Heparin (unfractionated)

[SH4:p505-511]

Structures

• Unfractionated heparin is a mixture of highly sulfated glycosaminoglycan
• Endogenous heparin is present in
  * Basophil
  * Mast cells
  * Liver

Pharmacodynamics

Mechanism of action

[SH4:p505]

• Heparin binds to antithrombin III (AT3)
  --> Ability of AT3 to inactivate coagulation enzymes is enhanced by 1000 times
• Heparin also inhibits platelet function
  * [SH4:p505]

NB:

• Antithrombin III (AT3)
  * Inactivate a number of coagulation enzymes (Thrombin (2a), 10a, 9a, 11a, 12a) [SH4:p505]
  * Factor 7/TF complex are also inhibited by AT3 [HH26:p603]

Side effects

Side effects include:
* Haemorrhage
* Thrombocytopenia
* Allergic reactions
* CVS changes
* Altered protein binding
* Altered cell morphology
* Decreased AT3 concentration

Haemorrhage

[SH4:p508]

• Haemorrhage is the most common serious side-effects
• Risks increases with
  * Higher intensity of anticoagulation required
  * Pre-existing coagulation defects
  * Concurrent use of other drugs affecting coagulations (e.g. aspirin)
  * Need for instrumentation
  * Serious concurrent illness
  * Chronic heavy alcohol consumption
• Advantage of heparin
  * Easy assessment of pharmacological effects (APTT, ACT)
  * Short elimination half-time
  * Availability of an antagonist (protamine)

Thrombocytopenia

[SH4:p508]

• Thrombocytopenia induced by heparin can be divided into two syndromes
  * Common and mild (due to drug-induced aggregation)
  * Severe and rare (immune-mediated)

Mild form of thrombocytopenia

• 30-40% of patients treated with heparin
• Platelet count <100 x 10^6 cells/mL
• Due to drug-induced platelet aggregation
• Manifests 3 - 15 days after initiation of therapy (median = 10 days)
• Platelet count returns to baseline within 4 days after discontinuation

Severe form of thrombocytopenia

• 0.5 - 6.0% of patients treated with heparin
• Platelet count <50 x 10^6 cells/mL
• Often associated with
  * Resistance to heparin effect
  * Thrombotic event (i.e. heparin-induced thrombocytopenia and thrombosis [HITT] syndrome)
• Manifests 6 - 10 days after heparin therapy
• Probably due to formation of heparin-dependent antiplatelet antibodies (?IgG)
  --> Triggering platelet aggregation

Allergic reactions

[SH4:p509]

• Obtained from animal tissues
  --> Higher risk of allergy

CVS changes

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Rapid IV infusion of large doses of heparin (300 U/kg)
--> Decreases in systemic vascular resistance (possible direct heparin-induced relaxation of vascular smooth muscles)
--> Modest decrease in MAP and pulmonary artery pressure
* Not related to changes in plasma concentration of ionised calcium

Altered protein binding

[SH4:p509]

• Heparin can displace alkaline drugs from protein-binding sites
• Drugs affected include:
  * Propranolol
  * Diazepam

Altered cell morphology

[SH4:p509]

• Heparin added to whole blood distorts the morphology of leukocytes and erythrocytes
• Heparinised blood cannot be used to test for
  * Complements
  * Isoagglutinins
  * Erythrocyte fragility

NB

• Hematocrit, WBC, and ESR are not effected

Decreased antithrombin concentration

Patients receiving heparin (intermittent or continuous) manifest progressive reduction of antithrombin activity
--> About 1/3 of normal

 

NB:

AT3 is also decreased in
* Patients taking oestrogen-containing contraceptives
* Genetic

Others

Osteoporosis
* Occurs with long term (>5 months) use of high dose heparin [SH4:p508]

Pharmacokinetics

[SH4:p505]

• Pharmacokinetics of heparin is complicated and poorly understood
• Dose-response relationship is NOT linear
  * Anticoagulant response increases disproportionately in intensity and duration with increased dose

Absorption

• Poorly absorbed from GIT
  * Due to poor lipid solubility and high MW
• Administered IV or SC
  * SC has variable bioavailability [SH4:p506]
• IM route is avoided due to risk of hematoma formation

Distribution

• Heparin binds to many plasma proteins
  --> Wide variability in response
• Heparin does NOT cross placenta
  --> Heparin is used for anticoagulation in pregnancy
  * Warfarin is contraindicated in pregnancy

