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THUỐC CHỐNG ĐÔNG MÁU, TAN HUYẾT KHỐI VÀ CHỐNG KẾT TẬP TIỂU CẦU GV: Nguyễn Thùy Dương Bộ môn Dược lực... Trình bày được cơ chế, tác dụng, chỉ định của các thuốc chống kết tập tiểu cầu: as

THUỐC CHỐNG ĐÔNG MÁU,

TAN HUYẾT KHỐI VÀ CHỐNG KẾT TẬP TIỂU CẦU

GV: Nguyễn Thùy Dương

Bộ môn Dược lực

Mục tiêu học tập

1 Trình bày được cơ chế, tác dụng, chỉ định của các

thuốc chống kết tập tiểu cầu: aspirin, clopidogrel

2 Trình bày được cơ chế tác dụng, chỉ định và các

tác dụng không mong muốn của heparin

3 Trình bày được đặc điểm dược động học, cơ chế

tác dụng, chỉ định, TDKMM và tương tác thuốc của đại diện nhóm thuốc chống đông kháng vitamin K: warfarin

4 So sánh giữa heparin và các heparin phân tử

lượng thấp (LMW) về cơ chế, tác dụng, chỉ định và các tác dụng không mong muốn

ĐẠI CƯƠNG

CÁC GIAI ĐOẠN HÌNH THÀNH CỤC MÁU ĐÔNG

Co mạch Kết tập tiểu cầu

Huyết khối động mạch

Huyết khối tĩnh mạch

Giai đoạn thành mạch

Giai đoạn tiểu cầu

Giai đoạn đông máu

CÁC GIAI ĐOẠN HÌNH THÀNH CỤC MÁU ĐÔNG

3 giai đoạn của quá trình kết tập tiểu cầu:

kết dính - hoạt hóa – kết tập

GIAI ĐOẠN TIỂU CẦU

GIAI ĐOẠN ĐÔNG MÁU

Cục máu đông được ly giải, di chuyển theo dòng máu, đến tắc nghẽn ở các mạch máu nhỏ và trở thành huyết khối bệnh lý

GIAI ĐOẠN TAN CỤC MÁU ĐÔNG

Phân biệt các khái niệm

- Cầm máu (hemostasis): ngừng chảy máu từ một mạch bị tổn thương (co mạch, bám dính và kết tập tiểu cầu, tạo fibrin)

- Huyết khối (thrombosis): hình thành cục máu đông ngay cả khi không có chảy máu Huyết khối động mạch hoặc tĩnh mạch Nguyên nhân

- Thay đổi lưu lượng dòng: rung nhĩ

- Tổn thương nội mạc: xơ vữa động mạch

- Tăng đông máu quá mức: di truyền hay mắc phải

- Thuyên tắc (embolus): vỡ cục máu đông, di chuyển, đọng lại trong lòng mạch Nguy hiểm khi đến tim, não, phổi

Huyết khối

động mạch

suy tim, đau thắt ngực,

nhồi máu cơ tim

Đột quị

Biến chứng của huyết khối động mạch

Huyết khối tĩnh mạch sâu và phù phổi tắc nghẽn

VTE= deep vein thrombosis (DVT) and pulmonary embolism (PE)

Huyết khối tĩnh mạch

Cục máu đông giàu fibrin

Thuốc tác dụng lên quá trình đông máu và tiêu fibrin

Thuốc ức chế kết tập tiểu cầu

CÁC THUỐC TÁC ĐỘNG VÀO GIAI ĐOẠN TIỂU CẦU

Tiểu cầu ở trạng thái nghỉ

Tiểu cầu ở trạng thái hoạt hóa

Aspirin – Cơ chế tác dụng

Trên tiểu cầu : ức chế ưu tiên và không hồi phục

COX-1 à ngăn cản tổng hợp TXA 2 (tác nhân

acti-to prostaglandin H2 by COX-1 (Figure 20.5) Prostaglandin H2 is ther metabolized to thromboxane A2, which is released into plasma

fur-Thromboxane A2 produced by the aggregating platelets further motes the clumping process that is essential for the rapid formation of

