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Sys. Pharm Week4 > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Haemostasis?

A

‘Arrest of blood loss from damaged blood
vessels

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2
Q

Haemostasis Mediated by

A

-Vasoconstriction
-Adhesion and activation of platelets: formation of haemostatic plug
-Formation of fibrin: reinforces the plug

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3
Q

Thrombosis is..

A

Pathological formation of a haemostatic plug

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4
Q

PREDISPOSING FACTORS TO THROMBOSIS

A

1.Injury to the vessel wall
-Atheromatous plug rupture

  1. Altered blood flow: blood stasis
    -Atrial fibrillation
    -Long flights

3.Abnormal coaguability
-Pregnancy
-Oral contraceptives (CI: previous venous thromboembolic events)
-Thrombophilia

-Thrombi can break away forming an embolus
-Can interrupt blood flow: ischemia or infarction

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5
Q

ARTERIAL THROMBI
-Ass. W/
- component..
+ drugs we use
….

A

-Usually associated with atherosclerosis
-Large platelet component
-Embolises from the left heart or a carotid artery
Usually lodges in an artery in the
brain or other organs, causing death, MI, stroke

 Drugs: Antiplatelet

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6
Q

VENOUS THROMBI
+ drug we use

A

-Small platelet component
-Large fibrin component

Manifestations:
- Deep vein thrombosis
- Pulmonary embolism

Drugs: anticoagulants

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7
Q

Drugs affect thrombosis in three distinct
ways

A

 Blood coagulation (fibrin formation)
 Platelet function
 Fibrin removal (fibrinolysis)

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8
Q

ANTICOAGULANTS examples

A

-Heparins
-Direct thrombin inhibitors
-Novel oral anticoagulants
- Vitamin K antagonists

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9
Q

Heparin and its 2 types

A

1.unfractioned heparin (HMWH)
-Reserved for special cases e.g. renal failure

  1. LMWH
    pentasaccharide (fondaparinux)
    - Generally preferred
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10
Q

Low Molecular Weight Heparin (LMWH)
Examples +CI

A

-Heparin fragments (e.g. enoxaparin, dalteparin)
- CI in renal failure

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11
Q

Heparin MoA

A

-Heparin inhibits thrombin (IIa) and
factor Xa activation
•Mediated via binding to ATIII
•Heparin binds to ATIII via a unique pentasaccharide sequence
•Activates ATIII by changing its conformation and increasing its affinity for serine proteases

•. Necessary for heparin to bind thrombin (and ATIII) for its inhibition

• For factor Xa inhibition
-,Necessary only for heparin to bind to ATIII

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12
Q

LMWH MoA

A

LMWH increases the action of ATIII on Xa only
-Cannot increase the action of ATIII on thrombin
-Cannot bind both simultaneously

ATIII deficiency is very rare
- Can cause thrombophilia and resistance to heparin
therapy

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13
Q

CLINICAL USES Of Heparin

A

•Prevention of VTE- venous thromboembolism (DVT/PE) - usually LMWH, as alternative to DOACs
• Treatment of VTE, as alternative to DOACs (oral)
• Adjunct treatment in acute coronary
syndrome

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14
Q

Unfractionated heparin PK

A

-Cannot be absorbed from the gut: charged and
large
- IV-immediate action
- Activated partial thromboplastin time (aPTT), or
other in vitro clotting test to monitor treatment
- Dose adjusted to achieve a value within a target
range (e.g. 1.5–2.5 times control)
- SC (subcutaneous) -delayed action by 60 minutes

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15
Q

LMWHs PK

A
  • Effects are sufficiently predictable
  • Monitoring not required routinely
  • Eliminated mainly by renal excretion
    •Monitoring via anti-Factor Xa assay
    -Unfractionated heparin is preferred in renal failure
    • With this exception LMWHs are at least as safe and effective as unfractionated heparin
  • More convenient to use
  • Patients can be taught to inject themselves at home - Generally no need for blood tests and dose adjustment
  • Safe in pregnancy
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16
Q

ADVERSE EFFECTS
heparin

A

1.The main hazard is haemorrhage
•Treated by stopping therapy and, if necessary,
giving IV protamine sulfate (HMWH)

  1. Thrombosis
    •Uncommon but serious adverse effect
    •May be misattributed to natural history of disease
    • Heparin-induced thrombocytopenia (HIT)
    -LMWHs are less likely than unfractionated heparin to cause thrombocytopenia and thrombosis
  2. Osteoporosis
    • Long-term treatment with heparin (usually during pregnancy)
  3. Hypoaldosteronism (with consequent
    hyperkalaemia) is uncommon
    •Increases with prolonged treatment
    • Recommended to check plasma K+ concentration if treatment is to be continued for > 7 days
  4. Hypersensitivity reactions are rare with heparin
    but more common with protamine (antidote)
17
Q

DIRECT THROMBIN INHIBITORS

Hirudins examples

A

Lepirudin, bivalirudin, argatroban (IV)

18
Q

, Hirudins
MoA

A

-Do not depend on activation of ATIII
- Bind irreversibly both to the fibrin-binding
and catalytic sites on thrombin
- Used as an alternative to heparins in
patients with type II HIT (and for HIT
treatment)
- Dose may be adjusted depending on
aPTT

19
Q

Hirudins side effects

A

Can cause bleeding or hypersensitivity
reactions

20
Q

What’s Type II HIT

A

Type 2 HIT is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications.

