Download Acute Coronary Syndrome Therapeutic Intervention

Acute Coronary Syndrome Therapeutic Intervention
Acute Coronary Syndrome includes
1. Acute unstable angina pectoris
2. Acute myocardial infarction
These conditions are due to the formation of unstable artheromatous plaque with hematoma that leads to stenosis of the blood
vessels calliber. Blockage will then lead to ishceamic attack of the post stenotic tissue. This is therefore, through emergency and
prophylaxis therapeutic intervention, the aim of therapy is to
1. Immediate reperfusion of the ischeamic tissue
a. Fibrinolytics/Thrombolytics
i. Fibrin specific fibrinolytic agent (Tissue Plasminogen Activator)/Direct Fibrinolytic
1. Alteplase (tPA)
ii. Non-fibrin specific fibrinolytic agent/Indirect Fibrinolytic
1. Streptokinase (SK) *a protein, not an enzyme
2. Prophylaxis of future ishceamic event
a. Antiplateletss
i. COX inhibitor
1. Aspirin
ii. Adenosine Diphosphate (ADP) inhibitor
1. Clopidogrel
iii. Additional Antiplatelet-Directed Drug
1. Dipyridamole
iv. Glycoprotein IIb/IIIa inhibitor
1. Abciximab
3. Anticoagulant
a. Heparin
b. Warfarin
1.
Fibrinolytics/Thrombolytic Agents
All fibrinolytics can cause heamorrhage; to counteract by giving
a. Aminocaproic acid
b. Tranxenamic acid
i. These agents bind to plasmin and hinders it from cleaving the fibrin
Drug Name/ Infos

Absolute contraindication
a. Prior or current heamorrhagic stroke
b. Intracranial neoplasm
c. Active internal bleeding
d. Aortic dissection
Non-Fibrin Specific Fibrinolytic Agent (Indirect Fibrinolytic)
Mechanism of Action
Streptokinase

2.
Not an enzyme per se, but it elicits a
reponse like an enzyme
Protein that is derived from Beta
Hemolytic Streptococcus bacteria
Pharmaceutical basis in choosing SK
Advantages
1. Relatively cheap
Disadvantages
1. It is not fibrin specific
a. Systemic bleeding may occur
2. Allergic reaction (bacterial product)
a. Rash
b. Fever
c. Anaphylactic shock
1.
Plasminogen is an zymogen that is needed to breakdown fibrin clot in
physiological mechanism
2. In order to activate the plasminogen into its active form; Plasmin, human kidneys
secrete an enzyme called Urokinase. Urokinase will cleave the Plasminogen to
Plasmin through proteolytic mechanism
3. Nevertheless, activated plasmin is vulnerable to be deactivated by plasma AntiPlasmin which can reduce it’s fibrinolytic properties.
4. Streptokinase is given in order to bind to the Plasminogen, which in return will
a. Allow Urokinase to cleave Plasminogen into Plasmin
b. Then, protect the Plasmin from being deactivated by plasma Anti-Plasmin
5. This will then allow plasmin to degrade firbin clot and therefore reperfuse the
ischeamic post stenotic tissues
Due to its affinity to bind to not only Plasminogen at the pathological blood clot but
to free circulating Plasminogen, it’s prone to cause systemic bleeding. Patient should
be notified on its possible heamorrhagic side effect
Adverse Effects
1. Bleeding
2. Hypersensitivity reaction
a. Fever
b. Rash
c. Anaphylactic shock
Fibrin Specific Fibrinolytic Agent/ Tissue Plasminogen Activator (tPA) (Direct Fibrinolytic)
Drug Name/ Infos
Mechanism of Action
Adverse Effects
Alteplase (tPA)
Derived through a genetic engineering
by which human tPA is being engineered
through Human DNA Recombinant
technology
Pharmacokinetics
Adsorption

