BASIC PHARMACOLOGY DRUGS on

HEMATOLOGY SYSTEM

dr. Putu Nita Cahyawati, MSc

Department of Pharmacology and Pharmacy, Faculty of Medicine and

Health Sciences, Warmadewa University
 TOPICS

FIBRINOLYTIC
ANTICOAGULANT ANTIPLATELET
(TROMBOLIYIC)

Inhibitors of
ANTINEOPLASTIC
Anticoagulation ANTIANEMIC
DRUGS
and Fibrinolysis
Introduction: The hemostatic process
ANTICOAGULANT DRUGS

Indirect Trombin Inhibitors

Direct Trombin Inhibitors

Oral direct factor XA inhibitors

Warfarin & other coumarin anticoagulants

 Indirect Trombin Inhibitors
• Their antithrombotic effect is exerted by their interaction with a separate protein,
antithrombin enhance its inactivation of factor Xa
• e.g., Unfractionated heparin (UFH)/high molecular-weight heparin (HMW), low
molecular-weight heparin (LWH) =enoxaparin,and the synthetic pentasaccharide
fondaparinux
• I: tromboembolic ds (DVT, pulmonary embolism)
• SEbleeding (Close monitoring of the activated partial thromboplastin time (aPTT or
PTT) esspecialy on UFH, vs LMH higher therapeutic index than UFH
• Elimination: kydneys
Direct Trombin Inhibitors
• their anticoagulant effect by
directly binding to the active
site of thrombininhibiting
thrombin’s downstream effects.
• Route: oral (dabigatran
etexilate mesylate) and
parenteral
(lepirudin,bivalirudin,
argatroban)
• I: tromboembolic ds (DVT)
• Elimination: kydneys (except
argatroban, via billiary
secretionsave on renal
insulficiency patient)
Oral direct factor XA inhibitors
• inhibit factor Xa, in the final
common pathway of
clotting
• e.g., rivaroxaban and
apixaban
• Given as fixed doses and do
not require monitoring.
• They have a rapid onset of
action and shorter half-lives
than warfarin
• Elimination: kydneys
Warfarin & other coumarin
anticoagulants
• Warfarin acts on the carboxylation
pathway, not by inhibiting the
carboxylase directly, but by
blocking the epoxide reductase
(VKORC1 ) that converts the
inactive vitamin K 2,3-epoxide into
the active form
• Vitamin K is required for the
normal hepatic synthesis of four
coagulation factors (II, VII, IX, and
X), protein C, and protein S.
• Oral :100 bioavailbility (99% bound
w/protein plasmalong
elimination half life (36h))
• Narrow therapeutic indexclosed
monitoring PT/INR
• Numerous drugs
interactionmetabolized by P450
enzyme)
• CI:pregnant women
FIBRINOLYTIC (TROMBOLIYIC)
DRUGS
• E.g., streptokinase, urokinase, anistreplase
(discontinued), t-PA (alteplase, tenecteplase, reteplase)
• Thrombolytic agents are used to lyse already-formed
clots, and thereby to restore the patency of an
obstructed vessel before distal tissue necrosis occurs.
• Thrombolytic agents act by converting the inactive
zymogen plasminogen to the active protease plasmin
• Plasmin is a relatively nonspecific protease that digests
fibrin to fibrin degradation products.
• Unfortunately, thrombolytic therapy has the potential to
dissolve not only pathologic thrombi, but also
physiologically appropriate fibrin clots that have formed
in response to vascular injury (systemic fibrinolysis).
• Thus, the use of thrombolytic agents can lead to
hemorrhage of varying severity
• I: pulmonary embolism with hemodynamic instability,
severe deep venous thrombosis, ascending
thrombophlebitis, acute myocardial infarction
• CI: recent hemoragic stroke
ANTIPLATELET DRUGS

COX Inhibitors

GPIIb/IIIa Antagonist

Phospodiesterase inhibitors

ADP receptor pathway inhibitor

COX INHIBITOR
• E.g., Aspirin
• Aspirininhibit COXinhibits
syntesis of prostaglandin
• In platelet cyclic endoperoxide
(PPG2) is convert to
TxA2vasocontrictor +pletelet
agregation
• Platelet do not contain
DNA/RNAcan’t regenerate new
COX enzymepermanently
inactivated cell (7-10d)
• In endotelial cells (not permanently
activated) cyclic endoperoxide is
convert to PGI2
vasodilatasi+inhibit platelet
agregation
• Antipletelet effect at low dose (81mg
once daily)

