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
What is the PK of heparin?
PK:
Orally inactive -> parenteral administration (IV, SC)
Metabolism in liver and renal excretion (hepatic and renal failure
prolong the action)
What are the clinical uses of heparin?
Initial treatment of deep vein thrombosis and pulmonary
embolism
Initial treatment of unstable angina and acute myocardial
infarction
For prevention of deep vein thrombosis in patients at risk
For prophylaxis of thrombosis in cardiovascular surgery
What are the adverse effects of Heparin?
Bleeding Antagonist – Protamine sulfate - 1 mg за 100 U To avoid bleeding – Laboratory monitoring: activated partial trhromboplastin time (aPPT = 1,5-2,5 х)
Thrombosis: paradoxically associated
with heparin-induced thrombocytopenia
(HIT)
Osteoporosis (mechanism unknown) -
with long-term (6 months or more) treatment with heparin
Hypersensitivity reactions
Alopecia
What are low molecular weight heparins?
Drugs:
Enoxaparin
Nadroparin
Molecular weight – 4000 to 15000
What is the mechanism of action of low molecular weight heparins?
Mechanism of action:
Predominantly anti-Ха activity
through binding to AT III
What is the PK of LMW heparins?
PK:
SC administration
Longer t1/2
Renal excretion
What are the adverse effects of LMW heparins?
Adverse effects:
Bleeding (lower risk?)
Thrombocytopenia (less frequent)
What are the clinical uses and advantages of LMW heparins?
Clinical use:
Initial treatment of deep vein thrombosis and pulmonary
embolism
Initial treatment of unstable angina and acute myocardial
infarction
For prevention of deep vein thrombosis in patients at risk
For prophylaxis of thrombosis in cardiovascular surgery
Advantages
Predictable and controllable effect
Allow outpatients treatment and self-application
What are synthetic pentasaccharides?
Synthetic pentasaccharides
Drugs: Fondaparinux
What is the mechanism of action of synthetic pentasaccharides?
Mechanism of action
High affinity to АТІІІ anti-Ха activity
What are the PK, advantages, and clinical uses of synthetic pentasaccharides?
PK: SC administration; long t1/2; renal excretion
Advantages:
Do not cause thrombocytopenia
Clinical use:
For prevention of deep vein thrombosis in orthopedic surgery
What are direct thrombin inhibitors? What is their clinical use?
Dabigatran etexilate
Oral application
Clinical use:
For prevention of deep vein thrombosis in
orthopedic surgery
For prevention of acute coronary syndrome and
stroke in patients with atrial fibrillation
Treatment of deep vein thrombosis
antagonist:
Idarucizumab – monoclonal antibody fragment
attaching firmly to dabigatran, and forming a
complex in the blood
What are direct inhibitors of factor Xa? What is their clinical use?
Rivaroxaban, Apixaban
Oral application
Clinical use:
For prevention of deep vein thrombosis in
orthopedic surgery
For prevention of stroke and systemic
embolism in patients with atrial fibrillation
Treatment of deep vein thrombosis
Antagonist:
Andexanet alfa – anticoagulants attach to
andexanet alfa are no longer available to block
factor Xa
What is fibrinolysis?
What do you mean by fibrinolysis?
Fibrinolysis is a normal body process. It prevents blood clots that occur naturally from growing and causing problems. Primary fibrinolysis refers to the normal breakdown of clots. Secondary fibrinolysis is the breakdown of blood clots due to a medical disorder, medicine, or other cause
What is fibrinolytics?
A fibrinolytic cascade is initiated concomitantly with
the coagulation cascade, resulting in the formation
within the coagulum of plasmin, which digests fibrin.
Various agents promote the formation of plasmin:
Streptokinase
Tissue plasminogen activators (tPAs):
Alteplase
Reteplase
All are given IV: by infusion (Alteplase) or bolus
(Reteplase)
What is the PD of fibrinolytics?
Mechanism of action: convert plasminogen deposited
on fibrin strands to plasmin. Reopen the occluded blood
vessel and provide reperfusion
directly – tPAs
indirectly (streptokinase) – by binding to plasminogen
activators
What are the unwanted effects and contraindications of fibrinolytics?
