Transcript Clinical uses

Chapter 29
Agents affecting blood and
hematopoietic organ
Dysfunctions of blood
• 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
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•
•
•
•
•
•
Anticoagulants
Antiplatelet drugs antithrombolic drugs
Fibrinolytic drugs
Hemostatics
Agents Used in Anemia
Hematopoietic growth factors
Plasma volume expanders
Clot formation
requires platelet
activation and
aggregation
(white clot or
platelet clot),
followed by
formation of a
fibrin clot (red
clot).
intrinsic pathway
Ⅻ
Ⅻa
process of normal blood coagulation
+
Ⅺ
Ⅺa
extrinsic pathway
+
Ⅸ
Ⅸa
+
Ⅹ
Ⅲ, Ⅶ
Ⅲa,Ⅶa
+
Ⅹa
ⅩIII
Ⅹ
+
+
Thrombin(Ⅱa)
Prothrombin(Ⅱ)
+
fibrinogen
ⅩIIIa
+
Fibrin
Fibrin
(soluble)
( Insoluble)
Fibrin clot
§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
pharmacokinetics
Absorption
• Administered by i.v or s.c
Metabolism
Excretion
1.2 Pharmacological effects
• 1. Anticoagulative effect
Mechanism: accelerate inactivation of
clotting factors.(Ⅱa, Ⅸa, Ⅹa, Ⅺa, Ⅻa )
by enhancing the anticoagulative activity
of ATⅢ ( antithrombin Ⅲ ).
Ⅻ
Ⅻa
+
Ⅺ
Ⅺa
+
Ⅸ
Ⅸa
+
Ⅹ
Ⅶ
Ⅶa
+
Ⅹa
ⅩIII
Ⅹ
+
+
Thrombin(Ⅱa)
Prothrombin(Ⅱ)
+
fibrinogen
ⅩIIIa
+
Fibrin
Fibrin
soluble
insoluble
Fibrin clot
ATⅢ: a plasma protease inhibitor
Mechanism of heparin
• This reaction happens
in normal
physiological state, but
it’s very slow and weak.
• In the presence of
heparin (which acts as
an catalyst), it will be
accelerated by more
than 1,000 times
Characteristics of anticoagulative effect
• effective both in vivo and in vitro
• quick onset and potent effects
• efficacy positively relative to mocular weight
1.2 Pharmacological effects
• 2.Other effects




adjusting blood lipid
anti-inflammatory effect
anti-proliferative effect on vascular
smooth muscle cell
inhibiting pletelet aggregation
…….
1.3 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 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. Bleeding tendency:
• Severe hypertension
• Ulcer
• surgery of the brain ,eye, spinal cord
2. pregnancy
3. Renal and hepatic dysfunctions
LMWHS (low molecular weight heparins)
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Weaker effect than heparin
Low incidence of hemorrage
Long-lasting effect
Small individual deviation
No need to monitor generally
Coumarin derivatives
---Oral anticoagulants
These agents are often referred to
as oral anticoagulants because they are
administered orally, which exists as the
main difference from heparin.
• Warfarin(华法林),
• Dicoumarin(双香豆素)
• Acenocoumarin (醋硝香豆素)
pharmacokinetics
• Absorption: rapid and complete (warfarin)
• Distribution: PPBR>90%
• Elimination: liver
• Excretion:
kindney
4.1 pharmacological effects
• Anticoagulative effect
1)
mechanism:
antagonizing Vit K→inhibiting the
synthesis of cloting factor Ⅱ,Ⅶ,Ⅸ,Ⅹ
Precursors of Ⅱ、Ⅶ、Ⅸ、Ⅹ
Vitamin K
(reduced)
mature Ⅱ、Ⅶ、Ⅸ、Ⅹ
Vitamin K epoXide reductase
warfarin
Vitamin K
(epoxide)
Mechanism of Oral anticoagulants
Several clotting factors
(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 factorⅡ,Ⅶ,Ⅸ,Ⅹ
→inhibiting coagulation
2)
•
•
•
•
characteristics
(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;
administration of vitamin K and fresh blood
4.3.2 others: birth defect (warfarin)
Allergic reaction
• 4.4 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
(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
+
(Fibrinolytic drugs)
plasmin
＋
Degration
products fibrinogen
+
fibrin
fibrin splits
products
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 CHARACTERISTICS
• ACTION
• All act either direct or indirect to convert
plasminogen to plasmin, which in turn
cleaves fibrin, thus lysing thrombi.