21
Q

DIRECT ORAL ANTICOAGULANTS (DOACs)
Examples

A

Rivaroxaban, apixaban, edoxaban

-Factor Xa selectivity rather than for thrombin
- Reversed by andexanet alfa: factor Xa decoy
receptor

22
Q

DOACs Adverse effects

A
  • commonest adverse effects of DOAC
    drugs are predictable (bleeding, anaemia)
  • Rivaroxaban commonly causes nausea
23
Q

CLINICAL USES
Of DOACs

A

Treatment (in hemodynamically stable
patients) and prevention of VTE
• Prevention of VTE in elective or knee
replacement surgery
• Non-valvular AFib

24
Q

DOACs:
Dabigatran
What it is + reversal agent

A

 Pro-drug direct thrombin
inhibitor
 Reversal agent (for bleeding):
idarucizumab
 Prothrombin complex concentrates or anti-
fibrinolytics may be used

25
Q

VITAMIN K
MoA

A

Fat-soluble vitamin
-. Essential for the formation of clotting factors II, VII, IX and X
. - Glycoproteins with several γ-carboxyglutamic acid (Gla) residues
- Gla residues are essential for interaction of factors with Ca 2+ and -vely phospholipids
- γ-carboxylation occurs after synthesis of the amino acid
- Carboxylase enzyme requires reduced vitamin K as a co-factor
- Other vitamin K-dependent Gla proteins, include
proteins C and S (anticoagulants) and osteocalcin in bone

26
Q

Natural vitamin K1 (phytomenadione) route of administration

A

-may be given orally or by injection,

A synthetic preparation, menadiol sodium phosphate,
takes longer to act than phytomenadione

27
Q

Clinical uses
Of Vitamin K

A

Treatment and/or prevention of bleeding
• From excessive oral anticoagulation (e.g. by warfarin)
• In babies to prevent haemorrhagic disease of the newborn
• Coeliac disease
• Lack of bile (e.g. with obstructive jaundice)
• Liver disease

28
Q

VITAMIN K ANTAGONISTS: WARFARIN

A
  • standard anticoagulant for treatment and prevention of thromboembolic disease
  • Alternatives e.g. phenindione used rarely in
    patients with idiosyncratic adverse reactions to
    warfarin
  • Narrow therapeutic index (TI)
    -Requires frequent monitoring
29
Q

Warfarin MoA

A

-Inhibits vitamin K epoxide reductase component 1
(VKORC1)
- Inhibits the reduction of vitamin K epoxide to its active hydroquinone form
- Interferes with the post-translational γ-carboxylation of glutamic acid residues in clotting factors II, VII, IX and X
- Competitive inhibition
- Genotyping to determine VKORC1 and CYP2C9 gene
variations
•Not routine: can reduce the variability in response
-Takes several days to work
- Heparin may be given with warfarin during initial
treatment

30
Q

CLINICAL USES
Warfarin

A

• Prevention of VTE (DVT/PE)-DOACs are usually preferred
• Prevention of embolism from atrial ‘ fibrillation (Afib), drug of choice for valvular Afib
• Prevention of embolism from mechanical heart valves

31
Q

Warfarin PK

A
  • Highly bound to albumin
  • Peak concentration in the blood: within an hour
  • Peak pharmacological effect: 48 h later
  • Warfarin is metabolised by CYP2C9, which is
    polymorphic
    • Variable half-life
    •Monitoring: Prothrombin Time or International
    Normalized Ratio (INR)
    , •Usually adjusted to give an INR of 2–4
    — Can cross the placenta: teratogenic
32
Q

FACTORS THAT POTENTIATE WARFARIN

A
  1. Liver disease
  2. CYP450 inhibitors
  3. Drugs that inhibit platelet function
  4. Drugs that displace warfarin from albumin
    - NSAIDs, 5-aminosalicylic acid, sulfonamides, phenytoin
  5. Drugs that decrease the availability of vitamin K
    - Broad spectrum antibiotics that depress intestinal flora normally synthesizing vitamin K
33
Q

FACTORS THAT LESSEN THE EFFECT OF WARFARIN
.

A
  1. Physiological state/disease
    -Increased coagulation factor synthesis e.g. pregnancy
    - Reduced degradation of coagulation factors in
    hypothyroidism
  2. Drugs
    • Vitamin K: Component of some parenteral feeds and vitamin preparations
    • CYP450 inducers e.g. rifampicin, carbamazepine,
    barbiturates
    •Drugs that reduce absorption
    • Drugs that bind warfarin in the gut e.g. cholestyramine
34
Q

Warfarin: ADVERSE EFFECTS

A
  • Haemorrhage
  • Treatment
    • Withhold warfarin (for minor problems)
    • Vitamin K, or fresh plasma or coagulation factor concentrates (for life-threatening bleeding)
  • Teratogenic: disordered bone , development
  • Hepatotoxicity is uncommon
  • Pro-coagulant state causing necrosis of
    soft tissues
  • Occurs shortly after starting treatment
    •Attributed to inhibition of protein C
    biosynthesis
    • Rare but serious
    • Treatment with heparin avoids this problem
    except in HIT

Sys. Pharm Week4 (2 decks)

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