AZL & YSP

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara

KBK FK USU, Medan

 Blood Composition
• connective tissue with cells suspended in plasma

Plasma (55%) Cellular Elements (45%)

water erythrocytes (red blood cells)
Ions / electrolytes (K+ Ca++) leukocytes (white blood cells)
plasma proteins (Fibrinogen) platelets
transported substances
 How blood clots
• Damage to endothelium (vessels)
• Platelet plug
• Coagulation Factors from
– plasma
– platelets
– and damaged cells
interact and activate a cascade that leads
to…
• Activated Fibrin: fibers woven into a patch

http://www.advanced-supplements.com/neprinol.html
 Blood Coagulation Cascade: Overview
Extrinsic pathway
Intrinsic pathway Xll
When a vessel is injured,
TF (tissue factor, or
Blood disturbances and platelet Xl
phospholipids activate factor XII thromboplastin) is released
lX from the endothelium
to initiate the intrinsic TF
coagulation pathway, which initiating the extrinsic
VII coagulation pathway, which
leads to the activation of VIIIa
(factor leads to the activation of X
X X).
(factor X).
X
Common pathway Va
II (factor II, or prothrombin) is converted by
Factor Xa:
II  Occupies a critical juncture of
factor Xa into factor IIa, or thrombin. the coagulation cascade,
common to both the intrinsic
Thrombin cleaves (factor
I I, or fibrinogen) to I and extrinsic pathways
 An attractive target for
form fibrin (factor Ia), a key component of clot anticoagulation
formation.
Fibrin Clot

Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl1):60-64.

Guyton AC, Hall JE. Hemostasis and blood coagulation. In: Textbook of Medical Physiology. 10th ed. Philadelphia, PA: WB Saunders Co; 2000:419-429.
Moake JL. Hemostasis. In: Porter RS, Kaplan JL, Homeier BP, eds. The Merck Manual Online. http://www.merck.com/mmpe/sec11/ch134/ch134a.html. Accessed March 4, 2008.
Hemostasis is the spontaneous arrest of bleeding
from a damaged blood vessel

phase of vasoconstriction: (TXA2, 5-HT)

platelet phase:
platelet adhesion - platelet aggregation (ADP)- viscous
metamorphosis platelet plug - a white thrombus

phase of coagulation
platelet plug is reinforced by fibrin for long-term
effectiveness a red thrombus

fibrinolysis: conversion of inactive plasminogen to

the proteolytic enzyme- plasmin
 myocardial
anti- infarction
platelet
white
thrombus
stroke
fibrinolytic
thrombosis
deep vein
anti- red thrombosis
coagulant thrombus

pulmonary
embolism
 Thrombosis
• Arterial Thrombosis :
– Adherence of platelets to arterial walls –
– White in color - Often associated with
MI, stroke and ischemia
• Venous Thrombosis :
– Develops in areas of stagnated blood flow
(deep vein thrombosis),
– Red in color- Associated with
Congestive Heart Failure, Cancer,
Surgery.
 Major Clinical Manifestations
of Atherothrombosis
Ischemic Transient ischemic
stroke attack

Myocardial Angina:
infarction • Stable
• Unstable

Peripheral arterial
disease:
• Intermittent claudication
• Rest Pain
• Gangrene
• Necrosis
Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.
 Factors which promote blood fluidity
Normal Hemostasis
Natural anticoagulant
- Protein C
- Protein S
- Antithrombin III
Endothelial-Derived Anti Platelet Substances
- Nitric Oxide
- Prostacyclin (PGI-2)
Fibrinolytic System “ Clot Busters”
- Plasmin
- Plasminogen
- Tissue Plasminogen Activator (tPA)
 When would we not want clots to form??

• Clotting is good at sites of injury because it minimizes blood

loss and prevents infectious agents from getting into our
systems.
• Clotting can be bad when occurs inappropriately in normal
vessels [called thrombus] …clot can break free [called
embolus] and lodge in heart, causing myocardial infarction, or
in brain, causing stroke.
• Thrombosis is caused by abnormalities in blood composition,
vessel wall quality, and/or nature of the blood flow
– Different types of thrombosis:
• Venous [i.e. VTE = venous thromboembolism;
DVT = Deep-vein thrombosis]
• Arterial
Principles Management and Therapy Of
Thrombosis
PATHOGENESIS THERAPY
PROTHROMBOTIC STATE REDUCED OF RISK FACTOR