Only be given IV
Distribution

Rapid onset

Highly effective when given within 3 hours
after the onset of symptom
Metabolism

Extensively being metabolized by the liver

Plasma t1/2 is about 5 minutes
Excretion

Renal clearence

1. Other than Urokinase, Plasminogen can also be activated through
endogenous Human Tissue Plasminogen Activator (tPA).
2. This enzyme, specifically cleaves fibrin bound Plasminogen instead of
free Plasminogen (like that of SK)
3. Due to hemodynamic instability presents in IHD patients, endogenous
tPA is not sufficient enough to fight against the fibrinogenesis.
4. This is therefore, human recombinant technology gives rise to Alteplase
(cloned tPA) to be given to ACS in order to eleviate the action of tPA to
as much as many folds.
5. Through degradation of fibrin clot, reperfusion is positive in post stenotic
ischeamic tissues.
It is then indicated for
1. ST Elevated Acute Myocardial Infarction (STEMI)
2. Non-heamorrhagic stroke
1.
Bleeding (less thant that of
SK)
Antiplatelet Agents
Cycloxygenase Inhibitor (COX Inhibitor)
Drug
Acetylsalicylate Acid
(ASPIRIN)
Pharmacological Effects
1. Anti-inflammatory
2. ↓coagulation (the ONLY NSAIDs)
3. Anti-pyretic
4. Analgesia
Contraindication
1. Relative C/I
a. Bronchial asthma
i. Inhibit synthesis of PG
(bronchodilator)
2. Absolute C/I
a. Gouty arthritis
i. ↓dose (anti-platelete)
1. No effect on uric acid renal
secretion
ii. Usual OTC dose
(analgesia/antipyretic)
1. Inhibits uric acid renal
secretion
iii. ↑dose (Tx of RA)
1. Blocks reabsorption of uric
acid (uricosuric effect)
b. Children with influenza or cold
i. Reye’s syndrome
1. Potentially fatal
c. Pregnant ladies
i. Antiplatelet effects on 3rd
trimester
1. ↑risk of bleeding
ii. PG prolongs labour
Therapeutic Uses
1. Fever
2. Ischeamic heart disease
3. Arthritis
Pharmacokinetic
Mechanism of Action
Absorption
1. Best absorp in acidic condition
a. It’s a weak acid in nature;
gastric environment is highly
acidic. Therefore aspirin will
remain unionized in the
stomach
b. Acidic drug tends to be lipid
soluble; readily being absorp
in through the GI mucosa
2. Most absorp at intestinal
mucosa due to high surface
area and low motility
Distribution
1. Hydrolyzes by esterases in tissue
and blood by
a. Acetic acid
b. Salicylate
2. Salicylate is highly plasma
protein bound (albumin)
Metabolism
1. Hepatic metabolism
(conjugation)
a. Conjugate with glycine =
salicyluric acid
b. Conjugate with glucuronic =
salicyl acyl + phenolic
glucuronide
Excretion
1. Renal excretion through
a. Glomerular filtration
b. Tubular secretion
2. Highly sensitive to pH changes
3. Interfere with uric acid
excretion*
1. Non-selective COX inhibitor, IRREVERSIBLY inhibits
both
a. COX 1 (constitutional enzyme) which coverts
arachidonic acid into
i. PGE2
1. Renal vasodilation
2. Bronchodilation
a. Inhibition of this will exarcebate asthmatic
pts (relative contraindication)
ii. TXA2
1. ↑platelete aggregation
a. Inhibition leads to anti-platelet activity
i. ↓risk for AMI
ii. ↓risk of CVA
iii. PGI2
1. ↑gastric mucus secretion
a. Inhibition of this will reduce mucus
secretion, exarcebate gastritis
b. COX 2 (inducible enzyme) which converts
arachidonic acid into
i. Prostaglandins which involved in
1. Inflammation
a. Vasodilation (hypereamia)
b. ↑capillary permeability (edema)
i. Inhibition will ↓inflammation
2. Pain sensation
a. Directly binds to pain receptor and elicit
pain sensation (not visceral pain)
i. Inhibition will lead to analgesia
3. Pyrexia (fever)
a. Prostaglandin together with IL-1b
stimulates thermostat at the OVLT to
increase temperature set point higher
than normal
i. Inhibition will return the temperature set
point to normal
Adverse Effects
1. Gastritis
a. Ion trapping inside
the gastric mucosa
b. Inhibition of PG12
synthesis ↓mucus
secretion
c. Prophylaxis tx with
Misosprostol (PGE1
analogue)
2. Hepatotoxicity
3. Allergic action
a. Periorbital edema
b. Rash
Drug-drug Interaction
1. Warfarin
a. Due to its higher
affinity towards
albumin compared
to warfarin, aspirin
may displace
warfarin and lead
to ↑in warfarin
toxicity
Drug Name/ Infos
Clopidogrel (Plavix®)


