April 11, 2013

http://www.youtube.com/watch?v=nfyb7G_4
HQ0
http://www.youtube.com/watch?annotation_id
=annotation_837607&feature=iv&src_vid=nf
yb7G_4HQ0&v=Yz8dRDB_Xv4
 Arrhythmias can be treated with the drugs
and with nonpharmacologic therapies such as
pacemakers, cardioversion, catheter ablation,
and surgery.
 The electrical impulse that triggers a normal
cardiac contraction originates at regular
intervals in the sinoatrial node.
 This impulse spreads through the atria and
enters the atrioventricular node.
 Conduction through the atrioventricular node
is slow, requiring about 0.15 s. (This delay
provides time for atrial contraction to propel
blood into the ventricles.)
 The impulse then propagates over the His-
Purkinje system and invades all parts of the
ventricles.
 Arrhythmias are caused by abnormal impulse
propagation.
 The aim of therapy of the arrhythmias is to
reduce abnormal activity.
This can be done by…
 (1) sodium channel blockade,
 (2) blockade of sympathetic
autonomic effects in the heart
 (3) prolongation of the effective
refractory period
 (4) calcium channel blockade.
Class
I Sodium 1A procainamide, quinidine Slows conduction velocity, ↑duration of AP
Slows conduction velocity, ↓ duration of AP
channel 1B lidocaine, mexiletine Slows conduction velocity

blockers 1C flecainide
Oldest class

II Beta Propranalol ↓conduction velocity, ↓contractility of heart

blockers acebutalol Sympatholytics , reduce adrenergic activity in
heart

III Potassium amiodarone ↑ duration of AP

channel
blockers

IV Calcium Verapamil ↓ conduction velocity and contractility

channel diltiazem
blockers

misc Adenosine
digoxin
The most widely used scheme utilises four
classes:
 Class 1 action is sodium channel blockade..
 Drugs with class 1A action prolong the APD
and dissociate from the channel with
intermediate kinetics; procainamide
 Drugs with class 1B action shorten the APD in
some tissues of the heart and dissociate from
the channel with rapid kinetics;
 Drugs with class 1C action have minimal
effects on the APD and dissociate from the
channel with slow kinetics.
 A given drug may have multiple classes of
action.
 For example, amiodarone shares all four
classes of action.
 Drugs are usually discussed according to the
predominant class of action.
 Inhibition of specific clotting
Prevention of clots
factors
Anticoagulant
-used in the treatment and prophylasis of thromboembolic disorders.
Indirect anticoagulants
(heparins and LMWHs)
Direct anticoagulants
(Coumarin, indaneoic derivatives)

Inhibition of platelet action Antiplatelet

Interfere with platelet aggregation
-by decreasing platelet aggregation inhibit thrombus formation
especially in the arterial circulation where thrombi are formed mainly
of platelets.
Aspirin

ADP receptor blockers

Clopidogrel (Plavix)and ticlopidine reduce platelet aggregation by
inhibiting the ADP pathway of platelets.
Glycoprotein IIb/IIIa receptor antagonist (abciximab)
-prevents fibrinogen linkage of platelets

Clot dissolved by drug Thrombolytic

Removal of existing Promote fibrinolysis or clot destruction by converting plasminogen to
clots plasmin.
-plasmin is a proteolytic enzyme that degrades fibrin and thus
produces dissolution of clots
Alteplase, Streptokinase

