pharmacology 301.6 module 6 drugs & blood anticoagulants, anti-platelet & fibrinolytics...
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Pharmacology 301.6Module 6
DRUGS & BLOOD Anticoagulants, anti-platelet &
fibrinolytics
Treatment of anemia
cancer
heart disease
other
lung
stroke injuries liver
Causes of death in Canada
1997: 661 deaths/100,000http://www.statcan.ca/english/Pgdb/health30b.htm
Heart disease and stroke = 1 of 3 deaths, due to clotting
Blood fluidity The endothelial lining is non-thrombogenic Balance between procoagulants (thromboxane,
thrombin, activated platelets, platelet factor 4) and anticoagulants (heparan sulfate, prostacyclin, nitric oxide, antithrombin)
1. heparin & derivatives – stimulate natural inhibitors of coagulant proteases (antithrombin)
2. coumarin anticoagulants – block multiple steps in the coagulation cascade
3. fibrinolytic agents – lyse pathological thrombi
4. antiplatelet agents – aspirin
The Hemostatic System
vasospasm platelets (5HT, TXA2)
platelet plug adhesion, activation, aggregation
Accidental injury vs. pathological injuryhypercholesterolemia, diabets,
hypertension
Coagulation cascade – platelet activation and coagulation
fibrin plug extrinsic, intrinsic (humoral)
Recanalization fibrinolysis
Platelet function
disruption of endothelium
platelet adhesion
platelet activation
platelet release
platelet aggregation
agonist binding
• thrombin
• serotonin
• ADP
• TXA2
Antiplatelet drugs
clotting
Increased cAMP
Prevents clotting
ADP
P2Y receptor
Lowers cAMP
Clopidogrelticlopidine
inhibitstimulates
TXA2 recep
Arachidonic acidAspirin
Thromboxane(from activated platelets)
GpIIb-IIIaReceptor for fibrinogen and platelet adhesion
Ca2+
Dipyridamole(prevents
breakdown by phosphodiesterase)
clotting
EptifibatideAbciximabTirofiban
Aspirin efficacy
Aspirin reduces clots by 15%, on average. 2% have a bleed, that is serious each year. Use in high risk clotters.
How does it work?Aspirin irreversibly inhibits platelet COX enzymePlatelets cannot synthesize new COX (no nucleus)No thromboxane (procoagulant, vasoconstrictor) synthesisLow dose aspirin (80-160 mg) does not inhibit endothelial COXProstacyclin (anticoagulant, vasodilator) formation not affected
Antiplatelet drugsTiclopidine (TICLID)- is a prodrug
Blocks platelet ADP receptor and prevents activation and aggregation Is often used in combination with aspirin (synergistic action), for angioplasty and stenting surgery To prevent secondary strokes and in unstable angina Severe neutropenia – 1% of patients
Clopidogrel (PLAVIX) Similar to ticlopidine and used same way Less incidence of neutropenia or thrombocytopenia Used in combination with aspirin
Activated partial thromboplastin time (aPTT) & prothrombin time
(PT) Blood clots in 4-8 min in a glass tube Chelation of ca2+ prevents clotting Recalcified plasma clots in 2-4 min Addition of negatively charged phospholipids and
kaolin (aluminium silicate) shortens clotting time to 26-33 sec – aPTT
Addition of ‘thromboplastin’ (a saline extract of brain – tissue factor and phospholipids) shortens clotting time to 12-14 sec – prothrombin time (PT)
Anticoagulants - Heparin Heparin is a glycoasminoglycan – alternating
glucuronic acid and N-acetyl-D-glucosamine residues – sulfate and acetyl groups.
