FIBRINOLYTIC AND

ANTIFIBRINOLYTIC DRUGS

Moderated by Presented by Dr Baraniraj

Dr Nishikant A ingole
Associate Professor Junior resident-1
Dept of Pharmacology
Jnmc, Wardha Dept of pharmacology
Scribe by
Jnmc, Wardha
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 CONTENTS

• INTRODUCTION
• FIBRINOLYTIC DRUGS
• ANTIFIBRINOLYTIC DRUGS

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 INTRODUCTION

• These are drugs used to lyse thrombi/clot to

recanalize occluded blood vessels (mainly
coronary artery).

• They are therapeutic rather than

prophylactic and work by activating the
natural fibrinolytic system

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• Venous thrombi are lysed more easily by fibrinolytics than arterial thrombi,
and recent thrombi respond better.

• Fibrinolytics have little effect on thrombi > 3 days old.

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 FIBRINOLYTIC DRUGS

• Streptokinase
• Urokinase
• Alteplase (rt-PA)
• Reteplase
• Tenecteplase

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The plasminogen-plasmin system 6
 STREPTOKINASE

• Obtained from B haemolytic Streptococci group C

• It is the first fibrinolytic drug to be used clinically, but is not

employed now because it is non-fibrin specific, i.e. activates both
circulating as well as fibrin bound plasminogen.

• Therefore, it depletes circulating fibrinogen and predisposes to

bleeding.

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• Compared to newer more fibrin-specific
tissue plasminogen activators (alteplase,
etc.) it is less effective in opening occluded
coronary arteries, and causes less
reduction in MI related mortality.

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• It is antigenic and pyrogenic.

• Antistreptococcal Ab are formed within 4-5 days

after streptokinase, which destroy the drug.

• So, should not be used again. If needed, can be

used after a gap of 1 year.

• Advantage- Cheapest 9
 ADVERSE EFFECTS

1. Bleeding
2. Allergic reactions like fever
3. Chills
4. Skin rash
5. Hypotension
6. anaphylactoid reaction

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• Dose- Loading dose 2.5lac units over 10min
followed by 1 lac units/hr for 1-3 days

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 UROKINASE

• It is an enzyme isolated from human urine

• But commercially prepared from cultured human kidney cells.
• Directly converts plasminogen to plasmin
• Due to availability of better fibrinolytics, it has
gone out of use.

• Dose- loading dose 3 lac units over 10min followed by 3 lac

units/hr for 12 hour
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 ALTEPLASE

• Recombinant tissue plasminogen activator (rt-PA)

• Produced by recombinant DNA technology from human tissue

culture, it catalyses the cleavage of endogenous plasminogen to
generate plasmin, and is moderately specific for fibrin-bound
plasminogen, so that circulating fibrinogen is lowered only by
50%.

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• It is rapidly cleared by liver and inactivated by
plasminogen activator inhibitor-1 (PAI-1).
• The plasma t1/2 is 4- 8 min.

• Because of the short t½, it needs to be given by

slow i.v. infusion and often requires heparin
coadministration. Aspirin is also routinely given after
establishing reperfusion.

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• Risk of bleeding (0.5 - 5%) is the most important concern.
• A/E- nausea, mild hypotension and fever may occur.
• It is expensive.

• ACTILYSE 50 mg vial with 50 ml solvent water.

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• For MI: 15 mg iv. Bolus injection followed by 50 mg over
30 minute, then 35 mg over the next 1 hr (total 100mg in
90min)

• For Pulmonary embolism: 100mg i.v infused over 2 hr

• For ischemic stroke- 0.9 mg/kg by i.v infusion over 60min,

with 10% of the dose injection in the first minute

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 RETEPLASE

• It is a nonglycosylated deletion mutant of rt.PA produced by

recombinant technology in which some amino acids of native
t-PA are missing.

• This change makes it longer acting, but somewhat less

selective for fibrin bound plasminogen. It is cleared by both
liver and kidney with an effective of13-16 min.

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• The longer action permits a double bolus i.v. administration of 18
mg (10U) over 2 min each 30 min apart in cases of STEMI and in
PE. Dose adjustment is needed in liver and kidney damage.

