PHARMACY BOARD EXAM REVIEW

Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

DRUGS FOR COAGULATION DISORDERS

Line of thinking: “Ang susuko, talo!”

Thrombosis –process of formation of clot (thrombus)

Physiology of Clot formation

a.) Vascular events - involves transient vasoconstriction  vasodilation to allow entrt of cellular /CHON
components

b.) Cellular and CHON events

2 Simultaneous events:
a. Platelet migration and aggregation
b. Activation of coagulation cascade

Stimuli for thrombosis

 Endothelial injury

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

 Presence of foreign body in bv/blood (IV catheters if not supplies with anti-
coagulants, blood will clot here)
 Stasis of blood (blood stays in one place for a long time)

 Platelet migration and aggregation

 Involves factors:
 Pro-aggregants factors - TXA2, ADP , 5HT [all are platelet products -
produced by platelets]
 Antiaggregants - PGI2, PGE1, cAMP [all are endothelial products] 
kaya pag nagkasugat masisira endothelium, bababa levels ng
antiaggregants dahil less production
** so in a normal state, walang favored sa dalawa

 Involves 2 type of receptors:

 Glycoprotein IIb / IIIa  impt in binding platelets to one another
 Glycoprotein Ia / Ib impt in binding platelets on to the endothelial
surface fibrinogen  bridge protein ; Von willebrand factor  will
make platelet stick to receptor on endothelial surface ; there is
interaction from receptor of platelets to site of injury
** Product of platelet aggregation = primary hemostasis = white thrombus
= platelet plug/clot
Feature of platelet clot: temporary clot (simply to further prevent any
further blood loss) but will deaggregate some time after

 Coagulation cascade
 Involves clotting factors (factor 1-13)
 Initially released as zymogens (inactive) and then activated
 Occurs simultaneous with platelet event

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

 Involves two pathways:

Extrinsic Intrinsic
Will converge both to final common pathway: Factor X factor VIIa, VIIIa,
V  Factor Xa
Factor II (prothrombin) F. Xa-  F. IIa (thrombin)
Factor I (fibrinogen) F. IIa  F. Ia (Fibrin - this is the end product
of the cascade)
 Role of Fibrin
 Deposit onto platelet plug and glues platelets together (fibrin is a
sticky mole.)
 Attracts other cells esp. RBC to deposit onto the platelet plug ---> red
thrombus / secondary hemostasis [stable / permanent blood clot]
**NOTE: it takes about 6-12 hrs from time of injury to time of
stabilization of clot (formation of stable / permanent clot) --->
implication in therapy
 Regulatory mechanisms:
 Presence of anti-thrombin (endogenous anti-coagulants) - primarily
inhibit factor IIa
 Protein C and S = endogenous anticoagulants similar to
antithrombin
 Plasmin = serine protease (breaks down CHON / causes proteolysis
at serine aa site)
Plasminogen ---tPA (tissue plasminogen activator) --->
plasmin
Plasmin acts on fibrin and fibrinogen and break them
apart into fibrin split products (FPS) / break fibirinogen
into fibrinogen degradation products (FDP)

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

I. Antithrombotic
A. Anticoagulants C. Fibrinolytics
1) Direct Thrombin Inhibitors 1) Streptokinase (Streplase)
a) Hirudin / Lepirudin 2) APSAC –Anisoylated
b) Bivalirudin Plasminogen-Streptokinase
c) Argatroban, Melagatran Activator Complex
d) Dabigatran (Pradaxa) (Eminase)
3) T-PA (Tissue Plasminogen
2) Indirect Thrombin Inhibitors Activator)
a) Heparin a) Alteplase (Activase)
b) Oral anticoagulants b) Reteplase (Retavase)
i) Historical drugs c) Tenecteplase (TNKase)
4) Urokinase (Abbokinase)
a. Dicoumarol
b. Indanediones II. Prothrombotics
c. Phenprocoumon A) Vitamin K
B) Fibrinolytic Inhibitor
ii) Warfarin a) E-Aminocaproic acid
(Coumadin) b) Tranexamic acid
B. Antiplatelet C) Serine Protease Inhibitor:
1) Thromboxane Synthesis Aprotinin
Inhibitor: Aspirin

2) ADP Inhibitors
a) Ticlodipine (Ticlid)
b) Clopidogrel (Plavix)
c) Prasugrel (Effient)

