Chapter 29Chapter 29Agents affecting blood and heAgents affecting blood and he

matopoietic organmatopoietic organ

• Thrombosis – the formation of an unwanted clot within the blood vessls or heart

• Bleeding disorders –due to failure of hemostasis and include hemophilia and vitamin K deficiency

• Anemia -- caused by nutritional deficiency

Dysfunctions of bloodDysfunctions of blood

• Anticoagulants• Antiplatelet drugs antithrombolic drugs

• Fibrinolytic drugs

• Hemostatics

• Agents Used in Anemia

• Hematopoietic growth factors

• Plasma volume expanders

Clot formation Clot formation requires platelet requires platelet activation and activation and aggregation aggregation ((white clotwhite clot or or platelet clot), platelet clot), followed by followed by formation of a formation of a fibrin clot (fibrin clot (red red clotclot).).

Ⅻ Ⅻa

Ⅺa

Ⅸa

Ⅹa

Ⅲa, aⅦ

Ⅺ

Ⅸ

Ⅹ

Ⅲ, Ⅶ

Ⅹ

+

+

+ +

+

Prothrombin( )Ⅱ Thrombin( a)Ⅱ

Fibrin( Insoluble)

Fibrin(soluble)fibrinogen

++

ⅩIII

ⅩIIIa

+

Fibrin clot

process of normal blood coagulationprocess of normal blood coagulation

extrinsic pathway

intrinsic pathway

§1 anticoagulants§1 anticoagulants

Anticoagulants are drugs employed in preventing blood coagulation. They inhibit certain clotting factors in the liver. The function of them is to:

• 1) prevent the formation of new blood clots.

• 2) keep existing blood clots from growing larger.

Classification of anticoagulants

ⅠAnticoagulants both in vivo and vitro:

e.g. Heparin

Ⅱ Anticoagulants in vivo: dicoumarol

Ⅲ Anticoagulants in vitro: Sodium citrate

1. Heparin 1.1 source and chemistry

(1)large amount of negative charge (2)strong acidity

pharmacokineticspharmacokinetics

Absorption• Administered by i.v or s.c

Metabolism

Excretion

1.2 Pharmacological effects1.2 Pharmacological effects

• 1. Anticoagulative effect

Mechanism: accelerate inactivation of clo

tting factors.( a, a, a, a, aⅡ Ⅸ Ⅹ Ⅺ Ⅻ ) by e

nhancing the anticoagulative activity of AT

Ⅲ ( antithrombin Ⅲ ).

Ⅻ Ⅻa

Ⅺa

Ⅸa

Ⅹa

Ⅶa

Ⅺ

Ⅸ

Ⅹ

Ⅶ

Ⅹ

+

+

+ +

+

Prothrombin( )Ⅱ Thrombin( a)Ⅱ

Fibrininsoluble

Fibrinsolublefibrinogen

++

ⅩIII

ⅩIIIa

+

Fibrin clot

AT : a plasma protease inhibitorⅢAT : a plasma protease inhibitorⅢ

Mechanism of heparinMechanism of heparin

• This reaction happens This reaction happens in normal in normal physiological state, but physiological state, but it’s very slow and it’s very slow and weak. weak.

• In the presence of In the presence of heparin (which acts as heparin (which acts as an catalyst), it will be an catalyst), it will be accelerated by more accelerated by more than 1,000 timesthan 1,000 times

CharacteristicsCharacteristics of anticoagulative effectof anticoagulative effect

• effective both in vivo and in vitro

• quick onset and potent effects

• efficacy positively relative to mocular weight

1.2 1.2 Pharmacological effectsPharmacological effects

• 2.Other effects adjusting blood lipid anti-inflammatory effect anti-proliferative effect on vascular

smooth muscle cell inhibiting pletelet aggregation

…….

1.3 Clinical uses1.3 Clinical uses

1) thromboembolic disease:

deep venous thrombosis(DVT),

pulmonary embolism, unstable angina,

acute myocardial infarction, cerebral infarction

2) DIC (Disseminated intravascular coagulation): early stage

3) extracorporal circulation

(eg. dialysis machine)

1.4 Adverse reactions1.4 Adverse reactions • Spontaneous hemorrhage :

monitoring of aPTT

antagonist: protamine sulfate(1mg:100u)

• Heparin-induced thrombocytopenia:

(a decrease in circulating platelets)

2 ～ 10 days of therapy, 3% ,

• Others : allergic reaction

osteoporosis( 骨质疏松 )

1.5 Contraindications:1.5 Contraindications:

1. Bleeding tendency:• Severe hypertension• Ulcer• surgery of the brain ,eye, spinal cord2. pregnancy3. Renal and hepatic dysfunctions

LMWHS (low molecular weight heparins)

• Weaker effect than heparin

• Low incidence of hemorrage

• Long-lasting effect

• Small individual deviation

• No need to monitor generally

Coumarin derivativesCoumarin derivatives --- ---Oral anticoagulantsOral anticoagulants

These agents are often referred to a

s oral anticoagulants because they are ad

ministered orally, which exists as the main

difference from heparin.

