Drugs & Blood - University of Saskatchewan
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Transcript Drugs & Blood - University of Saskatchewan
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