• Clot dissolution occurs with a higher
frequency when therapy is initiated early
after clot formation.
• CLINICAL USES:
• Used for the treatment of deep-vein
thrombosis, serious pulmonary embolism,
acute myocardial infarction, peripheral
arterial thrombosis, etc.
1. 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
products fibrinogen
+
fibrin
fibrin splits
products
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
products fibrinogen
+
fibrin
fibrin splits
products
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
streptokinase 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
Antipletelet drug---- Drug that inhibits
platelets from aggregating to form a plug.
They are used to prevent clotting and
alter the natural course of
atherosclerosis.
Platelets activation
processes involve
three steps:
1.adhesion to the
site of injury
2.release of
intracellular
granules
3.aggregation of
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
aspirins
TXA2
-
AA
COX
(－)
AC
COX
aspirinl
PGI2
(＋)
+
Dipyridamole
AC
PDE
cAMP ↓
↑aggregation
(PLT)
cAMP↑
5-AMP
↓aggregation
(endothelium)
Ⅰ Inhibitors of platelet metabolism
ⅰ Cyclooxygenase inhibitors: Aspirin
ⅱ PDE inhibitors : Dipyridamole
ⅲ TXA2 synthetase inhibitor: Ridogrel
ⅳ Activators of adenylate cyclase:
epoprostenol (PGI2)
ⅰ Cyclooxygenase inhibitors:
Aspirin
• Aspirin is a classic old drug which is used
as a NSAIDs for more than 100 years.
Besides antipyretic, analgesic and antiinflammatory activities, it can inhibit
platelet aggregation.
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 Uses
 Prophylaxis after cardiac operation
 to reduce the incidence of recurrent
myocardial infarction (MI)
 Prophylaxis for transient ischemic attacks
(TIA) or post TIA
ⅱ PDE 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 Agents inhibting platelet activity
induced by ADP: Ticlopidine
Broad spectrum inhibitor of PLT aggregation
• Mechanism: disturb the release of α-granule
and binding of fibrin to GP Ⅱb/ Ⅲ a receptor
induced by ADP
• Clinic use: thromboembolic disease
• Severe toxicity: nausea, bone marrow
depression
• 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.
hirudin
• 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 Vitamin 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 of vitamin K
Smoe clotting factors
(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
+
Ⅺ
Ⅺa
+
Ⅸ
Ⅸa
+
Ⅹ
Ⅶ
Ⅶa
+
Ⅹa
ⅩIII
Ⅹ
+
+
Thrombin(Ⅱa)
Prothrombin(Ⅱ)
+
fibrinogen
ⅩIIIa
+
Fibrin
Fibrin
soluble
insoluble
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 Anti-fibrinolysin(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
products fibrinogen
+
fibrin
fibrin splits
products
Ⅲ Thrombin (Factor Ⅱ)
• Extracted from animal blood
• Activate firinogen to fibrin
• Used to stop bleeding or hemorrhage.
§5 Agents Used in Anemia
• Anemia ---a deficiency in erythrocytes or
hemoglobin.
• Normal value
• Adult male
• Adult famale
RBC(104/μL)
12~16
11~15
Hb(g/dL)
400~550
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:
Absorption: Fe2+
Increase: Vitamin C, amino acid, gastric
acid
Decrease:
phosphorus, calcium，Tannic acid, Antacids,
H2-receptor blockers, Proton pump inhibitors,
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:
Iron is part of hemoglobin, the oxygencarrying component of the blood. Irondeficient people tire easily because their bodies
are starved for oxygen.
Iron is also part of myoglobin. Myoglobin
helps muscle cells store oxygen.
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 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 FH2
reductase inhibitors: methotrexate,
Pyrimethamine(乙嘧啶,息疟定)
Calcium Leucovorin ( not for regular
deficiency )
3. 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:
dUMP
dTMP
• 1) methyl transfer
• pernicious anemia
• 2) isomerization of
methylmalonyl-CoA to
succinyl-CoA
• destroy integrity of myelin
sheath→ nerve damage
TAC
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 colonystimulating factor (GM-CSF)
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-stimulating
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 colonystimulating factor (GM-CSF)
Pharmacological effects:
• stimulates proliferation and differentiation of
early 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,
myalgias, peripheral edema and pleural or
pericardial effusions, allergic reactions
Section 7
Plasma 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 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 Ⅱ; improve microcirclation
• Osmotic diuretic effect
Clinical uses
• hypovolemic shock
• Thrombolic disease
Adverse reaction
• Alergic effect
• Dysfunction of blood coagulation
• AHF