Lec 8 – ANTIANGINAL DRUGS / ANTICOAGULANTS / AGENTS USED
IN DYSLIPIDEMIA
TibbsNotes – MGC
HELLO TIVVVVSSSSSSS I LABYUUUU MWAH MWAHHHH
ANTIANGINAL DRUGS
Pathophysiology of Angina
 Angina pectoris occurs whenever
myocardial oxygen demand exceeds
oxygen supply resulting the clinical
manifestation of chest discomfort caused
by transient myocardial ischemia
PHARMACOLOGIC GOALS OF THERAPY
The treatment of angina is aimed at:
 Decreasing O2 demand through:
o Decrease in heart rate
o Decrease in myocardial
contractility
o Decrease in wall stress
 Increasing oxygen supply through
coronary vasodilation
 Shifting myocardial metabolism to
substrates that require less oxygen
Mechanisms of Vasodilation by Drugs:
1. Nitrates: Through increase in cGMP
2. Calcium Channel Blockers, -
blockers: Through increase in
intracellular Ca2+
3. K Channel Openers (NICORANDIL):
Through stabilization or prevention
of depolarization of the vascular
smooth muscle cell membrane
4. 2 Agonists, D1
Agonists(FENOLDOPAM): Through
increase in cAMP in the vascular
cells
I. NITRATES
Pharmacokinetics:
NITROGLYCERINE (Prototype) – High hepatic first-pass effect
because of the organic nitrate reductase in the liver that removes
Pathology the nitrate groups
 Classic Angina: Fixed - Thus, oral bioavailability of NITROGLYCERINE and
obstruction due to ISOSORBIDE DINITRATE is very low (<10-20%)
atherosclerotic plaque  Given sublingually – avoids 1st pass effect
 Coronary Spasm:  Denitrated metabolites – higher bioavailability w/ significant
Dynamic Obstruction vasodilator efficacy
o ISOSORBIDE DINITRATE
o ISOSORBIDE MONONITRATE (100% Bioavailability)
Drugs relieve angina through  Half Life:
the following mechanisms: o Nitroglycerine: 2-8mins
1. Decrease in myocardial o Isosorbide Dinitrate: 3 Hours
oxygen requirement by
 Excretion: Glucoronide derivatives of dinitrated metabolites are
decreasing the determinants
excreted by the way of the liver
of oxygen demand
- -blockers Pharmacodynamics:
- Calcium Channel Blockers A. Smooth Muscles: Effects of Nitric Oxide:
- Isosorbide Dinitrate is 1. Activates guanylyl cyclase which
(Non-dihydropyridine)
- Nitrates & Nitrites denitrated by releases cGMP, first step toward
- If Sodium Channel glutathione S smooth muscle relaxation
Blockers transferase, releasing 2. Production of prostaglandin E or
free nitrite ion in the prostacyclin (PGI2)
2. Increase in myocardial O2
delivery by reversing smooth muscle cell 3. Protects against thrombosis and
coronary arterial spasm - This is then converted atherogenesis through:
- Nitrates & Nitrites to Nitric Oxide by o Inhibition of proliferation and
- Calcium Channel Blockers mitochondrial migration of smooth muscle
3. Shift of free fatty acid aldehyde o Reduction of endothelial adhesion
oxidation to glucose - Nitric Oxide combines of monocytes and leukocytes due
with the heme group to inhibitory effect of NO on the
oxidation which uses less
ATP of soluble guanylyl expression of adhesion molecules
- TRIMETAZIDINE cyclase on the endothelial surface
- RANOLAZINE o Antioxidant action – block the
oxidation of LDL decreasing foam
cell formation
B. Organ System Effects II. OTHER NITRO-VASODILATORS
1. Vascular smooth muscle relaxation of veins, arteries, arterioles, NICORANDIL
and precapillary sphincters  Nicotinamide nitrate ester that has vasodilating properties in
2. Indirect effects by baroreceptors and hormonal mechanisms –
normal coronary arteries
tachycardia & retention of salt and water
3. Relaxation of smooth muscle of the bronchi, GIT, and GUT
 Releases Nitric Oxide
4. Platelets – increase in cGMP results in decrease in platelet  Potassium-channel opener
aggregation  Reduces both preload and after load
5. Nitrite ion reacts with hemoglobin (w/c contains ferric ion) to  Provides myocardial protection via preconditioning by activation
