I am professionally pharmacist. These slides for clinical subject especially for pharmacy department students. I hope these students get more benefits about it.

1. Heparin

2. Heparin
Chemistry
–Low molecular weight fractions
of heparin have a high affinity
for ACTIVATED FACTOR X
(Xa), but have less of an effect
on thrombin.

3. Interaction of Heparin-ATIII-Clotting Factors
• Heparin needs to interact with
both ATIII and Thrombin
(IIa)
• To enhance its effect on
Factor Xa, heparin needs only
to interact with ATIII
• LMWH can only increase the
action of ATIII on Factor Xa
and not on thrombin (IIa).
Heparin
ATIII IIa
Heparin
ATIII Xa
LMWH
ATIII Xa

4. Inhibition of thrombin and Factor Xa by the Heparin/AT III complex
through a unique pentasaccharide unit. Binding to thrombin requires a
minimum of 13 saccharide units. Low molecular weight heparin acts to
inhibit Factor Xa and requires that the latter only bind to AT III.
A T I I I T h r o m b i n
5 13 or more saccharide units
Heparin
Lysine
Sites
A T I I I F a c t o r X a
5
Low Molecular Weight Heparin
Lysine
Sites
<13

5. Anticoagulant Therapy
Heparin
–Actions of Heparin
»Inactive by itself as an anticoagulant
»Requires the presence of a plasma cofactor-
ANTITHROMBIN III (AT III)
»Heparin potentiates the action of AT III
»Heparin-AT III-complex neutralizes the actions of:
Factors II, IX, X, XI, XII and XIII
»Binds to lysine sites on AT III, leads to
conformational change at the arginine reactive center

6. Heparin-Contraindications
–Patients who are hypersensitive
–Presence of active bleeding or hemophilia
–Thrombocytopenia
–Severe hypertension
–Intracranial hemorrhage
–Bacterial endocarditis
–Active tuberculosis
–Ulcerative lesions of GI tract

7. Heparin-Contraindications
–Threatened abortion
–During or after surgery on the brain, spinal
cord or eye
–Patients undergoing lumbar puncture or
regional anesthesia block
–History of heparin-induced
thrombocytopenia

8. Heparin-Adverse Effects
Side Effects Dose Related Frequency
Major Bleeding Yes 5%
Thrombocytopenia Yes 5 - 15%
with thrombosis Yes 0.4%
Osteoporosis Yes Rare
Anaphylaxis No Rare
Skin necrosis ? Rare
Local urticaria ? Rare
Hypoaldosteronism ? Rare

9. Heparin-Adverse Effects
(continued)
Heparin-Induced Thrombocytopenia -
TWO FORMS:
–Mild reduction in platelet count, 2-15 days
after initiation of full-dose heparin therapy
–Platelet count usually remains above
100,000/µl. Bleeding risk is minimal

10. Heparin-Adverse Effects (continued)
Heparin-Induced Thrombocytopenia-and
Thrombosis
–Severe reduction in platelet count, 7-14 days
after initiation of therapy with full-dose or low-
dose heparin
–May be associated with thrombotic
complications, including arterial thrombosis with
platelet-fibrin clots that may cause MI or stroke

11. Heparin - Laboratory Monitoring
aPTT /ptt
–Therapy is routinely monitored by means of the
aPTT [Activated partial thromboplastin time]
–A clotting time of 1.5 to 2.0 times the normal
mean aPTT value (50 - 70 seconds) is therapeutic
–Initially the aPTT should be measured and the
infusion rate adjusted every 4 hours.
–Once a steady state is achieved, daily monitoring
is sufficient.

