14 - enoxaparin ( levonox ) ( lupenox )

How does it work?

Enoxaparin is a medicine known as a low molecular weight heparin. It is an anti-clotting or anticoagulant medicine, and works by interfering with the body's natural blood clotting mechanism. Blood clotting involves a complex series of pathways. Enoxaparin inactivates a compound in this pathway called thrombin, which plays an important role in blood clot formation. Therefore, enoxaparin prevents the formation of blood clots (thrombosis) in the body. Blood clots within the body can be dangerous as they can travel in the blood vessels and potentially block off blood supply to the heart, lungs or brain. Enoxaparin is given by injection under the skin, and is used to prevent clots forming in the blood. This can occur in various conditions where the normal blood circulation is disturbed. Surgery, particularly abdominal surgery, produces a risk of thrombosis, as does a heart attack and poorly controlled angina (unstable angina). Clots can also occur when people are bed-ridden for long periods of time. Enoxaparin is given to prevent thrombosis in these groups of people. In addition, enoxaparin is used to prevent blood clotting when it is filtered through a kidney dialysis machine. Enoxaparin is also used to treat blood clots which have formed in the veins of the leg (deep vein thrombosis), as these may otherwise detach and travel in the circulation to the lungs causing a pulmonary embolism.

What is it used for?

 Angina not well controlled by medical treatment

 Blood clot lodged in a vein of the leg

 Heart attack

 Prevention of blood clot formation in the veins after surgery

 Prevention of blood clot formation in the veins in people bedridden due to illness

 Prevention of blood clots during haemodialysis

Warning!

 This medicine is not recommended for use in children as no dose has been established.

 It is recommended that blood tests to monitor the levels of platelets in the blood are performed prior to and during treatment with this medicine.

 Blood potassium levels should be measured before starting treatment and at regular intervals throughout, particularly if treatment lasts longer than 7 days.

Use with caution in

 Decreased liver function

 Diabetes affecting the eyes

 History of reduced platelet count (thrombocytopenia) caused by heparin treatment

 People who have previously had a peptic ulcer

 People who have recently had a stroke

 People who have recently had eye surgery

 People who have recently had surgery of the brain or spinal cord (neurosurgery)

 People with problems stopping bleeding

 Severe uncontrolled high blood pressure

 Severely decreased kidney function

Not to be used in

 Active peptic ulcer

 Bacterial infection of the heart valves and the lining surrounding the heart (bacterial endocarditis)

 Major bleeding disorders such as haemophilia

 People with an increased risk of bleeding (haemorrhage)

 Reduced platelet count in the blood

 Stroke associated with internal bleeding of the brain

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy. If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.

Pregnancy and Breastfeeding

Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.

 This medicine is not recommended for use in pregnancy unless considered essential by your doctor. Seek medical advice from your doctor.

 It is not known whether this medicine passes into breast milk. Mothers who need to take this medicine should not breastfeed. Seek medical advice from your doctor.

Side effects

Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.

 Allergy to active ingredients (hypersensitivity)

 Alteration in results of liver function tests

 Bleeding (haemorrhage)

 High blood potassium level (hyperkalaemia)

 Thinning of the bones (osteoporosis) with long term use

 Decrease in the number of platelets in the blood (thrombocytopenia)

 Presence of blood clots in the spinal cord (intra-spinal haematoma)

 Blood clots which form a solid swelling at the injection site (haematoma)

 Pain and irritation at the injection site

 Death of skin cells (necrosis) at the site of injection

The side effects listed above may not include all of the side effects reported by the drug's manufacturer. For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.

13 - low molecular weight heparins

In medicine, low-molecular-weight heparin (LMWH) is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis.^[1]

Heparin is a naturally-occurring polysaccharide that inhibits coagulation, the process whereby thrombosis occurs (see Heparin: Mechanisms of action). Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of molecular weight from 5000 to over 40,000 Daltons, making up polydisperse pharmaceutical-grade heparin.^[2]

Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis (see anticoagulation). However, the effects of natural, or unfractionated heparin can be difficult to predict. After a standard dose of unfractionated heparin, coagulation parameters must be monitored very closely to prevent over- or under-anticoagulation.

