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Thrombolytic Drugs

(Fibrinolytics; "Lytic Drugs; Clot Busters") Fibrinolytics; Busters"

M2 Cardiovascular Sequence 2007 Wed. August 22, 9 - 10:30 Dr. M. Shlafer

© 2007, M. Shlafer You may download and print one copy of this presentation for your personal educational use. You may not distribute the computer file or a printed copy of it to others, as I created the file or with your edits; make additional copies in any form (printed or electronic), or make a public performance of it (including for teaching purposes), either for free or for payment, without my written permission. See my pharmacology home page for more information: http://www-personal.umich.edu/~mshlafer/pharm.html

Overview of Cardiovascular Drugs Affecting Hemostasis: The Three Main Classes Hemostasis:

Drug Class

Thrombolytics (fibrinolytics) Antiplatelet drugs

Prototypes Main Action

Streptokinase Alteplase (tPA) Aspirin Clopidogrel Abciximab Heparin

(parenteral) Warfarin (oral)

Main Use

Lysis of newlyformed thrombi (clots) Prophylaxis of arterial thrombosis Prophylaxis of venous thrombosis

Promote dissolution of thrombin Platelet aggregation (various mechanisms) Fibrin formation by inactivation of clotting factors or by clotting factor synthesis

Anticoagulants

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General Concepts About "Drugs Affecting Coagulation" Coagulation"

· Each of the 3 main classes of drugs, used individually, poses an risk of prolonged and/or excessive and/or spontaneous bleeding, including hemorrhage and hemorrhagic stroke. This "increased bleeding risk" typically is the main and common (but not only) adverse response caused by them all. Combining drugs from 2 or 3 classes, which is often done clinically, increases bleeding risks further because we've interfered with multiple "protective" clotting mechanisms. Specific antidotes to counteract excessive effects are available for heparin, warfarin, and thrombolytics. Anticoagulants and antiplatelet drugs are commonly administered to outpatients, in whom prompt recognition and intervention of problems is more difficult and poses added risks. Many drugs, including OTCs, interact with these "blood drugs."

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Key Steps In The "Coagulation Cascade" Cascade"

Intrinsic pathway

Tissue factors

Extrinsic pathway

· ·

· ·

·

Vitamin K-dependent factor inhibited by warfarin Affected by heparin, inactivated by antithrombin

Today we look here

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Plasminogen activator

Intrinsic (tPA) Extrinsic (e.g., streptokinase)

Plasma Fibrinolytic System Overview

Plasminogen activator inhibitor-1 (PAI-1)

Biologic Roles of the Plasminogen Activation System

· Vascular patency · Cell migration

­ wound healing ­ tumor cell migration ­ embryogenesis

Plasminogen

Plasmin: degrades fibrin in clots, fibrinogen and other clotting factors elsewhere

-2 antiplasmin

Fibrin

Fibrin degradation products

The Thrombolytic Drugs...

All directly or indirectly convert plasminogen to plasmin, which in turn plasmin, degrades the fibrin "scaffold" of thrombi. scaffold"

· · · · · · · ·

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When Might We Use Thrombolytic Therapy?

Acute myocardial infarction (AMI)* Deep venous thrombosis (DVT) Pulmonary embolism (PE) Thrombosed prosthetic cardiac valve Thrombosed vascular graft Peripheral arterial thrombosis Acute ischemic (not hemorrhagic) stroke Opening clogged/clotted vascular catheters

*In acute MI, thrombolytics serve as an alternative to angioplasty.

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Acute MI... One Indication for Thrombolysis MI...

Clinical presentation consistent with AMI ST elevation > 1 mm in two contiguous EKG leads (STE-MI) LBBB + clinical presentation consistent with AMI

Coronary Thrombosis and Lysis

Acute Anterior MI

LAD Occluded

LAD Patent

Thrombolytic Therapy for Acute MI (AMI): Rationale

· Occlusive coronary artery thrombus present in about 90% of transmural AMIs · Thrombolytic agents, by dissolving thrombi....