PLATELET ADHESION
ANTI-PLATELET
PLATELET AGGREGATION ANTI-
THROMBOTIC
BLOOD COAGULATION ANTI-COAGULANT
AGENT
THROMBOSIS THROMBOLYTIC AGENT
 Currently Available
Antithrombotic Drugs
ANTI-PLATELET ANTI- THROMBOLYTIC
AGENTs COAGULANTs AGENTs

ORAL PARENTERAL ORAL PARENTERAL PARENTERAL

Aspirin GPIIb/IIIa Coumarin Heparin Streptokinase

Dipyridamol Antagonists Warfarrin LMWH Urokinase
Ticlopidin Abciximab Melagatran Hirudin tPA
Clopidogrel Tirofiban Argatroban
Cilostazol Eptifibatide Fondaparinox
Sulfinpyrazone
Mechanism of action of antithrombotics
GP IIb/IIIa GP IIb/IIIa
receptors inhibitors

Agonist
Fibrinogen
ADP, TXA2,
Thrombin etc

Resting PLT Activating PLT

Fibrinolytic

Aspirin
Antiplatelet Dipyridamole
Clopidogrel
etc

Inactivated PLT
 Antiplatelets: mechanisms of action
ASPIRIN
Ticlopidine COX-1
Clopidogrel ADP Thrombin TxA2 AA
Adrenaline Collagen

PAF Serotonin

COX-2

Adenosine Prostacyclin
GP IIb/IIIa
AMP Dipyridamole
uptake FIBRINOGEN
GP IIb/IIIa
ADP ANTAGONIST

ATP GP IIb/IIIa PLATELET

 Antiplatelet drugs
 Prevents platelet aggregation /adhesion
 Clinical use - prevents arterial thrombus
– Myocardial infarction (MI), stroke, heart valve
replacement and shunts
 The first antiplatelet is aspirin
 Other antiplatelet drugs are :
– Dipyridamole
– Ticlopidin
– Clopidogrel
– Cilostazol
– Sulfinpyrazone
 Aspirin
 is the standard against which all other
antiplatelet agents are measured
 largely because of its relative safety and
extremely low cost
 cyclooxygenase inhibitor irreversible
– COX-1 in platelet (TXA2 ) by irreversible
acetylation of a specific serine moiety
• thromboxane A 2 , a proaggregatory and
vasoconstrictor substance
• aspirin is 170-fold more potent in inhibiting
COX-1 than COX-2
– COX-2 in vascular endothelial cells (PGI2 )
 Action mechanism of Aspirin
Arachidonic acid

Aspirin Cyclooxygenase(COX)
COX-1 dependent Endoperoxides COX-2 dependent
(PGG2, PGH2)
Thromboxane Prostacyclin
synthetase synthetase

Thromboxane A2 (TXA2) Prostacyclin (PGI2)

• Plt aggregation  • Plt aggregation 

• Vasoconstriction • Vasodilation

Platelet Endothelial cells

 Aspirin
 long lasting inhibition 7 to 10 days
 life span of the platelet 7 to 10 days
 Preliminary results from the International
Stroke trial suggest that aspirin use within
24 hours of stroke onset is associated
with a reduction of recurrent ischemic
stroke from 2.7% to 3.5%.
 Contraindication - DO NOT give to
patients with glucose 6-PO4
dehydrogenase deficiency
 Dipyridamol
 a platelet inhibitor that is thought to work
in part by inhibiting platelet
– cyclic-3',5'-adenosine monophosphate
phosphodiesterase and
– cyclic-3',5'-guanosine monophosphate
phosphodiesterase
• increase concentrations of cAMP in the platelet
– directly enhance prostacyclin-mediated
platelet inhibition and inhibit thromboxane A2
 highly bound to plasma proteins
Lenz T, Wilson A. Clinical pharmacokinetics of antiplatelet agents
used in the secondary prevention of stroke.
Clin Pharmacokinet. 42(10):909-20,2003.
 Cilostazol
selectively inhibit type III phosphodiesterase activity in
platelet
① Inhibition of platelet aggregation
a. intraplatelet cAMP level   inhibit TXA2
production
b. not inhibit prostacycline synthesis
c. inhibiting aggregation induced by ADP, collagen,
epinephrine, or arachidonic acid (10-30 times
more potent than aspirin)
② Arterial vasodilation
③ Inhibition of smooth muscle cell proliferation
④ Improvement of lipid metabolism(TC , TG , LDL ,
HDL )
 inhibit both platelet aggregation and intimal
hyperplasia
 Cilostazol
Inhibition of cAMP-Phosphodiesterase

