calcification of aortic valve, building up of pressure of LV
cyanotic
TOF - tetralogy of Fallot
TGV - transposition of great vessels
coarctation of aorta
non-cyanotic
VSD - ventricular septal defect
ASD - atrial septal defect => S2 split
PDA - patent ductus arteriosus = congenital
L/R shunt
PgE
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A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects; although they are technically hormones, they are rarely classified as such.
The prostaglandins together with the thromboxanes form the prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of eicosanoids.
Biochemistry
[edit] Biosynthesis
Prostaglandins are found in virtually all tissues and organs. These are autocrine and paracrine lipid mediators that act upon platelet, endothelium, uterine and mast cells, among others. They are synthesized in the cell from the essential fatty acids[3] (EFAs).
- Gamma-linolenic acid (GLA, an ω-6 EFA, via DGLA) - yielding the series-1 prostaglandins
- Arachidonic acid (AA, ω-6) - yielding series-2
- Eicosapentaenoic acid (EPA, ω-3) - yielding series-3
An intermediate is created by phospholipase-A2, then passed into one of either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. The lipoxygenase pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.
[edit] Release of prostaglandins from the cell
Prostaglandins are originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the prostaglandin transporter (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion can not explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the multidrug resistance protein 4 (MRP4, ABCC4), a member of the ATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear.
[edit] Cyclooxygenases
Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is that COX-1 is responsible for the baseline levels of prostaglandins, whereas COX-2 produces prostaglandins through stimulation. However, while COX-1 and COX-2 are both located in the blood vessels, stomach and the kidneys, prostaglandin levels are increased by COX-2 in scenarios of inflammation.
[edit] Prostaglandin E synthase
Prostaglandin E2 (PGE2) is generated from the action of prostaglandin E synthases on prostaglandin H2 (PGH2). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE2.
[edit] Other terminal prostaglandin synthases
Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and lipocalin prostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation of PGD2 from PGH2. Similarly, prostacyclin (PGI2) synthase (PGIS) converts PGH2 into PGI2. A thromboxane synthase (TxAS) has also been idenfitied. Prostaglandin F synthase (PGFS) catalyzes the formation of 9α,11β-PGF2α,β from PGD2 and PGF2α from PGH2 in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD2[4] and bimatoprost[5] (a synthetic analogue of PGF2α).
[edit] Function
There are currently nine known receptors of prostaglandins on various cell types. Prostaglandins ligate a subfamily of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2). Prostaglandins thus act on a variety of cells such as vascular smooth muscle cells causing constriction or dilation, on platelets causing aggregation or disaggregation and on spinal neurons causing pain. Prostaglandins have a wide variety of actions, including, but not limited to muscular constriction and mediate inflammation. Other effects include calcium movement, hormone regulation and cell growth control. Thromboxane is created in platelets and causes vascular constriction and platelet aggregation. Prostacyclin comes from cells in the blood vessel walls and is antagonistic to thromboxane.
Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they exert only a paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) function.
[edit] Role in pharmacology
[edit] Inhibition
NSAIDs inhibit cyclooxygenase and reduce prostaglandin synthesis. Corticosteroids inhibit phospholipase A2 production by boosting production of lipocortin, an inhibitor protein. Relatively new drugs, known as COX-2 selective inhibitors or coxibs, are used as specific inhibitors of COX-2. The development of these drugs allowed the circumvention of the negative gastrointestinal effects while effectively reducing inflammation. However, it was subsequently shown that both NSAIDs and Coxibs can raise the risk of myocardial infarction, when taken on a chronic basis for at least 18 months. One emerging hypothesis that may explain the cardiovascular effects is that coxibs create an imbalance in circulating TxA2 (thromboxane) and PGI2 (prostacyclin) levels. An increased in the ratio of TxA2/PGI2 could lead to increased platelet aggregation and dysregulation of platelet homeostatis.[citation needed]
[edit] Clinical uses
Synthetic prostaglandins are used:
- To induce childbirth, parturition or abortion (PGE2 or PGF2, with or without mifepristone, a progesterone antagonist);
- To prevent closure of ductus arteriosus in newborns with particular cyanotic heart defects
- To prevent and treat peptic ulcers (PGE)
- As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb
- In pulmonary hypertension
- In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity)
- To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).[6]
In medicine, a shunt is a hole or passage which moves, or allows movement of, fluid from one part of the body to another. The term may describe either congenital or acquired shunts; and acquired shunts (sometimes referred to as iatrogenic shunts) may be either biological or mechanical.
