Hematology Drugs D3
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Transcript of Hematology Drugs D3
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Agents affecting blood Agents affecting blood
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• 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
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• Anticoagulants• Antiplatelet drugs antithrombolic drugs
• Fibrinolytic drugs• Hemostatics • Agents Used in Anemia• Hematopoietic growth factors• Plasma volume expanders
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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).).
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Ⅻ Ⅻa
Ⅺa
Ⅸa
Ⅹa
Ⅲa,Ⅶa
Ⅺ
Ⅸ
Ⅹ
Ⅲ, Ⅶ
Ⅹ
+
+
+ +
+
Prothrombin(Ⅱ) Thrombin(Ⅱa)
Fibrin( Insoluble)
Fibrin(soluble)fibrinogen
++
ⅩIII
ⅩIIIa
+
Fibrin clot
process of normal blood coagulationprocess of normal blood coagulation
extrinsic pathway
intrinsic pathway
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Coagulation Cascade Animation - Physiology of Hemostasis.mp4
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§§1 anticoagulants1 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.
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Classification of anticoagulants
ⅠAnticoagulants both in vivo and vitro:
e.g. Heparin
Ⅱ Anticoagulants in vivo: dicoumarol
Ⅲ Anticoagulants in vitro: Sodium citrate
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1. Heparin 1.1 source and chemistry
(1)large amount of negative charge (2)strong acidity
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1.2 Pharmacological effects1.2 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 ).
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Ⅻ Ⅻa
Ⅺa
Ⅸa
Ⅹa
Ⅶa
Ⅺ
Ⅸ
Ⅹ
Ⅶ
Ⅹ
+
+
+ +
+
Prothrombin(Ⅱ) Thrombin(Ⅱa)
Fibrininsoluble
Fibrinsolublefibrinogen
++
ⅩIII
ⅩIIIa
+
Fibrin clot
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Mechanism of heparinMechanism of heparin
•• This reaction happens This reaction happens in normal in normal physiological state, but physiological state, but itit’’s very slow and 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
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CharacteristicsCharacteristics of anticoagulative effectof anticoagulative effect
• effective both in vivo and in vitro
• quick onset and potent effects
• efficacy positively relative to mocular weight
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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 …….
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1.3 Clinical uses1.3 Clinical uses1) thromboembolic disease: deep venous thrombosis(DVT), pulmonary embolism, unstable angina, acute myocardial infarction, cerebral infarction2) DIC (Disseminated intravascular coagulation):
early stage3) extracorporal circulation (eg. dialysis machine)
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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
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1.5 Contraindications:1.5 Contraindications: 1. Bleeding tendency:• Severe hypertension• Ulcer• surgery of the brain ,eye, spinal cord2. pregnancy3. Renal and hepatic dysfunctions
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Coumarin derivativesCoumarin derivatives --- ---Oral anticoagulantsOral anticoagulants
These agents are often referred to
as oral anticoagulants because they are
administered orally, which exists as the
main difference from heparin.
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• Warfarin• Dicoumarin• Acenocoumarin
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4.1 pharmacological effects4.1 pharmacological effects
• Anticoagulative effect
1) mechanism:
antagonizing Vit K→inhibiting the
synthesis of cloting factor Ⅱ,Ⅶ,Ⅸ,Ⅹ
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Mechanism ofMechanism of Oral anticoagulantsOral anticoagulants
Several clotting factors (ⅡⅡ, , ⅦⅦ, , ⅨⅨ, , ⅩⅩ) 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
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22)) characteristicscharacteristics
• (1) oral administration• (2) effective in vivo, not in vitro • (3) slow onset, long duration • (4) overcome by administration of
Vitamin K
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• 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
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4.3 adverse effects
4.3.1 Spontaneous hemorrhage :
monitoring of PT Treatment: withdrawal of the drug; administration of vitamin K and fresh blood
4.3.2 others: birth defect (warfarin)
Allergic reaction
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•• 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
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Ⅲ Anticoagulants in vitro Sodium citrate, potassium oxalate Mechanism: Ca2+ Uses: prevent blood coagulation in vitro
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§§22 antiplatelet drugs antiplatelet drugs
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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.
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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.