­ restore myocardial blood flow... ­ infarct size... ­ ventricular function... ­ mortality... ...to varying degrees

Window of Opportunity for Thrombolytic Therapy in AMI Is About 6 Hours Maximum: "Time Is Muscle"

"Pain to needle" time -- not which thrombolytic you use -- is the most important determinant of clinical effectiveness of thrombolytic therapy

· Maximal benefit if treated within 1 hour · Some benefit of late thrombolytic therapy (6-12 hours), but not much

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"Pain-to-Needle Time" and Reduction of Mortality by SK

Time (hr) Streptokinase (mortality, %) Placebo (mortality, %) Reduction (%)

Streptokinase ("SK")

(STREPTASE)

· Bacterial protein (Group A Streptococcus) · No intrinsic enzymatic activity · Binds to plasminogen to form activator complex · SK-plasminogen complex converts free plasminogen to plasmin · Not fibrin- (clot-) specific in terms of locus of activity

<1 1-3 3-6 6-9 9-12

8.2 9.2 11.7 12.6 15.8

15.4 12 14.1 15 13.6

51 26 20 13 -19

Get the gist. No, you don't have to "memorize the numbers"!

Main Advantages, Disadvantages of SK vs. Other Thrombolytics

· Advantage: relatively inexpensive · Disadvantages:

­ Lengthy infusion IV or IC (30-60 min) ­ Not clot-specific, so systemic effects ( generalized bleeding risk) ­ Presence or development of SK antibodies

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Bleeding Risk and Impact of SK's Sites and Mechanism of Action

· Dissolution of clots may (re)bleeding at sites of recent vessel injury... applies to all thrombolytics · Degradation of clotting factors (e.g., fibrin) systemically disrupts clotting cascade overall, can clot formation at other sites of vessel injury...

­ Contraindicates concomitant use of heparin with SK ­ Less a problem with most other thrombolytics, which are "clot-specific" at "low" (therapeutic) doses, and so usually are used + heparin

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SK and SK Antibodies

· Foreign protein (antigenic) · Use formation of anti-SK antibodies · Patients may have preexisting anti-SK antibodies from prior...

­ use of SK and/or ­ Streptococcal infection

Tissue Plasminogen Activator

("t-PA" -- ALTEPLASE) PA"

· Synthesized by r-DNA methods, is identical to human t-PA (a serine protease) · Nonantigenic · At low (therapeutic) doses, selectively activates plasminogen that's bound to clots (bleeding

tendency about same as for other thrombolytics but < SK)

· Anti-SK titers can be high enough to completely neutralize administered drug... and/or allergic reactions (anaphylaxis is rare) · Avoid readministration of SK (esp. within 5 days - 2 yrs)

· Given by IV bolus (loading dose), then 90 min IV infusion · Rapidly inactivated (hepatic), T1/2 about 5 min · Given + heparin ( efficacy, but also bleeding risk)

Streptokinase (SK) vs. t-PA

SK

Plasma clearance (min) 15-25 Fibrin specificity Minimal Plasminogen binding Indirect Potential allergenicity Yes How given IV infusion OK + heparin?

t-PA vs. SK for Acute MI

· Compared to SK, t-PA associated with:

­ Slight mortality ­ Significant rate of patency of infarct-related artery ­ Slight risk of hemorrhagic stroke

t-PA

4-8 Moderate Direct No IV bolus then infusion No Yes# #but be aware of bleeding risk

· t-PA can be used (often is) + heparin, whereas SK should not be

­ ...but recall: use + heparin, albeit common, is associated with bleeding risk

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Selected Clot-Specific t-PA Spin-Offs ClottSpin(Related Drugs) Made By r-DNA Technology* r· Tenecteplase (TNK; TNKase)

­ Structurally identical to t-PA except for 3 AA ­ Much more resistant to circulating inhibitors (plasminogen activator inhibitor-1) ­ Single IV bolus: no infusion monitoring, can be given "in the field" -- makes it quite easy/simple to give

The Last Ones*

· Antistreplase (APSAC)

­ Acylated complex of SK + human plasminogen ­ Gradual in vivo deacylation, conversion to plasmin ­ Main advantage over SK: give by slow IV injection (no infusion needed)

· Staphylokinase

­ ­ ­ ­ Staphylococcal protein Binds plasminogen to activator complex Fibrin specific (unlike SK) Antigenic (like SK, APSAC)

· Reteplase (r-PA; RETAVASE)

­ 355-AA plasminogen activating "core" of t-PA ­ Given by 2 IV boluses -- still relatively easy to give ­ Flow restoration > t-PA, mortality outcome about the same

* Not testable, but do see next slide for "take-home messages."

