of premature closure of the         ductus arteriosus.

Misoprostol (Cytotec) (Misotac)

- Misoprostol is a PGE1 analogue, with oxytocic properties. - It is approved for use in the prevention of NSAID-induced gastric ulcers;               - NSAIDS inhibit prostaglandin synthesis, and a deficiency of prostaglandins within the gastric                 mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the                 mucosal damage caused by these agents.               - It produces uterine contractions and is contraindicated during pregnancy. - Off-label uses of Misoprostol:               - Labor induction, abortion, missed miscarriage and postpartum bleeding;                         - Misoprostol effects are dose dependent and include cervical softening and dilation,                           uterine contractions.               - Routes of administration; include oral, vaginal, sublingual, buccal, or rectal.               - In abortions mainly used in combination with Mifepristone (Antiprogestin).   - Dear pharmacists this drug is prescribed only by obstetricians and gynaecologists by a trusted prescription; So don't prescribe this drug by any way because may be used by prostitutes for abortion (illegally).

 

 

Prostaglandin E2 Analogues

Dinoprostone (Cervidil)

- Dinoprostone is a PGE2 analogue, with oxytocic properties. - It administered vaginally (vaginal insert) for labor induction.          - It cause softening the cervix and causing uterine contraction.

 

 

Prostaglandin F2α Analogues
Carboprost (Hemabate)
- Carboprost is a PGF2 analogue, with oxytocic properties. - It induces contractions and can trigger abortion in early pregnancy. It also reduces postpartum   bleeding. - Used in treatment of postpartum hemorrhage in the presence of uterine atony that has not   responded to usual therapy (i.e., IV oxytocin, uterine massage, IM ergot alkaloids).
Latanoprost (Xalatan)	Bimatoprost (Lumigan)
Travoprost (Travatan)	Unoprostone (Rescula)
- Latanoprost , Bimatoprost , Travoprost  and Unoprostone  are used as ophthalmic solution to   control the progression of glaucoma or ocular hypertension by reducing intraocular pressure. - Latanoprost was the first prostanoid used for glaucoma, the success of Latanoprost has stimulated   development of similar prostanoids with ocular hypotensive effects. - Used once or twice daily. - Side effects; irreversible brown pigmentation of the iris and eyelashes, drying of the eyes and conjunctivitis.   -          Bimatoprost (LATISSE); is used in treatment of hypotrichosis (inadequate or not enough lashes) to grow eyelashes longer, fuller and darker, Only apply once daily at the base of upper lashes. Don't apply to lower lid, significant improvement by 2 months after starting treatment.

 

Prostacyclin Analogues

Epoprostenol (Flolan)

- Epoprostenol has 2 major effects:                         1) direct vasodilation of pulmonary and systemic arterial vascular beds,                         2) inhibition of platelet aggregation. - Used in treatment pulmonary arterial Hypertension (PAH). - Side effects; Flushing, headache, nausea/vomiting, hypotension, bradycardia and anxiety.

 

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H2-receptor Antagonists

 

