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Pharmacology > Thrombosis→ > Flashcards

Thrombosis→ Flashcards

1
Q

Definition of Thrombosis

A

Blood Clot in the Blood Vessel
→ decreased Blood Flow
→decreased Blood Supply to Organs and Peripheral Tissues

leading to Angina, Myocardial Infarction
Stroke
Pulmonary Embolus
Deep Vein Thrombosis

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2
Q

Formation of Thrombin

A

Activated clotting factors acts on prothrombin → thrombin (also acts on platelets ) which acts on soluble fibrinogen →insoluble fibrin and form thrombus with platelets

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3
Q

Drugs Used in Coagulation Disorders

A

Antiplatelet Drugs
- decreased activation/aggregation of platelet s

Anticoagulants [Blood Thinners]
-decreased formation of fibrin

Fibrinolytic Agents
- increased degradation of fibrin

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4
Q

Platelet Reaction

A

PGi2 from endothelial cells (inhibit) and TXA,ADP and 5-HT from platelets lead to adhesion of platelets → activation of platelet → aggregation of platelet

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5
Q

Mechanism, Effect and Adverse effect of Aspirin

A

Mechanism of Action
- irreversibly inhibits the activity of c yclooxygenase
→ decreased synthesis of thromboxane A 2 (TXA 2 by the platelets
→ decreased platelet aggregation
Very Potent as an Antiplatelet Drug
→ low doses are needed

Adverse Effects

gastrointestinal disturbances and risk of gastric damage in chronic users

[→ haemorrhage and ulceration]

→contraindicated in patients with gastric ulcer

prolonged bleeding
- due to inhibition of prostaglandins production in the gastrointestinal tract
decreased gastric mucus secretion and increased gastric acid secretion
- due to inhibition of thromboxane A 2 production in the platelets

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6
Q

Name, Mechanism, Effect and Adverse effect of ADP Receptor Inhibitors

A

clopidogrel , ticlopidine and ticagrelor
Mechanism of Action
- block adenosine diphosphate (ADP) receptors on platelets
→inhibit ADP pathway in platelets
→→inhibit the expression of fibrinogen receptors
→→→prevent linkage of platelets by fibrinogen
→→→→decreased platelet aggregation

Can be Used in Patients Who Cannot Tolerate Aspirin

Adverse Effects

  • gastrointestinal disturbances
  • haemorrhage
  • thrombotic thrombocytopenic purpura→ monitor platelet count
  • leukopenia → monitor white blood cell count

thrombotic thrombocytopenia purpura and leukopenia → rare with clopidogrel
→→ clopidogrel preferred over ticlopidine

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7
Q

Name, Mechanism, Effect and Adverse effect of Glycoprotein

IIb IIIa Inhibitors

A

e.g. abciximab , eptifibatide

Mechanism of Action
-block glycoprotein IIb IIIa (receptors for fibrinogen) in platelets
→inhibit linkage of adjacent platelets by fibrinogen
→→decreased platelet aggregation

•Used Intravenously for Short Term Treatment

Adverse Effects

  • bleeding
  • thrombocytopenia
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8
Q

Name, Mechanism, Characteristics and Adverse effect of Thrombin Receptor Antagonists

A

vorapaxar

Mechanism of Action
-binds to the proteinase-activation receptor 1 (PAR1;
thrombin receptors) in platelets
→→ compete with and prevent the activation of the receptor
by the “tethered ligand” (which is exposed following
the cleavage of the extracellular domain by thrombin)
→ decreased platelet activation and aggregation

Characteristics
-metabolized by hepatic cytochrome enzymes CYP3A4 and CYP2J2 → drug interactions

Adverse Effects
- bleeding →contraindicated in patients with a history of stroke, transient ischemic attack, or intracranial
haemorrhage

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9
Q

Mechanism and effect of Dipyridamole

A

mechanisms of actions

-inhibits adenosine uptake into cells
→adenosine remains in extracellular
space to activate A 2 receptors

-inhibits phosphodiesterase
→ decreased breakdown of cyclic nucleotides

  • both increases cAMP level→ decreased platelet aggregation
  • vasodilatoin

Limited therapeutic usage
-ineffective on its own
used in combination with aspirin or warfarin

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10
Q

Mechanism and effect of Cilostazol

A

mechanism of actions
- inhibits phosphodiesterase → increased cAMP level
→→decresed platelet aggregation
→→vasodilation

Limited therapeutic usage
- used primarily to treat intermittent claudication

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11
Q

Coagulation Process

A

Non-functional Prothrombin
→ functional prothrombin by (reduced form of vitamin K to the oxidized form of vitamin K)