• Warfarin(华法林 ),

• Dicoumarin(双香豆素 )

• Acenocoumarin (醋硝香豆素 )

pharmacokineticspharmacokinetics

• Absorption: rapid and complete (warfarin)

• Distribution: PPBR>90%

• Elimination: liver

• Excretion: kindney

4.1 pharmacological effects4.1 pharmacological effects

• Anticoagulative effect

1) mechanism:

antagonizing Vit K→inhibiting the sy

nthesis of cloting factor , , , Ⅱ Ⅶ Ⅸ Ⅹ

Vitamin K (reduced)

Vitamin K (epoxide)

warfarin

Precursors of Ⅱ 、Ⅶ、Ⅸ、Ⅹ mature Ⅱ 、Ⅶ、Ⅸ、Ⅹ

Vitamin K epo-Xide reductase

Mechanism ofMechanism of Oral anticoagulantsOral anticoagulants

Several clotting factors

( , , , Ⅱ Ⅶ Ⅸ Ⅹ, , , Ⅱ Ⅶ Ⅸ Ⅹ) depend on vit K

as a coenzyme in their complete synthesis by the liver.

Oral anticoagulants antagonize VitK →inhibiting the synthesis of clotting factorⅡⅡ, , ,Ⅶ Ⅸ Ⅹ

→inhibiting coagulation

22)) characteristicscharacteristics

• (1) oral administration

• (2) effective in vivo, not in vitro

• (3) slow onset, long duration

• (4) overcome by administration of Vitamin K

• 4.2 clinical uses: For long use• Prevent acute deep vein thrombosis

or pulmonary embolism

Prevent venous throboembolism in patients undergoing orthopedic or gynecological surgery

Prevent systemic embolization in patients with myocardial infarction, prosthetic heart valves or chronic atrial fibrillation

4.3 adverse effects

4.3.1 Spontaneous hemorrhage :

monitoring of PT ( 凝血酶原时间 )

Treatment: withdrawal of the drug; administra

tion of vitamin K and fresh blood

4.3.2 others: birth defect (warfarin)

Allergic reaction

• 4.4 drug interactions4.4 drug interactions

4.4.1 enzyme inducer ： barbiturates

4.4.2 competitive antagonist: Vit K

4.4.3 high PPBR: aspirin, quinidine,

sulfonamide, phenylbutazone

4.4.4 enzyme inhibitor: cimetidine, isoniazid

4.4.5 PLT inhibitors: aspirin

Ⅲ Anticoagulants in vitro

Sodium citrate, potassium oxalate

Mechanism: Ca2+

Uses:

prevent blood coagulation in vitro

§2 Fibrinolytic drugs§2 Fibrinolytic drugs (thrombolytic agents) (thrombolytic agents)

These agents can activate the conversion of plasminogen to plasmin, a serine protease that hydrolyzes fibrin and thus dissolves clots. Mainly used in acute thrombolism.

plasminogen

inhibitors － + activators

plasmin ＋ +

Degration fibrin splits

products fibrinogen fibrin products

(Fibrinolytic drugs)

Ⅰ Plasminogen activator from human body

Urokinase (UK) , Alteplase (t-PA)

Ⅱ Plasminogen activator form bacteria

Streptokinase (SK) , Anistreplase,

Stephylokinase

Ⅲ Plasminogen activator from snake

Snake venom antithrombus enzyme,

Ancrod, Acutase

SHARED CHARACTERISTICSSHARED CHARACTERISTICS

• ACTION

• All act either direct or indirect to convert plas

minogen to plasmin, which in turn cleaves fib

rin, thus lysing thrombi.

• Clot dissolution occurs with a higher frequen

cy when therapy is initiated early after clot fo

rmation.

• CLINICAL USES:

• Used for the treatment of deep-vein

thrombosis, serious pulmonary embolism,

acute myocardial infarction, peripheral

arterial thrombosis, etc.