Avg mol. wt - 12,000 daltons
Heparin is negatively charged Heparin HEPALEANHeparin HEPALEAN
Heparin – Source and function
Heparin - originally isolated from the liver Found in mast cells -storage of histamine
& proteases Rapidly destroyed by macrophages Normally not detected in the blood Heparan sulfate - similar to heparin but less
polymerized - contains fewer sulfate groups Found on the surface of endothelial cells and in
the extracellular matrix Interacts with circulating antithrombin to
provide a natural antithrombotic mechanism
Heparin & LMW Heparins difference in action
Heparin~ 45 saccaharide unitsMW ~ 13,500This reaction goes 1000 to 3000 times faster with heparin.
Low Mol. Wt. Heparin~ 15 saccaharide unitsMW ~ 4,500
circulates in the plasma - rapidly inhibits thrombin only in the presence of heparin
Antithrombin inhibits thrombin, Xa, IXa and to a lesser extent VIIa
Heparin – Toxicity - Hemorrhage
Hemorrhage – recent surgery, trauma, peptic ulcer disease, platelet dysfunction
Life-threatening bleeding can be reversed by protamine sulfate - 1 mg of protamine sulfate for every 100 U of heparin - slow iv infusion – 50 mg over 10 min)
Protamine sulfate interacts with platelets, fibrinogen, and other clotting factors - an anticoagulant effect – at higher doses
Anaphylactic reactions to protamine (a basic protein isolated from Salmon sperm)
Heparin-induced Thrombocytopenia
50% decrease in platelet count - <150,000/μl) Antibodies against complexes of heparin with
platelet factor 4 In 3-5% of patients 5 to 10 days after initiation of
heparin therapy Lower incidence with low mol wt heparin In 1/3 of pts is preceded by thrombosis Can be life-threatening Stop heparin immediately Alternative anticoagulants – lepirudin or
danaparoid
Low Molecular Weight Heparins Avg mol. wt 4,500 daltons - 15 monosaccharide units
Better absorbed - higher bioavailability
Longer biological half-life
More predictable dose-response - does not bind to plasma proteins, macrophages, or endothelial cells
Can be given s.c. without lab monitoring in an outpatient setting
Cleared unchanged by kidney (do not use in renal failure!) rather than by the reticuloendothelial system
Lower risks of thrombocytopenia and bleeding
Safety and use during pregnancy not evaluated
LMW heparins
Dalteparin (FRAGMIN) Enoxaparin (LOVENOX)
Uses:1. prevention of venous thromboembolism2. Treatment of venous thrombosis,
pulmonary embolism and unstable angina
3. prophylaxis following total knee arthroplasty
Other parenteral anticoagulantsDanaparoid (ORGARAN)
nonheparin glycosaminoglycans (84% heparan sulfate) Promotes inhibition of Xa by antithrombin Prophylaxis of deep vein thrombosis In patients with heparin-induced thrombocytopenia
Lepirudin (REFLUDAN) recombinant derivative of hirudin (a direct thrombin
inhibitor in leech) In patients with heparin-induced thrombocytopenia
Act
ion
of
Cou
mari
ns
Coumarins act here
Vitamin K
Coumarins are competitive inhibitors
Oral anticoagulants – 4-hydroxycoumarins
Gamma glutamic acid residues of clotting factors must be carboxylated for enzyme activity
Vit.K epoxide reductase
factors II, VII, IX, X, Prots C and S
Coumarins (warfarin)
• inhibits vitamin K reduction
• efficacy measured by INR (International Normalized Ratio), the patient’s PT divided by the PT in pooled plasma
• takes 4-5 days to become effective – active carboxylated factors in plasma need to be cleared
• small Vd, steep D-R curve, metabolized by CYP1A and CYP2C9 (interactions)
• Warfarin crosses placenta – is teratogenic – birth defects and abortion
• major indications: DVT, PE and atrial fibrillation
Warfarin COUMADINWarfarin COUMADIN
Warfarin – drug & other interactions
Any substance or condition is dangerous if it alters:
1. the uptake or metabolism of oral anticoagulant or vitamin K
2. the synthesis function or clearance of any factor or cell involved in hemostasis or fibrinolysis
3. the integrity of any epithelial surface
Warfarin - Clinical uses 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
Warfarin - AntidoteVitamin K (oral or parenteral)
INR = (PTpt / PTref)ISI Target 2.0 to 3.0
Fibrinolytic process
t-PA has to bind here – localized ation
Streptokinase binds here – generalized action
Tissue plasminogen activator (t-PA) – (alteplase, ACTIVASE)
activates fibrin bound plasminogen (less systemic plasmin formation)
More expensive than streptokinase
Streptokinase (STREPTASE)
Binds plasminogen- coverts to plasmin Dissolve clots after myocardial infarction, deep vein thrombosis, massive pulmonary emboli Side effects: Bleeding, allergic reactions, hypotension, fever.
