ANTICOAGULANTS/ANTIPLATELETS/

FIBRINOLYTICS (1 HR)

Dr. Maxine Gossell-Williams, Pharmacology Section

Email: maxine.gossell@uwimona.edu.jm
Learning Objectives

This lecture discusses the pharmacology of the drugs useful for heamostatic
disorders. These include
a. Anti-coagulants
b. Antiplatelets
c. Fibrinolytics
 HAEMOSTASIS

A: Primary Damage to vessel wall

Reflex vasoconstriction
Platelet adhesion Initiation of coagulation

Release of mediators Thrombin B: Secondary

Platelet aggregation Fibrin

Thrombus RESTRICTORS
PGI2, ANT III, Protein C,
C:Regulatory Fibrinolysis Protein S, t-PA, PAI
(produced by intact
endothelium in the vicinity
Fibrin degradation products
Haemostasis
 A: ANTICOAGULANTS

Injectables: HEPARIN
ENOXAPARIN Potentiator of ANTIII
DALTEPARIN LMWH

HIRUDIN

Oral: WARFARIN, DABIGATRAN, APIXABANDirect

RIVAROXABAN
Thrombin inhibitor

Vitamin K antagonist Direct factor X inhibitor

ANTICOAGULATION

http://www.nature.com/nrurol/journal/v8/n9/images/nrurol.2011.106-f1.jpg
 MOA-HEPARIN
Prevent the activation of
fibrinogen to fibrin
Cofactor of ANT III = BIND
to ANTIII =INCREASE ANTIII
activity
Increases the rate of
thrombin-ANTI III REACTION
(1000 times)
also increases inactivation
of , IXa, Xa, XIa XIIa

1:1 binding ratio with all

factors

ACTIVE IN VIVO
http://classconnection.s3.amazonaws.com/538/flashcar AND IN VITRO
ds/456538/jpg/picture41321498945269.jpg
 MOA- LMWH

Have only binding site for ANT-III

increase inactivation of IXa, Xa, XIa and XIIa
NOT IIa
Accounts for the better safety profile
HEPARIN
1 USP =
quantity that prevents 1.0 ml of
citrated sheep plasma from clotting
for 1hr after addition of 0.2 ml of 1%
CaCl2
Source: procine intestinal mucosa
bovine lung
Polar drug
sulphated glycosaminoglycans
MW range (5000-40000 daltons)
Notes
IV quick onset , SC onset =60 mins
Bioav =20% after SC
Loading Dose req: 5000 U initially
Why? Non-specific binding to plasma proteins,
endothelial cells, macrophages, vWF- need to saturate
t1/2 40-90 min
metabolized by heparinase enzymes
Low TI
unpredictable action - monitoring required
- aPTT should not be > 2.5 X normal
Does not cross placenta
Inhibits aldosterone =hyperkalemia
High HIT potential
Anticoagulants

LMW heparins: Only given SC 5000U.

ENOXAPARIN Greater Bioavailability 90% after SC
DALTEPARIN Longer t1/2 (2 times)
Elimination the same
More predictable response=less binding
for LMWH (1000-10000
daltons) using gel filtration
chromatography
to cells
No monitoring required as there is no
change in aPTT (no effect on IIa)
less HIT potential
Patients can be taught to self-medicate
10 to 20 times more expensive than
heparin
 HIT- Heparin-induced thrombocytopenia
Antibody formed against heparin-platelet complex
Platelet count reduced to <100,000 uL
occurs in:
2-14 days after start of therapy
5% of patients receiving heparin
1% of patients receiving LMWH

Sequelea Incidence
Thombosis 30-50%

Amputations 20%

Death 30%
TREATING HEPARIN OVERDOSE

PROTAMINE SULPHATE
Basic compound
Binds to and neutralize
heparin
Given by slow IV; at 1
mg/100U of heparin
remaining.
routinely used after cardiac
surgery to reverse heparin
effects
ADR- histamine release.
 Useful for
patients
DIRECT THROMBIN & XA INHIBITORS with HIT
potential