produce methemoglobin of cardiac KATP channels
Indications & Mechanisms of clinical Mechanisms of Nitrate Tolerance  Produced significant reduction in relative risk of fatal and nonfatal
effects – Develops if used more than a coronary events
1. Effort Angina few hours w/o interruption and
 Approved use in Europe and Japan: treatment of angina
o Decreased venous return to due to:
the heart resulting in 1. Diminished release of NO due
reduction of intracardiac to depletion of tissue thiol III. CALCIUM CHANNEL BLOCKERS
volume compounds, hence can be Pharmacokinetics: Pharmacodynamics
o Decreased blood pressure prevented or reversed w/ a  Orally active  Bind to L-type calcium channels,
2. Variant Angina sulfhydryl regenerating agent  High 1 Pass Effect
st converting the mode from one in which
o Relieves coronary spasm by 2. Systemic compensation –  High Plasma Protein openings occur consistently after
relaxing the smooth muscles tachycardia and salt & water Binding depolarization to one in which such
of the epicardial coronary retention  Extensive openings are rare – long lasting smooth
arteries 3. Decrease in tissue sulfhydryl muscle relaxation
Metabolism
3. Unstable Angina group
o Dilates the epicardial coronary 4. Increased generation of O2- Mechanism of Clinical Effects
arteries and at the same time free radicals during nitrate  Decrease oxygen requirement through:
decreases myocardial oxygen therapy o Decrease myocardial contractile force
demand 5. Diminished availability of o Decrease in arteriolar tone and systemic vascular resistance
o Decreases platelet aggregation calcitonin gene-related o Decrease in cardiac rate
4. Acute MI & Congestive Heart peptide (CGRP) which is a  Increase in myocardial oxygen supply through relief and
Failure potent vasodilator prevention of focal coronary spasm
Acute Adverse Effects Contraindications  Decrease AV nodal conduction
 Orthostatic hypotension  Systolic BP < 90mmHg o Effective for termination of supraventricular reentrant
 Tachycardia  Severe Bradycardia or Tachycadia tachycardia
 Throbbing headache  RV Infarction o Decrease in ventricular response in atrial fibrillation & flutter
 Use of SILDEFANIL w/in 24 hrs
Organ System Effects: IV. BETA-BLOCKERS
Effects Mechanism of Action
Smooth Muscle Vascular >>> Bronchial, GIT, Uterine  Decrease myocardial requirements at rest and during exercise
Arteriolar >>>>>> Vein through decrease in HR, BP, and contractility
Dihydropiridines: (NIFEDIPINE) Artery >>> Cardiac  Decrease mortality in patients with recent MI
Benzothiazepine: (DILTIAZEM) Artery = Cardiac
 Improve survival and prevent stroke in patients with HPN
Phenylalkylamine: (VERAPAMIL) Artery < Cardiac
Cardiac Muscle SA & AV node  Beta blockers of choice: Cardioselective w/o intrinsic
Cardiac muscle cells sympathomimetic activity
Skeletal muscle None (uses intracellular pools of calcium) Undesirable Effects in Angina
Cerebral Nimodipine (high affinity for cerebral vessels)  Increase in end-diastolic demand through:
Others: Inhibition of insulin release – VERAPAMIL o Increase in end-diastolic volume
Platelets Inhibition of aggregation o Increase in ejection time
P-glycoprotein Blocked by VERAPAMIL Contraindications Potential Complications
Comparison of the CCB Prototypes 1. Asthma and other 1. Fatigue
Compound Coronary Suppression Suppression Suppression bronchospastic conditions 2. Impaired Exercise Tolerance
Vasodilation of Cardiac of SA Node of AV Node 2. Severe bradycardia 3. Insomnia
Contractility 3. AV Blockade 4. Unpleasant Dreams
VERAPAMIL ++++ ++++ +++ ++++ 4. Sick Sinus Syndrome 5. Worsening claudication
5. Severe Unstable LV Failure 6. Erectile Dysfunction
DILTIAZEM +++ ++ ++++ +++
NIFEDIPINE +++++ + + 0
(0 – No effect, ++++ = most prominent)
Clinical Uses Calcium Channel Blockers
1. Hypertension  In unstable angina, immediate release