12. Heparin-Resistance to Heparin
(continued)
• Accelerated clearance of heparin may exist - as
in the case of massive pulmonary embolism
• Inherited AT III deficiency have 40 - 60 % of the
normal plasma concentration of AT III. They
respond normally to heparin
• Acquired AT III deficiency as with hepatic
cirrhosis, nephrotic syndrome or disseminated
intravascular coagulation; large doses of heparin
may not prolong the aPTT

13. Heparin - Managing Over-
Anticoagulation
•Anticoagulant effect of heparin disappears
within hours after discontinuation of the drug.
•Mild bleeding due to heparin can be
controlled without administration of an
antagonist.
•Antagonists are used if bleeding is life-
threatening.

14. Heparin - Managing of Over-
Anticoagulation
–Degree of over-anticoagulation
–Presence or absence of bleeding
–A specific, immediate heparin antagonist
–Protamine Sulfate
»Use 25 - 50 mg intravenously
»Side-effects largely allergic in nature
Management depends on:

15. • Protamine binds to the acidic (negatively charged)
heparin molecule - neutralizes heparin.
• Use smallest dose, give by slow IV infusion - do not
exceed 50 mg over 10 min. - Causes, flushing,
bradycardia, dyspnea, hypotension, anaphylaxis.
• Use 1 mg of protamine for every 100 units of heparin
remaining in the patient.
Heparin: Managing
Overanticoagulation (cont’d)

16. Heparin - Clinical Uses
• venous thrombosis and pulmonary embolism
• mural thrombosis after acute MI
• managing unstable angina
• prevention of coronary artery rethrombosis
• used to prevent blood clotting in extracorporeal
circulation - e.g. surgery, hemodialysis
• treat selected cases of disseminated intravas-cular
coagulation (DIC)
• treat fetal growth retardation in pregnant women
–Effective for the prevention and treatment of:

17. Heparin - Recommendations for
Clinical Use
Pregnancy - heparin is the anticoagulant of choice
–does not cross the placenta
–no untoward effects in the fetus or newborn
–given in therapeutic doses - 15,000 U sc q 12 hrs
to women with prosthetic heart valves or venous
thromboembolism
–doses in excess of 20,000 U per 24 hrs for more
than 5 months is questionable -due to risk of
OSTEOPOROSIS

18. Administration/ Preparation/
Storage
• Recommended infusion concentration for most patients is 25,000 units
in 500 mL D5W (50 units/mL premixed infusion solution)
• IV injection may be given undiluted or diluted in 50-100 mL NS or
D5W
• Invert IV bag at least 6 times to ensure mixing and prevent
pooling of medication
• Use constant-rate IV infusion pump
• Store heparin solutions at room temperature; do not freeze
• Do not use if discolored/precipitates
• Autoclavable

19. Dose
• Heparin lock solution: catheter flush to prevent
coagulation in the line. 1,2,10,100 units / ml
available but recommended one in practice are
10units/ml
• The required duration is every 6-8 hrs

20. Dose
• DVT & PE
» Prophylaxis during surgery
• 5000 units SC q8-12hr, OR
• 7500 units SC q12hr
–Treatment
» 80 units/kg IV bolus, THEN continuous infusion of 18 units/kg/hr, OR
» 5000 units IV bolus, THEN continuous infusion of 1300 units/hr, OR
» 250 units/kg (alternatively, 17,500 units) SC, THEN 250 units/kg q12hr
• Dosing considerations
– Numerous concentrations available; extreme caution is required to avoid
medication error

21. Dose
• Acute Coronary syndrome
–Initial IV bolus of 60-70 units/kg (max: 5000 units), THEN initial
IV infusion of 12-15 units/kg/hr (max: 1000 units/hr)
–Dose should be adjusted to maintain aPTT of 50-70 sec
• Anticoagulation
–IV injection
–8000-10,000 units IV initially, THEN 50-70 units/kg (5000-10,000
units) q4-6hr
• Continuous IV infusion
–5000 units IV injection, followed by continuous IV infusion of
20,000-40,000 units/24 hr

22. Low Molecular-Weight Heparins
Enoxaparin (Lovenox™)
Dalteparin (Fragmin™)
–contain a lower proportion of the critical
pentasaccharide sequence than the parent
compound.
–they increase the action of ATIII on factor Xa,
but not its action on thrombin.

