Drugs used in clotting disorders:

Anticlotting Drugs
o Anticoagulants:
Indirect thrombin inhibitors:
Heparins
One-third of heparin molecules contain a unique
pentasaccharide sequence with high-affinity binding to
antithrombin (ATIII). The interaction of heparin with
ATIII produces conformational change in ATIII, which
accelerates its ability to inactivate thrombin (factor
IIa), factor Xa, and factor IXa. Thrombin is most
sensitive to inhibition by the heparin/antithrombin
complex. The inactivation of factor Xa does not require
the heparin/antithrombin complex formation and occurs via
binding of ATIII to factor Xa. Heparin > 18
monosaccharides to bind to thrombin and ATIII
simultaneously. Low molecular weight heparin, as
exemplified by enoxaparin, dalteparin, tinzaparin,
nadroparin, differs from heparin is being unable to
accelerate the inactivation of thrombin by
antithrombin, but it retains the ability to catalyze the
inhibition of factor Xa by antithrombin. Lower MW
coincides with less risk of major bleeding.
o Heparin: 2 hour normally, and variable effects
in comparison to LMWH, which is 4 hours and
more predictable.
MOA: By inactivating thrombin, heparin not only prevents
fibrin formation but also inhibits thrombin-induced
activation of platelets and factors V and VIII. LMWH
catalyzes inhibition of factor Xa by ATIII. This has a lesser
effect upon PTT value. Since LMWH inhibits only factor Xa,
it has a lower impact upon the PTT test than does heparin,
which acts at several points in the intrinsic pathway. LMWH
dosing may be monitored using the factor Xa assay, a
chromogenic test
Factors affecting drug effectiveness :
o Heparin is depolymerized & desulfated to
inactive products
o Longer T with hepatic cirrhosis
o Metabolites and some parental drug eliminated
renally
o Renal insufficiency increases T

Contraindications and Side Effects: chief complaint of

heparin therapy is bleeding; heparin obtained from animal
sources, may be antigenic and produce chills, fever,
urticaria, and anaphylactic shock; Thormbocytopenia
 (30%) is common in hospitalized patients. An
autoantibody against a drug:platelet factor IIII
complex is released from alpha granules; the immune
response activates platelets, commonly causing
thrombocytopenia and, in some patients, life-threatening
venous and/or arterial thrombosis. With long-term
treatment, abnormal liver function tests and
osteoporosis.

Monitoring Dosing: using a PTT test, goal is 1.5-2.5x mean

normal value, Test at 6 hours during first day of therapy
and 6 hours after dose change. Prolonged PTT does not
occur with LMWH. If a PTT value is too high, slow infusion
rate or discontinue. Short half-life means drug levels
decline rapidly. In extreme circumstances, protamine
sulfate or whole blood/plasma may be given to block
heparins action.
Antidote: Protamine Sulfate
Strongly basic compound, forms complexes with heparin (Na or Ca),
which are acidic compounds. Fish hypersensitivity. Formation of
complex can result in disruption of heparin-ATIII complex responsible
for the anticoagulant activity of heparin; Protamine;heparin doesnt
have anticoagulant properties. Administered via IV infusion, 2 hours of
activity (avoid excess protamine; also has anticoagulant effext),
incompletely neutralizes enoxaparin (LMW heparin), but does not
reverse activity of fondaparinux. Protamine used for heparin overdose
and to neutralize heparin during extracorporeal circulation following
dialysis, arterial, or cardiac surgery. Rapid administration associated
with NO release from endothelium leading to decreased SVR and
increased pulmonary artery pressure. Can use morhine or meperidine,
diphenhydramine, saline administration in support of low BP.
Direct thrombin inhibitors:
Dabigatran
Bivalirudin
Antidote: Idarucizumab
Direct factor Xa inhibitors
Enoxaparin
Apixaban
Rivaroxaban
Fondaparinux
Inhibitors of clotting factor synthesis:
Warfarin
Now lets move on to talk about the other major
anticoagulant, warfarin. This is manufactured as a mixture
of R- and S-enantiomers. The S-enantiomer is the more
potent compound. S-warfarin is metabolized primarily by
the cytochrome p450 2C9 (CYP2C9) enzyme. (Immediately
you should be thinking of the possibility of drug-drug
interactions involving CYP activity.) R-warfarin has
redundant metabolism by other cytochrome P450
 enzymes.

