DRUGS USED IN MYOCARDIAC INFARCTION THROMBOLYTICS

BYPHARM. BASHIR YAHAYA

DEPARTMENT OF CLINICAL PHARMACYFEDERAL TEACHING HOSPITAL GOMBE

Objectives

To learn how Blood Clots are formed ? How the blood clots are broken down ?What drugs can be used to regulate

clotting/lyse thrombi ?

DEFINITION OF TERMS ADP = adenosine diphosphate ALT =alanine aminotransferase AST = aspartate aminotransferase APSAC = anisoylated plasminogen streptokinase activator complex CVD = cardiovascular diseases EACA = amino caproic acid ECG = electrocardiograph FDP = fibrinogen degradation products GP = glycoprotein MI = myocardial infarction ROS = reactive oxygen specie tPA = tissue plasminogen activator VWF = Von Willebrand Factor OS = oxidative stress

Blood Clotting

Vascular Phase

Coagulation Phase

Platelet Phase

Fibrinolytic Phase

Vascular Phase Inflammation; Pro-inflammatory cytokines

cause or exacerbate injury by a variety of mechanisms including enhanced vascular permeability, programmed cell death (apoptosis), recruitment of invasive leukocytes, and the promotion of ROS production

Exposure to tissues activate Tissue factor and initiate coagulation

Tissue Factor

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathwaycollagens

Extrinsic Pathway

Factors affected

By Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

Platelet phasesubendothelial collagen via GP1/b9, VWF

Expression of glycoprotein (+) ↓GP IIb/IIIa Receptors

Platelets → activation → platelets aggregationGPIb/IX ADP TXA2 5HT(Fibrinogen, vitronectin, Von Willeberand Factor)

CLINICAL PRESENTATIONS Chest pain – Burning, squeezing, Tightness or Heaviness Associated symptoms – Nausea, vomiting and Fatigue

especially for the patient with an inferior wall MI. Patients often describe the sensation as “someone sitting on

my chest.” The substernal pain can radiate to the neck, left arm, back, or

jaw. Unlike the pain of angina, the pain of an MI is often more

prolonged and unrelieved by rest or sublingual nitroglycerin. These GIT complaints are believed to be related to the severity

of the pain and the resulting vagal stimulation.

DIAGNOSISPhysical Examination

patients usually appear restless and in distress. The skin is warm and moist. Breathing may be labored and rapid. Fine crackles, coarse

crackles, or rhonchi may be heard when auscultating the lungs. an increased blood pressure related to anxiety or a decreased

blood pressure caused by heart failure. The heart rate may vary from bradycardia to tachycardia. When the patient is placed in the left lateral decubitus

position, abnormalities of the precordial pulsations can be felt. These abnormalities include a lack of a point of maximal impulse or the presence of diffuse contraction.

On auscultation, the first heart sound may be diminished as a result of decreased contractility.

DIAGNOSIS CONT.ECG Indications of an acute infarction

Usually no ECG changes are seen in the first few minutes after occlusion Appearance of tall narrow T-waves or ST-segment elevation

• 5 to 30 minutes post occlusion A few hours later, the T-waves invert (ischemia)

• in an MI, the T-wave inversion is symmetrical an may persist for years• inverted T-waves without other indications are not diagnostic of an MI

ST-segment elevation – indication of injury (although it may be reversible)• ST-elevation may also indicate transmural ischemia• usually the first definite sign of an infarction• may or may not be accompanied by T-wave inversion• the larger the ischemic area, the greater the ST displacement• ST elevation persisting for more than a few hours may indicate ventricular

aneurysm

DIFFERENTIAL DIAGNOSIS

CVD –Arrhythmias, pericarditis, myocarditis and aortic dissection

Pulmonary dxs –pneumothorax, pleuritis, pulmonary embolism

Skeletal disorders –Rip fracture/contusion and spine dxs

GI disorders –oesophagitis, pancreatitis and gall bladder dysfunction

Others –Herbs zoster and malignant dxs.

Fibrinolytic phase

Mechanism of Thrombolytic Drugs

The plasmin (ogen) molecule has lysine binding sites, which bind to and degrade fibrin

Fibrin-specific agents are much more active upon binding to fibrin, thereby increasing the affinity for plasminogen at the clot surface

Streptokinase Bacterial protein produced by group C (beta)-hemolytic

streptococci Acts on both bound and free plasminogen (non-fibrin specicific),

- depleting circulating fibrinogen, factor V & VIII = excessive bleeding

Antigenic 250 000 units /2 ml loading dose of 2000 units/kg to be given intravenously, followed

by continuous infusion of 2000 units/kg per hour for 6 to 12 hours Pharmacokinetics: The t½ of the activator complex is about 23 minutes The complex is inactivated by anti-streptococcal antibodies & by

hepatic clearance

Streptokinase cnot.

