Pharmacology 301.6
Module 6
DRUGS & BLOOD
Anticoagulants, anti-platelet &
fibrinolytics
Treatment of anemia
Causes of death in Canada
1997: 661 deaths/100,000
http://www.statcan.ca/english/Pgdb/health30b.htm
stroke
injuries liver
cancer
lung
other
heart disease
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
Accidental injury vs. pathological injury
hypercholesterolemia, diabets,
hypertension
Coagulation cascade – platelet activation and coagulation
vasospasm
platelet plug
fibrin plug
Recanalization
platelets (5HT, TXA2)
adhesion, activation, aggregation
extrinsic, intrinsic (humoral)
fibrinolysis
Platelet function
disruption of
endothelium
platelet adhesion
agonist binding
• thrombin
platelet activation
platelet release
platelet
aggregation
• serotonin
• ADP
• TXA2
Platelet adhesion
and aggregation
Platelet activation
Antiplatelet drugs
Arachidonic acid
Aspirin
ADP
stimulates
Thromboxane
(from activated platelets)
Clopidogrel
ticlopidine
inhibit
P2Y receptor
TXA2 recep
clotting
Ca2+
Lowers cAMP
Increased cAMP
clotting
Prevents clotting
GpIIb-IIIa
Receptor for
Eptifibatide
fibrinogen and
Abciximab
platelet adhesion
Tirofiban
Dipyridamole
(prevents
breakdown by
phosphodiesterase)
How does it work?
Aspirin efficacy
Aspirin irreversibly inhibits
platelet COX enzyme
Platelets cannot synthesize
new COX (no nucleus)
No thromboxane
(procoagulant,
vasoconstrictor) synthesis
Low dose aspirin (80-160
mg) does not inhibit
endothelial COX
Prostacyclin (anticoagulant,
vasodilator) formation not
affected
Aspirin reduces clots by 15%, on average. 2% have a
bleed, that is serious each year. Use in high risk clotters.
Antiplatelet drugs
Ticlopidine (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
Blood coagulation cascade
See the
figure in
textbook Brenner’s
Factor IIa
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 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 units
MW ~ 13,500
This reaction goes
1000 to 3000 times
faster with heparin.
Antithrombin
inhibits thrombin,
Xa, IXa and to a
lesser extent VIIa
Low Mol. Wt.
Heparin
~ 15 saccaharide
units
MW ~ 4,500
circulates in the plasma rapidly inhibits thrombin
only in the presence of
heparin
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 thromboembolism
2. Treatment of venous thrombosis,
pulmonary embolism and unstable angina
3. prophylaxis following total knee
arthroplasty
Other parenteral anticoagulants
Danaparoid (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
Oral anticoagulants – 4-hydroxycoumarins
Gamma glutamic acid residues of clotting factors must be
carboxylated for enzyme activity
factors
II, VII,
IX, X,
Prots C
and S
Vitamin K
Vit.K epoxide
Coumarins
reductase Coumarins
are
act here
competitive
inhibitors
Warfarin COUMADIN
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 – 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 - Antidote
Vitamin K (oral or parenteral)
INR = (PTpt / PTref)ISI
Target 2.0 to 3.0
Fibrinolytic process
Streptokinase
binds here –
generalized
action
t-PA has to
bind here
– localized
ation
Efficacy of thromobolytics
1.8% have serious bleeding;
0.7% have IC haemorrhage
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.
Tissue plasminogen activator (t-PA)
– (alteplase, ACTIVASE)
 activates fibrin bound plasminogen
(less systemic plasmin formation)
 More expensive than streptokinase
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 weight
Essential iron
Male
Female
Hemoglobin 31
28
Myoglobin
6
and enzymes
Storage iron 13
5
Total
37
50
4
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
deficiency
Folinic acid (leucovorin calcium,
citrovorum factor) – 5-formyl derivative of
tetrahydrofolic acid
 To circumvent the inhibition of
dihydrofolate reductase as a part of highdose methotrexate therapy
 To counteract the toxicity of folate
antagonists such as pyrimethamine or
trimethoprim
 More expensive