Increase in cAMP

Inhibition of Phospholipase/Cyclooxygenase
Inhibition of Intracellular Ca Release

Inhibition of TXA2 production Relaxation of contractile protein

Inhibition of platelet aggregation Vasodilatation

Platelet Effect Vascular Smooth Muscle Effect

 Ticlopidine and Clopidogrel
 Thienopyridine derivatives
 Inhibit ADP-induced binding of fibrinogen to platelet
 Pharmacokinetics
– Metabolism by the hepatic cytochrome P450
– Maximal inhibition of platelet aggregation reach after
3-5 days
 Severe neutropenia (<500/㎕)
– Ticlopidine :  1%
– Clopidogrel : 0.05%
– Aspirin : 0.04%
 Coronary artery stenting
– Aspirin (100 mg) + ticlopidine (250 mg bid) for 1
month
– Aspirin (100 mg) + clopidogrel(75 mg qd) for 1-9
month
 Stereoisomer of Antithrombotic
• Anti-platelet CLOPIDOGREL
– Form 1: S-clopidogrel & R-clopidogrel
(50%:50%)
– Form 2: S-clopidogrel (100%)
– R-clopidogrel is inactive and 40 x less well
tolerated
• Anti-coagulant WARFARIN
– a mixture of L- isomer (S- form) and D- isomer
(R-form)
– the former is 5 times more potent than the
latter
Mengapa enantiomers menyebabkan perbedaan
farmakokinetik dan farmakodinamik obat ?
Molekul mengadakan interaksi secara stereo spesifik
receptor, enzim, molekul transporter, molekul antiporter, molekul carrier

S-enantiomer R-enantiomer

R-enantiomer TIDAK boleh lebih dari 1.0 % dalam substansi obat (clopidogrel)
R-enantiomer TIDAK boleh lebih dari 1.0 % dalam produk saat dilepas
 PLAVIX vs. Generic Clopidogrel
Plavix Form 2 Form 1 Generic
(expired 2018) (expired since 1998)
Chirality Single enantiomer Recemic
(98.9% S) (50%S + 50%R)
Polymorphisme Form 2 Form 1
Purity ee = 99.2 % ee = 0 %
Lipophilicity Lipophilic (part.coef >) Hidrophilic
Action Rapid Mixed
Stability Stabil --
Crystal cell unit Well Defined (Orthorombic) Monoclinic
Chiral inversion -- ++
X ray crystallography 1 – 1 paired 2 -- 2 paired
Dosage Form +++ ---
Pharmacology Active Mixed
 Inactive
40 X less well tolerated

R.Petkovsska et al,Maced.Chem.Eng,27 (1),53-64,2008

Abstract
• In this study, 18 copies of PLAVIX tablets containing clopidogrel
hydrogensulfate were compared to the innovator drug product for
uniformity of mass, impurity profile, content, dissolution properties and
stability. In order to be able to separate the perform the assay. The
paddle method was used for dissolution testing.
• Most of the copies were not similar compared to the original drug
product: their amount of impurities was higher, the content of
clopidogrel lower, the dissolution profiles different and after 3 months
under stress conditions in the original packaging, the results for the
samples and the reference were significantly different in most of the
cases.
 . . 61% copies products
mengandung lebih banyak

.. .. senyawa produk yang ter-hydrolysis

67% copies product

.. .. mempunyai R-enantiomer
dengan konsentrasi 4x lebih banyak

.. .. 72% copies product

mempunyai ketidak murnian
4x lebih banyak daripada originalnya

.. ..
.. ..
.......... . . . . ....... .
 Some facts and statistics
• Factors to drug responses:
– Intrinsic factors: age, gender, race/ethnicity, disease
states, organ dysfunctions, and genetics
– Physiological changes: pregnancy, lactation
– Extrinsic factors: smoking, diet, concomitant
medications
• Adverse drug reactions (ADRs):
– Caused 5% of hospitalization
– 59% of drugs causing ADRs are metabolized by
polymorphic enzymes
– Polymorphisms occur in PK and PD are also associated
with interindividual variability in drug response.

