Blood Thinners

Maher Khdour
Clinical Pharmacy, BSc, MSc, PhD
 Drugs which affect blood clotting
 Normal clotting
 Abnormal clotting: thrombosis
 Drugs that inhibit clotting function of platelets
 antiplatelet drugs
 Drugs that inhibit protein clotting factors
 anticoagulants
 Drugs that lyse thrombi
 thrombolytic drugs
 Normal Blood Clotting
 Platelet clot formation

 “Intrinsic Pathway” of clotting factor activation

 “Extrinsic Pathway” of clotting factor activation

 Platelet Clot Formation

Damaged vessel wall

Platelet clot sealing breach

 Platelet Aggregation & Adhesion
1
Platelets don’t adhere Breach in endothelium reveals collagen
to normal endothelium
Platelets adhere to collagen

TxA2
More platelets aggregate

3
 Clotting Factor Activation
Intrinsic Extrinsic
Abnormal vessel wall Damaged tissue

XII XIIa VIIa VII

XI XIa
Thrombin-fibrin
IX IXa clot

X Xa

Prothrombin Thrombin Fibrinogen

 Thrombin Inactivation:
Antithrombin III (AT III)

AT III Thrombolyis

Thrombin-fibrin
AT III clot
Inactive Complex
Thrombin

Thrombin Fibrinogen
Platelet-fibrin clot
 PLATELET INHIBITORS

 ASA
 Clopidogrel (Plavix®), Ticlodipine (Ticlid®)
 Tirofiban (Aggrastat®)
 Abciximab (ReoPro®)
 Eptifibatide (Integrilin®)
 Mechanism of action for GP IIb-IIIa inhibitors

White HD. Am J Cardiol. 1997; 80(4A):2B-10B.

Synthesis of Thromboxane A2 (TxA2) in Platelets
Arachidonic acid
Cyclooxygenase (Pg Synthase)

Prostaglandin G2
Aspirin

Prostaglandin H2

TxA2
Other Pg’s
 Aspirin (acetyl salicylic acid)
COOH

OCOCH3

Salicylic acid -acetyl

COOH OCOCH3

Acetylation of NH2-terminal serine

of cyclooxygenase (irreversible)

Competitive blockage of cyclooxygenase

 Acetylation of NH2-terminal
serine of cyclooxygenase (irreversible)

Permanent loss of TxA2 production

Permanent defect in platelet clot formation

Protection from thrombotic disorders

Clopidogrel
 Also inhibit platelet activation
 Blocks platelet ADP receptors irreversibly
– Prevents ADP-induced activation.
 Prodrug, requiring activation by the liver.
Clopidogrel
 Clinical Use
 Alternative to aspirin (reserved for aspirin-
intolerant or unresponsive patients, because of
cost & ADR’s)
 Added to aspirin in management of some
coronary artery syndromes
Clopidogrel
 – Adverse Effects
diarrhea and nausea,
bleeding complications
 Ticlodipine (Ticlid®)
 Oral Tablets
 Interferes with platelet function by inhibiting ADP-induced platelet-
fibrinogen binding and platelet-platelet interactions
 Indication: to reduce the risk of thrombotic stroke (fatal or nonfatal) in
patients with stroke precursors, or thrombotic stroke
 Can cause life-threatening hematological reactions, including
neutropenia/ agranulocytosis, thrombocytopenic and aplastic anemia
 Should be reserved for patients who are intolerant or allergic to aspirin
therapy or who have failed aspirin therapy
 New Oral Antiplatelet Drugs
Adenosine Diphosphate-Receptor Antagonists
Ticagrelor *
Prasugrel  Cyclo-pentyl-triazo-pyrimidine
 Thienopyridine (CPTP)
 More rapid onset of action than
 More rapid onset of action
clopidogrel
than clopidogrel  Not a pro drug
 Pro drug  Reversible inhibitor of the P2Y12
 Irreversible inhibitor of the receptor
P2Y12 receptor  Sid effect dyspnea

* Not approved by FDA

 Gp IIb/IIIa ANTAGONISTS

 Platelet Gp IIb/IIIa receptors play a pivotal

role in platelet-mediated thrombus
formation, binding to fibrinogen and vWF

 IIb/IIIa antagonists differ in receptor

affinity, reversibility, and specificity
 Platelet Activation Pathways
Collagen Thrombin
Epinephrine ADP
Arachidonic
acid