pro-a hemostpro-atic plug Aspirin [AS-pir-in] inhibits thromboxpro-ane A2 synthesis from arachidonic acid in platelets by irreversible acetylation of a serine, preventing arachidonate from binding to the active site, thus, inhibi- tion of COX-1 (Figure 20.6) This shifts the balance of chemical mediators

to favor the antiaggregatory eff ects of prostacyclin, thereby impeding platelet aggregation The inhibitory eff ect is rapid, apparently occurring

in the portal circulation The aspirin-induced suppression of ane A2 synthetase and the resulting suppression of platelet aggregation last for the life of the anucleate platelet, which is approximately 7 to 10 days Repeated administration of aspirin has a cumulative eff ect on the function of platelets Aspirin is currently used in the prophylactic treat- ment of transient cerebral ischemia, to reduce the incidence of recurrent myocardial infarction, and to decrease mortality in pre- and post-myo- cardial infarct patients Complete inactivation of platelets occurs with

thrombox-160 mg of aspirin given daily The recommended dose of aspirin ranges from 50 to 325 mg, with side eff ects determining the dose chosen Higher doses of aspirin increase drug-related toxicities as well as the probability that aspirin may also inhibit prostacyclin production Formerly known

as “baby aspirin,” 81-mg aspirin is most commonly used in the United States Bleeding time is prolonged by aspirin treatment, causing com- plications that include an increased incidence of hemorrhagic stroke as well as gastrointestinal (GI) bleeding, especially at higher doses of the drug Aspirin is frequently used in combination with other drugs hav- ing anticlotting properties, such as heparin or clopidogrel Nonsteroidal anti-infl ammatory drugs (NSAIDs), such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic site Ibuprofen, if taken concomi- tantly with, or 2 hours prior to aspirin can obstruct the access of aspirin

to the serine residue and, thereby, antagonize the platelet inhibition by aspirin Therefore, aspirin should be taken at least 30 minutes before ibu- profen or at least 8 hours after ibuprofen Although celecoxib (a selective COX-2 inhibitor, see Chapter 39) does not interfere with the antiaggre- gation activity of aspirin, there is some evidence that it may contribute

to cardiovascular events by shifting the balance of chemical mediators

in favor of thromboxane A2 Aspirin is the only NSAID that irreversibly exhibits antithrombotic effi cacy

B Ticlopidine, clopidogrel, and prasugrel

Ticlopidine [ti-KLOE-pi-deen], clopidogrel [kloh-PID-oh-grel], and grel [PRA-soo-grel] are closely related thienopyridines that also block platelet aggregation, but by a mechanism diff erent from that of aspirin

prasu-1 Mechanism of action: These drugs irreversibly inhibit the binding

of ADP to its receptors on platelets and, thereby, inhibit the vation of the GP IIb/IIIa receptors required for platelets to bind to

acti-fi brinogen and to each other (Figure 20.7).

2 Therapeutic use: Although ticlopidine and clopidogrel are similar

in both structure and mechanism of action, their therapeutic uses

Platelet cyclooxygenase-1

Aspirin

Salicylic acid

COOH OH

COOH

C O

O O

N CH H

Figure 20.6

Acetylation of cyclooxygenase-1

by aspirin.

Acetylated cyclooxygenase-1

Polypeptide of cyclooxygenase-1

Serine side chain

Damaged endothelial cells

Active

GP IIb/IIIa receptors

Ticlopidine Clopidogrel Prasugrel

Figure 20.7

Mechanism of action of ticlopidine, clopidogrel and prasugrel GP = glycoprotein.

Damaged endothelial cells

Active

GP IIb/IIIa receptors

Ticlopidine Clopidogrel

Ticlopidine Clopidogrel

Ticlopidine Prasugrel

Clopidogrel Prasugrel Clopidogrel

Ticlopidine, clopidogrel and prasugrel inhibit ADP-mediated platelet aggregation.