Huang SM, Goodsaid F, Rahman A, et el. Toxicology Mechanisms and Methods. 2006;(16) 89-99.
Clopidogrel & CYP-450: inhibitor, inducer & genetic

1A2 3A4 2B6 2C9 2C19

Substrate
36% 1st 19% 1st 45% 1st
40% 2nd 33% 2nd 7% 2nd 20% 2nd
Inhibitor
amiodarone HIV Antivirals: Ticlopidine amiodarone cimetidine
cimetidine amiodarone fluconazole ketoconazole
ciprofloxacin erythromycin lovastatin omeprazole
fluoroquinolones ketoconazole sulfamethoxazol oxcarbazepine
verapamil ticlopidine
Inducer
broccoli HIV Antivirals: phenobarbital rifampin carbamazepine
insulin barbiturates rifampin secobarbital norethindrone
omeprazole carbamazepine
tobacco glucocorticoids
phenytoin
rifampin
Genetic
Chromosome 15 Chromosome 7 Chromosome 19 Chromosome 10 Chromosome 10
N/A N/A Polymorphic Polymorphic Polymorphic
N/A N/A 3-4% Caucasians 1-3% Caucasian PMs 3-5% Caucasian PMs
PMs 15-20% Asian PMs
 PK-PD of Clopidogrel
Inactive Metabolites
COOCH3 Carboxylic acid derivative
(85% of ingested clopidogrel)
N T ½ = 8 jam

S
Cl

S- Clopidogrel P2Y12
G protein
CYP 1A2 O O CH3 Irreversible binding
CYP 2B6 C
CYP2C9
CYP 2C19 N
O
S Cl
Hepatic
Metabolism 2-oxo Compound
O OCH3
CYP 3A4(5)
CYP 2C9
HOOC N
CYP 2C19
CYP 2B6 * HS Cl
Hepatic Active Metabolite
Metabolism S – enantiomer
R.Petkovsska et al,Maced.Chem.Eng,27 (1),53-64,2008 T ½ = 7 – 11 hari
Pharmacogenetic of Clopidogrel
 PK/PD of oral antiplatelets
Parameter Dipyridamole Aspirin Clopidogrel Ticlopidine
T-max (hr) 2 0.5 1 2
Onset of A min. min 2 hours < 4 days
Bioavailability 37-66 90 > 50 80-90
Prot. binding 99% 90% 95% 98%
Half-life 13 (ER) 2-3 8 12.6
St-S of anti-A hr hr 3-7 days 8-11 days
Hepatic no active no active ( + ) active (+) active
metabolism metabolites metabolites metabolites metabolites
Max. aggr. Alone 20% 54% 40-60% (after 3 60-70% (after 8
inhibition (after 3.5 days) (after 3.5 days) to 7 days) to 11 days)
Bleeding (4.7%) Bleeding (8.2%) lower incidence of neutropenia,
ADR thrombocytopenia,
Increase BP ec. neutropenia than elevated liver function
vasoconstriction ticlopidine tests, diarrhea, rash,
elevated serum
cholesterol
 Oral antiplatelet combination
Anti- Dipyri- Clopi- Ticlo-
Aspirin
platelet damole dogrel pidine
- addition
Aspirin synergist, Not
has not been
recommended recommended
established

Dipyri- synergist, - addition addition

damole recommended ??? ???

addition
Clopi- addition - not
has not been
dogrel ??? recommended
established

Ticlo- Not addition Not -

pidine recommended ??? recommended
 Anticoagulant drugs to treat
thromboembolism
Drug Class Prototype Action Effect
Anticoagulant Heparin Inactivation of Prevent venous
Parenteral clotting Thrombosis
Factors
Anticoagulant Warfarin Decrease Prevent venous
Oral synthesis of Thrombosis
Clotting factors
Antiplatelet Aspirin Decrease Prevent arterial
drugs platelet Thrombosis
aggregation
Thrombolytic Streptokinase Fibrinolysis Breakdown of
Drugs thrombin
 Heparin
 Sulphated carbohydrate
 Purified from pork or bovine lungs
 Different size
 Active in vitro and in vivo
 Administration - parenteral-
 Do not inject IM - only IV or deep s.c.
 Half-life 1 - 5 hrs - monitor aPTT
 Adverse effect - hemorrhage - antidote -
protamine sulphate
 Toxicity of heparin - Heparin-induced Platelet
Aggregation
 Heparin mechanism of action
Heparin
Thrombin
Antithrombin III