3) Phosphodiesterase
Inhibitors
a) Dypiridamole
(Persantine)
b) Cilostazol (Pletal)

4) Glycoprotein IIb/IIIa
Inhibitors
a) Abciximab (ReoPro)
b) Eptifibatide (Integrilin)
c) Tirofiban

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

I. Antithrombotic 2) Indirect Thrombin Inhibitors

-prevent clot formation -affects conc
-promote bleeding
a) Heparin
A. Anticoagulants
-affects the coagulation cascade / CFs -heterogenous mixture of sulphated
mucopolysaccharides, hence anionic
1) Direct Thrombin Inhibitors antidote: Protamine Sulfate
a) Hirudin (natural) 2 Types of Heparin
-from medicinal leaches (Hiridus i) Regular / Unfractionated (UFH) /
medicinalis) High MW Heparin (MW: 5,000-
30,000)
Lepirudin (recombinant form)
-(yeast or bacteria for production) MOA: activates antithrombin III which
INACTIVATES thrombin (factor IIa) and other
Use: Mx of thrombosis related with HITT active clotting factors (CF IXa, Xa, Xia, XIIIa)
(Heparin Induced Thrombosis and inhibition of the intrinsic pathway >Lab test:
Thrombocytopenia ) apt
b) Bivalirudin Routes: IV (preffered) or SQ
MOA: directly inhibits Factor IIa (Thrombin) Dosing: IV bolus (IV push –one big shoot)
and IV infusion (mix with diluents or
Use: given to prevent thrombosis post-PTCA
NSS)
(Percutaneous Transdermal Coronary
Angioplasty) Indication Dose
Venous 80U/kg bolus,
Recall: Virchow’s Triad of thrombus formation
thromboembolism Ro 18 U/kg/H
(SHE)
ACS (Acute Coronary 60 to 70 U/kg,
Stasis of the blood Syndrome) – heart Ro 12 to 15
attack U/kg/h
Hypercoagulability -Monitoring of Effect: aPTT (Goal: 60-85
secs delay using Dade-Actin FS reagent)
Endothelial injury
ii) Low MW/Fractionated Heparin
c) Argatroban, Melagatran
Enoxaparin (Clexane) (Lovenox)
Use: tx of HITT Fraxiparin
Dalteparin
d) Dabigatran (Pradaxa)
Tinzaparin (Innohep)
Use: prophylaxis of VTE following hip and knee Fondaparinux (Arixtra)
surgery Danaparoid

` MOA: specifically inactivates Factor Xa

by forming complex with antithrombin III

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

Route: SQ needed during pregnancy because

it does not cross the placenta
Dosing: depends on specific drugs-
6) APAS (antiphospholipid antibody
Enoxaparin (Clexane) (Lovenox) or Nadroparin:
syndrome) Give IV heparin
0.6 to 1.0 IU/ml BID

Monitoring: Not necessary unless there

is bleeding Side effects of Heparin
1) Bleeding or haemorrhage in the
HIGH MW LOW MW brain  antidote: Protamin
heparin heparin
sulphate
MOA Activates Activates
2) Heparin-induced thrombosis and
antithrombin antithrombin
thrombocytopenia
and and
Inhibits CFs Inhibits Xa
IXa, Xa, X1a, Why?
XIIIa (Intrinsic Development of IgG antibodies
pathway) (allergy) vs Heparin bound to
S/E More prone Less bleeding platelet factor 4 (PF4) antibody-
to bleeding heparin-PF4-complex activates
Monitoring Monitors No need to platelets thrombosis then
closely with monitor thrombocytopenia
aPTT unless there
is bleeding 3) Alopecia
Preparation Vial Pre-filled 4) Osteoporis chronic use
syringes
Route IV SQ Contraindications:
Ex: Regular Enoxaparin
1) Severe bleeding Menstruation
heparin (Clexane)
(Lovenox), NOT included
Fraxiparin, 2) Thrombocytopenia
Dalteparin 3) Severe Hypertension
Clinical uses of Heparin
b) Oral anticoagulants
1) When initiating anti-coagulant i) Historical drugs
therapy
2) Mx of Acute Coronary Syndrome a. Dicoumarol aka Bishydroxycoumarin
(ACS) Acute MI, Ustable Angina
-from spoiled sweet clover (Melilotus
Preferred: Low MW Heparin
officinalis)
3) Tx (IV) and prevention (IV, SQ) of
pulmonary embolism -before: potent anticoagulant
DVT Heart Lungs
-current use: rodenticide (Racumin)
4) Mx of DVT stock in pulmonary
embolism (Risk factor: Prolonged b. Indanediones (Anisidone;Phenindion)
Immobilization)
5) High MW or Regular Heparin is the -SE: thrombocytopenia, hypersensitivity
DOC when anticoagulation is c. Phenprocoumon long half life