Onset of action 1-2 days
Max effect 3-5 days
Drug Name/ Infos
Dipyridamole
1. Alone, less effective.
Always be given
together with
a. Dipyridamole + Aspirin
i. Cerebrovascular
accident
b. Dipyridamole +
Warfarin
i. Prevent
thrombogenesis in pts
with prothetic heart
valves
Adenosine Diphosphate Inhibitor (ADP Inhibitor)
Mechanism of Action
1. Clopidogrel is a non-competitive ADP receptor inhibitor, by
which it will irreversibly block the ADP receptor and lead to
these subsequent events:
a. Inhibits platelete aggregation
b. ↓platelets conformational change
c. ↓release of platelet granules, which contained
i. ADP
ii. TXA2
d. ↓platelet amplification
2. Advantages of Clopidogrel over other antiplatelets
a. ↓stroke and MI in pts with Coronary Arterial Disease
b. Better efficacy compared to aspirin eventhough relatively
expensive
c. ↓rethrombosis after coronary artery stenting
Adverse Effects
1. GI discomfort
a. Nausea
b. Vomitting
c. Constipation
2. Hardly cause neutropenia
compared to Ticlopidine
Additonal Antiplatelet-Directed Drugs
Mechanism of Action
Dipyridamole elicits response through numerous inhibitory
effects include
1. Inhibits Thromboxane Synthase
a. ↓production of TXA2
b. ↓TXA2, will instantly ↓platelet aggregation
2. Inhibits the reuptake of Adenosine into the platelet
a. ↑extracellular Adenosine level
b. ↓platelet activation
3. Inhibits Phosphodiaesterase
a. ↓conversion of cAMP to AMP
i. ↓platelet resposne to ADP
b. ↓conversion of cGMP to GMP
i. ↑cGMP, ↓intracellular Ca2+ level
ii. Vasodilatory effect (Synergistic with Nitric Oxide)
Adverse Effects
1.
2.
3.
4.
Fatigue
Flushing
Nausea
Headache
Drug Name/ Infos
Abxicimab
Chimeric monoclonal
antibody of Glycoprotein
IIb/IIIa platelet
membrane receptor
Main Clinical Uses
1. Percutaneous
Transluminal Coronary
Angioplasty (PTCA)
therapeutic intervention
2. Unstable angina
3. Non-STEMI
4. STEMI + Thrombolytics

Glycoprotein IIb/IIIa Platelet Membrane Receptor Blocker
Mechanism of Action
1. Glycoprotein IIb/IIIa complex is function as receptors on the
platelet for
a. Fibrinogen
b. Vitonectin
c. Fibronectin
d. Von Willerbrand factor
2. Activation of this receptor will complete the final common
pathway of fibrinogenesis (platelet aggregation)
3. Abciximab is given through parenteral infusion in order to
occupy the receptor, stopping the common ligands from
activating the complex. This will therefore lead to
a. Blocks formation of fibrin
b. Inhibits platelet aggregation
4. Receptor blockage activity is at about >80%
Adverse Effects
1. Bleeding
2. Thrombocytopenia