Elimination

A fraction of heparin is excreted in urine as a depolymerised and less sulfated molecules with 50% of original activity

Precise pathway of heparin excretion is uncertain

Action profile

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Elimination half-time

• After a dose of 100 U/kg
  --> Elimination half-time = 56 min (~1 hour)
• After a dose of 400 U/kg
  --> Elimination half-time = 152 min (~2.5 hours)
• c.f. Elimination half-time for LMWH = 4 - 5 hours [SH4:p511]

Elimination half-time is prolonged in
* Decrease in body temperature (<37C)
* Hepatic dysfunction
* Renal dysfunction

Onset of action

[SH4:p506]

IV --> Immediate onset

SC --> Onset in 1 - 2 hours

Physicochemical properties

Heparin is...

• Poorly lipid-soluble
• High MW substance
• Cannot cross lipid barriers in significant amounts

Pharmaceutics

[SH4:p505]

• Commercial preparations vary
  * MW range  from 3,000 to 30,000 daltons
• Only about 1/3 of heparin binds to AT3
  --> Responsible for most of the anticoagulant effect
• Most commonly prepared from
  * Bovine lung
  * Bovine or porcine GIT mucosa

Standardisation of heparin potency

[SH4:p505]

• Based on in vitro comparison with a known standard
• A unit of heparin is defined as
  ... the volume of heparin-containing solution that will prevent 1mL of citrated sheep blood from clotting for 1 hour after the addition of 0.2mL of 1:100 calcium chloride
• Heparin must contain at least 120 United States Pharmacopeia (USP) units per mL

Clinical

Factors affecting effect of heparin

Decrease heparin effect (i.e. an increased dose is required)

• Nitroglycerin [SH4:p506]
• Increased plasma protein (in inflammatory disorders and cancer) [SH4:p506]
• Deficiency in antithrombin [SH4:p509]
  * Oestrogen-containing contraceptives
  * Genetic
  --> May be corrected by administration of fresh frozen plasma

Use

• Prevention and treatment of venous thrombosis and pulmonary embolism
• Treatment of unstable angina and MI

 

DVT prophylaxis

[SH4:p508]

• 5000 U SC every 8 - 12 hours

NB:

• Risk of DVT is higher and more prolonged after hip surgery due to
  * Surgical technique which kinks the femoral vein
  * Impairment of venous haemodynamics (which may last several weeks)

Treatment of DVT

[SH4:p508]

• Bolus: 5000 U IV

Followed by

• Continuous infusion of 30,000 U every 24 hours
• Goal = Maintain APTT 1.5 to 2.5 times the control value
• Anticoagulation is maintained for 3 - 6 months

Treatment of unstable angina and MI

• Bolus = 5000 U IV

Followed by

• Continous infusion of 24,000 U every 24 hours

Variability in response

[SH4:p508]

Variability in response to heparin is due to

• 4 fold variation in heparin sensitivity
• 3 fold variation in rate of heparin metabolism

Monitoring of clinical effects

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• Two ways:
  * Activated plasma thromboplastin time (APTT)
  * Activated coagulation time (ACT)
• Low-dose heparin does not necessitate laboratory tests because dosage and schedule are well-known

 

Activated plasma thromboplastin time (APTT)

Target range = 1.5 - 2.5 times the predrug value

Predrug value = 30-35 seconds

 

Activated coagulation time (ACT)

• Supposed to have become the mainstay of heparin monitoring due to ease of use and reliability [SH4:p506]
• Test result may be influenced by other factors
  * Hypothermia
  * Thrombocytopenia
  * Contact activation inhibitors (e.g. aprotinin)
  * Pre-existing coagulation deficiencies (e.g. fibrinogen, factor 7 and 12)

NB:

• When aprotinin is present
  --> Use kaolin-ACT instead of celite-ACT
• Need to measure
  * Before
  * 3 min after IV administration
  * 30 min intervals after IV administration
  --> Due to variability

ACT determination methods

• ACT is performed by mixing whole blood with an activation substance with a large surface area, such as
  * Celite (diatomaceous earth, silicon dioxide)
  * Kaolin (aluminum silicate)
• Blood contacting the activation substance
  --> Initiate activation of clotting cascade
• Results from different commercial devices are not interchangeable
  * Especially if the type of activator is different