B: H2-receptor Antagonists
- The H2 receptor antagonists (H:RA) are a class of drugs used to block the action of histamine on parietal cells (specifically the histamine H2 receptors) in the stomach, decreasing the production of acid by these cells.
Cimetidine (Tagamet®)			Ranitidine (Zantac®)
Nizatidine (Ulcefree®)			Famotidine (Antodine®)
- Cimetidine, Ranitidine , Famotidine , and Nizatidine  are reduces the secretion of gastric acid by   blocking H2 receptors. - Cimetidine is largely replaced by other H2 receptor blocker due to side effects.
Pharmaco        -kinetics	- All four agents are rapidly absorbed from the intestine. - Cimetidine, Ranitidine and Famotidine first-pass hepatic metabolism (bioavailability = approximately  50%), Nizatidine has tittle first-pass hepatic metabolism. - Half-life of four agents approximately 1.1 to 4 hours, duration of action depend on the dose given. - Dose reduction is required in moderate to severe renal dysfunction and severe hepatic impairment.
	Drug	Relative potency		Usual dose	Parenteral form
	Cimetidine	1		400 mg twice or 800 mg at bedtime	50mg
	Ranitidine	4-10		150 mg twice or 300 mg at bedtime	50mg
	Nizatidine	4-10		150 mg twice or 300 mg at bedtime	Not available
	Famotidine	20-50		20 mg twice or 40mg at bedtime	20mg
Mechanism Of action	~Histamine released from enterochromaffin-like (ECL) cells in the fundus of the   stomach by gastrin or vagal parasympathetic stimulation (acetylcholine). ~H2 receptor antagonists block the actions of histamine at parietal cell H2 receptors   and supress basal and meal stimulated acid secretion. ~H2 receptor antagonists inhibit 60-70% of total 24- hours acid secretion.
Therapeutic uses	1) Peptic Ulcer Disease (PUD): - All four agents are equally effective in promoting the healing of duodenal and   gastric ulcers. - Proton pump inhibitors have largely replaced H2-antagonists in the   treatment of acute peptic ulcer (NSAID-induced ulcers and ulcer   caused by H.pylori), because these agents heal and prevent recurrence. - H2-antagonists used in Zollinger-Ellison Syndrome (ZES), ZES is a gastrin-secreting   tumor of the pancreas that stimulates the acid- secreting cells of the stomach,   cause mucosal ulceration. 2) Gastroesophageal Reflux Disease (GERD): - Is a chronic symptom which stomach acid coming up from the stomach into the    esophagus Heartburn. - H2-antagonists act by stopping acid secretion. Therefore, they may not relieve   symptoms for at least 45 minutes. - Antacids more quickly and efficiently neutralize stomach acid, but their action is   only temporary. - PPIS are now used preferred in the treatment of GERD. 3) Non-ulcer Dyspepsia:    - Commonly used for dyspepsia not caused by peptic ulcer. 4) Acute Stress Ulcers:    - Given as an IV infusion to prevent and manage acute stress ulcers.    - PPIS are favor for this indication.
Side effects	- H2-antagonists are extremely safe drugs. Side effects occur in less than 3% of   patient include diarrhea, headache and fatigue. - Cimetidine inhibits binding of dihydrotestosterone to androgen receptors (Anti-   androgenic effect) and↑ serum prolactin, long term use may cause:            - Impotence in male (Anti-androgenic effect).            - Gynecomastia in male (Increase prolactin).            - Galactorrhea and amenorrhea in female (Increase prolactin). Rapid IV infusion of H2-antagonists may rarely cause bradycardia and hypotension by blocking cardiac H2-receptors. - H2-antagonists in pregnancyà FDA category B.
Drug Interactions	-Cimetidine inhibits several cytochrome P450 isoenzymes (is a LME inhibitor) and  can interfere with the metabolism of many other drugs, such as Warfarin and  Phenytoin. - All of H2-antagonists except Famotidine inhibit gastric first pass metabolism of   Ethanol especially in women resulting in increased bioavailability of ethanol     increase blood ethanol level. - H2-antagonists compete with Creatinine and certain drugs (e.g. Procainamide) for   renal tubular secretion.

 

C: H3-& H4 receptor Antagonists

Although no selective H3 or H4 ligands are presently available for general clinical uses.

Betahistine (Betaserc®)

- Betahistine  is an anti-vertigo drug used in balance disorders or relieve vertigo symptoms associated with Ménière's disease . {MECHANISM OF ACTION} - Betahistine has a very strong affinity as an antagonist for histamine H3- receptors and a weak   affinity as an agonist for histamine H1-receptors. - Betahistine seems to dilate the blood vessels within the inner ear which can relieve pressure from   excess fluid and act on the smooth muscle. - Ménière's disease is a disorder of the inner ear that causes spontaneous episodes of vertigo,      fluctuating hearing loss, ringing in the ear (tinnitus) and affects only one ear.    N.B: Tiprolisant is a selective H3-receptor inverse agonist/antagonist, It is currently in clinical trials for schizophrenia and Parkinson's disease.

 

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