M3 L5: Anticoagulants

Question 1

antithrombotic agents (3)

Answer 1

1. antiplatelets (inhibit platelet function)
2. anticoagulants (inhibit coagulation factors)
3. thrombolytic (profibrinolytic) agents (breakdown fibrin)

Question 2

antiplatelet agents (6)

Answer 2

1. cyclooxygenase inhibitors
2. ADP receptor blockers
3. phosphodiesterase (PDE) inhibitors
4. prostacyclin (PGI2) analogues
5. adenosine reuptake inhibitors
6. glycoprotein 2b/3a receptor blockers

Question 3

cyclooxygenase inhibitors

Answer 3

mechanism: decreased cyclooxygenase (cox) enzyme -> decreased TxA2

include: acetylsalicylic acid (aspirin), other NSAIDS ex: ibuprofen

Aspirin is strongest
This group inhibits cyclooxygenase enzyme
Some inhibit platelets, some stimulate
When you inhibit cyclooxygenase, you decrease thromboxane you inhibit platelet aggregation

Question 4

aspirin

Answer 4

very powerful platelet inhibitor!
- effect is more prolonged than other NSAIDS

dose: 350mg/day for treatment of myocardial infarction. 81mg/day for prophylaxis (baby aspirin).

side effects: bleeding, peptic ulcer, bronchial asthma

Till very recently was #1 with very little competition, can be used as an anti-inflammatory
Very powerful very strong
If you go to Europe, it is a smaller dose for baby aspirin
The inhibition of cyclooxygenase can result in inhibition of not just platelets, that causes the other side effects other than bleeding

Question 5

ADP receptor blockers
1. mechanism
2. side effects

Answer 5

1. block ADP receptor (P2Y12) -> decreased ADP-induced platelet aggregation
   - safe when aspirin is contraindicated
2. neutropenia, TTP, bleeding

examples: thienopyridines (ticlopidine - clopidogrel)

Prefer this over aspirin because of the adverse affects
Block ADP and inhibit platelet receptors
Side effects are safer than aspirin
Neutropenia: low levels of neutrophils
TTP: thrombotic thrombocytic purapura

Question 6

phosphodiesterase inhibitors

Answer 6

PDE decreased that is used as an antiplatelet is… cilostazol

• selective decrease of PDE3 -> increase cAMP in platelets -> increase active PKA -> decrease platelet aggregation

indication: intermittent claudication in peripheral vascular disease (vasodilator effect)
- avoid in heart failure

Group of enzymes
1-11 enzymes with subtypes
PDE3 has A and B
PDE4 has A B C and D
Inhibits PDE3, increases cAMP level, high levels of this in platelets leads to decreased platelet aggregation
Intermittent claudication causes severe pain in legs and muscle cramping with swelling
Cilostazol - don’t use w pts w CHF bc it could affect the condition of the heart

Question 7

prostacyclin analogues

Answer 7

• synthetic analogues of prostacyclin (PGI2)
  mechanism: directly increases cAMP levels in platelets
  thru inhalation or IV
  ex: iloprost, carbacyclin

Also called PGI2
Part of a family with members, it is slightly smaller group than previous side but each member has a function to do with different parts of the body
Prostacyclin - platelet inhibitor
Cyclic AMP is a large factor for inhibiting platelets

Question 8

mechanism of clopidogrel, cilostazol, and prostacyclin analogues action: inhibition of platelet aggregation thru increased cAMP

Answer 8

Drugs that rely on increasing cAMP to keep platelets inhibited
Clopidogrel competes with ADP
Cilostazol inhibits PDE3, breaks down cAMP, then it becomes linear gets hydrolyzed to become 5-AMP

The drugs overall increase the level of cAMP

Question 9

adenosine reuptake inhibitors

Answer 9

mechanism:
- inhibit adenosine uptake by RBC’s, platelets, and endothelial cells
- increase extracellular adenosine concentration -> acts on receptors
- increase platelet cAMP synthesis
- cAMP inhibits platelet aggregation
ex: dipyridamole (+PDE5 decrease -> VD)
Dipyridamole: when it was found it was a new era of a treatment of platelet inhibition, was found after aspirin. Shortly after they found it was not as affective, and have adverse effects so now it is 2nd or 3rd choice.

Question 10

glycoprotein 2b/3a receptor blockers

Answer 10

mechanism: block glycoprotein 2b/3a receptors on platelets -> decrease platelet aggregation

side effects: thrombocytopenia

route of administration: IV

ex: abciximab

Have a big problem, only used through IV not orally
These receptors are on platelets, the bow looking thing has two ends one would connect to the receptor, the other would connect to another receptor on another platelet. This helps with platelet aggregation. These meds block these receptors. Very effective, pt has to be hospitalized

Thrombocytopenia is a side effect

Question 11

thromboxane inhibitors

Answer 11

• thromboxane synthase inhibitors
• thromboxane receptor antagonists

Inhibits thromboxane synthetase through inhibiting the enzyme, the other competes with the receptor

Question 12

example of thrombin receptor (protease-activated receptor-1 [PAR1]) antagonists

Answer 12

vorapaxar

Question 13

heparin

Answer 13

• unfractionated heparin
• low molecular weight heparin (LMWH)
• taken by injection