Non-functional clotting factors
→functional clotting factors (by reduced form of vitamin K to oxidized form of vitamin K)
→→Activated clotting factors

→→→form with functional prothrombin to thrombin

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12
Q

Effects of Anticoagulant Drugs

A

Increased Inactivation of Clotting Factors

  • indirect thrombin inhibitors
  • direct thrombin inhibitors
  • oral direct factor Xa inhibitors

Decreased Formation of Functional Clotting Factors
-vitamin K antagonists

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13
Q

Mechanism, Characteristics of Vitamin K Antagonists

A

e.g. warfarin

Mechanism of Action
- inhibit the action of vitamin K epoxide reductase
→inhibit conversion of inactive vitamin K epoxide (oxidized form) to active
hydroquinone form (reduced form)
→→ decreased  formation of functional
clotting
factors/prothrombin
→→→ decreased  thrombin formation

Characteristics
- oral anticoagulant
- protein bound → long half life in plasma
- metabolized by hepatic mixed P 450 enzymes →interaction with food and drugs
- delayed onset of action [by 8 12 hours the time required for the degradation of the clotting
factors]
- onset time can be reduced by using large initial doses
- narrow therapeutic index

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14
Q

Adverse effect and complication of Vitamin K Antagonists

A

e.g. warfarin

haemorrhage
→this risk can be reduced by
→→starting with a low dose and with careful dose adjustment
over a week [because of late onset of anticoagulant action of warfarin]

→→monitoring anticoagulant effect by Prothrombin
time (PT) ratio International
normalized ratio (INR)
- reversed by stopping warfarin therapy and/or administration
of vitamin K 1 ( fresh frozen plasma or
prothrombin
complex concentrates
-birth defects [because warfarin readily cross the placenta]
→avoided in pregnancy

-skin necrosis (rare) characterized by thrombosis of microvasculature

Complications

  • anticoagulant actions affected by
  • genetic variation
  • concurrent diseases
  • drug interactions
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15
Q

Name , mechanism, characteristics of Indirect Thrombin Inhibitors

A

e.g. heparin

Mechanism of Action
-bind to antithrombin
→increased  the activity of antithrombin
→→ increased the rate of inactivation of clotting factors IIa (thrombin) IXa and Xa
→→→ decreased  formation of fibrin

Characteristics

only for intravenous or subcutaneous administration
→because they are large and charged molecules
→→cannot be absorbed from the stomach

drugs for anticoagulation during pregnancy

  • because they do not cross the placenta
  • because their use are not associated with fetal malformations
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16
Q

Heparin and Its Derivatives (I)

A 
Unfractionated Heparin (UFH)
molecular weight range 5000 30000 Da
-repeating sulfated disaccharide units of D glucosamine
L-iduronic acid and D- glucosamine-D-glucuronic acid

High Molecular Weight (HMW) Fractions
- long chain with molecular weight 5400 Da (at least 18
saccharide units)
→ simultaneously bind to antithrombin and thrombin
- high affinity for antithrombin

Unpredictable pharmacokinetics
→bind to plasma proteins
→degraded mainly by
reticuloendothelial
system
→→need to monitor plasma
levels
17
Q

Name of Heparin and Its Derivatives (II)

A

Low Molecular Weight (LMW) Fractions
eg enoxaparin, dalteparin tinzaparin
- mean molecular weight 5000 Da 17 saccharide units)
- less effective than UFH in inactivating thrombin
-equal anticoagulant efficacy as UFH

Synthetic Form e g fondaparinux

  • pentasaccharide molecule
  • high affinity for antithrombin
  • not effective in inactivating thrombin
advantages over UFH
→decreased  binding to plasma proteins
→increased  bioavailability
→decreased drug resistance
long biological half life
→decreased  dosing frequency
mainly renal clearance
→predictable pharmacokinetics
decreased need to monitor plasma
levels]
contraindicated in patients with renal impairment
18
Q

Adverse Effects of Heparin and Its Derivatives

A

Haemorrhage
risk reduced by
- careful patient selection [contraindicated in patients with active bleeding, haemophilia or active
hepatic disease cautious in high risk patients such as elderly women and patients with renal failure]
- careful control of dosage with close monitoring by
- activated partial thromboplastin time aPTT or PTT 2 3 x normal value)
- protamine titration
- anti Xa activity

reversed by stopping heparin therapy and/or intravenous
administration of the heparin antagonist, protamine sulfate
[fondaparinux effect cannot be reversed by protamine]
Adverse Effects of Heparin and Its Derivatives