2. Supraventricular short-acting calcium channel blockers
Tachyarrhythmia can increase the risk of adverse
o Verapamil and cardiac events
Diltiazem, decrease AV  In Non-Q MI, Diltiazem can decrease
nodal conduction thus the frequency of post infarction angina
effective in  Slow release and long-acting CCBs in
supraventicular reentry combination w/ nitrates and beta
tachycardia and in blockers can decreas the frequency of
decreasing ventricular post-infarction angina
responses in atrial Toxicity
flutter/fibrillation  Cardiac Depression
3. Hypertrophic  Cardiac Arrest
Cardiomyopathy  Bradycardia
4. Reynaud’s Phenomenon  AV Block
5. Migraine  CHF
 V. NEWER ANTIANGINAL DRUGS VI. ACEI in ACS
Metabolic Modifiers Effects Indications
 TRIMETAZINE (pFOX inhibitor or metabolic modulator_  Early oral ACEI reduces mortality Greatest benefit in patients with:
 Patially inhibit the fatty acid oxidation pathway (long chain 3- and CHF associated with MI 1. Anterior Infarction
ketoacyl thiolase, LC-3KAT) in the myocardium  ACEI help prevent adverse LV 2. Prior Infarction
 With inhibition of the pathway, glucose is used instead which remodeling, delay progression of 3. Heart Failure
uses less ATP HF and decrease sudden death 4. Clinical signs of LV dysfunction
 ALLOPURINOL and recurrent MI 5. LV Ejection Fraction <40%
 Inhibits xanthine oxidase, an enzyme that contributes to Dose Administration
oxidative stress and endothelial dysfunction  Not administered in the first 6 hours after MI
 High dose allopurinol prolongs exercise time in patients with  Once fibrinolytics are administered and the patient is symptomatically
atherosclerotic angina and hemodynamically stable, a low oral dose is initiated and titrated to
RANOLAZINE a full dise in 24-48 hours
 Reduces a late sodium current (INA) that facilitates calcium entry via the
Na+-Ca2+ exchanger.
 The resulting reduction in intracellular valcium concentration reduces
diastolic wall stress and intramural small vessel compression and
reduces the deleterious effects attributed to sodium and calcium
overload during ischemia.
 It reduces ischemic episodes and need for nitroglycerine in chronic
stable angina
IVABRADINE
 Selective If sodium channel blocker w/c reduces cardiac rate by
inhibiting the hyperpolarization-associated sodium channel in the
sinoatrial node
 Bradycardic drug with no other hemodynamic effects
 An advantage is the lack of effect on GI and bronchial smooth muscles
FASUDIL
 Inhibitor of smooth muscle RhoA/Rho kinase (ROCK) and reduces
coronary vasospasm, pulmonary hypertension, apoptosis and other
conditions
 Improved stress test in patients with CAD
 ANTIPLATELETS
Mechanism of action of the Antiplatelet Agents
1. Inhibition of prostaglandin metabolism
o ASPIRIN
2. Inhibition of ADP-induced platelet activation
o CLOPIDOGREL
o TICLOPIDINE
o PRASUGREL
o TICAGRELOR
3. Blockade of GP IIb/IIIa receptors on platelets
o ABCIXIMAB
o TIROFIBAN
o EPTIFIBATIDE
 ASPIRIN ADP Inhibitors:
TICLOPIDINE, CLOPIDOGREL, PRASUGREL, TICAGRELOR
 Reduce platelet aggregation by inhibiting the ADP pathway of platelets
 Thienopyridine derivatives that irreversibly inhibit the binding of ADP to
its receptor on platelets
 CAPRIE – reduction in the rate of ischemic events in favor of clopidogrel
TICLOPIDINE
Indications Adverse Effects
 Prevention of stroke in patients  Nausea
with a history of Transient  Dyspepsia
Ischemic Attack (TIA) or  Diarrhea
thrombotic stroke, intolerant to  Hemorrhage
ASA  Leukopenia
 In combination with ASA for the  Thrombotic Thrombocytopenic
prevention of coronary stent Purpura
thrombosis  Useful for patients who cannot
tolerate Aspirin
CLOPIDOGREL
 Prodrug, requires activation via CYP2C19 Indications:
o Thus, in poor metabolizers, may be  Unstable Angina
inadequate drug effect  Non-ST Segment
 Antithrombotic effect is dose dependent Elevation Myocardial