Ức chế nhanh, không hồi phục trong suốt chu kỳ sống của tiểu cầu

(7- 10 ngày) à Dùng liều lặp lại sẽ tạo tác dụng tích lũy trên tiểu cầu

Tác dụng ức chế tối đa ở liều 160 mg/ngày

Đông máu - Dược lý 2

- Liều cao (500 mg – 2000 mg), giảm tổng hợp PGI2 Þ ¯ tác dụng chống kết tập

Tương quan giữa liều aspirin và hiệu quả điều trị

FDA: Liều tấn công 160-325 mg/ngày;

Liều duy trì 75-100 mg/ngày

Liều cao không cải thiện hiệu quả điều trị nhưng làm tăng TDKMM

Aspirin – Cơ chế tác dụng

Dự phòng huyết khối động mạch trong các trường hợp:

-Sau hội chứng mạch vành cấp: Nhồi máu cơ tim (có hoặc

không có đoạn ST chênh lên), đau thắt ngực không ổn định

-Sau can thiệp mạch vành: phẫu thuật bắc cầu, can thiệp mạch vành qua da

-Sau đột quỵ (thể nhồi máu), cơn thiếu máu cục bộ thoáng qua (TIA)

-Dự phòng tiên phát đột quỵ và nhồi máu cơ tim trên các bệnh nhân có nguy cơ cao (ví dụ, đau thắt ngực ổn định, bệnh động mạch ngoại vi, bệnh nhân có nguy cơ tim mạch cao)

Aspirin – Chỉ định

– Coumarin: nguy cơ chảy máu, đặc biệt ở liều cao.

– Ibuprofen: ¯ tác dụng của aspirin

– Corticoid, rượu: ­ tác dụng phụ trên tiêu hóa

– ACEI: giảm tác dụng của ACEI

ASPIRIN- TDKMM

CÁC THUỐC CHỐNG KẾT TẬP TIỂU CẦU KHÁC

- Chỉ định : Phối hợp với aspirin trong dự phòng tái phát nhồi máu

cơ tim, đột quỵ (thiếu máu), sau can thiệp mạch vành qua da

Clopidogrel: tiền thuốc, chuyển hóa qua CYP2C19 thành dạng có hoạt tính

Ticlodipin nhiều TDKMM hơn (giảm BC hạt, BC trung tính, giảm TC)

CÁC THUỐC CHỐNG KẾT TẬP TIỂU CẦU KHÁC

Thuốc ức chế receptor GP IIb/IIIa

- Cơ chế : Ức chế receptor GPIIb/IIIa

- Chỉ định : Kết hợp với aspirin (và clopidogrel) để dự phòng huyết khối trong can thiệp mạch vành qua da sau nhồi máu cơ tim/đau thắt ngực không ổn định

- Đặc điểm :

• Thời gian bán thải rất ngắn

• Chỉ dùng truyền tĩnh mạch

• Chỉ dùng ngắn hạn

Thuốc ức chế receptor GP IIb/IIIa

be fatal Prasugrel has black box warnings for bleeding, stroke, and abrupt discontinuation in patients undergoing percutaneous coro-

nary intervention Because these drugs can inhibit CYP450, they may interfere with the metabolism of drugs such as phenytoin, warfarin,

fl uvastatin, and tamoxifen if taken concomitantly Indeed, phenytoin toxicity has been reported when taken with ticlopidine

IIIa complex By binding to GP IIb/IIIa, the antibody blocks the binding of

fi brinogen and von Willebrand factor, and, consequently, aggregation does not occur (Figure 20.8) Abciximab is given intravenously along with either heparin or aspirin as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications It is also approved for unresponsive unstable angina and for prophylactic use in myocardial infarction After cessation of infusion, platelet func-

tion gradually returns to normal, with the antiplatelet eff ect persisting for 24 to 48 hours The major adverse eff ect of abciximab therapy is the potential for bleeding, especially if the drug is used with anticoagu-

lants or if the patient has a clinical hemorrhagic condition Abciximab is expensive, limiting its use in some settings.

