McLean, a medical student, discovered in 1916 that liver contains a powerful anticoagulant. Howell and Holt (1918) named it ‘heparin’ because it was obtained from liver. However, it could be used clinically only in 1937 when sufficient degree of purification was achieved.
HEPARIN
McLean, a medical student,
discovered in 1916 that liver contains a powerful anticoagulant. Howell and
Holt (1918) named it ‘heparin’ because it was obtained from liver. However, it
could be used clinically only in 1937 when sufficient degree of purification
was achieved.
Heparin is a nonuniform
mixture of straight chain mucopolysaccharides with MW 10,000 to 20,000. It
contains polymers of two sulfated disaccharide units:
D-glucosamine-Liduronic
acid
D-glucosamine-Dglucuronic
acid
*chain length and
proportion of the two disaccharide units varies. Some glucosamine residues are N-acetylated.
It carries strong
electronegative charges and is the strongest organic acid present in the body.
It occurs in mast cells as a much bigger molecule (MW ~75,000) loosely bound to
the granular protein. Thus, heparin is present in all tissues containing mast
cells; richest sources are lung, liver and intestinal mucosa. Commercially it
is produced from ox lung and pig intestinal mucosa.
Actions
1. Anticoagulant
Heparin is a powerful
and instantaneously acting
anticoagulant, effective both in vivo
and in vitro. It acts indirectly by
activating plasma antithrombin III (AT III, a serine proteinase inhibitor) and
may be other similar cofactors. The heparinAT III complex then binds to
clotting factors of the intrinsic and common pathways (Xa, IIa, IXa, XIa, XIIa
and XIIIa) and inactivates them but not factor VIIa operative in the extrinsic
pathway. At low concentrations of heparin, factor Xa mediated conversion of
prothrombin to thrombin is selectively affected. The anticoagulant action is
exerted mainly by inhibition of factor Xa as well as thrombin (IIa) mediated
conversion of fibrinogen to fibrin.
Low concentrations of
heparin prolong aPTT without significantly prolonging PT. High concentrations
prolong both. Thus, low concentrations interfere selectively with the intrinsic
pathway, affecting amplification and continuation of clotting, while high
concentrations affect the common pathway as well.
Antithrombin III is itself a substrate for the protease clotting
factors; binds with the protease to form a stable complex (suicide inhibitor).
However, in the absence of heparin, the two interact very slowly. Heparin
enhances the action of AT III in two ways:
·
Long heparin molecule provides a scaffolding
for the clotting factors (mainly Xa and IIa) as well as AT III to get bound and
interact with each other.
·
Heparin induces conformational change in AT
III to expose its interactive sites. Recently, it has been shown that a
specific pentasaccharide sequence, which is present in only some of the heparin
molecules, binds to AT III with high affinity to induce the conformational
change needed for rapid interaction with clotting factors.
Inhibition of IIa requires both the mechanisms, but Xa
inhibition can occur by mechanism ‘b’ alone. This probably explains why low molecular
weight heparin, which is insufficient to provide a long scaffolding,
selectively inhibits factor Xa.
Higher doses of heparin given for some time cause reduction in
ATIII levels, probably a compensatory phenomenon. Sudden stoppage of conventional-dose
therapy may result in rebound increase in coagulability for few days.
2. Antiplatelet
Heparin in higher
doses inhibits platelet aggregation and prolongs bleeding time.
3. Lipaemia
Clearing
Injection of heparin clears turbid postprandial lipaemic by releasing
a lipoprotein lipase from the vessel wall and tissues, which hydrolyses
triglycerides of chylomicra and very low density lipoproteins to free fatty
acids; these then pass into tissues and the plasma looks clear. This action
requires lower concentration of heparin than that needed for anticoagulation.
Facilitation of fatty acid transport may be the physiological
function of heparin; but since, it is not found in circulating blood and its
storage form in tissues is much less active, this seems only conjectural.
Pharmacokinetics
Heparin is a large,
highly ionized molecule; therefore not absorbed orally. Injected i.v. it acts
instantaneously, but after s.c. injection anticoagulant effect develops after
~60 min. Bioavailability of s.c. heparin is inconsistent. Heparin does not
cross blood-brain barrier or placenta (it is the anticoagulant of choice during
pregnancy). It is metabolized in liver by heparinase and fragments are excreted
in urine.