Promotion of clot Inhibition of fibrin destruction

formation
 Hemostasis refers to the finely regulated
dynamic process of maintaining fluidity of the
blood, repairing vascular injury, and limiting
blood loss while avoiding vessel occlusion
(thrombosis) and inadequate perfusion of
vital organs.
 Either extreme—excessive bleeding or
thrombosis—represents a breakdown of the
hemostatic mechanism.
 Common causes of dysregulated hemostasis
include hereditary or acquired defects in the
clotting mechanism and secondary effects of
infection or cancer.
Mechanisms of Blood Coagulation
 The vascular endothelial cell layer lining
blood vessels has an anticoagulant
phenotype, and circulating blood platelets
and clotting factors do not normally adhere
to it to an appreciable extent.
 In the setting of vascular injury, the
endothelial cell layer rapidly undergoes a
series of changes resulting in a more
procoagulant phenotype.
 Injury exposes reactive subendothelial matrix
proteins such as collagen and von Willebrand
factor, which results in platelet adherence
and activation, and secretion and synthesis of
vasoconstrictors and platelet-recruiting and
activating molecules.
 Thromboxane A2 (TXA2) is synthesized from
arachidonic acid within platelets and is a platelet
activator and potent vasoconstrictor.
 Products secreted from platelet granules include
adenosine diphosphate (ADP), a powerful inducer
of platelet aggregation, and serotonin (5-HT),
which stimulates aggregation and
vasoconstriction.
 Activation of platelets results in a conformational
change in the αIIb β III integrin (IIb/IIIa) receptor,
enabling it to bind fibrinogen, which cross-links
adjacent platelets, resulting in aggregation and
formation of a platelet plug .
 Simultaneously, the coagulation system
cascade is activated, resulting in thrombin
generation and a fibrin clot, which stabilizes
the platelet plug.
 Blood coagulates due to the transformation of
soluble fibrinogen into insoluble fibrin by the
enzyme thrombin.
 Several circulating proteins interact in a
cascading series of limited proteolytic reactions.
At each step, a clotting factor zymogen
undergoes limited proteolysis and becomes an
active protease (eg, factor VII is converted to
factor VIIa).
 Each protease factor activates the next clotting
factor in the sequence, culminating in the
formation of thrombin (factor IIa).
 Several of these factors are targets for drug
therapy.
 In clotting, thrombin proteolytically cleaves small
peptides from fibrinogen, allowing fibrinogen to
polymerize and form a fibrin clot.
 Thrombin also activates many upstream clotting
factors, leading to more thrombin generation,
and activates factor XIII, a transaminase that
cross-links the fibrin polymer and stabilizes the
clot.
 Thrombin is a potent platelet activator.
 It should therefore be apparent that the response
to vascular injury is a complex and precisely
modulated process that ensures that under
normal circumstances, repair of vascular injury
occurs without thrombosis
 The main initiator of blood coagulation in
vivo is the tissue factor (TF)-factor VIIa
pathway .
 Tissue factor is a transmembrane protein
ubiquitously expressed outside the
vasculature, but not normally expressed in an
active form within vessels.
 The exposure of TF on damaged endothelium
or to blood that has extravasated into tissue
binds TF to factor VIIa.
 Fibrinolysis refers to the process of fibrin
digestion by the fibrin-specific protease,
plasmin.
 The fibrinolytic system is similar to the
coagulation system in that the precursor form of
the serine protease plasmin circulates in an
inactive form as plasminogen.
 In response to injury, endothelial cells synthesize
and release tissue plasminogen activator (t-PA),
which converts plasminogen to plasmin.
 Plasmin remodels the thrombus and limits its
extension by proteolytic digestion of fibrin.
 The ideal anticoagulant drug would prevent
pathologic thrombosis and limit reperfusion
injury, yet allow a normal response to
vascular injury and limit bleeding.
 At this time such a drug does not exist; all
anticoagulants and fibrinolytic drugs have an
increased bleeding risk as their principle
toxicity.
 Unfractionated heparin has a molecular weight range
of 5000–30,000. In contrast, the shorter-chain low-
molecular-weight (LMW) fractions of heparin inhibit
activated factor X but have less effect on thrombin
than the HMW species.
 Nevertheless, numerous studies have demonstrated
that LMW heparins such as enoxaparin, dalteparin,
and tinzaparin are effective in several
thromboembolic conditions.
 In fact, these LMW heparins—in comparison with
UFH—have equal efficacy, increased bioavailability
from the subcutaneous site of injection, and less
frequent dosing requirements (once or twice daily is
sufficient).
 Commercial heparin is extracted from porcine
intestinal mucosa and bovine lung.
 Enoxaparin is obtained from the same
sources as regular heparin, but doses are
specified in milligrams.
 Dalteparin, tinzaparin, and danaparoid (an
LMW heparanoid containing heparan sulfate,
dermatan sulfate, and chondroitin sulfate), on
the other hand, are specified in antifactor Xa
units.
 The direct thrombin inhibitors (DTIs) exert their
anticoagulant effect by directly binding to the
active site of thrombin, thereby inhibiting
thrombin's downstream effects.
 This is in contrast to indirect thrombin inhibitors
such as heparin and LMWH which act through
antithrombin.
 Hirudin and bivalirudin are bivalent DTIs in that
they bind at both the catalytic or active site of
thrombin as well as at a substrate recognition
site.
 Argatroban and melagatran are small molecules
that bind only at the thrombin active site.
Parenteral Direct Thrombin Inhibitors
 Hirudin is a specific, irreversible thrombin
inhibitor from leech saliva that is now
available in recombinant form as lepirudin.
 Bivalirudin, another bivalent inhibitor of
thrombin, is administered intravenously, with
a rapid onset and offset of action. The drug
has a short half-life with clearance that is
20% renal and the remainder metabolic.
Bivalirudin also inhibits platelet activation and
has been FDA-approved for use in
percutaneous coronary angioplasty.
 were initially used as rodenticides
 In the 1950s warfarin (under the brand name Coumadin) was introduced
as an antithrombotic agent in humans. Warfarin is one of the most
commonly prescribed drugs, used by approximately 1.5 million
individuals, and several studies have indicated that the drug is
significantly underused in clinical situations where it has proven benefit.
 Mechanism of Action
 Coumarin anticoagulants block the γ-carboxylation of several glutamate
residues in prothrombin and factors VII, IX, and X as well as the
endogenous anticoagulant proteins C and S). The blockade results in
incomplete coagulation factor molecules that are biologically inactive.
The protein carboxylation reaction is coupled to the oxidation of vitamin
K. The vitamin must then be reduced to reactivate it. Warfarin prevents
reductive metabolism of the inactive vitamin K epoxide back to its active
hydroquinone form (Figure 34–6). Mutational change of the responsible
enzyme, vitamin K epoxide reductase, can give rise to genetic resistance
to warfarin in humans and especially in rats.
 Fibrinolytic drugs rapidly lyse thrombi by
catalyzing the formation of the serine
protease plasmin from its precursor
zymogen, plasminogen .
 Streptokinase is a protein (but not an enzyme
in itself) synthesized by streptococci that
combines with the proactivator plasminogen.
This enzymatic complex catalyzes the
conversion of inactive plasminogen to active
plasmin.
 Platelet function is regulated by three categories of
substances.
1. The first group consists of agents generated
outside the platelet that interact with platelet
membrane receptors, eg, catecholamines, collagen,
thrombin, and prostacyclin.
2. The second category contains agents generated
within the platelet that interact with membrane
receptors, eg, ADP, prostaglandin D2, prostaglandin
E2 , and serotonin.
3. The third group comprises agents generated within
the platelet that act within the platelet, eg,
prostaglandin endoperoxides and thromboxane A2,
the cyclic nucleotides cAMP and cGMP, and calcium
ion.