Drugs affecting haemostasis Flashcards
What is hemostasis?
Hemostasis is the arrest of blood loss from a
damaged vessel and is essential to life.
What happens when there is a wound in a blood vessel?
Vasoconstriction
Adhesion and activation of platelets
Formation of fibrin
What is thrombosis?
is the pathological formation of a ‘haemostatic’ plug within
the vasculature in the absence of bleeding (‘haemostasis in the
wrong place’).
What are the predisposing factors (Virchow’s triad) of thrombosis?
Injury to the vessel wall – e.g. an atheromatous plaque ruptures or becomes
eroded;
Altered blood flow – e.g. in the left atrium of the heart during atrial fibrillation;
Abnormal coagulability of the blood – as occurs, for example, in the later
stages of pregnancy or during treatment with certain oral contraceptives
What are the different types of thrombosis?
1) arterial thrombus
2) venous thrombus
3) thrombus in the heart
What is an arterial thrombus?
“white thrombus” consisting mainly of platelets in a fibrin
mesh – associated with atherosclerosis
What is a venous thrombus?
“red thrombus” consists of a small white head (platelet
component) and a large jelly-like red tail (fibrin component); usually
associated with stasis of blood;
thrombus can break away from its attachment
and float through the circulation, forming an embolus; venous emboli usually lodge in the lungs
What is a thrombus in the heart?
thrombus that embolizes from the left heart usually
lodges in an artery in the brain or other organs
What is the coagulation cascade?
The coagulation cascade refers to the series of steps that occur during the formation of a blood clot after injury by activating a cascade of proteins called clotting factors.
There are three pathways: intrinsic, extrinsic, and common.
What happens in the coagulation cascade?
The components (called
factors) are present in blood as inactive precursors of
proteolytic enzymes and cofactors.
Activation of a small amount of
one factor catalyzes the
formation of larger amounts of the next factor.
The main event is the conversion by thrombin of soluble fibrinogen to insoluble strands of fibrin, the last step in a complex enzyme cascade.
What are the stages of the coagulation cascade?
The mechanism of hemostasis can divide into four stages.
1) Constriction of the blood vessel.
2) Formation of a temporary “platelet plug.”
3) Activation of the coagulation cascade.
4) Formation of “fibrin plug” or the final clot.
What is involved in the anticoagulation system?
Antithrombin ІІІ
↓ ІІа, Ха
Protein С (Vitamin K-dependent factor)
– Proteolysis of factors Va and VIIIa
Protein S
Co-factor of protein С
What are the drugs that affect hemostasis?
Drugs affect haemostasis and thrombosis
in three distinct ways, by influencing:
1) Blood coagulation (fibrin formation) –
Anticoagulants
2) Fibrin removal (fibrinolysis) – Fibrinolytics
3) Platelet function – Antiplatelet drugs
What are some examples of anticoagulants?
Vitamin K antagonists
Heparin and similar drugs
Heparin
Low-molecular-weight heparins (LMWHs)
Synthetic pentasaccharides
Direct thrombin inhibitors
Direct inhibitors of factor Xa
What are examples of vitamin k antagonists and what is their PK?
Drugs: Warfarin, Acenocoumarol
PK:
Complete and rapid oral absorption with
excellent bioavailability
Highly and loosely bound to plasma proteins
(> 95%)
Metabolized in the liver
Long t1/2 - 40 h
What is the mechanism of action of vitamin k antagonists?
Vitamin K is essential for the
formation of clotting factors
II, VII, IX, and X
Mechanism of action of vitamin K antagonists: inhibit the γ-carboxylation of the vitamin K dependent clotting factors: - II, VII, IX, X
Other vitamin K-dependent
proteins:
- Protein C and protein S
- Osteocalcin in bone
What is the PD of vitamin K antagonists?
PD:
Effective only in vivo
10-24 h delay in the action,
according to the
t1/2 of the factors: VІІ – 6 h, ІХ – 24 h, Х – 36
h, ІІ – 50 h)
What is the clinical use of vitamin k antagonists?
After heparin treatment of deep vein thrombosis and pulmonary embolism (by
overlapping in time with heparin for 3-5 days)
For prevention of:
- Deep vein thrombosis
- Thrombosis in the heart in patients with atrial
fibrillation, prosthetic heart valves, etc.)
What is the clinical use of vitamin k antagonists?
After heparin treatment of deep vein thrombosis and pulmonary embolism (by
overlapping in time with heparin for 3-5 days)
For prevention of:
- Deep vein thrombosis
- Thrombosis in the heart in patients with atrial
fibrillation, prosthetic heart valves, etc.)
What are the adverse effects of vitamin k antagonists?
Adverse effects:
Hemorrhages (antagonist – vitamin K)
Teratogenic and fetotoxic (contraindicated
in pregnancy)
Hepatotoxicity (rarely)
Necrosis of soft tissues, e.g. breast (due to
venous thrombosis secondary of
depression of protein C synthesis; protein
C t1/2 – relatively short – 8 h)
Drug interactions: numerous and risky
What is Heparin?
A family of mucopolysaccharides (m.w. from 5000 up to 30000) Pentasaccharide sequence (sulfated glucosamine, glucuronic acid and iduronic acid)
What is the mechanism of action of Heparin?
Mechanism of action:
Via a unique pentasaccharide sequence it binds to and activates АТ III changing its conformation and increasing its activity
To inhibit factor IIa, it is necessary for heparin to bind to the enzyme as well as to АТ III; To inhibit factor Xa, it is necessary only for heparin to bind to АТ III