Clinical Uses Acute Myocardial Infarction: administered by either the

intravenous or the intracoronary route for the reduction of infarct size & congestive heart failure associated with AMI

Pulmonary Embolism DVT Arterial Thrombosis – Ischemic stroke Side-Effects: Bleeding - activation of circulating plasminogen Back pain, proteinuria, iritis, Raised serum AST& ALT, acute

respiratory distress syndrome Hypersensitivity

Anistreplase (APSAC) Anisoylated Plasminogen Streptokinase Activator Complex

(APSAC) is acylated plasminogen combined with streptokinase

It is a prodrug, de-acylated in circulation into the active plasminogen-SK complex

Similar to SK, it has minimal fibrin specificity & is antigenic Single IV dose of 30 units over 5 minutes, as soon as

possible after the onset of symptoms. T1/2 is 70-120 min Metabolized by the liver & excreted via kidneys

Alteplase (rt.PA) Produced by recombinant DNA technology of 527 amino acids Clot specific – acting mainly on fibrin-bound plasminogen No hypersensitivity rxn A total dose of 100 mg over 3hours as- 10 mg as IV bolus, then 50

mg by intravenous infusion over 1 hour, followed by the remainder infused over the subsequent 2 hours.

Therapeutic Uses AMI Acute Ischemic Stroke for improving neurological recovery and

reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage

Acute Pulmonary Embolism

Alteplase cont.

PharmacokineticCleared rapidly from the plasma, mainly by

metabolism in the liver. It has an initial T1/2 of 4 to 5 minutes and a terminal T1/2 of about 40 minutes

Side-EffectsBleeding including GIT & cerebral hemorrhage laryngeal edema, rash, and urticaria have been

reported very rarely (<0.02%)

Reteplase Reteplase is another human t-PA prepared by recombinant

mutation technologyIt is fibrin-specificIt has longer duration than alteplaseThe dose is 10 units given by slow intravenous injection

(but over not more than 2 minutes), and this dose of 10 units is repeated once, 30 minutes after the start of the first injection.

have an initial T1/2 of about 14 minutes and a terminal T1/2 of 1.6 hours in patients with myocardial infarction

Tenectaplase Tenectaplase is another genetically modified human t-PA

prepared by recombinant technology It is more fibrin-specific & longer duration than alteplase It is given IV as a single bolus dose over 5 to 10 seconds as

soon as possible after the onset of symptoms. The dose is based on body-weight and ranges from 30 mg in patients less than 60 kg to a maximum of 50 mg in those 90 kg or above.

Has an initial T1/2 of 20 to 24 minutes and a terminal T1/2 of 90 to 130 minutes. It is cleared mainly by hepatic metabolism.

Urokinase

Produced by the kidney, and found in the urine It is mainly used in the low molecular weight

form of urokinase obtained from human neonatal kidney cells grown in tissue culture

Mechanism: It acts on the endogenous fibrinolytic system

converting plasminogen to the enzyme plasmin that degrades fibrin clots as well as fibrinogen and some other plasma proteins (Non-fibrin selective)

Urokinase

Given by intravenous infusion in initial doses of 4400 units/kg over 10 minutes, followed by 4400 units/kg per hour for 12 hours.

Cleared by the liver with an elimination T1/2 of 20 minutes

Clinical Uses:Pulmonary embolismDVTPeripheral arterial thromboembolism

Contraindications to Thrombolytic Therapy

Absolute contraindications include:Recent head trauma or caranial tumorPrevious hemorrhagic shockActive internal bleedingMajor surgery within two weeksRelative contraindications include:Active peptic ulcer, diabetic retinopathy,

pregnancy, uncontrolled HTN

Fibrinolytic InhibitorsAminocaproic Acid & tranexamic acid They have lysine-like structure They inhibit fibrinolysis by competitive inhibition of plasminogen

activation Adjuvant therapy in hemophilia, fibrinolytic therapy-induced

bleeding & postsurgical bleeding Giving as IV loading dose of 5g over 30 min. then 30mg/kg every

6hours Metabolized by the liver an cleared via kidneysAprotinin is a serine protease inhibitorIt inhibits fibrinolysis by free plasmin, also inhibit plasmin -

streptokinase complexUsed to stop bleeding in some surgical procedures

SUMMARY

MERCI BOUKU