TxA2

GP IIb/IIIa
Abciximab (ReoPro®)
 Monoclonal antibody that binds to glycoprotein (GP)
IIb/IIIa receptor of human platelets and inhibits platelet
aggregation.
 Abciximab is intended for use with aspirin and heparin
and has been studied only in that setting
 Abciximab is indicated for prevention of cardiac ischemic
complications like unstable angina or if coronary
intervention is planned within 24 hours
 GP IIb/IIIa antagonist

Inhibition of platelet
aggregation
Agonist
GP IIb/IIIa receptors occupied by
ADP, antagonists
thrombin,
Resting collagen
platelet Fibrinogen
GP IIb/IIIa
receptors in
unreceptive
state

Aggregating
platelets
 Tirofiban (Aggrastat®)
 Tirofiban is a nonpeptide inhibitor of the platelet glycoprotein (GP)
IIb/IIIa receptor, the final common pathway for platelet aggregation.
 Tirofiban is available as an IV drug only
 Tirofiban is a safe and effective agent in combination with heparin
and aspirin in the setting of an acute coronary syndrome.
 It has also been shown to significantly reduce cardiac events in
patients with an acute coronary syndrome who undergo angioplasty
Eptifibatide (Integrilin®)
 Eptifibatide is a cyclic six amino acids peptide
 Eptifibatide binds to the platelet receptor glycoprotein (GP)
IIb/IIIa of human platelets and inhibits platelet aggregation
 Efficacy of eptifibatide established with concomitant use of
heparin and aspirin
 Available as IV drug only
 Dose adjusted based on renal function
 Damaged endothelium

Thrombin-fibrin clot
Platelet clot
2

Thrombus
3
Thrombosis Syndromes
 Venous thrombosis
 myocardial infarction (heart attack)
 cerebral artery occlusion (stroke)
 peripheral artery thrombosis
 etc.......
 Preventing & Treating Thrombosis
 Antiplatelet drugs
 Drugs that deplete functional clotting factors
 Warfarin
 Heparins
 Drugs that accelerate clot lysis
 Interference with synthesis of clotting
factors: Warfarin

Factors II, VII, IX & X

–Post-translational carboxylation of glutamic acid groups.

–Vitamin K is a cofactor for carboxylation

–Warfarin is an analogue of Vitamin K

–Warfarin inhibits Vitamin K recycling

 O
CH3
Factors II VII IX X are Vit K dependant
O coagulation factors
R

O
KO
Vitamin K
Epoxide
Reductase

OH
CH3
Warfarin

KH2 OH
 COO- COO- COO-
Decarboxy- CH2 (prothrombin)
CH2
(prothrombin)
CH2 CH2

CO2 Carboxylase
O2

OH O
CH3 CH3

R R

OH O
KH2 KO

Warfarin
Pharmacokinetics of Warfarin
 Weak acid
 Well absorbed orally
 Hepatic clearance, using Cytochrome P450
 Strongly bound to plasma protein albumin
Pharmacodynamics of Warfarin
 Clotting factors deplete at a rate determined
by half-life [ i.e protein c and factor VII less T1/2 so depleted
First than other vit K dependent coagulation factors II, IX & X]
 Protein S and Protein C are quickly depleted:
they are anticoagulant. Congenital deficiency
of Protein S or C permits a transient
hypercoagulable state, manifest as skin
necrosis on starting warfarin.
Uses and Adverse Effects of Warfarin
 Long-term oral anticoagulation
 Prevent thromboses from extending

 Prophylaxis against thrombosis on mechanical

heart valves
Adverse Effect
 Risk of bleeding: coagulation needs regular

monitoring
 Teratogenic: can’t be used in pregnancy
Warfarin: Contraindications and
Cautions
 Peptic ulcer, without confirmation of healing
 History intracranial bleeding
 Hypertension (relative)
 Liver disease with defective clotting factor
synthesis
 Renal failure (dependent on degree)
 Pre-existing platelet clotting defects (eg,
thrombocytopaenia)
 Warfarin: Contraindications and
Cautions
 Therapy with anti-platelet agents
 Old age (relative)
 Pregnancy (teratogenic)
 Alcohol abuse
 History of protein S or protein C deficiency:
increased risk of coumarin skin necrosis
(start with heparin)
Warfarin Induced Skin necrosis
Drug Interactions with Warfarin
 Absorption  Protein Binding
 cholestyramine anion  weak acid
binding resin antiinflammatory drugs
 antacids and oil
laxatives
Drug Interactions with Warfarin
 P450 Induction  P450 Inhibition
 Barbiturates  Ketconazole
 Carbamazepine  Metronidazole
 Phenytoin  Cotrimoxazole
 Rifampicin  HMG-CoA Reductase
 Griseofulvin inhibitors ("Statins")
 ⇒ ⇓ efficacy
 Omeprazole
 Cimetidine
 Amiodarone
 Allopurinol
 ⇒ ⇑ bleeding risk
Monitoring Warfarin
 Measure activity in the extrinsic and
common pathways, by activating with
“Thromboplastin”
– Prothrombin time
 Standardised to International Normalised
Ratio (INR)
 INR 2 to 3 for most indications
Reversing Warfarin
 FFP (Fresh Frozen Plasma).
 Vitamin K, subcutaneously,
-INR 4-5 [omit a dose, doses]
-INR 5-9 But no bleeding [add Vit k 1-2.5 mg orally]
- INR > 9 [2.5-5 mg Vit K]
-Bleeding regadless INR [10mg Vit K i.v infusion with
fresh frozen Plasma]
Inactivation of thrombin: heparin
 Mixture of glycosaminoglycans
 Molecular weight ranges 3000 to 58000