Heparin
Heparin
 Comparison
Standard
Parameter Heparin
LMWH
Molecular Weight ~15,000 Daltons ~5,000 Daltons
Bioavailability Poor Good
Lab Monitor aPPT None
Route IV or SQ SQ
Bleeding Risk 3+ 2+
Antithrombotic 3+ 4+
Effect
 Oral anticoagulants :
warfarin, dicumarol
 Coumarins - warfarin, dicumarol
 Isolated from clover leaves
 Structurally related to vitamin K
 Inhibits production of active clotting factors
 Absorption rapid - binds to albumin
 Clearance is slow - 36 hrs
 Delayed onset 8 - 12 hrs
 Overdose - reversed by vitamin K infusion
 Can cross placenta - do not use during late
pregnancies
Mechanism of action
Descarboxy
Prothrombin
Prothrombin

Reduced Oxidized
Vitamin K Vitamin K

NAD NADH

Warfarin
Therapeutic range for warfarin in
AF and stroke

a specified international sensitivity index (ISI)

 The variability of warfarin dosage

• age, body size

• genetic polymorphism of :
– CYP2C9 – the enzyme that metabolize S-warfarin
– VKOR (vit. K epoxide reductase) – the target enzyme
for warfarin
 ethnicity (warfarin dose in Asian < Caucasian)
 concurrent disease
 (hepatocellular damage, cardiac disease, pyrexia)
• dietary vitamin K intake
• drug interactions
 Drug interaction - Warfarin
Drugs that Decrease synthesis of Antibiotics (oral)
promote Clotting Factors
bleeding Decrease binding to Aspirin
Albumin Sulfonamide
Inhibition of clotting factors Heparin
antimetabolites
Inhibit metabolizing enzymes Cimetidine,
Disulfiram
Drugs that Induction of metabolizing enzymes Barbiturates
decrease Phenytoin
warfarin Promote clotting factor synthesis Vitamin K
activity OC
Reduced absorption Cholestyramin
Colestipol
 Blood Coagulation Cascade: Overview
Extrinsic pathway
Intrinsic pathway Xll
When a vessel is injured,
TF (tissue factor, or
Blood disturbances and platelet Xl
phospholipids activate factor XII thromboplastin) is released
lX from the endothelium
to initiate the intrinsic TF
coagulation pathway, which initiating the extrinsic
VII coagulation pathway, which
leads to the activation of VIIIa
(factor leads to the activation of X
X X).
(factor X).
X
Common pathway Va
II (factor II, or prothrombin) is converted by
Factor Xa:
II  Occupies a critical juncture of
factor Xa into factor IIa, or thrombin. the coagulation cascade,
common to both the intrinsic
Thrombin cleaves (factor
I I, or fibrinogen) to I and extrinsic pathways
 An attractive target for
form fibrin (factor Ia), a key component of clot anticoagulation
formation.
Fibrin Clot

Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl1):60-64.

Guyton AC, Hall JE. Hemostasis and blood coagulation. In: Textbook of Medical Physiology. 10th ed. Philadelphia, PA: WB Saunders Co; 2000:419-429.
Moake JL. Hemostasis. In: Porter RS, Kaplan JL, Homeier BP, eds. The Merck Manual Online. http://www.merck.com/mmpe/sec11/ch134/ch134a.html. Accessed March 4, 2008.
 New Oral Anticoagulants
Potential Alternatives to Warfarin
Thrombin inhibitors Factor Xa inhibitors
Ximelagatran Rivaroxaban
Dabigatran Apixaban
Edoxaban
Dabigatran Others
Rivaroxaban Apixaban Otomaxiban

2010 2011 2012 2013

 Comparison of Features of New
Anticoagulants with those of Warfarin
Features Warfarin New Agents
Onset Slow Rapid
Dosing Variable Fixed
Food effect Yes No
Drug
Many Few
interactions
Monitoring Yes No
Half-life Long Short
Antidote Yes No
 Why thrombin is an excellent target?

PROTHROMBIN

Resting Platelet

THROMBIN AMPLIFI-
CATION
Active Platelet

Fibrinogen
DTI
Fibrin

CLOT
 ADME Dabigatran
Absorption
• F = 6.5%
• Requires acidic environment
• Peak plasma concentration = 6 hrs
Distribution
• Vd = 0.85 – 1.0 L/kg
• 35% protein bound
Metabolism
• Rapidly and completely converted from pro-drug
(dabigatran etexilate) to active form (dabigatran)
Elimination
• Excreted unchanged in the urine primarily via
glomerular filtration
 Pharmacokinetics of NOACs
Parameter Apixaban Rivaroxaban Dabigatran E
MW (Dalton) 460 436 628
Pro-drug No No Yes
Peak conc. (hour) 3 4 2 (ACIDIC)
Bioavailability (%) 66 > 80 6
Plasma protein
80 95 35
binding (%)
Half-life (hour) 9-14 5-9 (young) 12-17
11-13 (elderly)
Renal (66%);
Elimination Renal (25%) Renal (85%)
half is inactive
Transporters P-gp P-gp/BCRP P-gp
Involvement of CYP CYP3A4 (15%) CYP3A4 (32%) No
Laboratory Dil. Prothrombin Prothrombin Thrombin
monitoring Time Time time