1. 1. Streptokinase(SK)Streptokinase(SK) • 1.1 mechanism: acts indirectly

SK-plasminogen complex → activate plasminogen

• 1.2 clinical uses:

thrombolytic therapy: early,< 6h intravenous route: DVT, multiple pulmonary emboli

intra-arterial route: myocardial infarction

• 1.3 adverse reactions: • bleeding, hypotension, allergic reaction

plasminogen

inhibitors － + SK- plasminogen

complex

plasmin

＋ +

Degration fibrin splits

products fibrinogen fibrin products

2. Urokinase(UK) 2. Urokinase(UK)

• mechanism: activating plasminogen directly

• clinical uses: Same use as SK, especially cerebral embolism

• adverse reactions: bleeding, but no antigenicity

plasminogen

inhibitors － + UK

plasmin

＋ +

Degration fibrin splits

products fibrinogen fibrin products

3.tissue plasminogen activator (t-PA)3.tissue plasminogen activator (t-PA)

Mechanism: act directly

Charateristics:

• act selectively , risk of bleeding ↓

(High affinity to plasmnogen bound to fibrin in the embolism ， low affinity to free plasmnogen)

• superior to SK and UK

4. anistreplase (anisoylated plasminogen str4. anistreplase (anisoylated plasminogen str

eptokinase activator complex)eptokinase activator complex)

• a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme’s active site.

• When administered, the acyl group spontaneously hydrolyzes, activating streptokinase-proactivator complex.

• greater clot selectivity (ie, more activity on plasminogen associated with clots than on free plasminogen in the blood)

§3 antiplatelet drugs§3 antiplatelet drugs

Antipletelet drug---- Drug that inhibits p

latelets from aggregating to form a plug.

They are used to prevent clotting and alt

er the natural course of atherosclerosis.

Platelets activation Platelets activation processes involve processes involve three steps: three steps: 1.adhesion to the 1.adhesion to the site of injury site of injury 2.release of 2.release of intracellular intracellular granules granules 3.aggregation of 3.aggregation of the platelets.the platelets.

Classification

Ⅰ Inhibitors of platelet metabolism

Ⅱ Agents inhibting platelet activity

induced by ADP: Ticlopidine

Ⅲ Thrombin inhibitor: argatroban

IV GPΠb / Шa receptor blocker:

abciximab

AA TXA2 (－ ) (＋ )

AC AC PDE

cAMP ↓ cAMP↑ 5-AMP

↑aggregation ↓aggregation (PLT) (endothelium)

aspirins -

Dipyridamole

-

+

aspirinl

COX COX

-

PGI2

Ⅰ Ⅰ Inhibitors of platelet metabolismInhibitors of platelet metabolism

ⅰ Cyclooxygenase inhibitors: Aspirin

ⅱ PDE inhibitors : Dipyridamole

ⅲ TXA2 synthetase inhibitor: Ridogrel

ⅳ Activators of adenylate cyclase:

epoprostenol (PGI2)

ⅰ ⅰ Cyclooxygenase inhibitors: ACyclooxygenase inhibitors: Aspirinspirin

• Aspirin is a classic old drug which is used as a NSAIDs for more than 100 years. Besides antipyretic, analgesic and anti-inflammatory activities, it can inhibit platelet aggregation.

Pay attention!Pay attention!

• at small dose (50 ～ 75mg/d) ： inhibit the synthesis of TXA2 –

which causes platelet aggregation

• at higher doses (> 320 mg/day) ： inhibits the synthesis of PGI2 –

which inhibits platelet aggregation.

Clinical UsesClinical Uses Prophylaxis after cardiac operation to reduce the incidence of recurrent myoc

ardial infarction (MI) Prophylaxis for transient ischemic attacks

(TIA) or post TIA

ⅱ ⅱ PDE inhibitors : DipyridamolePDE inhibitors : Dipyridamole

Mechanism : 1) ↓PDE → cAMP ↑ ↓ aggregation

2) ↓ the uptake of adenosine →↑AC Clinical use: Substitute of aspirin

prosthetic heart valves, etc.