Heparin released from
mast cells is degraded by tissue macrophages—it is not a physiologically
circulating anticoagulant.
After i.v. injection
of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dosedependent
inactivation is seen and t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotics
and kidney failure patients, and shorter in patients with pulmonary embolism.
Because of variable molecular size, heparin is standardized only
by bioassay: 1 U is the amount of heparin that will prevent 1 ml of citrated
sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2
solution. Heparin sod. 1 mg has 120–140 U of activity.
HEPARIN SOD., BEPARINE,
NUPARIN 1000 and 5000 U/ml in 5 ml vials for injection.
Heparin should not be
mixed with penicillin, tetracyclines, hydrocortisone or NA in the same syringe
or infusion bottle. Heparinized blood is not suitable for blood counts (alters
the shape of RBCs and WBCs), fragility testing and complement fixation tests.
Dosage
Heparin is
conventionally given i.v. in bolus doses of 5,000–10,000
U (children 50–100 U/kg) every 4– 6 hours, or the initial bolus dose is
followed by continuous infusion of 750–1000 U/hr which may reduce the total
dose needed and the incidence of bleeding. The dose and frequency is controlled
by aPTT measurement which is kept at 50–80 sec. or 1.5–2.5 times the patient’s
pretreatment value. If this test is not available, whole blood clotting time
should be measured and kept at ~2 times the normal value.
Deep s.c. injection of
10,000–20,000 U every 8–12 hrs can be given if repeated i.v. injection or
infusion is not possible. Needle used should be fine and trauma should be
minimum to avoid haematoma formation. Haematomas are more common with i.m.
injection—this route should not be used.
Low Dose (s.c.) Regimen 5000 U is injected
s.c. every 8– 12 hours, started
before surgery and continued for 7–10 days or till the patient starts moving
about. This regimen has been found to prevent postoperative deep vein
thrombosis without increasing surgical bleeding. It also does not prolong aPTT
or clotting time. However, it should not be used in case of neurosurgery or
when spinal anaesthesia is to be given. The patients should not be receiving
aspirin or oral anticoagulants. It is ineffective in highrisk situations, e.g.
hip joint or pelvic surgery.
Adverse Effects
1. Bleeding due to
overdose is the most serious complication of heparin therapy. Haematuria is
generally the first sign. With proper monitoring, serious bleeding is reported
in 1–3% patients.
2. Thrombocytopenia is
another common problem. Generally it is mild and transient; occurs due to
aggregation of platelets. Occasionally serious thromboembolic events result. In
some patients antibodies are formed to the heparinplatelet complex and marked
depletion of platelets occurs— heparin should be discontinued. Even LMW
heparins are not safe in such patients.
3. Transient and
reversible alopecia is infrequent. Serum transaminase levels may rise.
4. Osteoporosis may
develop on long-term use of relatively high doses.
5. Hypersensitivity
reactions are rare—urticaria, rigor, fever and anaphylaxis. Patients with
allergic diathesis are more liable.
Contraindications
·
Bleeding disorders, heparin induced thrombocytopenia.
· Severe hypertension, (risk of cerebral haemorrhage),
threatened abortion, piles, g.i. ulcers (risk of aggravated bleeding).
·
Subacute bacterial endocarditis (risk of embolism),
large malignancies (risk of bleeding in the central necrosed area of the
tumour), tuberculosis (risk of hemoptysis).
·
Ocular and neurosurgery, lumbar puncture.
·
Chronic alcoholics, cirrhosis, renal failure.
· Aspirin and other antiplatelet drugs should be
used very cautiously during heparin therapy.
Low Molecular Weight (LMW) Heparins
Heparin has been
fractionated into LMW forms (MW 3000–7000) by different techniques. LMW
heparins have a different anticoagulant profile; selectively inhibit factor Xa
with little effect on IIa. They act only by inducing conformational change in
AT III and not by bringing together AT III and thrombin. As a result, LMW heparins
have smaller effect on aPTT and whole blood clotting time than unfractionated
heparin (UFH) relative to antifactor Xa activity. Also, they appear to have
lesser antiplatelet action—less interference with haemostasis. Thrombocytopenia
is less frequent. A lower incidence of haemorrhagic complications compared to
UFH has been reported in some studies, but not in others. However, major
bleeding may be less frequent. The more important advantages of LMW heparins
are pharmacokinetic:
• Better subcutaneous
bioavailability (70–90%) compared to UFH (20–30%): Variability in response is
minimized.