23. Low Molecular-Weight Heparins
•The LMWHs are not inactivated by platelet
factor 4, therefore activity extends to factor Xa
bound to platelet membranes.
•In clinical doses, no affect on platelet reactivity,
PT or aPTT.
•Currently approved for prevention of deep vein
thrombosis:
•After hip or knee surgery or abdominal surgery.
•Unstable angina (NQWMI).

24. Low Molecular Weight Heparins
• Do not require routine monitoring of INR, PT,
or aPTT.
• One fixed dose administered subcutaneously.
–30 mg every 12 hours.
• Must not be administered IM and is not
intended for IV administration.
• Use with caution in patients with a history of
heparin-induced thrombocytopenia.
• Reversed by protamine, 1 mg for each mg of
LMWH.

25. LMWH
• Epidural or spinal hematomas may occur in patients
anticoagulated with low-molecular-weight heparin (LMWH)
or heparinoids who receive neuraxial (epidural/spinal)
anesthesia or spinal puncture
• Patients should be frequently monitored for signs and
symptoms of neurologic impairment (eg, tingling, numbness,
muscular weakness)
• If neurologic compromise is noted, urgent treatment is
necessary

26. Factors increasing risk of epidural or
spinal hematomas
• Indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis
(eg, NSAIDs, platelet inhibitors, other
anticoagulants)
• History of traumatic or repeated epidural or spinal
punctures
• History of spinal deformity or spinal surgery

27. Contraindications LMWH
• Active major bleeding, thrombocytopenia with antiplatelet
antibody in presence of enoxaparin or heparin
• History of heparin-induced thrombocytopenia (HIT) within
past 100 days or in presence of circulating antibodies
• Hypersensitivity to enoxaparin, heparin, pork products,
benzyl alcohol (multiple dose formulations only) or other
ingredients

28. Cautions
• Epidural or spinal hemorrhage (see Black Box Warnings)
• Use with caution in patients with a bleeding diathesis,
uncontrolled arterial hypertension or a history of recent
gastrointestinal ulceration, diabetic retinopathy, renal
dysfunction and hemorrhage
• Multidose formulation contains benzyl alcohol preservative,
linked to fatal "gasping syndrome" in premature neonates
• Monitor for hyperkalemia (possibly from aldosterone
suppression);

29. Cautions
• Heparin-induced thrombocytopenia with thrombosis
(HITTS) may lead to organ infarction, limb ischemia, or
death; monitor thrombocytopenia of any degree closely
• Not for IM administration
• Use caution in patients with renal impairment
• Safety and efficacy not established in obese patients (>30
kg/m²)
• Risk of bleeding may increase in women <45 kg and men
<57 kg
• Use of therapy for thromboprophylaxis in pregnant women
with mechanical prosthetic heart valves may result in valve
thrombosis

30. Monitoring parameters
• Local reactions at the injection site (eg, nodules,
inflammation, oozing), systemic allergic reactions
(eg, pruritus, urticaria, anaphylactic/anaphylactoid
reactions including shock),
• Hyperkalemia
• Cases of headache, hemorrhagic anemia,
eosinophilia, alopecia, hepatocellular and cholestatic
liver injury reported
• Osteoporosis following long-term therapy

31. Calcium supplementation
• Heparin causes increased bone resorption by
stimulating osteoclasts and suppressing osteoblast
function, leading to decreased bone mass.
• Other proposed mechanisms include depletion of
mast cells in bone marrow and enhancement of
parathyroid hormone (PTH) function, an important
regulator of calcium in the body.