Warfarin inhibits the hepatic synthesis of vitamin K-

dependent coagulation factors II, VII, IX, and X and
anticoagulant proteins C and S. Specifically, warfarin
inhibits the C1 subunit of the vitamin K epoxide reductase
(VKORC1) enzyme, which reduces the regeneration of
vitamin K epoxide. Vitamin K is a cofactor for the
carboxylation of glutamate residues to gamma-
carboxyglutamates on the N-terminal regions of vitamin K-
dependent proteins. Carboxylation allows the coagulation
proteins to undergo a conformational change, which is
necessary for their activation.The degree of effect on the
vitamin K-dependent proteins is dependent upon the dose
of warfarin and, to some extent, the patient's VKORC1
genotype. The speed of inhibition of the individual
cofactors reflects their relative half-lives; those with a
shorter half-life are depleted most rapidly.

Warfarin prolongs the prothrombin time (PT), which is

responsive to depression of three of the four vitamin K-
dependent coagulation factors (factors II, VII, and X).
During the first 25 days of warfarin therapy, the PT
primarily reflects the depression of factor VII. With
subsequent warfarin treatment, the PT is prolonged by
depression of factors II and X. Therapeutic doses of
warfarin decrease the total amount of active vitamin K-
dependent clotting factors produced by the liver by 30
50%.
Antidote: Prothrombin complex, Phytoadione
o Thrombolytics:
T-PA derivatives
Aminocaproic acid, Tranexamic acid
o Antiplatelet drugs:
Contraindications for Platelet Inhibitors:
PMH including active pathological bleeding (GI, and intracranial,
retinal, and retroperitoneal); Patients who may be at risk of
increased bleeding from trauma, surgery, or other pathological
conditions (especially GI or intraocular); If a patient is to undergo
elective surgery and an antiplatelet effect is not desired, drugs
should be discontinued a sufficient period of time before surgery to
permit effects to dissipate. This interval varies depending upon the
persistence of the antiplatelet action of the individual drugs and
drug classes.

COX inhibitors:
Difference between aspirin, which irreversibly
acetylates the cyclooxygenase, thereby rendering it
inactive for the life of the platelet, and the reversible
effects produced by non-salicylate drugs such as
ibuprofen.

The relative platelet specificity of the aspirin is based

upon the inability for the platelet to recover functionality,
thereby reducing the production of pro-aggregatory
thromboxane A2 (TXA2), versus the ability of
endothelial cells to regenerate cyclooxygenase and
thereby continue to release PGI2, which is itself
inhibitory of platelet activation. TXA2 is particularly
sensitive to aspirin, such that very low doses will
produce the required clinical effect; no additional clinical
activity is derived from increased dosage, rather, what is
increased is the risk of adverse effects. Both inhibit COX-1
 at low doses and COX-2 at high doses; neither affects PT
or PTT.

Aspirin:
o Irreversibly inhibits COX-1 and reduces TxA2
production, leading to reduced platelet
aggregation, and inhibits PGI2 in endothelial
cells.
o Used for secondary prevention of CV events
in patients with coronary artery,
cerebrovascular, or peripheral vascular
disease.

Ibuprofen

Drug Toxicities/Contraindications of COX Inhibitors: GI

toxicity common, dyspepsia, erosive gastritis, ulcers with
bleeding and perforation, hepatic and renal toxicity with
aspirin overdose, avoid PMH of aspirin characterized by
bronchospasm, avoid in patients with asthma.

Glycoprotein IIb/IIIa inhibitors:

Normally, binding of fibrinogen and other ligands, such as
vWF, to the GPIIb/IIIa receptor results in cross-linking
between platelets and is the final common pathway of
platelet aggregation, which ultimately leads to thrombus
formation.

MOA: GPIIb/IIIa antagonists block the binding of Fg to the

activated platelet integrin-receptor IIb3. Essentially,
blocks aggregation by steric hindrance and/or
conformational changes to block access of fibrinogen and
vWF to GP IIb/IIIa receptor sites. Maximal inhibition occurs
when greater than 80% receptors blocked by drug/

Utility: unstable angina, percutaneous coronary

intervention, post-angioplasty.

