Antithrombotic drugs (antiplatelet &anticoagulants) .pdf

Antiplatelet drugs and anticoagulants drug

1. Antithrombotic drugs
Dr. khaulah Al-shoomi

2. Introduction
•Hemostasis
•Thromboembolic disorders
•Antithrombotic drugs (Antiplatelet and
Anticoagulants)

3. Hemostasis
Hemostasis is the physiological process by which a bleeding stops. Its final
result is a thrombus (blood clot), by Primary hemostasis : platelet plug (white
thrombus)
and Secondary hemostasis: fibrin clot (red thrombus)

Primary hemostasis
Endothelial injury results in:
Exposure of sub endothelial collagen → circulating vWF binds to the
exposed collage then platelets activated by 4 different processes:
1.Platelet adhesion: platelets bind to vWF via platelet GpIb receptor at
the endothelial injury site
2.Platelet activation: activation of more platelets (positive feedback) by
release of mediators :
 Adenosine diphosphate (ADP):bind to G-protein (P2Y1 and
P2Y12) promotes adhesion and aggregation

4. Thromboxane A2 (TXA2): synthetic by COX-1:activates
additional platelets and promotes vasoconstriction
Calcium: required for secondary hemostasis
Platelet-activating factor (PAF): a phospholipid mediator that
is produced by platelets and inflammatory cells), involved
in platelet aggregation and activation and local inflammatory
response
3. Platelet aggregation
Mediated by GpIIb/IIIa-receptor and fibrinogen → formation
of a white thrombus composed of platelets and fibrinogen
A white thrombus is transient, unstable, and easily dislodged.
It stabilizes through the process of secondary hemostasis
of secondary hemostasis.
4. Procoagulant activity

5. Primary hemostasis

6. Secondary hemostasis :
Coagulation cascade: activation of the intrinsic or extrinsic pathway of
coagulation that results in the formation of a stable thrombus
Extrinsic pathway of coagulation: triggered by endothelial injury
Tissue factor (factor III) activates factor VII to VIIa Then form a complex
(TF-FVIIa) that activates factor X and factor IX.
Intrinsic pathway of coagulation
Exposed collagen activate factor XII to Factor XIIa activates factor XI.
Thrombin activates factor XI and factor VIII.
Factor XIa activates factor IX.
Factors VIIIa -IXa complex activates factor X.
Common pathway of coagulation: The extrinsic and intrinsic pathway both
end in the common pathway. : Xa-Va complex that cleaves prothrombin (factor
II) to thrombin (factor IIa).
Thrombin cleaves fibrinogen (factor I) into insoluble fibrin (factor Ia)
monomers.
Cross-links fibrin network are stabilized by factor XIIIa → formation of
a fibrin network → fibrin closely binds to the platelet plug, forming a
stable thrombus

8. Thromboembolic disorders
Thromboembolic disorders are major causes of
morbidity and mortality. Thrombosis can occur in
arteries or veins.
 Arterial thrombosis is the most common cause of
acute myocardial infarction (MI), ischemic stroke,
and limb gangrene.
 Venous thromboembolism encompasses deep vein
thrombosis (DVT), which can lead to
postthrombotic syndrome, and pulmonary
embolism(PE)

9. Arterial and venous thrombi are composed of platelets,
fibrin, and trapped red blood cells.
Arterial thrombi are rich in platelets because of the
high shear in the injured arteries. In contrast, venous
thrombi contain relatively few platelets and are
predominantly composed of fibrin and trapped red
cells

10. Antiplatelet drugs
Aspirin.1
2.ADP receptor antagonists
3.Dipyridamole
4.Gp IIB/IIIA receptor antagonists .
5.Vorapaxar

11. Antiplatelet drugs
C.I S.E indication dose MOA drug
1.Febrile illness
<19 years
2.Acute gout
.GI :dyspepsia,
Gastric
ulceration
&hemorrhage,
Perforation
.Coagulopathy:
increase PT
•Tinnitus
•AKI &ATIN
•Salicylate
poisoning

secondary
prevention of
cardiovascular
events (MI
,stroke,
Angina)
Prevention of
stent
thrombosis
75-325 mg once
Daily
(300-2400
mg\day):
antipyretic
&analgesic
(2400-4000
mg/day):
anti
inflammatory
Irreversible
COX-1
inhibitor.
COX-2
inhibitor at
high dose
Aspirin
Complication :
1.Aspirin-
exacerbation
respiratory
disease
2.Reye
syndrome