D Eptifi batide and tirofi ban

These two antiplatelet drugs act similarly to abciximab, namely, by blocking the GP IIb/IIIa receptor (see Figure 20.8) Eptifi batide [ep-ti-

FIB-ih-tide] is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine-glycine-aspartic acid sequence of fi brino-

gen Tirofi ban [tye-roe-FYE-ban] is not a peptide, but it blocks the same site as eptifi batide These compounds, like abciximab, can decrease the incidence of thrombotic complications associated with acute coronary syndromes When intravenous (IV) infusion is stopped, these agents are rapidly cleared from the plasma, but their eff ect can persist for as long as 4 hours [Note: Only IV formulations are available, because oral preparations of these GP IIb/IIIa blockers are too toxic.] Eptifi batide and its metabolites are excreted by the kidney Tirofi ban is excreted largely unchanged by the kidney and in feces The major adverse eff ect of both drugs is bleeding Figure 20.9 summarizes the eff ects of the GP IIb/IIIa–

receptor antagonists on mortality and myocardial infarction

E Dipyridamole

Dipyridamole [dye-peer-ID-a-mole], a coronary vasodilator, is used phylactically to treat angina pectoris It is usually given in combination

pro-with aspirin or warfarin Dipyridamole increases intracellular levels of cAMP

by inhibiting cyclic nucleotide phosphodiesterase, resulting in decreased thromboxane A 2 synthesis It may potentiate the eff ect of prostacyclin to antagonize platelet stickiness and, therefore, decrease platelet adhesion

to thrombogenic surfaces (see Figure 20.2) The meager data available suggest that dipyridamole makes only a marginal contribution to the anti-

thrombotic action compare to that of aspirin In combination with farin, however, dipyridamole is eff ective for inhibiting embolization from

war-prosthetic heart valves It has been described as “inappropriate” for use in the elderly as a sole agent due to adverse GI and orthostasis problems.

Figure 20.9

Effects of glycoprotein (GP) IIb/IIIa–

receptor antagonists on the incidence of death or nonfatal myocardial infarction following percutaneous transluminal

coronary angioplasty [Note: Data are from several studies; thus,

reported incidence of complications with standard therapy, such as

heparin, is not the same for each drug.]

Tirofiban Key:

Eptifibatide Abciximab

Standard therapy plus GP IIb/IIIa antagonists Standard therapy

DEATH OR NONFATAL MYOCARDIAL INFARCTION

Abciximab Eptifibatide Tirofiban

Fibrinogen

Abciximab, eptifibatide and tirofiban block the GP IIb/IIIa receptor of platelets.

Lợi ích điều trị khi thêm các thuốc ức chế receptor GPIIb/IIIa vào phác đồ chống kết tập tiểu cầu trên bệnh nhân nhồi máu cơ tim

Thuốc tác dụng lên quá trình đông máu và tiêu fibrin

Thuốc ức chế kết tập tiểu cầu

Geerts WH et al Chest 2008;133:381S–453S

CÁC THUỐC CHỐNG ĐÔNG

Các thuốc chống đông đường tiêm

Heparin không phân đoạn Heparin phân tử lượng thấp Các chất ức chế gián tiếp yếu tố Xa (fondaparinux)

Các thuốc chống đông đường uống

Kháng Vitamin K Dabigatran (chất ức chế trực tiếp ytố IIa) Apixaban ( chất ức chế trực tiếp yếu tố Xa) Edoxaban, rivaroxaban

(-) trực tiếp Yếu tố IIa, đưởng uống 2004

AT + Xa + IIa (Xa > IIa)

LMWHs 1980s

II, VII, IX, X (Protein C, S)

VKAs 1940s

Xa

(-) trực tiếp Yếu tố Xa, đường uống

2008

IIa

(-) trực tiếp Yếu tố IIa 1990s

Perzborn E et al Nat Rev Drug Discov 2011;10:61-75

LỊCH SỬ PHÁT TRIỂN THUỐC CHỐNG ĐÔNG

Heparin không phân đoạn và heparin phân tử lượng thấp (LMWH)

