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E4.PHARM > L35.Treatment of Thrombosis: Heparin Anticoagulants I > Flashcards

L35.Treatment of Thrombosis: Heparin Anticoagulants I Flashcards

1
Q

Heparin-MOA

A
  • complex with ATIII and induces a conformational change resulting in 1000x greater binding affinity to clotting factor proteases
  • [it can then leave and do the same with another AT3]
  • indirect effect on thrombin, acts like a catalyst in an enzymatic rxn.
  • also inhibits factors 10a and 2a.
  • monitored by APTT (2-2.5 baseline therapeutic).
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2
Q

Heparin-Route of Admin

A
  • mainly iv and also given subcutaneous (NOT absorbed via oral or rectal route).
  • usually given as an iv bolus followed by an iv infusion, monitored daily to keep in range
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3
Q

Heparin-Indications

A

surgical anticoagulation

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4
Q

Heparin-Adverse Effects

A
  • **hemorrhagic complications (bleeding); adrenal, gut, etc
  • HIT** (heparin induced thrombocytopenia) and HiThrombosis
  • ->generation of ANTI-hep/PF4 complex antibodies
  • ->Ab bind to & activate platelets and endothelial cells (can lead to loss of limbs!!)
  • osteoporosis-manifestation with spontaneous fracture following chronic admin and large doses
  • alopecia-from LT usage
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5
Q

LMW Heparins (B&G)-MOA

A

complex with AT and inhibits factors 10a and 2a. monitored by anti-10a.

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6
Q

LMW Heparins (B&G)-Route of Admin

A

subcutaneous

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7
Q

LMW Heparins (B&G)-Indications

A

prophylaxis and treatment of DVT and ACS

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8
Q

LMW Heparins (B&G)-Adverse Effects

A

bleeding

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9
Q

Fondaparinux (pentasaccharide)-MOA

A

complex with AT and inhibits factor 10a

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10
Q

Fondaparinux-Route of Admin

A

subcutaneous

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11
Q

Fondaparinux-Indications

A

management of DVT

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12
Q

Fondaparinux-Adverse Effects

A

bleeding

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13
Q

Argatroban-MOA

A

directly inhibits 2a

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14
Q

Argatroban-Route of Admin

A

intravenous

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15
Q

Argatroban-Indications

A

anticoagulant management of HIT patients

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16
Q

Argatroban-Adverse Effects

A

bleeding

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17
Q

Bivalirudin-MOA

A

directly inhibits 2a

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18
Q

Bivalirudin-Route of Administration

A

intravenous

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19
Q

Bivalirudin-Indications

A

anticoagulant management of HIT patients

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20
Q

Bivalirudin-Adverse Effects

A

bleeding

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21
Q

Hirudin-MOA

A

directly inhibits 2a

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22
Q

Hirudin-Route of Admin

A

intravenous

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23
Q

Hirudin-Indications

A

anticoagulant management of HIT patients

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24
Q

Hirudin-Adverse Effects

A

bleeding

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25
Q

Antithrombin Concentrate-MOA

A

directly inhibits 2a

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26
Q

Antithrombin Concentrate-Route of Admin

A

intravenous

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27
Q

Antithrombin Concentrate-Indications

A

anticoagulant management of HIT patients

28
Q

Antithrombin Concentrate-Adverse Effects

A

NONE

29
Q

Protamine Sulfate-MOA

A

heparin antagonist

30
Q

Protamine Sulfate-Route of Admin

A

intravenous

31
Q

Protamine Sulfate-Indications

A

anticoagulant management of HIT patients

32
Q

Protamine Sulfate-Adverse Effects

A

Bradycardia, hypOtension

33
Q

What are anticoagulant drugs used for?

A

drugs used to anticoagulate blood for the treatment of thrombosis and for prophylaxis in surgical indications

34
Q

Where is heparin found?

A

it is a naturally occuring anticoagulant in the granules of MAST CELLS along with histamine and serotonin.

35
Q

What is the chemistry of heparin?

  • acidic or basic?
  • _____poly_____
  • repeating units of ____ and _____
A
  • strongly acidic (highly ionized)
  • mucopolysaccharide
  • composed of repeating units of sulfated glucuronic acid and sulfated glucosamine.
36
Q

What is the molecular heterogeneity of heparin?