12. ADP RECEPTOR ANTAGONISTS
S.E Indication dose Route of
admin.
Metabolic
activity
MOA drug
thienopyridine
1.Alleregic
reaction
2.Bleeding
3.
1.Dual
antiplt.
Therapy:
.STEMI
.NSTEMI\
unstable
angina
.2ry
prevention
post PCI or
stent
2.Alternati
ve to
aspirin
maintenance:
75mg
Load dosing:
300mg
Oral prodrugs
that require
metabolic
activation
by hepatic
cytochrome
P450 (CYP)
enzyme
system
irreversibly
blocking
P2Y12

clopidogrel

maintenance:
10mg,5mg
Load dosing:
60mg

Oral irreversibly
blocking
P2Y12
prasugrel
Neutropeni
a
\agranuloc
ytosis
250mg twice
daily
Oral irreversibly
blocking
P2Y12
Ticlodipine
(not available
in US
Non-thienopyridine
Dyspnea Mmaintenance:
60 ,90mg twice
Load dosing:
180mg
Oral No need reversibly
blocking
P2Y12

ticagrelor
50mg\vial IV Cangrelor

13. Dipyridamole
•Dipyridamole (Aggrenox )is a relatively weak antiplatelet agent
•MOA :By inhibiting phosphodiesterase, increase of(cAMP) that lead
reduce intracellular calcium and inhibit platelet activation
•Indication : , used for secondary prevention in patients with transient
ischemic attacks or ischemic stroke
•Dose : Aggrenox is given twice daily. Each capsule contains 200 mg
of dipyridamole and 25 mg of aspirin.
•S.E : Gastrointestinal complaints, headache, facial flushing, dizziness,
and hypotension

14. GP IIB/IIIA RECEPTOR ANTAGONISTS.
abciximab, eptifibatide, and tirofiban.
• MOA: Gp IIb/IIIa receptor on surface of activated platelets that
prevention platelets binding to fibrinogen
•Indications: Abciximab and eptifibatide :percutaneous coronary
interventions.
Tirofiban :high-risk patients with unstable angina.
•Dose:
abciximab is a bolus of 0.25 mg/kg followed by an infusion of 0.125
μg/kg to a maximum of 10 μg/kg for 12
eptifibatide is given as two 180 μg/kg boluses given 10 min apart,
followed by an infusion of 2.0 μg/kg per minute for 18–24 h
. Tirofiban is started at a rate of 0.4 μg/kg per minute for 30 min; the
drug is then continued at a rate of 0.1 μg/kg per minute for up to 18 h.
• S. E : bleeding, thrombocytopenia is the most serious complication..

15. VORAPAXAR
•MOA :Reversible inhibition of protease-activated receptor-1(PAR-1)
blocks thrombin-induced platelet activation.
Vorapaxar has a half-life of about 200 h.
•Indication :secondary prevention prior MI, ischemic stroke, or
peripheral arterial disease.
Give for >75 years without Hx of stroke , ICH
•Dose: 2.08 mg once daily
•S.E : increased rates of bleeding, including intracranial bleeding.

16. anticoagulants

oral anticoagulants parenteral anticoagulants.

1.oral thrombin inhibitor:
Warfarin
Dabigatran etexilate
2.oral factor Xa inhibitors:
Rivaroxaban
Apixaban
Edoxaban
:1.UFH
((Heparin
:2.LMWH
(enoxaparin , dalteparin
,tinzaparin,nadroparin , certoparin )
:3.Synthetic heparin
((Fondaparinux
4.Direct thrombin inhibetors:
(Desirudin ,Bivalirudin
,Argatroban , Lepirudin )

17. Heparin
MOA: inhibition of anti-thrombin(block the conversion of fibrinogen to
fibrin) and Xa
Administration :
:1.SC for prophylaxis
.Fixed dose 5000 units SC two or three times daily
Onset of action within 1-2 hours
:2.IV for treatment
weight-based heparin nomograms , bolus: 80units\kg Maximum
10000units))
Initial infusion rate:18 units\kg\hrs
( Maximum 2000 units\hrs )
Monitoring : aPTT
Clearance : hepatic , so safe for pt with renal impairment