Contraindications/Undesired Side Effects: bleeding,

anaphylaxis, thrombocytopenia associated with abciximab,
cost, sty bleeding
Abciximab
o Fab fragment of humanized monoclonal antibody
o Persists for 2 days

o Thrombocytopenia associated with Abciximab

 Eptifibatide

o Synthetic hepta-peptide from snake venom

o Lasts 4 hours

Tirofiban

o Non-peptide
inhibitor

o Lasts 4 hours

ADP inhibitors: Oral, non-competitive allosteric ADP Rc

inhibitors
The ADP-activated platelet P2Y1 receptor induces shape
change and aggregation. The P2Y12 receptor couples to Gi
and, when activated by ADP, inhibits adenylyl cyclase,
resulting in lower levels of cyclic AMP and thereby less
cyclic AMPdependent inhibition of platelet
activation. Both receptors must be stimulated to result in
platelet activation, and inhibition of either receptor is
sufficient to block platelet activation. PY12 inhibitors
bind to the ADP binding site on the receptor, and
prevent ADP from activating the receptor.

Factors of Drug Effectiveness:

Pro-drugs (Ticagrelor) requiring metabolic activation,
so issue of bioactivation for clopidogrel, ticlopidine
and prasugrel, but NOT for ticagrelor; patient genetics or
drug-drug interactions can have a significant effect upon
drug effectiveness; Poor 2C19 metabolizers have a
decreased response to Clopidogrel (can test genetics).

Drug Toxicities associated with ADP Inhibitors:

Ticlopidine use is problematic due to hematologic
toxicitiy (eg. granulocytosis, neutropenia,
thrombocytopenia, thrombotic thrombocytopenic purpura
(TTP), anemia), which renders it second-line therapy. One of
the recurring issues with all of these platelet inhibitors is
the increased risk of bleeding. Prasugrel and ticagrelor
used with aspirin in patients with STEMI. STEMI is ST
elevation myocardial infarction.

P2Y12 Receptor antagonists (Clopidogrel, Ticlopidine,

Prasugrel) inhibit platelet function by blocking the
effects of ADP at P2Y12 receptors.
Clopidogrel
 Ticlopidine
Prasugrel
Ticagrelor

PDE/adenosine uptake inhibitors: Oral/IV

MOA: Drug-induced elevations in cAMP concentrations

block the release of ARA and reduce TXA2

Factors of Drug Effectiveness: Extensive CYP/hepatic

metabolism

Dipyridamole:
o Inhibits PDE, an enzyme that catalyzes the
hydrolysis of the cyclic nucleotides cAMP and
cGMP.
o prophylaxis of thromboembolism in patients with
prosthetic heart valves (with warfarin)
o Directly stimulates release of prostacyclin, which induces
adenylate cyclase activity, which raises the intra-platelet
concentration of cAMP and further inhibits platelet aggregation
vasodilation.

Cilostazol:
o Prophylaxis in peripheral vascular disease.
Contraindications: Hypotension, may exacerbate, asthma
by causing bronchospasms

Inhibitors of Par-1: oral drug, slow onset

MOA: antagonizes platelet activated receptor-1 expressed on
platelets and blocks aggregation
Factors of Drug Effectiveness: Hepatic metabolism (CYP3A4),
fecal elimination of products, drug interactions
Side Effects/Contraindications: Bleeding

Vorapaxar: oral drug, slower onset than for GPIIb/IIIA

inhibitor
o Binds to PAR-1 with high affinity and blocks
thrombin-induced platelet aggregation
o Reversible PAR-1 antagonist, its long half-life
makes it effectively irreversible (long
durability of clinical activity)
Elimination half life of 8 days.
Platelet inhibition persists for up to 4 weeks.
Holding a dose does nothing to correct
bleeding event or reduce risk.
 Herbal Product Interactions:
A number of herbal products have been demonstrated to
possess antiplatelet activity or to induce platelet
aggregation; Some professional organizations, e.g.,
American College of Anesthesiologists, recommend cessation
of all herbal products at least 2 weeks before scheduled
surgery.

Ginkgo biloba: antiplatelet properties

Garlic: antiplatelet properties

Ginger: inhibits thromboxane synthetase, a platelet
aggregation inducer

Drugs that Facilitate Clotting

o Replacement factors
o Vitamin K
o Antiplasmin drugs