· Urokinase (ABBOKINASE)

­ Human enzyme from fetal kidney cells ­ Promotes plasminogen plasmin conversion ­ Nonantigenic * Not testable

Some Comparisons Between Selected Thrombolytics Used for Acute MI*

Drug Streptokinase ("SK") t-PA (ALTEPLASE) t-PA (RETEPLASE) t-PA (TENECTEPLA SE) Bolus/Loading Dose? No Maintenance Dose/Infusion? Yes, 1 hr Yes, 90 min with dose reduction after first 30 min No Concurrent Heparin? No; too great an bleeding risk Yes, OK#

Adjuncts to Thrombolytic Therapy for Acute MI*

· Heparin (or LMW heparin) -- except with SK · Antiplatelet drugs

­ Aspirin ­ Glycoprotein IIb/IIIa inhibitors

Yes Two boluses separated by 30 min Just 1 initial bolus

Yes, OK#

· Thrombin inhibitors (usually heparin)

­ Particularly important with t-PA to reocclusion * ...but be careful because of bleeding risk -- see below

No

Yes, OK#

· Not testable, but take-home messages: Some of the newer t-PAs (ALTEPLASE "spin-offs") are easier to give than the prototype, ALTEPLASE; note, too, some comparisons with SK. · # There are bleeding risks when any of these is used with heparin, but the risk is far greater with SK, and so SK + heparin should be avoided. 23

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Bleeding: The Main Complication With Any Thrombolytic

· Hemorrhagic stroke in 0.5 - 1% of patients · Minor bleeding 5%

­ Vascular access sites (compress to bleeding) ­ Gastrointestinal ­ Genitourinary

Anticoagulants, Antiplatelet Drugs, Increase Bleeding Risk

· Heparin often used with t-PA and related PAs, but use cautiously, monitor for bleeding or signs/symptoms of it · Avoid heparin with SK · Always avoid high-dose anticoagulants, antiplatelet agents, with thrombolytics, until thrombolytic effects have waned sufficiently 26

Absolute Contraindications to Any Thrombolytic

· Prior or current hemorrhagic stroke · Other strokes or cerebrovascular events (within past year) · Intracranial neoplasm (known or suspected) · Active internal bleeding (other than menstrual) · Aortic dissection (known or suspected)

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Relative Contraindications (Significant Precautions)

· · · · · · · · · HTN, esp. current severe, uncontrolled (>180/>110 mm Hg) Prior stroke, other intracranial pathology (see also previous slide) Aneurysms Recent trauma (in last 2-4 wks), head or other; or CPR Current anticoagulants (INR > 2-3) Recent internal bleed (in last 2-4 wks) Major surgery, noncompressible vessel puncture, organ biopsy (in last 10 days) Active gastric and/or duodenal ulcer Pregnancy: obstetric delivery in last 10 days

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Angioplasty: An Alternative to Thrombolysis in AMI

· Potential advantages of angioplasty: · We can: Define coronary anatomy and stratify risk Confirm flow restoration angiographically Dilate/stent stenotic vessel(s) · Outcomes with angioplasty rate of restoring normal flow risk of stroke hospital stay

Potential Disadvantages of Angioplasty (vs. Thrombolysis) in AMI

· Not practical/feasible/safe in all hospitals or at all times · Technical difficulties (e.g., difficult arterial access) could delay coronary reperfusion

The Bottom Line

Either `lytics or angioplasty are acceptable strategies, but angioplasty with stenting is preferred in most centers with cath labs so long as "doorto-balloon" time < 60-90 min.

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