• RETELEX 18 mg (10U)/vial injection kit.

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 TENECTEPLASE

• This genetically engineered substitution mutant of native t-

PA has higher fibrin selectivity, slower plasma clearance
(longer duration of action) and resistance to inhibition by
PAI-1.

• It is the only fibrinolytic agent that can be injected i.v. as a

single bolus dose over 10 sec, while alteplase requires 90
min infusion and reteplase needs 2 injections at 30 min
interval. 19
• This feature makes it possible to institute fibrinolytic
therapy immediately on diagnosis of STEMI, even
during transport of the patient to the hospital. Several
randomized multicentric trials have assessed its
efficacy in STEMI and found it to be at least equally
efficacious to alteplase.

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• Risk of noncerebral bleeding was found to be lower with
tenecteplase in the ASSENT-2 trial, but cranial bleeding
incidence was similar:

• Dose: 0.5 mg/kg single i.v. bolus injection.

• ELAXIM 30 mg, 50 mg per vial inj.

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 USES OF FIBRINOLYTICS

• 1. Acute Myocardial infarction- The chief indication for

fibrinolytic therapy is STEMI. They are not indicated or may
even be harmful in UA and in low risk NSTEMI.

• In STEMI fibrinolytics are an alternative first line approach to

emergency percutaneous coronary intervention (PCI) with
stent placement.

• Recanalization of thrombosed coronary artery has been

achieved in50-90% cases. Time lag in starting the infusion is
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critical for reducing area of necrosis, preserving ventricular
function and reducing mortality.
• Aspirin with or without heparin is generally started
concurrently or soon after thrombolysis to prevent
reocclusion.

• Recanalization efficacy is similar with alteplase, reteplase

and tenecteplase, but tenecteplase has the simplest
regimen.

• Risk of hypotension and allergic reactions is also

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comparable among
• 2. Deep vein thrombosis (DVT)- In leg, pelvis, shoulder etc.;
up to 60% patients of DVT can be successfully treated by
fibrinolytics.

• They can decrease subsequent pain and swelling, but the

main advantage is preservation of venous valves and may
be a reduced risk of PE, though at the risk of haemorrhage.

• Comparable results have been obtained with Stk,

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urokinase and alteplase.
• 3. Pulmonary embolism- Fibrinolytic therapy is indicated in large, life-
threatening PE. Lung function may be better preserved, but reduction in
mortality is not established.

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• 4. Peripheral arterial occlusion- Fibrinolytics recanalise ~40% limb
artery occlusions, especially those treated within 72 hr.

• However, it is indicated only when surgical thrombectomy is not

possible.
•
• Regional intraarterial fibrinolytics have been used for limb arteries
with greater success.

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• Peripheral arterial thrombolysis is followed by short-
term heparin and long-term aspirin therapy.

• Fibrinolytics have no role in chronic peripheral

vascular diseases.

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• 5. Stroke- Thrombolytic therapy of ischaemic stroke is dependent on
time-lapse since symptom onset; earlier, the better.

• Possibility of improved neurological outcome is to be balanced with

risk of intracranial haemorrhage.

• Alteplase is approved for use in ischaemic stroke, and current opinion

strongly recommends use of i.v.

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• alteplase in carefully selected patients who can be treated within 3
4.5 hours of onset, and in whom intracranial haemorrhage is ruled
out along with all risk factors for bleeding.

• After 4.5 hours of symptom onset, the risk of intracranial

haemorrhage outweighs the likelihood of benefit.

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 CONTRAINDICATION

• 1. H/o intracranial haemorrhage

• 2. H/o ischaemic stroke in past 3 months
• 3. H/o head injury in past 3 months
• 4. Intracranial tumour/vascular abnormality/ aneurysms
• 5. Active bleeding/bleeding disorders

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• 6. Patients receiving anticoagulants
• 7. Peptic ulcer, esophageal varices
• 8. Any wound or recent fracture or tooth extraction
• 9. H/o major surgery within 3 weeks
• 10. Uncontrolled hypertension
• 11. Pregnancy

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 ANTIFIBRINOLYTIC DRUGS

• They block the conversion of plasminogen to plasmin and inhibit fibrinolytic

activity

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 EPSILON AMINO- CAPROIC ACID (EACA)

• Well absorbed orally. Excreted via kidney, so dose to be reduced in renal

dysfunction.
• Adverse effects - Dyspepsia, Hypotension arrythmia and bradycardia.
• Un lysed clots can cause ureteric obstruction. Mainly given to reverse
bleeding due to fibrinolytics
• Dose: 4-5 g over 60 min followed by 1 g/hr.