• ⅲ TXA2 synthetase inhibitor: Ridogrel

• More effective than aspirin

• Fewer adverse reaction

Ⅱ Ⅱ Agents inhibting platelet activity Agents inhibting platelet activity induced by ADP: Ticlopidine induced by ADP: Ticlopidine

Broad spectrum inhibitor of PLT aggregation

• Mechanism: disturb the release of α-granule a

nd binding of fibrin to GP b/ a receptor iⅡ Ⅲnduced by ADP

• Clinic use: thromboembolic disease

• Severe toxicity: nausea, bone marrow depressi

on

• Ⅲ Thrombin inhibitor:

• Argatroban

• Thrombin inhibitor

• has a short half-life, is given by continuous intravenous infusion, and monitoring is done by aPTT.

• Its clearance is not affected by renal disease but is dependent on liver function.

hirudinhirudin

• irreversible thrombin inhibitor from the leech

• now available in recombinant form as lepirudinin.

• has a short half-life, but it accumulates in renal insufficiency and no antidote exists.

• Mainly used after surgery

IV GPΠb / Шa receptor blocker: abciximab(阿昔单抗 )

• activation of glycoprotein receptor on PLT membrane is the final common pathway for platelet aggregation.

• Mechanism: blockade of glycoprotein receptors on PLT membrane

§4 Hemostatics

Ⅰ Coagulants

Vitamin K Ⅱ Antifibrinolytic drugs

Tranexamic acid

Aminomethylbenzoic acid

Ⅲ Thrombin

Ⅳ Vasoconstrictors Etamsylate

Posterior pituitary(垂体后叶素 )

ⅰ ⅰ Vitamin KVitamin K

• [Source and types]

• Vitamin K is found in meats, dairy

products, leafy green vegetables

• Two natural forms : VitK1,VitK2

• Two synthesized forms: VitK3,VitK4

Mechanism ofMechanism of vitamin Kvitamin K

Smoe clotting factors ( , , , Ⅱ Ⅶ Ⅸ Ⅹ, , , Ⅱ Ⅶ Ⅸ Ⅹ) that are involved in the coagulation reactions depend on vitamin K as a coenzyme in their complete synthesis by the liver.

Ⅻ Ⅻa

Ⅺa

Ⅸa

Ⅹa

Ⅶa

Ⅺ

Ⅸ

Ⅹ

Ⅶ

Ⅹ

+

+

+ +

+

Prothrombin( )Ⅱ Thrombin( a)Ⅱ

Fibrininsoluble

Fibrinsolublefibrinogen

++

ⅩIII

ⅩIIIa

+

Fibrin clot

• Clinical uses:

Hemorrage resulting from VitK deficiency

1) Excess of oral anticoagulants

2) Obstructive jaundice and biliary fistula

(vitamin K is a fat-soluble vitamin )

3) long term use of broad spectrum antibiotics:

(some vitamin K is synthesized by intestinal bacteria.)

4) Prevent hemorrhage in newborn baby and premature infants.

Ⅱ Ⅱ Anti-fibrinolysin(Anti-fibrinolysin( 抗纤溶剂抗纤溶剂 ))

• Aminomethylbenzoic acid

• Mechanism:

• 1) inhibit plasminogen activation

2) inhibit the activity of plasmin (large dose)

• Clinical uses

bleeding due to high activity of plasmin

• Adverse reactions intravascular thrombosis

plasminogen

inhibitors － + activators (Anti-fibrinolysin)

plasmin

＋ +

Degration fibrin splits

products fibrinogen fibrin products

Ⅲ Ⅲ Thrombin (Factor )ⅡThrombin (Factor )Ⅱ

• Extracted from animal blood

• Activate firinogen to fibrin

• Used to stop bleeding or hemorrhage.

§5 Agents Used in Anemia§5 Agents Used in Anemia

• Anemia ---a deficiency in erythrocytes or hemoglobin.

• Normal value RBC(104/μL) Hb(g/dL)

• Adult male 12~16 400~550

• Adult famale 11~15 350~500

Types of anemia

• Iron-deficiency anemia

• megaloblastic anemia

• aplastic anemia

• hemolytic anemia

1. Iron

• p.o.: Ferrous sulfate （硫酸亚铁） Ferric ammonium citrate （枸橼酸铁铵） Ferrous fumarate （富马酸亚铁）• i.m.: Iron dextran

Pharmacokinetics:Pharmacokinetics:

Absorption: Fe2+

Increase: Vitamin C, amino acid, gastric acid

Decrease:

phosphorus, calcium ， Tannic acid, Antacids, H2-receptor blockers, Proton pump inhibitor

s, Tetracyclines

• Transfer: transferrin

• Utilization:

transferrin-R on proliferating erythroid cells.

• Storage:

ferritin(Fe3+) in intestinal mucosal cells and in macrophages in the liver, spleen, and bone.