ANT III independent

anti-coagulants
DABIGATRAN
MOA: Bind to catalytic site of thrombin and prevents function.. competitive
Given as DABIGATRAN etexilate

RIVAROXABAN
MOA: Bind to catalytic site of factor Xa and competitively inhibits both free and
clot-bound form.
http://resus.me/reversing-new-oral-anticoagulants/
Anticoagulants Elimination
DABIGATRAN Oral use (75- 150 mg) Converted
etixilate Low bioavailability(6-7%) to
Pradaxa. t1/2 7-14 hrs Dabigatran
by esterases
35% PPB then R
Distributes in tissues
(Vd 50-70L)
Influenced by p-glycoprotiens
RIVAROXABAN Oral use (10-20 mg) CYP3A4
Xarelto Low bioavailability(80-
100%)
t1/2 7-11 hrs
92-95% PPB
Vd= 50L
 ORAL ANTI-COAGULANTS-WARFARIN

Coumarin
Isolated from Clover leaves
Structurally related to Vit K
Mechanism of action
-Carboxyglutamic
Glutamic acid acid residues of II
residues of VII IX X
II VII IX X (Protein C & S)

Reduced Vitamin K Oxidized Vitamin K

NAD Vit K NADH

reductase

Competitive inhibition

Warfarin
Anticoagulants Notes Elimn

Warfarin absorbed O (pk 2-8 hrs). CYP450

Slow onset = 48 hrs (2c9)
(t (hrs): duration 4-5 days
VII =6
PPB= 99%
IX=24
t 25 - 60hrs
X= 36
II=60* Crosses placenta-
Protein C = 8 teratogenic
Protein S = 30 intracranial bleeding

* Onset dependent on factor with longest

t1/2
 ADR/ Toxic effects
diarrhea
Overdose = bleeding
Reversed with Vitamin K
Drug interactions

Warfarin induced Skin Necrosis

Seen 3-6 days after initiation
rare ADR
(>1/1000 less than 1/1000)
 WARFARIN VS BLEEDING

Low TI
Monitoring of International Normalized ratio
(INR)
the ratio of a patient's prothrombin time to a normal (control) sample

Therapeutic range = 2-3

Overdose management: VIEW
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1305837/table/T2
DRUG INTERACTIONS WITH WARFARIN

Inhibition of liver enzymes by

Metronidazole, Isoniazid,
Fluconazole

= clearance of warfarin
DRUG INTERACTIONS WITH WARFARIN

Induction of liver enzymes by

Rifampin, Phenytoin, St. Johns wort
= clearance of warfarin
DRUG INTERACTIONS WITH WARFARIN

Displacement from plasma proteins

Disulfiram
= free warfarin
DRUG INTERACTIONS WITH WARFARIN

Decrease absorption of Vitamin K

Broad spectrum antibiotics
= clotting factors

= warfarin activity
DABIGATRAN /RIVAROXABAN VS WARFARIN

QUICKER ONSET
LESS DDI
NO DIETARY RISTRICTIONS
CAN CAUSE BLEEDING.. HARDER TO MANAGE (warfarin uses INR)
CASE: HEPARIN VS WARFARIN
A 65-year-old woman , 20 years history of type II diabetes
was admitted to with diagnosis of deep vein thrombosis
(DVT) of her left calf. A loading dose of 80 units/kg
heparin followed by a continuous infusion of 1000u/hr
was initiated and at the third day of the heparin
therapy, warfarin (5mg/day) was also started for that
patient.