 Strong acid, so strong electronegative

charge
 Heparin: mechanism of action

Binds to Lysine on ATIII

 Conformational change to ATIII.

  affinity for factors XIIa, XIa, IXa, Xa, IIa (thrombin).

 Accelerated inactivation of XIIa, XIa, IXa, Xa, IIa

 Prevents conversion of fibrinogen to fibrin

 Stops clot propagation.

 Heparin: Action on AT III

Hep
AT III

Thrombin-fibrin
AT
HepIII clot
Inactive Complex
Thrombin

Thrombin Fibrinogen
 Uses & Adverse Effects of Heparin
 Given parenterally
 Rapid anticoagulation

 Clinical Uses of Heparin

 Arterial and venous thrombi and emboli

 Treatment

 Prophylaxis

 Not teratogenic: can be used in pregnancy

Adverse Effects of Heparin
 Bleeding
 Immune-mediated platelet activation
 bleeding from thrombocytopenia
Monitoring Heparin
 Measure activity of Intrinsic and Common Pathway
 “Activated Partial Thromboplastin Time (APTT)”

 Therapeutic goal

 Normal – 30 sec

 Heparin Therapy – 2-2.5 times normal control

value (60-70 sec)

 Antidote: Slow IV injection of Protamine Sulfate

1 mg bind 100 units

Low MW Heparin:
Enoxaparin, Dalteparin, Nadroparin
 Fractionated from total heparin
 More predictable: can be given on a weight
adjusted basis
 Longer half-life, so can be given by
subcutaneous injection
 Less heparin-induced thrombocytopenia
 More expensive, but saves staff time &
hospitalization
 Low MW Heparin

Administered by SC injection
No need for therapeutic monitoring
Lower Risk of Bleeding than unfractioned Heparin

Antidote: Slow IV injection of Protamine Sulfate

Direct Thrombin Inhibitors
 Natural Product: hirudin
 Recombinant Derivatives:
 lepirudin
 Synthetic Derivatives:
 bivalirudin
 Related Small Molecules:
 argatroban
Direct Thrombin Inhibitors
• MOA
– Binds directly to thrombin
– Pure thrombin inhibitor (IIa), no Xa activity
• Adverse effects
• Monitoring
– Bleeding
– aPTT
 UH inhibit 1:1 Ratio Xa : Thrombin
 LMWH inhibit 3:1 Ratio Xa : Thrombin
 Fondapaniux Pure Xa Inhibitor
 Bivalirudin Pure Thrombin Inhibitor
Promoting Clot Lysis: Tissue
plasminogen activator (t-PA)
Plasminogen

t-PA

Plasmin

Thrombin-fibrin Degradation
clot products
 Streptokinase:

Streptokinase binds to plasminogen and forms an

activator complex by which plasmin is formed
 Tissue plasminogen activator (t-PA):
Alteplase or Reteplase

 Recombinant human protein

 Given by intravenous infusion
 Used to relieve blockage of critical vessels, e.g.
coronary artery occlusion (heart attack)
ICH = intracranial hemorrhage; MI = myocardial infarction; TIMI = Thrombolysis in Myocardial Blood Flow
The in vivo pathway The in vitro contact system
(extrinsic pathway) (intrinsic pathway)
Contact
Tissue damage (e.g. with endoth)

Tissue factor XIIa XII

VIIa
PL XIa XI
Ca2+
IXa IX Platelets
VIIIa, PL, Ca2+ +
X Xa +

Va, PL, Ca2+ +

XIII
Ca2+
II (Prothrombin IIa (Thrombin)
XIIIa
Fibrinogen Fibrin Stabilised fibrin