  • types
  • sizes
  • roles
A
  • HMW, MMW, and LMW all contrib to anticoag effects.
  • MW varies from 2000 to 40,000 DA (mnea 12,000)
  • only 1/3 of heparin has anti coag effects, rest has anti-inflamm, anti-adhesion
37
Q

What is the use of the heparin pentasaccharide sequence?

A

It is required for heparin to bind to cofactor (antithrombin 3)

38
Q

Are all swine species the same?

A

NO! there are variations in heparin composition between species

39
Q

What is the source of heparin?

What are different heparin preparations?

A
  • Extracted from tissue rich in mast cells (beef lung and porcine [pig] intestine).
  • Prep #1: Mucosal.
  • ->sheep (rare)
  • ->*porcine (derived from pig intestine)
  • Prep #2: Different salts of heparin (Na+–US, Ca2+–Euro)
40
Q

Why is heparin standardized?

A

Because of variability in its molecular composition heparin is assayed using methods to determine the anti-10a and anti-2a potencies.

41
Q

What should 1 mg of heparin be equivalent to?

A

1mg of heparin should be equivalent to approx 120 USP units (1 micro g=1 unit??…)

42
Q

What happens to patients with arterial or venous line?

A

pt with arterial or venous line will have lines flushed a few times a day with a low dose heparin

43
Q

What are the THREE things that Heparin INHIBITS?

  1. main TWO factors
  2. others
  3. at [HIGH]
A
  • *1. INHIBITS the action of activated Factor 10a and Factor 2a (thrombin…converts fibrinogen to fibrin)
    2. INHIBITS the action of several other serine protease enzymes (12a, 11a)
    3. INHIBITS the aggregation of platelets (at HIGH concentration)
44
Q

What are the THREE actions of Heparin?

A
  1. PLASMA CLEARING EFFECT-turbid plasma is rapidly cleared of fat chylomicrons by a release of lipase from the blood vessels
  2. binds to VASCULAR LINING (of lumen of blood vessel) and neutralizes positive charge
  3. causes a release of TFPI (tissue factor pathway inhibitor) from the endothelial cells. TFPI can bind and inhibit TF-F7a complex that activates the extrinsic
45
Q

How is heparin monitored and why? When is therapeutic range achieved?
-Provide an example

A
  • anticoag effect carefully monitored using APTT
  • there is poor correlation between dose of heparin and pt weight
  • therapeutic range is achieved when the APTT is 2-2.5x baseline. b-line=careful of bleeding.
  • Ex: pts baseline is 28.0 secs, therapeutic range for APTT: 56-70 secs (at this value the pt will be properly anticoagulated)
46
Q

What is the metabolism of heparin?

A

> 20-25% excreted in urine
some heparin picked up by mast cells
endothelium unable to bind heparin
metabolized in liver by HEPARINASE into small components (that can then be easily cleared)

47
Q

What is heparin’s duration of action?

A

> t1/2 of iv heparin=1-3 HOURS (depending on dose)

>rapid onset of action=5-10 MIN (as measured by APTT method)

48
Q

Are the PK of heparin dose dependent?

A

YASSSS!!

-as you increase dose=increase half-life

49
Q

What are the FOUR modulators of heparin action that hep CANNOT work without?

A
  1. AT (main heparin co-factor); AT3 deficiency–> pt wont respond, have to check their level beforehand
  2. Heparin cofactor 2 (2nd cofactor) has weaker activity
  3. TFPI (tissue factor pathway inhibitor)
  4. PF4 (platelet factor 4, heparin neutralizing protein)
    - PF4 circulation in [low] in blood
    - when platelets are activated PF4 can get released
    - if there is enough PF4 in the blood then heparin can be neutralized
50
Q

What type of pt should be monitored while they are on heparin? WHAT should be monitored?

A
  1. If they have had previous attacks, monitor platelet count.
  2. pt with open heart surgery with huge dose of heparin during bypass, monitor platelet count
51
Q

What are the six clinical uses of heparin?

A
  • *1. Surgical anticoagulation (when on bypass pump, to prevent clot formation)
    2. therapeutic anticoagulation (only drug to flush out arterial and venous lines)
    3. prophylactic anticoagulation (bedridden or immobile: 5000 units subcutaneously 3x/day)
    4. unstable angina and related coronary syndromes (during stent replacements)
    5. adjunct therapy with thrombolytic drugs (for revascularization of different arteries)
    6. thrombotic and ischemic stroke
52
Q

What is used to neutralize heparin and what is its mechanism?

