L1: Anticoagulants drugs

Question 1

What is the source and chemistry of heparin?

Answer 1

• Natural sulfated polysaccharide present in mast cells & carries –ve charge
• It is high molecular weight 30000 dalton. “Widely changes which causes problems”

Question 2

What is the route of administration of heparin?

Answer 2

Not taken orally as it precipitated by gastric HCl (given by IV, SC)

Question 3

Does heparin cross BBB?

Answer 3

Cannot cross BBB or placenta (safe in pregnancy).

Question 4

What is the onset and duration of heparin?

Answer 4

Rapid onset & short duration (t1/2 60 min.) “used in emergencies”

Question 5

What is the mechanism of action of heparin?

Answer 5

• Its action depends on the presence of a natural clotting inhibitor called antithrombin III.
• Small quantities of heparin can activate antithrombin III inhibition of several clotting factors especially [factor X & thrombin (factor II)].

Question 6

where does Heparin act?

Answer 6

In vivo & in vitro

Question 7

What are the therapeutic uses of heparin?

Answer 7

• Treatment of established thrombosis “prevent propagation”
• Prevention of thrombosis “bid-ridden patients and artificial parts of the body”
• Keep coagulation time & activated partial thromboplastin time (APTT) at 2-3 times of its normal value (for Control of Therapy).

Question 8

What are the adverse effects of Heparin?

Answer 8

• Bleeding is the most common and dangerous SE can be reversed by antidote protamine sulfate “physical antagonism” a basic +ve charged protein that combines with heparin.
• Heparin-induced Thrombocytopenia “decreased platlets” (HIT) (autoimmune). arises from the development of antibodies to the heparin–platelet factor 4 complex. “Thrombocytopenia + thrombosis”
• Hematoma if given IM
• Osteoporosis
• Alopecia

Question 9

What is the nature of LMWH (enoxaparin)?

Answer 9

❖ Standard (unfractionated) heparin is a mixture of different molecular weight fractions (MW 3000-30,000 Da) that can affect more than one coagulation factor and produce thrombocytopenia (↑ risk of bleeding).

LMWH has molecular weight less than 8000 dalton which causes more specificity

Question 10

What is the molecular weight of LMWH and what is the significance of that?

Answer 10

❖ LMWH has a MW less than 8000 Da that makes it specific for factor X with minimal effects on platelets and other clotting factors. “Not like heparin which activates antithrombin III that inhibits many factors”

Question 11

Compare between unfractionated heparin and LMWH according to:-

Molecular weight range
anti-factor 10 activity
Nonspecific binding to plasma proteins
Bioavailability after subcutaneous injection
Half-life
Thrombocytopenia
Risk of bleeding
Lab monitoring

Answer 11

High - low

Less specific - more specific

High - low

Low (due to binding to S.C tissue) - High

Short (3 daily) - long (once daily)

Common 10% - less common (<2%) (less affinity for platlet factor 4)

High “all coagulation factors” - low

APTT (essential) - extent of inhibition of factor Xa (may br unnecessary)

Question 12

Give examples for synthetic factor X inhibitors.

Answer 12

Fondaparinux

Rivaroxaban

Question 13

What is the nature of Fondaparinux?

Answer 13

Synthetic pentasaccharide that have the same mechanism like LMWH (i.e. selective inhibitor of factor Xa).

Question 14

What is the route of administration of Fondaparinux?

Answer 14

It is given by s.c. injection once daily (has long t1⁄2).

Question 15

What is the route of administration and it is the mechanism of action of Rivaroxaban?

Answer 15

• Oral inhibitor of (factor Xa).

- Bind to the active site of factor Xa Preventing its ability to convert prothrombin to thrombin

Question 16

Give examples for direct thrombin inhibitors.

Answer 16

 Argatroban (parenteral)  Dabigatran (Oral)

Question 17

What is the use of DTIs?

Answer 17

alternative to heparin to treat patients with heparin- induced thrombocytopenia

Question 18

What is the Chemistry and nature of DTIs?

Answer 18

A “SDCTI” selective direct competitive thrombin inhibitor that binds to and inhibits both circulating and thrombus-bound thrombin (factor II a).

Question 19

What is the source and the chemistry of warfarin?

Answer 19

Synthetic coumarin compound

Question 20

What is bioavailability of warfarin?