• Longer and more
consistent monoexponential t½: once daily s.c. administration.
• Since aPTT/clotting
times are not prolonged, laboratory monitoring is not needed; dose is calculated
on body weight basis.
Most studies have
found LMW heparins to be equally efficacious to UFH. Indications of LMW
heparins are:
1. Prophylaxis of deep
vein thrombosis and pulmonary embolism in highrisk patients undergoing surgery;
stroke or other immobilized patients.
2. Treatment of
established deep vein thrombosis.
3. Unstable angina.
4. To maintain patency
of cannulae and shunts in dialysis patients, and in extracorporeal circulation.
A number of LMW
heparins have been marketed. They differ in composition, pharmacokinetics and
dosage.
Enoxaparin: CLEXANE 20 mg (0.2 ml) and 40 mg (0.4 ml) prefilled syringes; 20–40 mg OD, s.c. (start 2 hour before surgery).
Reviparin: CLIVARINE 13.8 mg (eq. to 1432 anti Xa IU) in 0.25 ml prefilled syringe; 0.25 ml s.c. once
daily for 510 days.
Nadroparin: FRAXIPARINE 3075 IU (0.3 ml) and 4100 IU (0.4 ml) inj., CARDIOPARIN 4000 anti Xa IU/0.4
ml, 6000 anti Xa IU/0.6 ml, 100, 000 anti Xa IU/10 ml inj.
Dalteparin: 2500 IU OD for prophylaxis; 100 U/Kg 12 hourly or 200 U/Kg 24 hourly for treatment of
deep vein thrombosis. FRAGMIN 2500, 5000 IU prefilled syringes.
Pamparin: 0.6 ml s.c. OD for unstable angina and prophylaxis of DVT; FLUXUM 3200 IU (0.3
ml), 6400 IU (0.6 ml) inj.
Ardeparin: 25005000 IU OD; INDEPARIN 2500 IU,
5000 IU prefilled syringes.
Fondaparinux: The pentasaccharide
with specific sequence that binds to AT III
with high affinity to selectively inactivate factor Xa has been recently
produced synthetically and given the name fondaparinux.
It has been marketed in USA and some other countries.
Heparinoids
Heparan sulfate It is a heparinlike
natural substance found on cell surface
and intercellular matrix in many tissues. It is a less potent anticoagulant
than heparin, but may have a more favourable profile of action.
Danaparoid is a preparation containing mainly heparan sulfate, obtained from pig gut mucosa, which
is used in cases with heparin induced thrombocytopenia.
Lepirudin This recombinant preparation of hirudin (a polypeptide anticoagulant secreted by salivary
glands of leech) acts by inhibiting thrombin directly. It is indicated in
patients with heparin induced thrombocytopenia.
Ancrod It is an enzyme obtained from Malayan pit
viper venom. It degrades
fibrinogen into an unstable form of fibrin which is taken up by RE cells. Thus,
fibrinogen gets depleted and an apparent heparin like effect results. It is
given only by slow infusion: 2 U/kg over 6 hours for deep vein thrombosis in
patients who develop thrombocytopenia or hypersensitivity reactions to heparin
and require immediate anticoagulation.
Protamine sulfate
It is a strongly
basic, low molecular weight
protein obtained from the sperm of certain fish. Given i.v. it neutralises heparin
weight for weight, i.e. 1 mg is needed for every 100 U of heparin. For the treatment
of heparin induced bleeding, due consideration must be given to the amount of
heparin that may have been degraded by the patient’s body in the mean time.
However, it is needed infrequently because the action of heparin disappears by
itself in a few hours, and whole blood transfusion is indicated to replenish
the loss when bleeding occurs. Protamine is more commonly used when heparin
action needs to be terminated rapidly, e.g. after cardiac or vascular surgery.
In the absence of
heparin, protamine itself acts as a weak anticoagulant by interacting with
platelets and fibrinogen. Being basic in nature it can release histamine in the
body. Hypersensitivity reactions have occurred. Rapid i.v. injection causes
flushing and breathing difficulty.
PROTA, PROTAMINE
SULFATE 50 mg in 5 ml inj.
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