DR.khaalid

1. Group 2
Pharmacology
DRUGS & BLOOD
Anticoagulants, anti-platelet & fibrinolytics
Treatment of anemia
pre: Khalid Hassan elmi

2. 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

3. The Hemostatic System
vasospasm platelets (5HT, TXA2)
platelet plug adhesion, activation, aggregation
Accidental injury vs. pathological injury
hypercholesterolemia, diabets,
hypertension
Coagulation cascade – platelet activation and
coagulation
fibrin plug extrinsic, intrinsic (humoral)
Recanalization fibrinolysis

4. Platelet function
disruption of
endothelium
platelet adhesion
platelet activation
platelet release
platelet
aggregation
agonist binding
• thrombin
• serotonin
• ADP
• TXA2

5. Platelet adhesion
and aggregation
Platelet activation

6. Antiplatelet drugs
clotting
Increased cAMP
Prevents clotting
ADP
P2Y receptor
Lowers cAMP
Clopidogrel
ticlopidine
inhibit
stimulates
TXA2 recep
Arachidonic acid
Aspirin
Thromboxane
(from activated platelets)
GpIIb-IIIa
Receptor for
fibrinogen and
platelet adhesion
Ca2+
Dipyridamole
(prevents
breakdown by
phosphodiesterase)
clotting
Eptifibatide
Abciximab
Tirofiban

7. 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 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

8. 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

9. Factor IIa
Blood coagulation cascade
See the
figure in
textbook -
Brenner’s

10. 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)

11. 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

12. 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

13. Heparin & LMW Heparins
difference in action
Heparin
~ 45 saccaharide units
MW ~ 13,500
This reaction goes
1000 to 3000 times
faster with heparin.
Low Mol. Wt.
Heparin
~ 15 saccaharide
units
MW ~ 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

14. 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)

15. 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

16. ActionofCoumarins
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

17. 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

18. 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

19. 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

20. Fibrinolytic process
t-PA has to
bind here
– localized
ation
Streptokinase
binds here –
generalized
action

21. Efficacy of thromobolytics
1.8% have serious bleeding;
0.7% have IC haemorrhage

22. 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.

23. 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.

24. 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.

25. 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

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

27. 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

28. 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

29. 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

30. 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

31. 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