Pharmacology 301.6 Module 6

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Pharmacology 301.6Module 6

• DRUGS BLOOD
• Anticoagulants, anti-platelet fibrinolytics
• Treatment of anemia

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Heart disease and stroke 1 of 3 deaths, due to
clotting
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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

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The Hemostatic System
Accidental injury vs. pathological
injury hypercholesterolemia, diabets,
hypertension Coagulation cascade platelet
activation and coagulation
vasospasm platelets (5HT, TXA2)
platelet plug adhesion, activation, aggregation
fibrin plug extrinsic, intrinsic (humoral)
Recanalization fibrinolysis
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Platelet function
disruption of endothelium
agonist binding
platelet adhesion

• thrombin
• serotonin
• ADP
• TXA2

platelet activation
platelet release
platelet aggregation
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Platelet adhesion and aggregation
Platelet activation
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Antiplatelet drugs
Arachidonic acid Aspirin Thromboxane (from
activated platelets)
Clopidogrel ticlopidine
ADP
stimulates
inhibit
P2Y receptor
TXA2 recep
Lowers cAMP
clotting
Ca2
Increased cAMP
clotting
Prevents clotting
Dipyridamole (prevents breakdown by
phosphodiesterase)
GpIIb-IIIa
Receptor for fibrinogen and platelet adhesion
Eptifibatide Abciximab Tirofiban
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Aspirin efficacy
How does it work? 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.
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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

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Blood coagulation cascade
See the figure in textbook - Brenners
Factor IIa
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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)

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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
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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

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Heparin LMW Heparins difference in action
circulates in the plasma - rapidly inhibits
thrombin only in the presence of heparin
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
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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)

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Heparin-induced Thrombocytopenia

• 50 decrease in platelet count - lt150,000/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

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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

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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

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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

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Action of Coumarins
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 reductase
Coumarins act here
Coumarins are competitive inhibitors
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Coumarins (warfarin)
Warfarin COUMADIN

• inhibits vitamin K reduction
• efficacy measured by INR (International
  Normalized Ratio), the patients 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

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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

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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
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Fibrinolytic process
Streptokinase binds here generalized action
t-PA has to bind here localized ation
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Efficacy of thromobolytics
1.8 have serious bleeding 0.7 have IC
haemorrhage
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Tissue plasminogen activator (t-PA) (alteplase,
ACTIVASE)

• 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.

• activates fibrin bound plasminogen (less systemic
  plasmin formation)
• More expensive than streptokinase

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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.

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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.

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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 a-glycerophosphate oxidase
• Iron deficiency has also been associated with
  learning problems in children

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Iron in the body
mg/kg of body weight mg/kg of body weight
Male Female Female
Hemoglobin 31 28 28
Myoglobin and enzymes 6 5 5
Storage iron 13 4 4
Total 50 37 37
Essential iron
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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

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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

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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

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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

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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 high-dose methotrexate
  therapy
• To counteract the toxicity of folate antagonists
  such as pyrimethamine or trimethoprim
• More expensive