Bleeding from GIT and stroke.
Allergic reactions and hypotension (streptokinase)
Contraindications: Active internal bleeding Hemorrhagic cerebrovascular disease Bleeding diathesis Pregnancy Metastatic cancer Invasive procedures and recent trauma
What are the clinical uses of fibrinolytic drugs?
The main use is:
Acute myocardial infarction, within 6-12
hrs of onset
Other uses: Acute thrombotic stroke within 3 hrs of onset (tPAs) Deep vein thrombosis, acute pulmonary embolism, acute arterial thromboembolism
What happens to platelets when they are activated?
Adhesion following vascular damage
Secretion of the granule contents
(including platelet agonists, such as
ADP and 5-hydroxytryptamine)
Biosynthesis of labile mediators such
as platelet-activating factor and
thromboxane A2 (TXA2)
Aggregation, which is promoted by various agonists, including collagen, thrombin, ADP, 5-hydroxytryptamine and TXA2, acting on specific receptors on the platelet surface; activation by agonists lead to expression of GPIIb/IIIa receptors that bind fibrinogen, which links adjacent platelets to form aggregates
What are antiplatelet drugs?
Inhibitors of СОХ-1 in platelets: Acetylsalicylic
acid (ASА, Aspirin)
Adenosine (P2Y) receptor antagonists:
Clopidogrel
Prasugrel (introduced recently)
Ticagrelor (introduced recently)
Phosphodiesterase inhibitors: Dipiridamol
Antagonists of GPІІb/ІІІа receptors
Abciximab (monoclonal ab)
Cyclic oligopeptides: Tirofiban, Eptitibatide
Stable analogs of PgІ2
Iloprost
Epoprostenol
What is acetylsalicylic acid? How does it work as an antiplatelet drug?
Aspirin inhibits COX1 by irreversible acetylation of a serine residue in its active site which results in:
At lower doses – reduction of TxA2 synthesis in platelets
At higher doses – reduction of PgI2 synthesis in the endothelium
Endothelial cells can synthesize new enzyme, whereas the anucleate
platelets can not and synthesis does not recover until new platelets are
formed (7-10 days).
The balance between TxA2 and PgI2 is thus shifted to PgI2 which inhibits
platelet aggregation
The effect of aspirin on platelet aggregation is rapid
The recommended dose is: a daily dose of ~ 100 mg
What are the adverse effects and possible drug interactions of aspirin?
Adverse effects:
Bleeding from GIT
Increased incidence of hemorrhagic stroke
Drug interactions
Synergy with other antiplatelet drugs (clopidogrel, dipiridamol) and fibrinolyitics or anticoagulants.
Caution with warfarin
What are the clinical uses of aspirin?
Clinical use: for the treatment and prevention of arterial thrombosis
Acute myocardial infarction
High risk of myocardial infarction, including a history of myocardial infarction, angina, or intermittent claudication
Unstable coronary syndromes
Primary and secondary prophylaxis of angina pectoris
Following coronary artery bypass grafting
Following coronary artery angioplasty and stenting
(clopidogrel or abciximab in addition to aspirin)
Transient cerebral ischaemic attack (‘ministrokes’) or
thrombotic stroke, to prevent a recurrence
Atrial fibrillation, if oral anticoagulation is contraindicated
What are inhibitors of P2Y12 receptors? What is the mechanism of action?
Mechanism of action
Antagonists of adenosine (P2Y) receptors of platelets; thereby they inhibit
platelet responses to ADP.
Drugs: Clopidogrel , Prasugrel, Ticagrelor, Ticlopidine
Clopidogrel is a prodrug and is converted into its active sulfhydryl
metabolite by CYP enzymes in the liver including CYP2C19. Slow onset of
effect (3-5 days).
Patients with variant alleles of CYP2C19 (poor
metabolisers) are at increased risk of therapeutic failure.
There is a
potential for interaction with other drugs, such as omeprazole, that are
metabolised by CYP2C19 and current labelling recommends against use
with proton pump inhibitors for this reason.