Why would it be necessary to give patient both heparin &

warfarin?
MOA COX/TXA2 inhibitor
grouping ASPIRIN

ADP receptor Phosphodiesterase

antagonist Antiplatelet inhibitor
TICLOPIDINE drugs DIPYRIDAMOLE
CLOPIDOGREL

GPIIb/IIIa receptor
antagonist
ABCIXIMAB
 ASPIRIN
MOA
Irreversible inhibition of COX
specific interest COX 1

1. in platelets prevents
formation of TX A2
2. prevents glycoprotein
IIb/IIIa (GP IIb/IIIa) receptor
expression
3. platelet aggregation
prevented
ASPIRIN-USED AT LOW DOSE

Prevents platelet aggregation

WHY?
Inhibition of PGI2 formation in endothelium at
higher concentrations
Anti Notes Elimn
platelets
Aspirin Oral:Dose= 50- 325 mg /d ; Hepatic
Onset: 30-60 mins metab to
Chewable aspirin for quicker salicylate
onset
Duration: 7-9 days
ADR GIT irritation
DIPYRIDAMOLE:MOA

inhibits
phosphodiasterase=
increase cAMP =
increases protein
kinase A= decrease
platelet aggregation

VASODILATOR: (higher doses)

cAMP associated with dilation of blood
vessels

Low efficacy
Combined with Aspirin or Warfarin.
Source: D. Golan
Prophylactic use
Anti Elimn
platelets
Dipyridamole Well absorbed O. Liver M
Pk in 75 mins and then
High PPB excreted
by bile
ADR headaches, dizziness
Overdose= hypotension
CLOPIDOGREL, TICLOPIDINE
ADP RECEPTOR ANTAGONISTS

MOA
Irreversible ADP
antagonist of P2Y
receptor
= prevent the ADP
inhibition of AC
Results in increase
CAMP = Increase
PKA

Used alone or in combination with

Source: D. Golan Aspirin
Anti platelets

Clopidogrel Route:O. Pk =2hrs

(Plavix) Pro-drug activated by CYP450 (2C19)
Onset= 4-8 days
Duration: 14 days
High PPB for both pro-drug and
metabolite(>93% )
ADR: diarrhea
T/E: bleeding

Slow metabolizers at
risk of treatment failure

CYP2C19 phenotyping
recommended

N Engl J Med 2009; 360:363-375

ABCIXIMAB:
GPIIB/IIIA RECEPTOR ANTAGONISTS
Monoclonal antibody

MOA:
irreversible binds to and
blocks GP IIb/IIIa receptor

Preventing platelet
aggregation

X
Used WITH aspirin and
heparin

Source: D. Golan
Anti Elimn
platelets
Abciximab Route: IV infusion Hepatic
Onset= rapid
t1/2 =10 mins
Duration: 48 hours
ADR: fever, headaches,
thrombocytopenia
T/E: bleeding
 C: FIBRINOLYTIC (THROMBOLYTIC) DRUGS

STREPTOKINASE, ANISTREPLASE
RETEPLASE, TENECTEPLASE

MOA: Increase the conversion of plasminogen to plasmin

Dissolve the clot

Only useful in emergency setting

need to be given with 12 hrs of event to reopen occluded vessels associated with
stroke
RETEPLASE , TENECTEPLASE FIBRINOLYTIC DRUGS
Recombinant tPA has a special affinity
for fibrin-bound plasminogen; potentiates
the conversion plasminogen to plasmin

STREPTOKINASE
Forms SK:Plasminogen complex

This complex converts other

plasminogen, both thrombusbound
and circulating to active plasmin

ANISTREPLASE
Pro-drug: inactive
SK:plasminogen complex
activated in plasma
Fibrinolytics
(removing fibrin formation)
STRETOKINASE
Non-enzymatic protein from
-hemolytic Streptococci Given with hydrocortisone IV
Dependent on plasminogen
availability
NOT SO FOR ANISTREPLASE
1.5 mil units IV; loading dose given
(to overcome plasma antibodies)
t1/2= 40-80 mins
Hepatic metabolism
Duration 12 hrs
ADR= antibody formation =
ANAPHYLAXIS (contra-indicated in
previous use patients)
non-specific activity can result in
systemic fibrinolysis
 REFERENCE

Katzung -11th edition Chapter 34