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ClassificationⅠ Inhibitors of platelet metabolism Ⅱ Agents inhibiting platelet activity induced by ADP: Ticlopidine Ⅲ Thrombin inhibitor: argatrobanIV GPΠb / Шa receptor blocker: abciximab
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AA TXA2 (-) (+)
AC AC PDE
cAMP ↓ cAMP↑ 5-AMP
↑aggregation ↓aggregation (PLT) (endothelium)
aspirins -
Dipyridamole
-
+
aspirinl
COX COX
-
PGI2
AC= Adenylate Cyclase
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ⅠⅠ Inhibitors of platelet metabolism Inhibitors of platelet metabolism
ⅰ Cyclooxygenase inhibitors: Aspirinⅱ PDE (Phosphodiesterase) inhibitors :
Dipyridamoleⅲ TXA2 synthetase inhibitor: Ridogrelⅳ Activators of adenylate cyclase: epoprostenol (PGI2)
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ⅰⅰ Cyclooxygenase inhibitors: Cyclooxygenase inhibitors: AspirinAspirin
• 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.
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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.
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Clinical Uses Clinical Uses Prophylaxis after cardiac operation to reduce the incidence of recurrent
myocardial infarction (MI) Prophylaxis for transient ischemic attacks
(TIA) or post TIA
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ⅱⅱ PDE inhibitors : Dipyridamole PDE inhibitors : Dipyridamole
Mechanism : 1) ↓PDE → cAMP ↑ ↓ aggregation
2) ↓ the uptake of adenosine →↑AC Clinical use: Substitute of aspirin prosthetic heart valves, etc.
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• ⅲ TXA2 synthetase inhibitor: Ridogrel
• More effective than aspirin• Fewer adverse reaction
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ⅡⅡ 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 and binding of fibrin to GP Ⅱb/ Ⅲ a receptor induced by ADP
• Clinic use: thromboembolic disease
• Severe toxicity: nausea, bone marrow depression
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• 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.
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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
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IV GPΠb / Шa receptor blocker: abciximab
• activation of glycoprotein receptor on PLT membrane is the final common pathway for platelet aggregation.
• Mechanism: blockade of glycoprotein receptors on PLT membrane
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§43 Hemostatics
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Ⅰ Coagulants Vitamin KⅡ Antifibrinolytic drugs Tranexamic acid Aminomethylbenzoic acidⅢ ThrombinⅣ Vasoconstrictors Etamsylate
Posterior pituitary(垂体后叶素)
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ⅰⅰ Vitamin K 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
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Mechanism ofMechanism of vitamin Kvitamin K
Smoe clotting factors (ⅡⅡ, , ⅦⅦ, , ⅨⅨ, , ⅩⅩ) that are involved in the coagulation reactions depend on vitamin K as a coenzyme in their complete synthesis by the liver.
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Ⅻ Ⅻa
Ⅺa
Ⅸa
Ⅹa
Ⅶa
Ⅺ
Ⅸ
Ⅹ
Ⅶ
Ⅹ
+
+
+ +
+
Prothrombin(Ⅱ) Thrombin(Ⅱa)
Fibrininsoluble
Fibrinsolublefibrinogen
++
ⅩIII
ⅩIIIa
+
Fibrin clot
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• 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.
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§§5 Agents Used in Anemia5 Agents Used in Anemia
• Anemia ---a deficiency in erythrocytes or hemoglobin.
• Normal value RBC(104/μL) Hb(g/dL)• Adult male 400-550 12 -16• Adult famale 350-500 11-15
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Types of anemia
• Iron-deficiency anemia• megaloblastic anemia• aplastic anemia• hemolytic anemia
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1. Iron • p.o.: Ferrous sulfate Ferric ammonium citrate Ferrous fumarate• i.m.: Iron dextran
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Pharmacological actions:Pharmacological actions: Iron is part of hemoglobin, the oxygen-
carrying component of the blood. Iron-deficient people tire easily because their bodies are starved for oxygen.
Iron is also part of myoglobin. Myoglobin helps muscle cells store oxygen.
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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
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Adverse reactions 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
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• 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
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• Clinical uses:
• 1. Megaloblastic anemia• 2. Pernicious anemia• 3. Megaloblastic anemia caused by FH2
reductase inhibitors: methotrexate, Pyrimethamine(
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3. Vitamin B123. Vitamin B12
Source:• Meat (especially liver), eggs,
and dairy products.Pharmacokinetics:• Requirements of Vitamin B12:
1μg/d• Storage: in liver
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Pharmacological Action:
• 1) methyl transfer• pernicious anemia
• 2) isomerization of methylmalonyl-CoA to succinyl-CoA
• destroy integrity of myelin sheath→ nerve damage
TAC
dTMPdUMP
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Clinical uses: 1. Megaloblastic anemia 2 .Pernicious anemia 3 .Nervous system diseases 4. Hepatopathy
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