3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.1. Scrap
                  3.1.1.2. Drugs affecting coagulation
                      3.1.1.2.2. Anticoagulants
 3.1.1.2.2.1. Heparin 

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

[SH4:p509]

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

[SH4:p505]

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

[SH4:p506]

  • 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