Answer 20

Good (bioavailability is 100%).

Question 21

Can warfarin pass BBB and the placenta?

Answer 21

Yes

Question 22

Does warfarin bind highly to plasma proteins?

Answer 22

Highly bound to the plasma proteins “causes drug interactions”

Question 23

What is the enzyme that is responsible for Biotransformation of warfarin?

Answer 23

hepatic CYP450.

Question 24

What is the mechanism of action of warfarin?

Answer 24

• Warfarin inhibits vitamin K epoxide reductase enzyme in the liver leading to inhibition of formation of the active form of vitamin K → ↓ synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X).
• The action of warfarin could be antagonized by vitamin K.

Question 25

What are the therapeutic uses of warfarin?

Answer 25

Warfarin is given oral 2-10 mg/day for prevention and treatment of thrombosis. “But not in emergency”

Question 26

How is warfarin monitored?

Answer 26

• Monitoring is by prothrombin time (PT) or International Normalized Ratio (INR): It is the ratio of the PT in the patient to that of normal person.
• It must be kept 2-3 times as the normal value. “Like heparin”

Question 27

What are the adverse effects of warfarin?

Answer 27

• Bleeding: gingival “related to gums” bleeding, nose bleeding…

 It could be treated by the following:
• Immediate stopping of the drug.
• Fresh frozen plasma (FFP). “Has clotting factors”
• Vitamin K1(phytomenadione): to enhance synthesis of clotting factors.

• Teratogenicity: serious birth abnormalities “fetal warfarin syndrome”
• Serious thrombosis: on sudden withdrawal

Question 28

What are the drug interactions of warfarin?

Answer 28

• Drugs that potentiate↑ warfarin action:
  1) Liquid paraffin: ↓ vit K absorption
  2) Oral antibiotics: ↓ vit K synthesis by killing the gut flora
  3) NSAIDs: displace warfarin from pp.
  4) Microsomal enzyme inhibitors (e.g. cimetidine, chloramphenicol) ↓ metabolism of warfarin.
• Drugs that inhibit warfarin:
  1) Aluminum hydroxide: ↓ warfarin absorption
  2) Oral contraceptives and vit K. ↑ synthesis of clotting factors
  3) Microsomal enzyme inducers (e.g. phenobarbital, rifampin) ↑ metabolism of warfarin.

Question 29

And compare between heparin and warfarin according to: –

Source
Action
Kinetics
Mechanism of action
Dose
Control
Onset
Duration
Antidote

Answer 29

Natural - Synthetic

In vivo and in vitro - In vivo

Absorbed from GIT, Cross the placenta and milk

It activates antithrombin III - They compete with Vit. K. on vit K epoxide reductase

S.C - oral

Blood coagulation time APTT - prothrombin time, INR

Immediate - Delayed1-3 days

Short 2-4 hrs - Long 4-7 days

Protamine sulphate + Fresh blood transfusion - Vitamin K +Fresh blood transfusion

Question 30

why is pregnancy considered as a hypercoagulable state?

Answer 30

due to increase levels of coagulation factors and venous stasis.

Question 31

What does pregnancy increase the risk of? “related to blood”

Answer 31

Pregnancy increases the risk of venous thrombosis and pulmonary embolism in susceptible female.

Question 32

What does the use of warfarin in the first trimester and in the last trimester cause?

Answer 32

The use of warfarin in the first trimester is associated with birth defects (5%), while its use near full-term increases the risk of fetal hemorrhage.

Question 33

What are the side effects of heparin and low molecular weight heparin during pregnancy?

Answer 33

Neither UFH nor LMWH cross the placenta; therefore, do not cause fetal bleeding or teratogenicity, but they can reduce bone mass density and cause osteoporosis if used through pregnancy.

Question 34

What is anticoagulation recommended for pregnant women?

Answer 34

Anticoagulation is recommended in most pregnant patients with a mechanical heart valve.

Question 35

What does the American College of chest physicals recommend regarding the use of anticoagulants during pregnancy?

Answer 35

• The American College of Chest Physicians (ACCP) recommends the use LMWH until 13 weeks’ gestation, then change to warfarin until the patient is close to delivery (34 weeks), and then restart LMWH.
• Long-term anticoagulants should be resumed postpartum