Pharmacological actions:Pharmacological actions:

Iron is part of hemoglobin, the oxygen-car

rying component of the blood. Iron-deficient p

eople tire easily because their bodies are starve

d for oxygen.

Iron is also part of myoglobin. Myoglobin

helps muscle cells store oxygen.

Clinical uses:Clinical uses:

• treatment or prevention of iron deficiency anemia

• 1) chronic blood loss in heavy menstrution or hemorrhoid

• 2) insufficient intake during periods of accelerated growth in children, or in pregnant women.

10~14d 4~8w 2~3m

Adverse reactionsAdverse reactions

• 1) p.o. : marked gastrointestinal irritation

• 2) i.m. : remarkable local irritation

• 3) acute iron toxicity: >1g

gastric irrigation→shock→death

lavage: phosphate or carbonate

deferoxamine: a potent iron chelating compound

• 2. Folic acid • Process in body

FA → FH2 → FH4 → 5-CH3-FH4

• Machinism: One carbon unit carrier

•  ☆   Reduction of folic acid →

↓dTMP →↓ DNA→megaloblastic anemia

↓amino acid biosynthesis

• Clinical uses:

• 1. Megaloblastic anemia

• 2. Pernicious anemia• 3. Megaloblastic anemia caused by FH

2 reductase inhibitors: methotrexate, Pyrimethamine(乙嘧啶 ,息疟定 )

Calcium Leucovorin ( not for regular deficiency )

3. Vitamin B123. Vitamin B12

Source:• Meat (especially liver), eggs,

and dairy products.

Pharmacokinetics:• Requirements of Vitamin B12:

1μg/d• Absorption: intrinsic factor• Storage: in liver

Pharmacological Action:

• 1) methyl transfer• pernicious anemia

• 2) isomerization of methylmalonyl-CoA to succinyl-CoA

• destroy integrity of myelin sheath→ nerve damage

 

TAC

dTMPdUMP

Clinical uses:

1. Megaloblastic anemia

2 .Pernicious anemia

3 .Nervous system diseases

4. Hepatopathy

Section 6

Hematopoietic growth factors

Erythropoietin (EPO)Granulocyte colony-stimulating

factor (G-CSF)

Granulocyte-macrophage colony- stimulating factor (GM-CSF)

Erythropoietin (EPO)Erythropoietin (EPO)

source: produced by the kidney in response to tissue hypoxia.

Pharmacological effects:

• stimulates erythroid proliferation and differentiation

• Stimulates maturation of red blood cell

• also induces release of reticulocytes from the bone marrow

Clinical uses:

• patients with chronic renal failure

• patients with aplastic anemia

• anemias associated with chronic inflammation, AIDS, and cancer

Adverse reaction:

• a rapid increase in hemoglobin

• hypertension and thrombotic complications.

Granulocyte colony-stimulatingGranulocyte colony-stimulating factor (G-CSF) factor (G-CSF)

Pharmacological effects:• stimulates proliferation and differentiation

of progenitors to neutrophils• Increase release of neutrophils from bone

marrow • activates the phagocytic activity of mature

neutrophils and prolongs their survival in the circulation.

Clinical uses: neutropenia

Granulocyte-macrophage colony- Granulocyte-macrophage colony- stimulating factor (GM-CSF)stimulating factor (GM-CSF)

Pharmacological effects:• stimulates proliferation and differentiation of earl

y and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors

• stimulates the function of mature neutrophils

• Clinical uses: neutropenia • Adverse reaction: fevers, malaise, arthralgias, m

yalgias, peripheral edema and pleural or pericardial effusions, allergic reactions

Section 7 Section 7 Plasma volume expandersPlasma volume expanders

• Used to replace or maintain blood vol

• Charactristics:– ↑ plasma Osmotic pressure – Slowly eliminated– Not toxic– No antigenicy

dextran

Dextran 70 (medium molecular dextran)

Dextran 40 (low molecular dextran)

Dextran 10 (small molecular dextran)

Pharmacological actionsPharmacological actions

• Increase plasma Osmotic pressure ↑ blood volume

( dextran 70 > dextran 40 >dextran 20 )

• Anti-coagulative effect: ↓aggregation of red blood cell, platelet ; inhibit clotting factor ; improve microcirclationⅡ

• Osmotic diuretic effect

Clinical uses • hypovolemic shock

• Thrombolic disease

Adverse reaction

• Alergic effect

• Dysfunction of blood coagulation

• AHF