GPIIb/IIIa Antagonist
• E.g.,abciximab, eptifibatide,
tirofiban
• GPIIb–IIIa antagonists
inhibit platelet aggregation
by preventing activation of
GpIIb–IIIa leading to
decreased platelet cross-
linking by fibrinogen.
Phospodiesterase
inhibitors
• E.g., Dipyridamole
• Inhibits phosphodiesterase
(PDE)preventing the
breakdown of cAMP and ↑
cytoplasmic cAMP
decrease platelet
agregation (not well
understood)
• Weak antiplatelet effectin
combination w/warfarin or
aspirin
ADP receptor pathway
inhibitor
• E.g., ticlopidine,
clopidogrel, prasugrel
(prodrug)
• antagonists of the
P2Y(ADP) receptor
• In combination w/
aspirin
• Require loding dose to
achieve max antiplatelet
effect
Inhibitors of Anticoagulation and
Fibrinolysis
1. Protamine (antagonist of heparin)
– Protamine is administered iv to reverse the effects
of heparin in situations of life-threatening
hemorrhage or great heparin excess (ex: coronary
artery bypass graft surgery)
2. Serine-Protease Inhibitors (inhibitor of the
serine proteases plasmin, t-PA, and
thrombin) eg., Aprotinin
– By inhibiting fibrinolysis, aprotinin promotes clot
stabilization.
– Inhibition of thrombin may also promote platelet
activity by preventing platelet hyperstimulation.
3. Lysine Analogues (bind to and inhibit
plasminogen and plasmin) eg.,
Aminocaproic acid and tranexamic acid
– used to reduce perioperative bleeding during
coronary artery bypass grafting
 ANTIANEMICS DRUGS

Iron Absorption, transport, storage and eliminatin of iron

• For hemoglobin syntesis

• Oral : mucosal block,
how long? SE: >nausea
• Parenteral: when?
Toxicity: acute (tx/ whole
bowel irrigation,
deferoxamine) chonic
(tx/phlebotomy in
absence anemia,
deferoxamine less
efficient)

divalent metal transporter 1 (DMT1) , heme carrier protein 1 (HCP1), FO (ferroxidase),

ferroportin (FP), apoferritin (AF), ferritin (F).
Elimination
There is no mechanism for excretion of iron. Small amounts are lost in the feces by
exfoliation of intestinal mucosal cells, and
trace amounts are excreted in bile, urine, and sweat.
 ANTIANEMICS DRUGS
Vit B12 (cobalamin) Folic acid

• For DNA syntesis • For DNA syntesis

• Oral: requires • Pregnant women
intrinsic factor (300-400mcg/d,
• Parenteral : no report normal 50-200mcg/d)
for toxicity • Body store low, daily
• Ex: hydroxycobalamin requirement high
and cyanocobalamin deficiency develop 1-
(100-1000mcg/day 6m after intake stop
im for 1-2 w  • Absorbedproximal
maintenance 1 inj/m) jejunum

• Methylfolate trap
• Deficiency cause
accumulation of
homocysteine
deoxyuridine monophosphate
(dUMP)
deoxythymidine
monophosphate (dTMP)
Antineoplastic drug classes
 THE PLATINUM DRUGS
• They kill cells in a similar way with alkylating agentsCross-linking of DNA
cytotoxic action
• Targeting nucleophilic center in guanine (N-7 and O-6), adenine (N-1 and N-3),
cytosine (N-3)
• Alkylation of guanine can result in miscoding through abnormal base pairing with
thymine or in depurination by excision of guanine residues.
• These drugs could be used at the maximum-tolerated dose
• cisplatin, carboplatin, and oxalaplatin
 THANK YOU
Refferences:
1. Golan, DE., Tashjian, AH., Armstrong, EJ., Armstrong, AW. 2012. Principles of
Pharmacology : The Pathophysiologic Basis of Drug Therapy 3rd ed. Lippincott
Williams & Wilkins.
2. Katzung, BG., Masters, SB., Trevor, AJ. 2012. Basic & Clinical Pharmacology
12nd ed. The McGraw-Hill