fibrinolytic agents

FIBRINOLYTICS[THROMBOLYTICS]

DR.SOMASHEKARA.S.C DEPARTMENT OF PHARMACOLOGY

SVS MEDICAL COLLEGE

FIBRINOLYTIC AGENTS

1. Streptokinase, Anistrplase

2. Tissue plasminogen activator (t-PA) Alteplase, Reteplase, Tenecteplase.

3. Urokinase

STREPTOKINASE

• Protein obtained from Group-C ß haemolytic streptococci.• No intrinsic enzyme activity.• Forms a stable non covalent 1:1 complex with plasminogen.• Causes conversion of plasminogen to plasmin.• Relatively cheap.

STREPTOKINASESTREPTOKINASEStreptokinaseStreptokinase

• Dose: 7.5-15lac IU, 15lac IU/vial• MI: 7.5-15lac IU infused over 1hr • To be avoided in

- patients with recent major streptococcal infection.- Previous treatment by streptokinase because

antibodies diminish efficacy.• Adverse effects: Bleeding, antigenic, fever, hypotension & arrhythmias

Streptokinase

Anistreplase

Prodrug - Streptokinase-plasminogen complex

Slowly hydrolysed releasing streptokinase activated plasminogen which converts endogenous plasminogen to plasmin

Long duration of action (1-2hrs)

Urokinase

Isolated from cultured human kidney cells

Indicated in pts in whom streptokinase has been used for an earlier episode

Dose: M.I: 2.5lac IU i.v over 10min….

5lac IU over next 60min

Use limited lacks fibrin specificity, very expensive.

Saruplase selective to fibrin.

tissue Plasminogen activator (t-PA)

Tissue plasminogen activator (t-PA)

Bind to fibrin via lysine binding sites & activates plasminogen several hundred fold more rapidly.

Specific to fibrin bound plasminogen (Half life = 5-10 min)

Alteplase (rt-PA) recombinant DNA technology from human tissue culture

Rapidly metabolised by liver (Half life = 5-10 min)

Non antigenic, nausea, mild hypotension, fever, hemorrhage

Dose: 50mg vial + 50ml solvent(water)

15mg i.v bolus…50mg over 30min, then 35mg over next 1hr

Tissue plasminogen activator (t-PA)

Reteplase and tenecteplase are recombinant mutant variants of t-PA

Resistant to inhibition by plasma activator inhibitor

Have faster onset of action & longer duration of action

Similar to t-PA in efficacy and toxicity

USES OF FIBRINOLYTICS

• 1. Acute Myocardial Infarction• 2. Deep vein thrombosis• 3. Pulmonary Embolism• 4. Peripheral vascular disease

Hemorrhagic toxicity

Major toxicity – hemorrhage because of

1. Lysis of fibrin in physiological thrombi at site of vascular injury

2. Systemic lytic state systemic formation of plasmin.

If heparin used concurrently bleeding 2-4%

intracranial hemorrhage (most serious)

Contraindications to thrombolytics

1. Surgery within 10 days.2. Serious gastrointestinal bleeding within 3 months.3. History of hypertension (DBP>110mm Hg)4. Active bleeding or hemorrhagic disorder.5. Previous cerebrovascular accident.6. Aortic dissection.7. Acute pericarditis.

Fibrinolytic therapy

• Initiate within 30 min of presentation (i.e. door -to-needle time 30 min) • Reduces the relative risk of in-hospital death by up to 50%

when administered within the first hour of the onset of symptoms of STEMI.

• Fibrinolysis is generally preferred to PCI for patients presenting in the first hour of symptoms of MI..

Antifibrinolytic drugsAntifibrinolytic drugs

Aminocaproic acid

Tranexamic acid

Aprotinin

Epsilon Aminocaproic acid

Lysine analog

MOA: acts by combining with lysine binding sites of plasminogen & plasmin, and prevents the binding of these to fibrin – prevents its lysis

Specific antidote for fibrinolytic agents

Dose: Initial priming dose 5gm oral/i.v….

1g hrly till bleeding stops(max.30g in 24hrs)

ANTIFIBRINOLYTICS

• USES:• 1.Overdose of Fibrinolytic agents• 2.To prevent recurrences of subarachnoid & GI hemorrhage• 3.Certain traumatic & Surgical bleeding, prostectomy, tooth extraction in hemophiles• 4.Abruptio placentae, PPH & certain cases of menorrhagia

ANTIFIBRINOLYTICS

• DISADVANTAGES:• 1.In treatment of haematuria it can cause ureteric obstruction by unlysed clots• 2.Can cause intravascular thrombosis• 3.Rapid i.v - hypotension, bradycardia, arrhythmias• 4.Myopathy, careful in renal impaired pts