Thromb Haemost 2010; 103: 34-39; Thromb Haemost 2010;103: 572-585

 Pharmacodynamics of NOACs
Parameter Apixaban Rivaroxaban Dabigatran
MoA FXa inhibitor Fxa inhibitor Thrombin inhibitor
Dosing ARISTOTLE ROCKET-AF RE-LY
Dosing BID all indication OD (VTEp, VTEL, OD (VTEp)
(VTEp,VTEL, AF) BID (VTEL, AF)
AF,ACS) BID (ACS)
5.0 (2.5) 20 (15) 150, 110
Linear PK Yes No Yes
Drug interaction Strong CYP3A4 Strong CYP3A4 P-gp inhibitors
and P-gp and P-gp (Amiodaron) and
inhibitors and inhibitors inducers
inducers Strong CYP3A4 (Verapamil)
inducers PPI decrease
absorption
Intersubject ? 35% 30%
variability
Hot Topics in Cardiology 2010;4:7-14; Clin Pharmacokinet 2009;48:1-22;
Thromb Haemost 2010; 103: 34-39; Thromb Haemost 2010;103: 572-585
 Fibrinolysis
 Enhance degradation of clots
 Activation of endogenous protease
 Plasminogen (inactive form) is converted to
Plasmin (active form)
 Plasmin breaks down fibrin clots
 Fibrinolysis
 Exogenously administered drugs
– Streptokinase - bacterial product - continuous use -
immune reaction
– Urokinase - human tissue derived - no immune response
– Tissue plasminogen activator (tPA) - genetically cloned -
no immune reaction - EXPENSIVE

 Inhibitors of fibrinolysis - aminocaproic acid

– Lysine analog- inhibits proteases
 Other preparations to lyse clots

 Alteplase recombinant (tPA, Activase)

– 20, 50 mg Lyophilized powder - reconstitute for
iv
 Streptokinase (Kabikinase, streptase)
– Parenteral : 250000 - 1.5 million units per vial.
Lyophilized powder. Reconstitute for iv
 Urokinase ( Abbokinase)
– Parenteral : 250000 units per vial. Powder to
reconstitute to 5000 u/ml for injection
 Drug preparations clotting deficiencies

 Vitamin K ( Phytonadione (K1), Mephyton

– Oral : 5 mg tablets
 Plasma fractions - for hemophilia
– Antihemophilic factor ( VIII, AHF)
– Parenteral
 Factor IX complex (konyne HT, proplex T)
– Parenteral : in vials
 Due to HIV risks in blood products recombinant
proteins of the factors are made
– E.g. transgenic goats secreting factors into milk
 FIBRINOLYTICS
Plasminogen
Activation Inhibition
Various stimuli
+
Blood Blood
+ -
aminocaproic acid
proactivator activator
Antiactivators
urokinase + -
Streptokinase
Activator + aprotinin
Tissue proactivator
Plasmin - Antiplasmins
t-PA Anistreplase
+
+
Thrombin
Degradation Fibrin split
Fibrinogen Fibrin products
products
 Drug preparations clotting
deficiencies
 Vitamin K ( Phytonadione (K1), Mephyton
– Oral : 5 mg tablets
 Plasma fractions - for hemophilia
– Antihemophilic factor ( VIII, AHF)
– Parenteral
 Factor IX complex (konyne HT, proplex T)
– Parenteral : in vials
 Due to HIV risks in blood products recombinant
proteins of the factors are made
– E.g. transgenic goats secreting factors into milk
 Coagulant
Drug preparations to stop bleeding
Systemic use :
 Aminocaproic acid (Amicar);
 Tranexamic acid (cyclokapron),
 Vitamin K
Local adsorbable drugs
 Gelatin sponge (Gelfoam)
 Gelatin film
 Oxidized cellulose ( Oxycel)
 Microfibrillar collagen (Avitene)
 Thrombin
 The reality ….
Arachidonic
Pro-drug acid

CYP COX
Active
metabolite
POLYMORPHISM
Tx

Platelet
Dose etc
Co-
prescription
Co-morbid

Effect