w/in 5 hours after oral loading dose of Infarction (NSTEMI) in
 Inhibits the synthesis of thromboxane A2 by Precautions: 300mg, with 80% of platelet activity combination w/ ASA
irreversible acetylation of the enzyme 1. Active peptic inhibited  STEMI
cyclooxygenase ulcer disease  Duration of antiplatelet effects: 7-10  Recent MI, stroke or
 A dose of 160-325mg causes immediate and near- 2. History of days established peripheral
total inhibition of thromboxane A2 production hypersensitivity  Fewer side effects than ticlopidine arterial disease
 Reduces coronary re-occlusion and recurrent or allergy  Rarely associated with neutropenia Dose: Loading – 300mg
events after fibrinolytic therapy in patients with 3. Bleeding then 75mg od
unstable angina disorders, PRASUGREL
 Significantly reduces the incidence of nonfatal MI severe hepatic
 Similar to Clopidogrel
 Dose, route: In the early hours after infarction, disease
 Loading dose 60mg then 10mg/day
ASA is absorbed more quickly when chewed than  TRITON-‘TIMI38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
swallowed Platelet Inhibition with Presugrel) – RCT, double blind trial with ASA and other standard
 ASA suppositoris 325mg are recommended for therapies with PCI, showed reduction of primary composite endpoints with prasugrel
compared with clopidogrel
patients with severe nausea, vomiting, or upper
o But with major and minor bleeding risk is increased with prasugrel
GI disorders
 Contraindications: Patients w/ history of TIA or stroke
TICAGRELOR PHOSPHODIESTERASE INHIBITORS
 Allosteric antagonist of adenosine diphosphate (ADP) receptors or 1. DYPYRIDAMOLE
subtype P2Y12  Inhibits adenosine uptake and cGMP phosphodiesterase activity
 Block is reversible which can be useful before surgery  Used primarily in combination with ASA (to prevent
 Does not need hepatic activation (unlike clopidogrel) cerebrovascular ischemia) and with WARFARIN (primary
 Higher incidence of non-lethal bleeding prophylaxis of thromboemboli in patients with prosthetic heart
 Act faster and shorter than clopidogrel valves
2. CILOSTAZOL
GLYCOPROTEIN IIB/IIIA INHIBITORS  Promotes vasodilation and inhibition of platelet aggregation
 IIb/IIIa receptor Glycoprotein IIb/IIIa Inhibitors:  Used primarily to treat intermittent claudication
complex functions 1. ABCIXIMAB – humanized chimeric monoclonal
as a receptor antibody directed against the IIb/IIIa complex
mainly for - For use in PCI and acute coronary
fibrinogen & syndromes (ACS)
vitronectin and 2. EPTIFIBATIDE – analog of the sequence at the
for fibronectin & extreme carboxyl terminal of the delta chain of
von Willebrand fibrinogen which mediates the binding of
factor fibrinogen to the receptor
 Activation of the 3. TIROFIBAN – contains the amino acid sequence
receptor is the Arg-Gly-Asp (RGD), which is the main
“final common recognition sequence for integrin receptors
pathway” fpr such as IIb/IIIa
platelet EPTIFIBATIDE & TIROFIBAN inhibit ligand binding
aggregation by their occupancy of the receptor but do not block
the vitronectin receptor
Indications: Contraindications:
1. Non-Q MI 1. Active internal bleeding or bleeding
2. Unstable Angina disorder in the last 30 days
managed medically 2. History of intracranial hemorrhage,
3. Unstable angina/ Non- neoplasm, AV malformation, aneurysm,
Q wave MI patients or stroke in the last 30 days
undergoing PCI 3. Major surgical procedure or trauma w/in
1 month
4. Hypersensitivity to concomitant use of
another GP IIb/IIIa
5. Platelet count <150000
 ANTICOAGULANTS Heparin for Acute Coronary Syndrome (ACS)
Classifications Drug Class Specific Drugs
Class I – Effective, supported by definitive evidence
I. Indirect Thrombin High-molecular-weight UFH or  IV Heparin administration - Patients undergoing direct or adjunct