Allergic Response to Heparin of Animal Origin

Increased Loss of Hair and Reversible Alopecia

Thrombocytopenia
→ thrombosis in severe case (→ monitor the platelet counts
- treated by stopping heparin therapy or by administration of a direct thrombin inhibitor

19
Q

Mechanism of Direct Thrombin Inhibitors (I)

A

Mechanism of Action

directly bind to the active site of thrombin
→inhibit its effects

anticoagulant action is independent of antithrombin
→inactivate fibrin bound thrombin in thrombi

20
Q

Name. Type and characteristics of Direct Thrombin Inhibitors (II)

A

Parenteral Direct Thrombin Inhibitors

Hirudin, Lepirudin

  • bivalent inhibitor of thrombin
  • bind at both active and substrate recognition sites of thrombin
  • usage needs to be closely monitored by aPTT
  • excreted by kidneys → cautious in patients with renal insufficiency

Bivalirudin

bivalent inhibitor of thrombin that also inhibits platelet activation
useful in percutaneous coronary angioplasty

Argatroban
small molecule binding only at thrombin active site eg argatroban

clearance depended on liver function → cautious in patients with liver diseases

21
Q

Name. Type and characteristics of Direct Thrombin Inhibitors (III)

A

Oral Direct Thrombin Inhibitors e.g dabigatran

-competitively and reversibly blocks the active site of free and
clot bound thrombin

Advantages over parenteral anticoagulant drugs and warfarin
-predictable pharmacokinetics and bioavailability
→ allow for fixed dosing
→ decreased need for routine monitoring

  • rapid onset
  • no interaction with P 450 interacting drugs

-renal clearance
→dosage reduction is required in patients with severe renal impairment
- adverse effect bleeding
→→can be reversed by idarucizumab a humanized monoclonal antibody fragment that binds to dabigatran

22
Q

Name, Mechanism of Action, advantages, Adverse effect, and Precautions of Oral Direct Factor
Xa Inhibitors

A

e.g. rivaroxaban , apixaban

Mechanism of Action
-directly bind to free and clot bound factor Xa
→inhibit conversion of prothrombin to thrombin

Advantages

  • fixed dosage no need for monitoring
  • rapid onset of action

Adverse Effects

  • risk of bleeding
  • can be reversed by andexanet alfa, a recombinant analogue of factor Xa

Precautions

  • prolonged action in elderly patients or patients with renal impairment
  • interact with drugs that inhibit or induce P-glycoprotein or CYP3A4
23
Q

Mechanism of Fibrinolysis

A

Plasminogen to Plasmin

  • act on fibrinogen to fibrinogen degradation process
  • act on insoluble fibrin to fibrin degradation products
24
Q

Name, Mechanism of Action, Adverse effect, Therapeutic use of Fibrinolytic Drugs

A

e.g. streptokinase, urokinase , alteplase , tenecteplase

Mechanism of Action
increased formation of plasmin from plasminogen
→increased degradation of insoluble fibrin
[drugs with selectivity on fibrin bound plasminogen e.g alteplase, tenecteplase
→→confine fibrinolysis to the formed thrombus (“clot selective”)

Intravenous or Intra Arterial Administration

Therapeutic Use

  • acute myocardial infarction → reopen occluded coronary artery
  • multiple pulmonary emboli, central deep venous thrombosis

Adverse Effects
- bleeding → gastrointestinal haemorrhage stroke]
- reversed by administration of antifibrinolytic agent aminocaproic acid, fresh
frozen plasma or coagulation factors
→→contraindicated in patients with internal bleeding, peptic ulcer, pregnancy and concurrent use of
anticoagulants

25
Q

Name Effect and Adverse effect of Drugs Used in Bleeding Disorders

A

Vitamin K 1 ( Phytonadione)[essential for the formation of bioactive clotting factors]
- for treatment of excess warfarin or vitamin K deficiency

Plasma Fractions Concentrated with Clotting (Coagulation) Factors
- treated with heat and/or extracted with solvents and detergents
→ decreased risk of the transmission of viral diseases eg hepatitis B, hepatitis C and HIV
[risk of other transmissible diseases such as prions→ recombinant clotting factor preparations preferred]
- for treatment of clotting factor deficiency e g haemophilia

Fibrinolytic Inhibitors (Antifibrinolytic Drugs)
- bind to plasminogen and plasmin → block their interaction with fibrin
eg aminocaproic acid, tranexamic acid
- for treatment of conditions of bleeding or risk of bleeding
eg adjunct therapy in haemophilia, prevention of bleeding from intracranial aneurysms
- excreted by kidneys → dose reductions in patients with renal impairment

Adverse effects

  • intravascular thrombosis
  • hypotension, myopathy, abdominal discomfort

Pharmacology (30 decks)

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