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

ii) Warfarin (Coumarin) -prosthetic heart valves

-the ONLY ORAL anticoagulant -Rheumatic heart disease

(S: active form) (autoimmune diseaseStreptococcus
pyogenes)
MOA:
Side effects of Warfarin
1) inhibits VKOR (Vitamin K Epoxide
Reductase) hence caanot form Vit K 1) Bleeding (antidote: Vitamin K, FFP
hydroquinone which results to the (Fresh Frozen Plasma)
inhibition of CFs X, IX, VII and II (1972) 2) Cutaneous necrosis within 1st week of tx
if NOT combined with heparin
2) Inhibits Protein C and S vitamin K-
3) Purple toe syndrome
dependent activation
4) Necrotizing enterocolitis
-Onset of anticoagulant effect: 5) Teratogenic Complications in
(dependent on the haf life of pre- Pregnancy
formed factors) a. Abnormal bone formation
within 1st trimester
Factors Half life b. Haemorrhagic disease of the
Pro-clotting (1972) 6-60 hours new born within 3rd trimester
Anticlotting (Protein C,S) 6-24 hours
 Hence, warfarin is a Drug interactions:
PROCOAGULANT within the first few
-Warfarin is always the OBJECT drug
days of use
o Remedy: Co-administer with •INCREASE PT-INR
Heparin
Pharmacokinetics
Monitoring (more on EXTRINSIC pathway):
Enzyme INHIBITORS -MEDVICK GA
Prothrombin time / international normalized
ratio (PT-INR) Pharmacodynamics

PTPx / PTcontrol Aspirin, Heparin, Chronic liver disease

•DECREASE PT-INR
Normal 1
Most Pxs in Warfarin 2-3 Pharmacokinetics
therapy
Px with prosthetic 2.5-3.5 Enzyme INDUCERS -GO PRCS
heart valves
Cholestyramine

Pharmacodynamics
Clinical use:
Consumption Vit K rich food and
For chronic anticoagulation
Hypothyroidism
-DVT prophylaxis

-prevention of thromboembolism

-cardiac thrombus

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

Heparin Warfarin B. Anti-platelets

Structure Large, anionic Small, -inhibitors of platelet aggregation;
acidic polymer nonpolar (lipid blocks pro-aggregants
(polar) soluble)
Route Parenteral PO 1) Thromboxane Synthesis Inhibitor:
IV: HMWH Aspirin (<325 mg/day)
SC: LMWH
Site of Blood Liver CFs MOA:
action
-Irreversible acetylation of COX at
Onset of Rapid Slow,
action (seconds) dependent of platelets
the half life of Use:
preformed
Clotting -1st line in primary and secondary
factors (1972) prophylaxis of acute thrombotic event
MOA Activates Inhibits VKOR
Antithrombin Note: antiplatelet effects of aspirin lasts for
Inhibits CFs 1 week  give Platelet Concentrate
Regular: 10, 9, 7, 2
2) ADP Inhibitors
Inhibits CFs
a) Ticlopidine (Ticlid)
9,10,11,13
AE:
LMWH: Inhibits
CF 10 -Nuetropenia Increase risk for
Duration of Acute (H) Chronic (days) infection
action
-Thrombotic thrombocytopenic purpura
Inhibit YES NO
coagulation b) Clopidogrel (Plavix)
in vitro
Treatment Protamine Vit K -replaced Ticlopidine because it has
od acute FFP better safety profile
over dose
Monitoring apTT PT-INR Use:
Crosses the NO YES -Acute Coronary Syndrome: given with
placenta Teratogenic Aspirin (ASA) for a no of months then
combined with clopidogrel
INSIDE THE APARTMENT W/ HARRY POTTER

(Intrinsic aPTT Heparin Protamine)