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 TRANEXAMIC ACID

• Given oral, i.v. and topical. More potent than

EACA. More commonly used.

• Adverse effect: Thromboembolic events,

disturbed colour vision, allergic reactions.

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 USES

• a) To control bleeding due to overdose of fibrinolytics.

• b) Bleeding after tooth extraction, prostatic surgery in patients of
haemophilia.
• c) Menorrhagia, post-partum haemorrhage.
• d) Haematuria
• e) Post-operative bleeding.
• f) To prevent intracranial haemorrhage.
• g) Recurrent epistaxis.
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 REFERENCE

• Essentials of Medical Pharmacology, K.D.Tripathi- 8th

edition- Jaypee Brothers Medical Publishers

• Pharmacology Essentials, Harsh Joshi, Foreword KK

Sharma, HL Sharma- Paras medical Publisher

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 QUESTION AND ANSWER

• What is anaphylaxis and anaphylactoid reaction?

• Anaphylaxis is an acute, systemic allergic reaction that occurs rapidly after exposure to an allergen.
• it involves the immune system and is typically mediated by immunoglobulin E (IgE) antibodies,
which trigger a release of histamine and other chemicals from mast cells and basophils.
• Common allergens that can trigger anaphylaxis include certain foods (like peanuts or shellfish),
medications (such as penicillin or aspirin), insect stings, and latex.
• Symptoms of anaphylaxis can include difficulty breathing, swelling of the throat and tongue, hives,
rapid heartbeat, dizziness, and a drop in blood pressure.
• It can progress quickly and lead to shock if not treated promptly with epinephrine and supportive
care.
• - Anaphylactoid reactions, also known as non-allergic anaphylaxis or pseudoallergic
reactions, resemble anaphylaxis in their clinical presentation but do not involve the immune
system or IgE antibodies.
• These reactions are triggered directly by certain substances (e.g., radiocontrast media,
opioids, some medications) that can directly activate mast cells and basophils or cause the
release of inflammatory mediators.
• The symptoms of anaphylactoid reactions are similar to those of anaphylaxis and can be
equally severe, including respiratory distress, skin reactions, and cardiovascular collapse.
• Treatment for anaphylactoid reactions also involves immediate administration of
epinephrine and supportive measures to stabilize the patient.
• Why fibrinolytic drugs contraindicated the patient with history of ischaemic
stroke in past 3 months?

• Risk of Hemorrhagic Transformation: Ischemic strokes are caused by a

blockage in a blood vessel supplying the brain, leading to reduced blood flow and
oxygen. After an ischemic stroke, there may be areas of damaged or weakened
blood vessels in the brain. Administering fibrinolytic drugs to dissolve blood clots
in these patients can increase the risk of bleeding into the brain (hemorrhagic
transformation), worsening the initial stroke or causing new neurological deficits.
• Time Window for Safety: The first few months after an ischemic stroke are
critical for the brain to heal and stabilize. During this period, the risk of
bleeding complications is higher because the brain tissue may still be
vulnerable and not fully recovered.
• Clinical Trials and Guidelines: Clinical trials and guidelines have
established the 3-month window as a safety measure based on evidence that
shows the risk of hemorrhage decreases significantly beyond this timeframe.
Administering fibrinolytic therapy outside of this window could significantly
increase the risk of serious bleeding complications.
• Balance of Risks and Benefits: While fibrinolytic therapy can potentially
dissolve clots and improve outcomes in acute ischemic stroke if given within
a few hours of symptom onset (typically up to 4.5 hours in some cases), the
risk of hemorrhage becomes prohibitive when there's been a recent stroke.
Therefore, clinicians prioritize patient safety and avoid fibrinolytic therapy in
these situations to prevent potential harm.
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