Cardiac shunt
Cardiac shunts may be described as right-to-left, left-to-right or bidirectional, or as systemic-to-pulmonary or pulmonary-to-systemic. The direction may be controlled by left and/or right heart pressure, a biological or artificial valve, or both. The presence of a shunt may also affect left and/or right heart pressure either beneficially or detrimentally.
[edit] Congenital
The most common congenital heart defects (CHDs) which cause shunting are the atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), and patent foramen ovale (PFO). In isolation, these defects may be asymptomatic, or they may produce symptoms which can range from mild to severe, and which can either be acute or have delayed onset. However, these shunts are often present in combination with other defects; in these cases, they may still be asymptomatic, mild or severe, acute or delayed, but they may also work to counteract the negative symptoms caused by another defect (as with d-Transposition of the great arteries).
[edit] Acquired
[edit] Biological
Some acquired shunts are modifications of congenital ones: a balloon septostomy can enlarge a foramen ovale (if performed on a newborn), PFO or ASD; or prostaglandin can be administered to a newborn to prevent the ductus arteriosus from closing. Biological tissues may also be used to construct artificial passages.
[edit] Mechanical
Mechanical shunts are used in some cases of CHD to control blood flow or blood pressure. One example is the modern version of the Blalock-Taussig shunt.
[edit] Cerebral shunt
In cases of hydrocephalus, a one-way valve is used to drain excess cerebrospinal fluid from the brain and carry it to other parts of the body. This valve usually sits outside the skull, but beneath the skin, somewhere behind the ear.
Although a shunt generally works well, it may stop working if it disconnects, becomes blocked, or it is outgrown. If this happens the cerebrospinal fluid will begin to accumulate again and a number of physical symptoms will develop such as listlessness, headaches, irritability, light sensitivity, sound sensitivity, nausea, vomiting, dizziness, vertigo, migraines, some extremely serious, like seizures.
The shunt failure rate is also relatively high and it is not uncommon for patients to have multiple shunt revisions within their lifetime.
The diagnosis of cerebro-spinal buildup is complex and requires expertise.
[edit] Spitz-Holter
A common pediatric shunt is the Spitz-Holter shunt. It is a tiny one-way valve that releases controlled amounts of CSF from the brain to the heart. Spitz refers to the American neurosurgeon Eugene B. Spitz. Holter refers to the designer of the valve, John Holter, who was unable to save his son Casey from hydrocephalus, but his design, the Spitz-Holter valve/shunt, has helped millions around the world since the late 1950s.
[edit] Pulmonary shunt
Pulmonary shunts exist when there is normal perfusion to an alveolus, but ventilation fails to supply the perfused region. This will lead to a situation where the blood supply leaving a shunted area of the lung will have lower levels of oxygen and higher levels of carbon dioxide (i.e., the normal gas exchange doesn't occur).
[edit] Portosystemic shunt
A portosystemic shunt (PSS), also known as a liver shunt, is a bypass of the liver by the body's circulatory system. It can be either a congenital or acquired condition. Congenital PSS is an uncommon condition in dogs and cats, found mainly in small dog breeds such as Miniature Schnauzers and Yorkshire Terriers, and in cats such as Persians, Himalayans, and mix breeds. Acquired PSS is also uncommon and is found in older dogs with liver disease causing portal hypertension, especially cirrhosis.