LMWH » 15 monosaccarid

HEPARIN & HEPARIN PHÂN TỬ LƯỢNG THẤP

Các heparin phân tử lượng thấp

HEPARIN - CƠ CHẾ

AT III = Antithrombin III

HEPARIN - CƠ CHẾ

Heparin ức chế đông máu in vitro và in vivo thông qua hoạt hóa antithrombin III (AT III)

Heparin thay đổi cấu dạng không gian của ATIII, đẩy nhanh tốc

độ gắn của ATIII với các yếu tố đông máu

Heparin tách khỏi phức hợp và gắn với ATIII tiếp theo

Phức hợp

hoạt (T)

HEPARIN - CƠ CHẾ

LMWH tăng cường lk của ATIII với ytố Xa

> IIa ( tỉ lệ 2:1 -4:1)

Fondaparinux: là chuỗi

pentasaccharid tổng hợp, có cấu trúc phân tử xác định, ức chế đặc hiệu yếu tố Xa

Heparin: II, X (IX, XI, XII)

- Chống đông

- Tương tác với tiểu cầu

LMWH: X

HEPARIN - CƠ CHẾ

v Heparin và heparin PTLT không qua được hang rào nhau thai =>

dự phòng và điều trị huyết khối trên PNCT

HEPARIN – CHỈ ĐỊNH

HEPARIN – TDKMM

Chảy máu

- 1-5% BN huyết khối TM điều trị bằng UFH, it gặp hơn với LMWHs

- Theo dõi sát thời gian máu chảy, aPTT

- Cấp cứu: protamin sulfat, truyền TM chậm (1 mg protamin sulfat trung hòa 100 UI heparin)

à CCĐ: có tiền sử chảy máu, có nguy cơ chảy máu, đang có chảy máu bên trong hoặc bên ngoài cơ thể

Quá mẫn

- Heparin có nguồn gốc từ lợn

Tăng men gan

Loãng xương Þ gãy xương Ít gặp, chủ yếu ở liều cao (> 20 000 U/ngày), dùng dài ngày (3-6 tháng)

planted by the LMWHs, such as enoxaparin and dalteparin, because these agents can be conveniently injected subcutaneously on a patient weight–adjusted basis, have predictable therapeutic eff ects, and have a more predictable pharmacokinetic profi le (Figure 20.15)

Specifi cally, LMWHs do not require the same intense monitoring that heparin needs, subsequently saving laboratory costs as well as nurs-

ing time and costs Therefore, these advantages make LMWHs useful for inpatient and out patient therapy

3 Pharmacokinetics:

a Absorption: Whereas the anticoagulant eff ect with heparin

oc-curs within minutes of IV administration (or 1 to 2 hours after subcutaneous injection), the maximum anti–Factor Xa activity

of the LMWHs occurs about 4 hours after subcutaneous tion [Note: This is in comparison to the vitamin K–antagonist

injec-anticoagulants, such as warfarin, the activity of which requires 8

to 12 hours.] Heparin must be given parenterally, either in a deep subcutaneous site or intravenously, because the drug does not readily cross membranes (Figure 20.16) The LMWHsare admin-

istered subcutaneously [Note: Intramuscular administration of either agent is contraindicated because of hematoma formation.]

Heparin is often administered intravenously in a bolus to achieve immediate anticoagulation This is followed by lower doses or continuous infusion of heparin for 7 to 10 days, titrating the dose

so that the activated partial thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control It is usually not necessary to obtain such an index with the LMWHsbecause the plasma levels and pharmacokinetics of these drugs are predictable However, for those patients with renal impairment, the dose should be

reduced to account for decreased renal function

b Fate: In the blood, heparin binds to many proteins that neutralize

its activity, thereby causing resistance to the drug and able pharmacokinetics Heparin binding to plasma proteins is

unpredict-variable in patients with thromboembolic diseases Although generally restricted to the circulation, heparin is taken up by the monocyte/macrophage system, and it undergoes depolymeriza-

tion and desulfation to inactive products [Note: Heparin, fore, has a longer half-life in patients with hepatic cirrhosis.] The