18. Heparin
•Indication:
1)Venous thromboembolism prophylaxis : initial bolus of 5000
units or 80 units/kg, followed by an infusion of 18 units/kg per
hour
2)acute coronary syndromes : IV heparin bolus of 5000 units or
70 units/kg, a heparin infusion rate of 12–15 units/kg per hour
•Low-dose therapy
•DVT prophylaxis for prolonged bed rest, peri- and postoperative state,
immobility
•High-dose therapy
•Immediate anticoagulation effect for
oAtrial fibrillation
oDVT, acute arterial thrombosis, pulmonary embolism
oAcute coronary syndrome, myocardial infarction
oMechanical heart valve replacement
oVTE prophylaxis for patients with hemodialysis, heart-lung machine, etc.

19. Complications of Heparin
1. Bleeding: antidote protamine sulfate(IV) to neutralize the heparin. (1 mg
of protamine sulfate neutralizes 100 units of heparin
2. Thrombocytopenia:
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated response
to heparin lead to thrombocytopenia and increase risk of thrombosis
. The clinical features of HIT are thrombotic manifestation (DVT,PE ,acute
mesenteric ischemia ,stroke , MI ,acute limb ischemia )
HIT occurs 5–14 days after initiation of heparin therapy
. A platelet count <100,000/μL, no decrease below 20,000\ μL
Treated by :
Stop heparin and an alternative IV anticoagulant should be administered
as(argatroban , bivalirudin , fondaparinux) or oral
as (DOACs , warfarin )
3.Osteoporosis :due to Treatment with therapeutic doses of heparin
for >1 month
4. Elevated Levels of Transaminases , NL bilirubin

20. Low-Molecular-Weight Heparin
•enoxaparin , dalteparin ,tinzaparin, nadroparin , certoparin )

21. Low-Molecular-Weight Heparin
•MOA : like heparin
•Administration : SC , plasma half-life of ∼4 h.
• clearance by the kidneys(C.I in renal insufficiency)
•Monitoring : Anti-factor Xa (not generally recommended)
•Antidote : protamine sulfate
•Dose: For prophylaxis, once-daily SC doses of 4000–5000 units, whereas
doses of 2500–3000 units are given when the drug is administered twice
daily.
• For treatment of VTE, a dose of 150–200 units/kg once daily. Or a dose of
100 units/kg a twice-daily
e.g : In patients with unstable angina give dose of 100 units/kg a twice-daily
•Indication :
1.Prophylaxis of DVT in orthopedic and abdominal surgery, prolonged
immobility
2.Treatment of DVT
3.Acute coronary syndrome

22. synthetic heparin (fondaparinux)
•MOA : like heparin
•Administration : SC , plasma half-life of ∼17 h.
• clearance by the kidneys(C.I in renal insufficiency)
•Monitoring : Anti-factor Xa (not generally recommended)
•Antidote : protamine sulfate
•Dose: For prophylaxis, 2.5 mg once daily.
• For treatment a dose of 7.5 mg once daily.
•5 mg once daily for those weighing <50 kg and increased to
10 mg for those >100 kg
•S.E:
1.Bleeding:has no antidote . possibly activated prothrombin
complex concentration
2.not cause HIT because it does not bind to PF4 fondaparinux
appears to be effective for treatment of HIT patients.

23. Direct thrombin inhibitors
Lepirudin, Argatroban, Bivalirudin, Desirudin
\Desirudin
Lepirudin
Bivalirudin, Argatroban
min & SC 60 ∼I.V
∼120-180min
IV
∼25min
IV
∼45 min
Administration&
half-life

no yes no Clearance by
kidney
No No Yes Hepatic
metabolism
activated clotting
time
aPTT Monitoring
Not use in US HIT patients HIT patients indication

24. ORAL ANTICOAGULANTS
Warfarin
•MOA : A water-soluble vitamin K. Like other vitamin K antagonists,
warfarin interferes with prothrombin (factor II) and factors VII, IX, and
X. proteins C and S, is also reduced by vitamin K antagonists.
•Administration : oral , plasma half-life of 36–42 h, and >97% of
circulating warfarin is bound to albumin. Only the small fraction of
unbound warfarin is biologically active.
•metabolized in the liver
• clearance : kidney
•Monitoring : PT\INR , the therapeutic range 2-3.
•Antidote : FFP\ prothrombin complex concentration
•Dose: initial dose 1-5mg
• Loading dose :10mg
•INR-based initial dose adjustment