Question 14

oral anticoagulants

Answer 14

• warfarin and dicoumarol
• direct thrombin inhibitors
• direct FXa inhibitors

Question 15

unfractionated heparin

Answer 15

mechanism:
- augments the effect of AT
- inhibition of thrombin (factor 2a) and factor Xa

side effects:
- bleeding, thrombocytopenia, allergic reactions, osteoporosis

administration:
- IV or SC injection

Natural substance in the body
Antithrombin: acts thru heparin, inhibits Factor 2 and Factor 10

Thrombocytopenia: reduction in platelet count

Taken by IV or subcutaneous injection

Question 16

low molecular weight heparin

Answer 16

compared to unfractionated heparin:
- lower molecular weight
- more selective inhibition of factor Xa w relative sparing of thrombin
- improved pharmacokinetics
- less side effects
- no need for coagulation monitoring
- administered mainly thru SC injection

ex: tinzaparin, enoxaparin

Piece of heparin, not the whole piece
Unfractionated: is 15kg (or something w a k)
Has lower molecular weight, smaller than heparin. This will make them have better pharmakinetics, mainly used by subcutaneous injections, safer than heparin, and lower risk of bleeding. This can be taken when patient is ambulatory, whereas heparin you have to be in the hospital and you have to follow up to monitor levels.

Low molecular weight: focus on factor 10, not both.**** Figure out the difference between low molecular weight and unfractionated guaranteed question on midterm

Question 17

warfarin

Answer 17

mechanism:
- Vitamin K is required for activation of factors 2, 7, 9, 10 in the liver by carboxylation.
- vitamin k has to b in reduced form under effect of vitamin k epoxide reductase enzyme
- enzyme in inhibited by warfarin

Vitamin K must be in reduced form to activate these factors, and to be in this it must be reduced by the reductase enzyme. Then reduced vitamin K will activate factors through carboxylase reactions.

Vitamin K stimulates the coagulation process

Warfarin will inhibit Vit K epoxide reductase enzyme

Question 18

heparin vs warfarin
1. chemistry
2. source
3. mechanism
4. administration
5. onset
6. duration of action
7. monitoring
8. antidote

Answer 18

1. chemistry
   heparin: mucopolysaccharide (-‘ve charge_
   warfarin: vitamin k antagonist
2. source
   heparin: natural product
   warfarin: vitamin k antagonist
3. mechanism
   heparin: activates AT -> decreased thrombin and FXa
   warfarin: decreases vit k epoxide reductase enzyme
4. administration
   heparin: SC, IV
   warfarin: oral
5. onset
   heparin: immediate
   warfarin: >2 days
6. duration of action
   heparin: short (hrs)
   warfarin: long (days)
7. monitoring
   heparin: PTT
   warfarin: PT (INR)
8. antidote
   heparin: protamine (+’ve charge)
   warfarin: vit k

Heparin is natural, short acting (starts fast, ends after a few hours)
Warfarin is a synthetic, late onset (take once a day)
Start them together, bc warfarin will take a while to start
Both need monitoring because they are both strong (talking about unfractioned heparin)
Warfarin can accumulate bc it is long lasting which can lead to toxic effects
Protamine is a +’ve charged substance by itself

Question 19

direct thrombin inhibitors

Answer 19

• recent oral anticoagulants
• directly inhibit thrombin (factor 2a)
• no specific monitoring test
• don’t require frequent monitoring
• antidote: approved by WHO in 2015
  ex: dabigatran
  *know this has an antidote

Question 20

direct FXa inhibitors

Answer 20

• recent oral anticoagulants
• directly inhibit factor 10a
• rapid onset of action
• don’t require frequent monitoring
• antidote: approved by WHO in may 2018
  ex: rivaroxaban
  “oxaban” is Fxa inhibitor

Question 21

thrombolytic agents

Answer 21

• activate plasminogen -> plasmin

include:
- tissue plasminogen activator (t-PA)
- urokinase
- streptokinase

Have a huge advantage - Try to break down the thrombus, thrombus has to be quite fresh so it can be dissolved - can dissolve the clot

Tissue plasminogen activator - most useful drug of this group

Question 22

tissue plasminogen activator (t-PA)

Answer 22

• initially isolated from a tumor cell line (melanoma)
• directly promotes the conversion of plasminogen -> plasmin
• selective for fibrin-bound plasminogen
• low antigenicity: repeated uses

Natural in our body
When it was found it was isolated from melanoma cells, now they make it available to use it as a drug
Also specific for plasmid, that is connected to the fibrin
T-PA can work on the area with the thrombus
Less allergenic, and causes bleeding

Question 23

streptokinase vs. t-PA
1. plasminogen binding
2. potential allergic reaction
3. antigenicity
4. risk of bleeding
5. plasma clearance (mins)
6. relative cost

Answer 23

1. plasminogen binding
   streptokinase: indirect
   t-PA: direct
2. potential allergic reaction
   streptokinase: yes
   t-PA: no
3. antigenicity
   streptokinase: high
   t-PA: low
4. risk of bleeding
   streptokinase: more
   t-PA: less
5. plasma clearance (mins)
   streptokinase: 15-25
   t-PA: 4-8
6. relative cost
   streptokinase: +
   t-PA: +++

T-PA is much better, the only advantage for streptokinase is that it is cheaper.