Hi guys and welcome to another episode of chem rounds where we bring you the latest in chemistry today we’re going to be talking about pravastatin but first let’s take a look at what its useful with julianna thanks guys today i’m going to talk to you about hypercholesterolemia cholesterol is a fatty modified steroid which is insoluble in water it can be taken in
Through the diet or synthesized in the body and as a precursor for many important steroid hormones cholesterol and proteins combine in the blood to form lipoproteins used for transport there are two main types of lipoprotein high density lipoprotein or hdl this is known as good cholesterol and low-density lipoprotein or ldl was loaded bad cholesterol many factors
Can cause high cholesterol a diet high in saturated fat can increase your bad cholesterol levels as well as a lack of exercise obesity and regularly drinking large amounts of alcohol a chemical in secret cigarettes could acrolein stops haich-d out transporting cholesterol from fatty deposits to the liver leading to cholesterol building up in the arteries some
Underlying conditions such as diabetes can also cause high cholesterol as well as several fixed factors such as age gender and a family history of hypercholesterolemia as cholesterol is insoluble in water when it accumulates in the wrong place for example within the wall of an artery it’s hard to remove if we eventually lead into an atherosclerosis platforming
These plaques can cause the artery to harden and narrow restricting the blood flow and oxygen supplied to vital organs such as the heart or brain if left to get worse these can lead to a number of serious conditions known as cardiovascular disease or cvd types of cvd includes coronary heart disease peripheral arterial disease stroke and heart attack thank you
Julie island that was pravastatin snooze and now back to the beginning with the discovery of pravastatin either to marry a man he going discovery of pravastatin the search for lost rose into this inhibitor became an important aspect of research after a genetic connection between heart attack and cholesterol was made in 1939 inspired by fleming success with
Modes akiro endo a japanese microbiologist discovered started during his research of a mentation blood of penicillin subpoena he found in natural product with a powerful inhibitory effect on the heat energy reductase enzyme the active ingredient in the broth was known as citrine named although it was later discovered to be toxic to the kidneys there are other
Discoveries like compacted they were very effective but failed the animal cell since age of drug trials amongst maori with use of compaction was profits in sodium its potency as tissue selectivity is one of the reasons if half the job trial all obtains from a historical perspective on discovery of statins by akira endo series b page four eight four two four nine
Three and that was miriam and hugo with the discovery of promise that in now we’re going to look at the synthesis structure and mechanism of action over to ford in the lab so let’s talk about the sequences of power status so horse time began from this fungi man for her called personal chicken and this was fermented in the lab to give us compaction also known
As mara style this was unified in the lab before sodium hydroxide was then reacted and it is the ester from the latin link does this open to give us a salt on one end and alcohol on the next so this undergoes a bio transmission step with the bacteria called bacterium septum isis cover for us and this contains a cytochrome p450 enzyme that selectively hydroxylase
The c6 end of this structure to give us palestine ok so now we understand the symphysis of rather stuff in it’s time to move on and talk about the structure of the drug to begin here is the structure of pravastatin working our way through the functional groups we can see we have abi’s hydroxyl group here which will show polarity and alpha ester functional group
Attached to the first cyclic ring this group would be prone to hydrolysis within the body jerry metabolism and extrusion of the drug 2 beta hydroxyl groups attached to the side chain here and finally a carboxylic acid group at the end of the side chain which is converted into sodium salt were manufactured into the drug on the shelves which we know as pravastatin
Sodium tablet let’s take a look at the mechanism of action but first let’s see the synthesis of cholesterol cholesterol is made by reacting acetal coa with acetyl acetone coa to make the cholesterol precursor hmg-coa next you use hmg-coa to make pavlin eight isoprene units squalene and finally cholesterol you use the reductive power of nadph and the enzyme hmg
Co-reductase to make methyl innate this is a rate limiting step and joggers are going to use this area to competitively inhibit hmg reductase so that marilyneg cannot be made and consequently cholesterol here are the structures of the natural substrate hmg coa and pravastatin as you can see they are structurally similar the hydrolyzed lactone ring on pravastatin
Mimics a tetrahedral intermediate produced by h mg reductase on hmg-coa this allows pravastatin to bind to the active site to a much greater affinity than its natural substrate it is the by cyclic portion as cycled over there that is going to bind to the coenzyme a portion of the active site and consequently cause reversible inhibition okay let’s take a look at
The active site interactions a pravastatin is going to change the confirmation ability of the enzyme what’s this bind to it this allows it to have as many interactions as possible and it causes a hydrophobic groove in the enzyme this can accommodate pravastatin hydrophobic groups such as this over here and liter vander well forces there are also going to be
Polar interactions taking place in the system of the enzyme with amino acids such as serine and lysine and also madonna kinter actions forming a salt bridge with the amino acids there’s also gonna be hydrogen bonding with the hydroxyl groups on this molecule and pi pi stacking umple of a saturn blocking the active site of air the hmg-coa reductase finally it works
By reversibly inhibiting hmg-coa reductase reducing cholesterol pools and in the same way it has triglyceride lowering properties this time by inhibiting hepatic synthesis of very low density lipoproteins pravastatin is one of the lower potency studies but it’s increased hydrophilicity means minimal penetration through life filling membranes of peripheral cells
And the blood-brain barrier this means increased selectivity in hepatic tissues and fewer side-effects when compared to similar statin it’s also taken up by the liver by the active transport carrier systems such as the independent sodium bile acid transporter it’s oral inactive form with an absorption of 34% and a low bioavailability of 17% due to incomplete
Absorption in first part extraction in the liver it reaches the peak plasma concentration are one to one and a half hours so now we know the structure of pravastatin and how it’s made and how it works inside the body we’re now going to look at side effects now i were to jenny alright thanks guys let’s take a look is some side effects so there are two types of
Effects on psycho side effects and all tucker side effects and now we will look into more details that the on tucker side effects of pravastatin fest these are exaggerated nfs pharmacological effects at a target of interest like all the other statutes pravastatin competitively inhibit hip hip attack hmg-coa reductase an enzyme involved in cholesterol synthesis
It changes the hepatocellular lipid concentration and plasma membrane permeability which means calls trans amoenus enzyme leak and therefore an associated information response giving rise to a biochemical hepatitis it could also cause jaundice which is a yellowing of the skin and whites of the eyes this is one of the relevant consequences of livers dysfunction so
It is a vice to be avoided by patients with liver disease moving on to the old turkish side effects the rfs effects as a result of modulation of the other targets this may be related biologically or totally unrelated to the target of interest muscle effects is the main of tata side-effects which is most likely to be caused by the integral pravastatin mitochondria
Dysfunction is believed it ben main mechanism must – induce myoga the– it has been suggested that statins can play a non tokenistic row on the conductance of chloride channels of muscular cells and reduce the flux through the cholesterol synthesis pathway but they also may also induce a chronic muscle contract our state eventually leading to malba the– it could
Also cause mouse touches in which you can see from the picture here patient could possibly different information without infiltration within skeletal muscles this results in skin rashes on the face and the back of the hands it appears to be a natural healing process secondary to the muscular damage and in other words the consequences of marbeth ii that we have
Just discussed own although in the overall pravastatin it’s just usually about tolerated drug experience of a serious and fatal side effects is rare a more conclusive solution is to remove the additional cholesterol being put into your body by managing diets and exercising as such a safe healthy level cholesterol can be maintained very effectively thanks for
Watching this has been rebecca this has been mariam reporting from camera round
Transcribed from video
B5 Pravastatin By Fuad Mahamud