Summary
• we have lots of drugs that affect hemostasis
• they can inhibit platelet function, fibrin formation, or fibrinolysis.
• using combinations prevents more clots, but causes more bleeding.
• look at the risk/benefit ratio.
Anemia a reduction in the hemoglobin, hematocrit ( % of whole blood that is comprised of red blood cells) or red cell number Erythropoiesis - Pluripotent stem cells differentiate under the influence of growth factors (erythropoietin) to form erythrocytes controlled by a feedback system in the kidney - responds to changes in oxygen delivery - secretes erythropoietin (a glycoprotein) from peritubular interstitial cells - stimulates the marrow cells Feedback - disrupted by kidney disease, marrow damage or a deficiency in iron or an essential vitamin.
Anemia Iron deficiency is the most common cause
of anemia
Results in microcytic hypochromic anemia
Iron deficiency also affects iron-dependent enzymes such as cytochromes, catalase, peroxidase, xanthine oxidase and mitochondrial enzyme α-glycerophosphate oxidase
Iron deficiency has also been associated with learning problems in children
Iron in the body
mg/kg of body weightMale Female
Hemoglobin
31 28
Myoglobin and enzymes
6 5
Storage iron
13 4
Total 50 37
Ess
en
tial
iro
n
Treatment of Iron Deficiency
The ability of the patient to tolerate and absorb medicinal iron is important
Gastrointestinal tolerance to oral iron is limited Mainly absorbed only in the upper small
intestinal (delayed-release preparations ?)
Parenteral iron Iron dextran injection (INFED, DEXFERRUM)
Acute hypersensitivity, including anaphylactic reactions, can occur in from 0.2% to 3% of patients.
Iv is preferred – more reliable response Im route – more local side effects – skin
discoloration, long-term discomfort, concern about malignant change at injection site
Megaloblastic (macrocytic) anemias
Due to lack of folic acid or vitamin B12
Deficiency more common in older adults
Folate – food fortification – masks cobalamin deficiency (neurologic damage)
In pregnancy - prevention of folate deficiency and permanent neural tube defects in children minimized
Folate and Vitamin B12 Interaction
Tetrahydrofolate is necessary for DNA synthesis Cobalamin and folate are cofactors for tetrahydrofolate production Deficiency of either impairs cell division in the bone marrow while RNA and protein synthesis continues – enlarged erythrocytes Cobalamin deficiency – impairs synthesis of S-adenosylmethionine – necessary for proper nervous system functioning
Pernicious anemia
Lack of intrinsic factor – Vit. B12 not absorbed
Injury to parietal cells or autoantibodies Vitamin B12 - must be administered– is not
synthesized in body
Treating deficiencies Distinguishing B12 deficiency from folic acid
deficiency Folic acid will supply folate needed for DNA
synthesis Anemia corrected It DOES NOT correct the lack of
methionine and succinyl Co-A synthesis – this will cause neurological deficits
Folic acid therapy Rule out underlying cobalamin deficiencyFolinic acid (leucovorin calcium, citrovorum
factor) – 5-formyl derivative of tetrahydrofolic acid
To circumvent the inhibition of dihydrofolate reductase as a part of high-dose methotrexate therapy
To counteract the toxicity of folate antagonists such as pyrimethamine or trimethoprim
More expensive