(Extrinsic PT-INR Warfarin Vit K)

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

-prevent thrombosis in PTCA

3) Phosphodiesterase inhibitors
A) Fibrinolytics
-thrombolytics
Clinical uses:
1) Mx of massive ppulmonary edema
2) Central deep vein thrombosis
3) Mx of acute MI
Inclusion criteria:
a) Heart attack must be STEMI (ST-
elevated Myocardial Infarction)
b) Acute MI must nvolve the
Increase cAMP anti-aggregant:
anterior wall (left ventricular
vasodilator
AMI)
c) Duration of MI must be <12
Use: Antiplatelet aggregant but useful
Hours
only in combination with other
antiplatelets
Acute Coronary Syndrome
a) Dipyridamole (Persantine)
Unstable
AE: Angina
Non-ST
elevation
-Coronary steal phenomenon Non-STEMI
ECG
Application: ST
STEMI
Elevation
-Diagnostic agent for pharmacologc
stress test

b) Cilostazol (Pletaal)
ACS Description Tx
Use: STEMI Classical MI Fibrinolytics
are beneficial
-vasodilator in the Mx of intermittent Occlusive
claudication (constriction of blood thrombus 
vessels secondary to cold) complete block
Non Non occlusive Firbrinolytics
4) Glycoprotein IIb/IIIa inhibitor
STEMI thrombus  are not
a) Abciximab (Reopro)
Partial block recommended
b) Eptifibatide (Integrilin) because there
c) Tirofiban is an increase
MOA: risk of
complication
-blocks receptors necessary for Unstable Non-occlusive, no
interpolate binding angina elevation of
cardiac biomarkes
Use: (Troponin)

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

*Use biomarkers such as Troponin to classify

whether the Non-STEMI or Unstable Angina

Absolute contraindication:

-presence of active bleeding

-visceral CA

-PUD

-Pregnancy
Advantage of t-PA:
-Recent surgery
-less chances of allergy and this can be given
-Ischemic stroke several times (for severe episodes of AMI)

-Hemorrhagic stroke Disadvantage of t-PA:

-requires co-administration of heparn

increase risk of bleeding
1) Streptokinase (Streplase)
Forms of t-PA:
-protein derived from B-hemolytic streptococci
a) Alteplase (Activase)
AE:
-recombinant human t-PA
-Hypersensitivity reactions
b) Reteplase (Retavase)
•Remedy: Pre-medicate with IV
Diphenhydramine (Benadryl) -recombinant t-PA with deletions in the
amino acid sequence
Caution:
c) Tenecteplase (TNKase)
-Do not give the same Px another
dose of streptokinase for the next 2 -more specific mutant form of t-PA
years

2) APSAC –Anisoylated Plasminogen-

4) Urokinase (Abbokinase)
Streptokinase Activator Complex (Eminase)
-synthesize by the kidneys
-more selective to plasminogen but
associated with blood clot

3) T-PA (Tissue Plasminogen Activator)

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.
 PHARMACY BOARD EXAM REVIEW
Pharmacology (Pharmacotherapeutics) by: Jerico Isaiah S. Dumbrique, BSIP

II. Prothrombotics
-promote clotting; prevent bleeding

A) Vitamin K

Vit K1 - phytonadione (most useful clinically - ito

lahat sa market)
- from green leafy vegetables, cruciferous
vegetables (richest sources: cauliflower, brussel
sprout, brocolli)

Vit K2 - menaquinone - produced by the Normal

flora (normal bacteria in intestines)

Vit K3 - menadione - not clinically impt.

Uses:
1) Prophylaxis against hemorrhagic
disorder of newborn (IM of vit K in all
newborns)
2) Mx. Of bleeding assoc. with all vit. K
deficiency states (e.g. Warfarin use)

A) Epsilon aminocaproic acid

Analogue: Tranexamic acid (Hemostan)

MOA: Prevents the conversion of

plasminogen to plasmin

Uses:
1. Minimize post-surgical /
post-dental procedure
bleeding
2. May reduce the severity
of hemarthroses [when
they have a minor
accident  blood can
accumulate inside their
joints] among
haemophiliacs

*Haemophilia A –CF8
Haemophilia B –CF9

This review material was prepared and developed by Jerico Isaiah S. Dumbrique, BS Industrial Pharmacy.