A

protamine (sulfate) is a powerful heparin ANTAGONIST.

  • it has LMW and is a HIGHLY BASIC PROTEIN found in fish (most commonly salmon) sperm
  • it combines with STRONGLY ACIDIC HEPARIN to form a stable salt with loss of anticoagulant activity
  • available as a 1% solution and generally used on a weight basis.
  • **one USP unit of heparin is neutralized by 10 micro g of protamine (2500 units of heparin is neutralized by 25 mg of protamine)
53
Q

What are two things that may be caused by intravenous injection of protamine?…therefore, what must the iv injection be administered?

A

Iv injection of protamine may cause:
-fall in blood pressure
-bradycardia
so it needs to be given as a slow infusion

54
Q

A patient was initially administered with 25,000 units of heparin for a surgical procedure. Forty mins after the surgical procedure, he was administered with an additional 10,000 units of heparin. The surgical procedure was completed in 100 minutes and the patient was found to have 8700 units of heparin in his circulation. How much protamine is needed to neutralize this circulating heparin?

A

87 mg. It doesn’t matter how much was given and then followed up with. Only amount that matters is what is there when you have to neutralize it.

55
Q

What is the relationship between coronary clots and heparin?

A

Heparin is the only drug that can be used with a coronary clot.

56
Q

How is LMW heparin prepared?

A

-LMW heparin is prepared by fractionation or depolymerization of native heparin (enzymatic cleavage).

57
Q

What is the basis of synthetic heparin pentasaccharide?

A

Hep pent was made to mimic pentsac sequence required to bind to AT3 (will give it its anticoag effect). They got rid of the isoteric chemical structure used for the other effects (aka the useless background nonsense)

58
Q

How is LMW> than regular hep? What are the clinical advantages of LMW heparins?

A
  • LMW is more homogenous (and can more easily pass through the subcutaneous barrier).
  • LMW F=100% (heparin=LMW given 1x/day, hep given 3x/day
  • LMW is dosed in mg (30 or 40 mg per kilo)
  • LMW: better F, longer duration of action (t1/2=6hrs, can also release TFPI)
  • LMW: less bleeding and lesser thrombocytopenia (BUT, if pt has problem with regular hep, antibodies may cross react with LMW hep-to avoid HIT, dont give it to these pts)
59
Q

Clinical Uses of LMW and synthetic heparin

A
  • prophylaxis of DVT
  • treatment of DVT
  • management of acute coronary syndromes
  • other uses such as anticoagulation for surgical and interventional cardiovascular procedures (if theres no hep around)
  • can send a pt home with it
60
Q

What are generic LMW heparins?

A
  • Enoxaparin-Sandoz has been approved for same indications as the branded enoxaparin.
  • a second generic enoxaparin from Amphastar was released
61
Q

What is the use of Antithrombin-concentrates (AT)?

A
  • AT is used to treat pts with acquired or congenital antithrombin-deficiency.
  • AT also useful in SEPSIS and DIC
62
Q

What is hirudin? Where is it from?

A

a protein from the saliva of the MEDICINAL LEECH which contains several pharmacologically active substances.

63
Q

What is hirudin’s role as a thrombin inhibitor?

A
  • 65 amino acids
  • DTI (direct thrombin inhibitor)
  • keeps the blood flowing, stops it from forming small blood clots in small vessles
  • only available via iv
  • currently r-hirudin is used in the anticoag management of heparin induced thrombocytopenic pts
  • a commercial preparation, namely, REFLUDAN is available for clinical use
64
Q

What are three different thrombin inhibitors?

A
  • hirudin
  • argatroban (arginine derivative)
  • Bivalirudin (Angiomax)
65
Q

What is Argatroban?

A
  • SYNTHETIC anti-thrombin agent used as an anticoag in pts who cannot be treated with heparin
  • special usage in the management of HIT (heparin induced thrombocytopenia)
  • dont have to worry about antibody formation
66
Q

What is Bivalirudin?

A
  • SYNTHETIC antithrombin agent
  • hybrid molecule between a component of hirudin and a tripeptide.
  • approved for PTCA anticoagulation
  • approved for CV pts that have to undergo stent placement
  • thrombin inhibitor AND antiplatelet effects

E4.PHARM (10 decks)

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