there-inactive metabolites, as well as some of the parent heparin and LMWHs, are excreted into the urine Therefore, renal insuffi ciency also prolongs the half-life Neither heparin nor the LMWHscross the placental barrier The half-life of heparin is approximately 1.5 hours, whereas the half-life of the LMWHs is two to four times

longer than that of heparin, ranging from around 3 to 7 hours

4 Adverse eff ects: Despite early hopes of fewer side eff ects with

LMWHs,complications have proven to be similar to those seen with heparin However, exceptions are thromboembolic problems, which

are less common

a Bleeding complications: The chief complication of heparin

therapy is hemorrhage (Figure 20.17) Careful monitoring of the bleeding time is required to minimize this problem Excessive bleeding may be managed by ceasing administration of the drug

or by treating with protamine sulfate When infused slowly, the latter combines ionically with heparin to form a stable, 1:1 inac-

Heparin and LMWH are mostly confined to the vascular system

Heparin and LMWHs

Partially degraded heparin and LMWHs appear in the urine.

Figure 20.16

Administration and fate of heparin and low-molecular- weight heparins (LMWHs).

Heparin:

IV, deep SC LMWHs: SC

Figure 20.17

Adverse effects of heparin

Bleeding

A A A

Hypersensitivity

cytopenia

Thrombo-Pharm 5th 3-21-11.indb 253 3/21/11 2:24:54 PM

planted by the LMWHs, such as enoxaparin and dalteparin, because these agents can be conveniently injected subcutaneously on a patient weight–adjusted basis, have predictable therapeutic eff ects, and have a more predictable pharmacokinetic profi le (Figure 20.15)

Specifi cally, LMWHs do not require the same intense monitoring that heparin needs, subsequently saving laboratory costs as well as nurs-

ing time and costs Therefore, these advantages make LMWHs useful for inpatient and out patient therapy

3 Pharmacokinetics:

a Absorption: Whereas the anticoagulant eff ect with heparin

oc-curs within minutes of IV administration (or 1 to 2 hours after subcutaneous injection), the maximum anti–Factor Xa activity

of the LMWHs occurs about 4 hours after subcutaneous tion [Note: This is in comparison to the vitamin K–antagonist

injec-anticoagulants, such as warfarin, the activity of which requires 8

to 12 hours.] Heparin must be given parenterally, either in a deep subcutaneous site or intravenously, because the drug does not readily cross membranes (Figure 20.16) The LMWHsare admin-

istered subcutaneously [Note: Intramuscular administration of either agent is contraindicated because of hematoma formation.]

Heparin is often administered intravenously in a bolus to achieve immediate anticoagulation This is followed by lower doses or continuous infusion of heparin for 7 to 10 days, titrating the dose

so that the activated partial thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control It is usually not necessary to obtain such an index with the LMWHsbecause the plasma levels and pharmacokinetics of these drugs are predictable However, for those patients with renal impairment, the dose should be

reduced to account for decreased renal function

b Fate: In the blood, heparin binds to many proteins that neutralize

its activity, thereby causing resistance to the drug and able pharmacokinetics Heparin binding to plasma proteins is

unpredict-variable in patients with thromboembolic diseases Although generally restricted to the circulation, heparin is taken up by the monocyte/macrophage system, and it undergoes depolymeriza-

tion and desulfation to inactive products [Note: Heparin, fore, has a longer half-life in patients with hepatic cirrhosis.] The

there-inactive metabolites, as well as some of the parent heparin and LMWHs, are excreted into the urine Therefore, renal insuffi ciency also prolongs the half-life Neither heparin nor the LMWHscross the placental barrier The half-life of heparin is approximately 1.5 hours, whereas the half-life of the LMWHs is two to four times

longer than that of heparin, ranging from around 3 to 7 hours

4 Adverse eff ects: Despite early hopes of fewer side eff ects with

LMWHs,complications have proven to be similar to those seen with heparin However, exceptions are thromboembolic problems, which

are less common

a Bleeding complications: The chief complication of heparin

therapy is hemorrhage (Figure 20.17) Careful monitoring of the bleeding time is required to minimize this problem Excessive bleeding may be managed by ceasing administration of the drug

or by treating with protamine sulfate When infused slowly, the latter combines ionically with heparin to form a stable, 1:1 inac-

Heparin and LMWH are mostly confined to the vascular system

Heparin and LMWHs

Partially degraded heparin and LMWHs appear in the urine.

