PARACETAMOL

Post-2         PARACETAMOL ASPIRIN AND OTHER NSAIDs                 Pharmacology,Toxicology,& Therapy

1)

(a) Paracetamol

Paracetamol the commonly used drug as a painkiller is available in all retail pharmacies as a OTC medicines by various trade names like Tylenol,Dolo etc.The medicine is available as Tablets,Liquid orals and injecions.Although it is not as strong as Aspirin and other NSAIDs it is prefered by physicians for pains and fever as it is mostly stomach friendly.Paracetamol is the drug of choice for women to get relieved from painfull periods.The above video describes the functions and toxicity of Paracetamol in lecture.

The following video would describe a detailed view of this drug's toxic effect.

After Paracetamol is administered orally it is readily absorbed into the body system but mostly metabolized  in  liver into the toxic N-acetyl-p-quinone which is necrotic to the liver muscles if attacked  directly. But thank God it may not happen as if there is sufficient presence of the enzyme Glutathione in Liver.The sulfydryl group of the enzyme would neutralise the toxic metabolite of Paracetamol before it get access to the hepatic muscles.But frequent and careless administration especially to children as it is available in palatable flavoured syrups and may be in some occations prescribed by some paediatricians would lead to disaster.

Please see the following video:

CHEMISTRY

About 100 years ago a chemical known as Acetanilide is included in the patients prescription which after administration converted by the body into paracetamol and aniline.While paracetamol works as analgesic aniline on the other hand very toxic.To avoid this the chemists later on worked hardly and modified acetanilide into N-acetyl-para-aminophenol known as Acetaminophen in U.S.A and Paracetamol in other parts of the world.

Paracetamol in its chemical structure is resembling that of Aspirin and hence recognised by the same enzymes which are responsible for the synthesis of Prostaglandin.Hence paracetamol too is used as analgesic like aspirin but unlike aspirin which is an acid paracetamol is basic and hence it is harmless to stomach
Pharmacokineics

Paracettamol once absorbed is meabolised mainly in liver and to a lesser exent intestine.Paraceamol in therapeuic doses is metabolised to a major exend to phrmacologically inactive glucouranide and sulfide canjugates and to a minor extend to highly active NAPQI (N-amino-p-quinone) which is mostly causing hepato toxicity and is detoxified by the precence of a protecive enzyme Glutathione in the Liver.Glutathione combines wih NAPQI wih its sufidryl bond to form a bondage and ultimately excreted in urine as cysteine and mercapturic acid conjugates.

Pharmacodynamics

Paracetamol has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid receptors. Prostaglandin H₂ synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable PGH₂. The two major forms of this enzyme are the constitutive PGHS-1 and the inducible PGHS-2. PGHS comprises of two sites: a cyclooxygenase (COX) site and a peroxidase (POX) site. The conversion of arachidonic acid to PGG₂ is dependent on a tyrosine-385 radical at the COX site. Formation of a ferryl protoporphyrin IX radical cation from the reducing agent Fe³⁺ at the POX site is essential for conversion of tyrosine-385 to its radical form. Paracetamol acts as a reducing cosubstrate on the POX site and lessens availability of the ferryl protoporphyrin IX radical cation. This effect can be reduced in the presence of hydroperoxide-generating lipoxygenase enzymes within the cell (peroxide tone) or by swamping the POX site with substrate such as PGG₂. Peroxide tone and swamping explain lack of peripheral analgesic effect, platelet effect, and anti-inflammatory effect by paracetamol. Alternatively, paracetamol effects may be mediated by an active metabolite (p-aminophenol). p-Aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts effect through cannabinoid receptors. It may also work through PGHS, particularly in areas of the brain with high concentrations of fatty acid amide hydrolase.

(Thanks to http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9592.2008.02764.x/full)

Also see the following video:-

For further details go to the foiiowing links:-http://fileam.com/file/0558l56

http://okayfiles.com/file/0558l63http://okayfiles.com/file/0558l63

(b) Aspirin

Acetyl salicylic acid as it is generically known by a chemist is made into familiar and well branded as ASPIRIN commercially by Bayer company.But it is now world wide manufactured and distribued by various companies by various commercial names.
To have a further full details of NSAIDs please click here the downloadable link to download into your computer for your reference

Diclofenac

http://reliabledownloads.org/file/05595969