Low-molecular-weight heparins (LMWHs), in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin. They have a potency of greater than 70 units/mg of anti-factor Xa activity and a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5.^[3]

Low-molecular-weight heparin products

The anhydromannose in IdoA(2S)-anhydromannose can be reduced to an anhydromannitol

Various methods of heparin depolymerisation are used in the manufacture of low-molecular-weight heparin.^[4] These are listed below:

• Oxidative depolymerisation with hydrogen peroxide. Used in the manufacture of ardeparin (Normiflo®)
• Deaminative cleavage with isoamyl nitrite. Used in the manufacture of certoparin (Sandoparin®)
• Alkaline beta-eliminative cleavage of the benzyl ester of heparin. Used in the manufacture of enoxaparin (Lovenox® and Clexane®)
• Oxidative depolymerisation with Cu²⁺ and hydrogen peroxide. Used in the manufacture of parnaparin (Fluxum®)
• Beta-eliminative cleavage by the heparinase enzyme. Used in the manufacture of tinzaparin (Innohep® and Logiparin®)
• Deaminative cleavage with nitrous acid. Used in the manufacture of dalteparin (Fragmin®), reviparin (Clivarin®) and nadroparin (Fraxiparin®)

Deaminative cleavage with nitrous acid results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannitol using a suitable reducing agent as shown to the left.

UA(2S)-GlcNS(6S)

Likewise both chemical and enzymatic beta-elimination result in the formation of an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as shown to the left.

Differences between low molecular weight heparin products

Comparisons between LMWHs prepared by similar processes vary. For example, a comparison of Dalteparin and Nadroparin suggests they are more similar than products produced by different processes. However comparison of enoxaparin and tinzaparin shows they are very different from each other with respect to chemical, physical, and biological properties.

As might be expected, products prepared by distinctly-different processes are dissimilar in physical, chemical, and biological properties.

see references.^{[5][6][7][8][9][10]}.

Differences from unfractionated heparin

Its differences with unfractioned heparin include:

• Average molecular weight: heparin is about 20000 Da and LMWH is about 3000 Da
• Once-daily dosing, rather than a continuous infusion of unfractionated heparin
• No need for monitoring of the APTT coagulation parameter
• Possibly a smaller risk of bleeding
• Smaller risk of osteoporosis in long-term use
• Smaller risk of heparin-induced thrombocytopenia, a feared side-effect of heparin.
• The anticoagulant effects of heparin are typically reversible with protamine sulfate, while the effect on LMWH is limited
• Has less of an effect on thrombin compared to heparin, but maintains the same effect on Factor Xa.

Clinical uses

Because it can be given subcutaneously and does not require APTT monitoring, LMWH permits outpatient treatment of conditions such as deep vein thrombosis or pulmonary embolism that previously mandated inpatient hospitalization for unfractionated heparin administration

The use of LMWH needs to be monitored closely in patients at extremes of weight or in-patients with renal dysfunction. An anti-factor Xa activity may be useful for monitoring anticoagulation. Given its renal clearance, LMWH may not be feasible in patients that have end-stage renal disease.

Use in venothromboembolic disease associated with cancer

The CLOT study, published in 2003, showed that, in patients with malignancy and acute venous thromboembolism, dalteparin was more effective than coumarin in reducing the risk of recurrent embolic events.^[11]

References

1. ^ Weitz JI (1997). "Low-molecular-weight heparins". N Engl J Med 337 (10): 688-98. PMID 9278467.
2. ^ Linhardt, R.J. Gunay, N. S. (1999). "Production and chemical processing of low molecular weight heparins". Sem. Thromb. Hem. 25 (3): 5-16.
3. ^ European Pharmacopedia Commission (1991). "{{{title}}}". Pharmeuropa 3: 161-165.
4. ^ Linhardt, R.J. Gunay, N. S. (1999). "Production and chemical processing of low molecular weight heparins". Sem. Thromb. Hem. 25 (3): 5-16.
5. ^ Green, D. Hirsh, J. Heit, J. et al (1991). "Low molecular weight heparin: A critical analysis of clinical trials". Pharmacol. Rev. 2: 45-50.
6. ^ Barrowcliffe, T. W. (1995). "Low molecular weight heparin(s)". Br. J. Haematol. 90: 1-7.
7. ^ Donayre C. E. (1996). "Current use of low molecular weight heparins". Semin. Vascul. Surg. 9: 362-371.
8. ^ Hunt, D. (1998). "Low molecular weight heparins in clinical practice". Southern Medical J. 91: 2-10.
9. ^ Fareed, J. Jeske, W. Hoppensteadt, D. Clarizio, R. Walenga, J. M. (1998). "Low molecular weight heparins: Pharmacologic profile and product differentiation". Am. J. Cardiol. 82: 3L-10L.
10. ^ Ramos-Sánchez MC, Barrio-Arredondo MT, De Andrés Santos AI, Martín-Gil J, Martín-Gil F.J. (1995). "Thermal analysis of aqueous solutions of heparins". Thermochim Acta 262: 109-115.
11. ^ Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M (2003). "Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer". N Engl J Med 349 (2): 146-53. PMID 12853587.