Figure 20.16

Administration and fate of heparin and low-molecular- weight heparins (LMWHs).

Heparin:

IV, deep SC LMWHs: SC

Figure 20.17

Adverse effects of heparin

Bleeding

A A A

Hypersensitivity

cytopenia

Thrombo-Pharm 5th 3-21-11.indb 253 3/21/11 2:24:54 PM

planted by the LMWHs, such as enoxaparin and dalteparin, because these agents can be conveniently injected subcutaneously on a patient weight–adjusted basis, have predictable therapeutic eff ects, and have a more predictable pharmacokinetic profi le (Figure 20.15)

Specifi cally, LMWHs do not require the same intense monitoring that heparin needs, subsequently saving laboratory costs as well as nurs-

ing time and costs Therefore, these advantages make LMWHs useful for inpatient and out patient therapy

3 Pharmacokinetics:

a Absorption: Whereas the anticoagulant eff ect with heparin

oc-curs within minutes of IV administration (or 1 to 2 hours after subcutaneous injection), the maximum anti–Factor Xa activity

of the LMWHs occurs about 4 hours after subcutaneous tion [Note: This is in comparison to the vitamin K–antagonist

injec-anticoagulants, such as warfarin, the activity of which requires 8

to 12 hours.] Heparin must be given parenterally, either in a deep subcutaneous site or intravenously, because the drug does not readily cross membranes (Figure 20.16) The LMWHsare admin-

istered subcutaneously [Note: Intramuscular administration of either agent is contraindicated because of hematoma formation.]

Heparin is often administered intravenously in a bolus to achieve immediate anticoagulation This is followed by lower doses or continuous infusion of heparin for 7 to 10 days, titrating the dose

so that the activated partial thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control It is usually not necessary to obtain such an index with the LMWHsbecause the plasma levels and pharmacokinetics of these drugs are predictable However, for those patients with renal impairment, the dose should be

reduced to account for decreased renal function

b Fate: In the blood, heparin binds to many proteins that neutralize

its activity, thereby causing resistance to the drug and able pharmacokinetics Heparin binding to plasma proteins is

unpredict-variable in patients with thromboembolic diseases Although generally restricted to the circulation, heparin is taken up by the monocyte/macrophage system, and it undergoes depolymeriza-

tion and desulfation to inactive products [Note: Heparin, fore, has a longer half-life in patients with hepatic cirrhosis.] The

there-inactive metabolites, as well as some of the parent heparin and LMWHs, are excreted into the urine Therefore, renal insuffi ciency also prolongs the half-life Neither heparin nor the LMWHscross the placental barrier The half-life of heparin is approximately 1.5 hours, whereas the half-life of the LMWHsis two to four times

longer than that of heparin, ranging from around 3 to 7 hours

4 Adverse eff ects: Despite early hopes of fewer side eff ects with

LMWHs,complications have proven to be similar to those seen with heparin However, exceptions are thromboembolic problems, which

are less common

a Bleeding complications: The chief complication of heparin

therapy is hemorrhage (Figure 20.17) Careful monitoring of the bleeding time is required to minimize this problem Excessive bleeding may be managed by ceasing administration of the drug

or by treating with protamine sulfate When infused slowly, the latter combines ionically with heparin to form a stable, 1:1 inac-

Heparin and LMWH are mostly confined to the vascular system

Heparin and LMWHs

Partially degraded heparin and LMWHs appear in the urine.

Figure 20.16

Administration and fate of heparin and low-molecular- weight heparins (LMWHs).

Heparin:

IV, deep SC LMWHs: SC

Figure 20.17

Adverse effects of heparin

Bleeding

A A A

Hypersensitivity

cytopenia

Thrombo-Pharm 5th 3-21-11.indb 253 3/21/11 2:24:54 PM

Giảm tiểu cầu do heparin (HIT) (1-4% BN dùng UFH)