Prasugrel (prodrug; effective in most individuals, faster onset of the effect
compared to Clopidogrel)
Ticagrelor (not a prodrug; allosteric antagonist; superior to Clopidogrel)
Ticlopidine – rarely used because of adverse effects (neutropenia and
thrombocytopenia)
What are the clinical effects and clinical use of aspirin?
Clinical effect – additive with aspirin
Clinical use: following coronary artery angioplasty and stenting (in addition
to aspirin)
What are PDA inhibitors?
Dipiridamol
increase in сАМР -> decreased aggregation
Synergism with ASA
Clinical use: in addition to aspirin in some
patients with stroke or transient ischaemic
attack
What are other antiplatelet drugs?
Antagonists of GPІІb/ІІІа receptors: Abciximab,
Tirofiban, Eptitibatide
Short-term IV administration following coronary
angioplasty (+ Heparin + ASA)
Stable analogs of PgІ2:
Vasodilating and antiplatelet effects
Iloprost
IV infusion in severe peripheral arterial occlusive disease
Unwanted effects: headache, flushing, hypotension,
tachycardia, arrhythmia, extrasystoles and anxiety
Epoprostenol
To prevent blood clotting during haemodialysis
To treat ‘pulmonary arterial hypertension’
What are the drugs used in bleeding? Mechanism of action and clinical use
Phytomenadione (Vitamin K)
Mechanism of action: Co-factor in the posttranslational activation of factors ІІ, VІІ, ІХ, Х (γ-carboxylatiaon of glutamic acid residues) Onset of the effect - after 6 hrs, full effect - after 24 hrs
Clinical use: In oral anticoagulants-induced bleeding To prevent hemorrhagic disease in the newborn (due to hypoprothrombinemia) As supplementation for patients receiving some cefalosporins (cefoperazone, etc.) In vit. K deficiencies, e.g. sprue, lack of bile
Inhibitors of fibrinolysis - what is the PD, indications, ADRs and contraindications of Para-aminomethylbenzoic acid?
Applied IV or IM
PD: prevents the degradation of the blood
clot (antifibrinolytic effect)
Indications: In case of fibrinolytics overdose Local bleeding due to increased fibrinolysis: uterine bleeding of unknown origin; bleeding after tonsillectomy, dental operations; local bleeding in urological and gynecological operations; in case of overdose with anticoagulants. Massive fibrinolytic bleeding: in operations in the chest and abdomen; in prostate cancer; in leukemia; in obstetric practice
ADR: GIT: nausea, abdominal pain, vomiting CNS: dizziness, very rarely seizures CVS: arrhythmias and bradycardia; hypotension Musculoskeletal system: myopathy, myoglobinuria
Contraindications:
Renal failure
Thrombosis and
embolism
What are the PK, PD, clinical use, ADRs, and contraindications of aminocaproic acid?
Аminocaproic acid
Synthetic inhibitor of fibrinolysis PK: Rapid oral absorption Renal excretion PD: Competitively inhibits the activation of plasmin
Clinical use Adjunctive therapy in haemophilia Bleeding from fibrinolytic therapy Prevention of re-bleeding of intracranial aneurysm Bleeding after gastrointestinal surgery and prostatectomy Bleeding in hemorrhagic cystitis (radiation-or drug-induced)
Adverse effects:
Intravascular thrombosis
Hypotension
GI discomfort
Contraindications: Bleeding from the upper genitourinary system: kidney and uterus because of the danger of excessive blood clotting
Explain Etamsylate - hemostatics for systemic use.
Hemostatics for systemic use
Etamsylate Affects the interaction of the endothelium with platelets Suppresses capillary bleeding Applied IV or orally: In parenchymal hemorrhages in surgery In dentistry In ophthalmology
Explain Terlipressin - hemostatic for systemic use.
Terlipressin Analog of ADH (vasopressin) Applied IV To stop bleeding from esophageal varices before surgery in patients with liver cirrhosis
Hemostatics containing gelatin, collagen, or thrombin?
gelaspon
Hemostatics for local use – containing gelatin, collagen or thrombin Gelaspon Sterile gelatin sponge Absorbs blood and facilitates clotting Completely absorbed Use: Haemorrhages in surgery of parenchymal organs After tooth extraction Capillary bleeding