26. SIDE EFFECTS :
1.bleeding:
INR = 3.5 and 10 warfarin should be withheld
the INR is > 10: oral vitamin K at a dose of 2.5–5 mg , given 5–10 mg of
vitamin K by slow IV infusion wyuth serious bleeding
2.skin necrosis :skin necrosis usually is seen 2–5 days after initiation of
therapy
3. Pregnancy Warfarin crosses the placenta and can cause fetal
abnormalities. Consequently, warfarin should not be used during
pregnancy

29. direct oral anticoagulants (DOACs)

30. Remember :
Direct factor Xa inhibition : alternative with Warfarin
Direct factor IIa inhibition : alternative with Heparin
INDICATIONS :
1.Prophylactic of DVT ,PE , After immobilization.
2.stroke prevention in patients with non-valvular atrial fibrillation
S.E :
Bleeding :
antidote for Dapigatran : Idarucizumab
Rivaroxapan &Apixapan : Andexanet alfa
Argatroban & Bivalirudin : no antidote , PCC

31. Cases

32. CG is a 57 year old male admitted to the emergency department and
diagnosed with a new pulmonary embolism (hemodynamically stable). Past
medical history Is significant for diabetes mellitus, hypertension,
hyperlipidemia, and osteoarthritis. Labs upon admission are WNL. He weighs
80kg, is 6'0" tall and has NKDA. He initially receives enoxaparin 80mg SQ
BID for therapy. On day 3 of hospitalization the team wishes to transition him
to a DOAC instead of warfarin therapy. Which of the following DOAC
regimens is appropriate to transition CG from his enoxaparin assuming
he can afford therapy?

A. Rivaroxaban 20mg orally daily with evening meal

B. Apixaban 10mg orally twice daily

C. Dabigatran 150mg orally twice daily

D. Edoxaban 30mg orally once daily

33. KA is a 37-year-old female who presented to the emergency department with unilateral
swelling, erythema, and tenderness in her left lower extremity. Her PMH is significant for
depression, and her family history is significant for Factor V Leiden mutation. She denies
feeling any chest tightness/pain, SOB, or dyspnea. Her doppler ultrasonography reveals
a DVT in her leg, and her chest CTA was negative for PE .

SH: Smokes ½ ppd, denies alcohol use

Medications: fluoxetine 20 mg QD, ethinyl estradiol and norethindrone 1.5 mg/30 mcg
QD

Pertinent Labs :

BP: 127/81

HR: 77

Weight: 155 lbs

Height: 5’7 ”

D-Dimer: 1500 ng/mL

CrCl: 120 mL/min
Which of the treatment regimens are correct for the
initial treatment of her DVT? Select all that apply .

A. dabigatran 150mg PO BID

B. rivaroxaban 15 mg PO BID

C. enoxaparin 70mg SQ once daily

D. Enoxaparin 40 mg SQ once daily

E. warfarin 5 mg PO once daily

F. apixaban 10mg PO BID

34. An 85 year old female (5’7”, 54 kg) presents to your ambulatory clinic for management of
newly diagnosed atrial fibrillation. Her physician referred this patient to you to assess
which direct oral anticoagulant (DOAC) be most appropriate for the patient for stroke
prevention. Her past medical history includes hypertension, diabetes, and depression.
She is currently taking metformin 1g BID, lisinopril/HCTZ 40/12.5mg daily, and sertraline
100mg daily. Lab values from her most recent basic metabolic panel (BMP) drawn one
week ago are listed below:

Sodium: 134 mEq/L

Potassium: 4.2 mEq/L

Chloride: 103 mmol/L

Calcium: 9.8 mg/dL

CO2: 24 mmol/L

BUN: 12 mg/dL

SCr: 1.1 mg/dL

Glucose: 128 mg/dL

Which of the following would be the most
appropriate recommendation to the
physician?

A. Apixaban 5 mg BID

B. Apixaban 2.5 mg BID

C. Rivaroxaban 20 mg daily

D. Anticoagulation Is not indicated in this patient

35. :References
1.Harrisons principles of internal medicine
2.Amboss
3.UpToDate
4.Medscape

36. Thank you …

If you have question I prefer to
search for the answer ,
searching helps in good
realization of information