32. LMWH dosing
DVT/PE Prophylaxis Adult Pediatric Geriatric
40 mg SC qDay; initiate 2
hr preoperatively
<2 months: 0.75 mg/kg SC
q12hr
≥2 months: 0.5 mg/kg SC
q12hr
Dosing Based on Anti-
Factor Xa Concentrations
should be 0.5 - 1 units/mL
Assess the risk : benefit
Increased risk of bleeding
with doses of 1.5
mg/kg/day or 1 mg/kg
q12hr
DVT/PE Treatment 1 mg/kg SC q12hr
OR
1.5 mg/kg SC qDay
(administer at same time
each day)
Angina 1 mg/kg SC q12hr
Regimen includes aspirin
(100-325 mg/day PO)

33. LMWH dose modification in renal
disorders
Severe (CrCl <30 mL/min): Dosage reductions
required
• Prophylaxis in abdominal surgery: 30 mg SC qDay
• Prophylaxis in hip or knee replacement surgery: 30
mg SC qDay
• Prophylaxis in medical patients with restricted
mobility: 30 mg SC qDay
• DVT treatment (inpatient or outpatient)
coadministered with warfarin: 1 mg/kg SC qDay

34. For drug interactions
• Please read the interactions with enoxaparin
• It is examinable in midterm or final exam

35. Case 1
• HS is a 61-year-old man who comes to your
community pharmacy to have his blood pressure
checked.
• Your measurement, performed while he rests
comfortably in a chair, reads 148/90 mm Hg.

36. Case 1
• His medical history includes several transient
ischemic attacks over the past 9 months, and he takes
81 mg of aspirin and 12.5 mg hydrochlorothiazide
daily.
• HS wants your opinion on whether he should ask his
doctor to change his antihypertensive treatment

37. Answer
• Recent American College of Physicians (ACP) and
American Academy of Family Physicians (ACFP)
hypertension guidelines recommend that adults aged
60 years and older with a history of TIA or stroke
achieve a target systolic blood pressure (SBP) of
<140 mmHg to reduce the risk for recurrent stroke.

38. Answer
• This recommendation is based upon the results of a meta-
analysis which showed that treating patients with a history of
TIA or stroke to a SBP of 130-140 mmHg reduces stroke
risk by about 24% (95% CI, 8-34%; absolute risk reduction,
3.02%, number-needed to treat, 34) compared with treatment
targeting higher SBP goals.
• To achieve his goal SBP of 130-140 mmHg, HS needs
additional pharmacologic therapy. HS’s doctor could
consider adding an angiotensin-con- verting enzyme
inhibitor such as lisinopril

39. Case 2
• HC is a 64-year-old man with prostate cancer who
went to the emergency department (ED) complaining
of pain and swelling in his left leg.
•
• His physician orders a D-dimer test and a venous
ultrasound of his legs.
• HC’s D-dimer is found to be elevated and his
ultrasound reveals a blood clot proximal to his left
knee.

40. Case 2
• The diagnosis is deep vein thrombosis (DVT), and
because of his active prostate cancer, HC is
immediately started on a low-molecular weight
heparin (LMWH), enoxaparin 1 mg/kg administered
twice daily) and admitted to the medicine floor.
• After 2 days in the hospital, HC is discharged;
however, he is reluctant to administer himself
subcutaneous injections of a LMWH as an outpatient.
HC says that he lives alone and does not have
anybody who could administer injections for him.

41. Case 2
• His physician is considering starting an oral
anticoagulant and asks your opinion as the clinical
pharmacist.
• What will be dose of warfarin if you administer this
to the patient?
• Can we give ASA? Or ASA+Clopidogrel ?

42. Answer
• Due to HC’s refusal to use a LMWH as an outpatient,
the pharmacist might suggest edoxaban (60 mg once
daily) or rivaroxaban (15 mg once daily for 21 days
followed by 20 mg once daily).
• Warfarin may also be considered in HC, though it
has been found to be inferior to LMWH therapy in
regards to preventing recurrent VTE and requires
frequent monitoring of international normalized ratio
range