Inhibitors heparin UNFRACTIONATED Percutaneous Coronary Intervention (PCI)
HEPARIN Class IIa – Effective, weight of evidence SC administration of unfractionated
Low-molecular-weight ENOXAPARIN strongly supports use heparin (7500u BID) or SC LMWH –
heparin FRAXIPARIN  The relatively fibrin-specific All patients not treated w/
DALTEPARIN fibrinolytic agents have a fibrinolytic who do not have a
TINZAPARIN variable effect on coagulation contraindication to heparin
Synthetic Pentasaccharide FONDAPARINUX  IV unfractionated heparin – Patients
o Conjunctive heparin is
II. Direct Thrombin Parenteral direct thrombin HIRUDIN at high risk for embolism
necessary to reduce re-
Inhibitors inhibitors LEPIRUDIN  IV administration of unfractionated
BIVALIRUDIN occlusion of the infarct heparin – Patients treated with
ARGATROBAN vessel nonselective fibrinolytic agents
Oral direct thrombin DABIGATRAN  IV administration – Patients (streptokinase, APSAC) who are at
inhibitors receiving ALTEPLASE or increased risk for systemic emboli
III. Direct Factor Xa Oral direct factor Xa RIVAPROXABAN RETEPLASE (large anterior MI, atrial fibrillation,
Inhibitors inhibitors APIXABAN  IV administration unfractionated known LV thrombus, or previous
IV. Warfarin WARFARIN heparin or SC LMW heparin – embolic event)
Patients with NSTEMI
I. INDIRECT THROMBIN INHIBITORS Class IIb – Effective, supported by less Class III – Not beneficial, possibly harmful
definitive evidence  Routine IV Heparin – (w/in 6hrs) to
HEPARIN  SC administration – Pulmonary patients receiving a nonselective
 Heterogenous mixtures of sulfated mucopolysaccharides
embolism prophylaxis until fibrinolytic agent (STREPTOKINASE,
 Bind tightly to antithrombin & produce a conformational change to
fully ambulatory, part. In the APSAC) who are not at high risk for
antithrombin which exposes its active site for more rapid interaction with systemic emboli is not
presence of CHF
proteases recommended
 HMW fraction have high affinity for antithrombin Toxicity Contraindications
 LMW fractions inhibit activated factor X but have less effect on  Major: Bleeding  Hypersensitivity Reaction
antithrombin  Reversible Alopecia  Presence of active bleeding
Unfractionated Heparin Low molecular weight heparin  Long Term  Hemophilia
Efficacy Equal Equal o Osteoporosis  Significant
Bioavailability Lesser (SC) More (SC) o Spontaneous Fractures thrombocytopenia
Dosing More Lesser o Mineralocorticoid Deficiency  Purpura
Administration IV, SC SC  Platelet Effects  Severe Hypertension
Monitoring aPTT, protamine None, AntiXa units o Transient Thrombocytopenia (25%) – forst  Intracranial Hemorrhage
titration, antiXa units (2- 5 days, mild, dut to heparin-induced  Infective Endocarditis
2.5x control) aggregation  Active TB
o Severe Thrombocytopenia (5%)  Ulcerated lesions of the GIT
Examples UFH ENOXAPARIN, DALTEPARIN,
TINZAPARIN o Paradoxical Thrombosis – Antibody  Threatened Abortion
Reversal of PROTAMINE SULFATE Enoxaparin – Partial against heparin-platelet factor 4 complex
Action 1mg: 100 units neutralization w/ protamine which binds to Fc receptors on adjacent
platelets
Danaparoid – Plasmaparesis
 III. FACTOR XA INHIBITORS
II. DIRECT THROMBIN INHIBITORS  Renal excretion  No antidote
Exert their anticoagulant effect by directly binding to the active site of 1. RIVAROXABAN 2. APIXABAN
thrombin, thereby inhibiting thrombin’s downstream effects  Prevention of venous  In clinical development
Parenteral Direct Thrombin Inhibitors thromboembolism  Lower rates of venous thromboembolism and similar
bleeding compared with enoxaparin 40gm SC
1. HIRUDIN – specific, irreversible 4. ARGATROBAN – Small following hip or knee
 Studies in MI: prematurely terminated because of
thrombin inhibitor (from leech saliva) molecule thrombin inhibitor surgery increase in bleeding risk w/o a significant decrease in
2. LEPIRUDIN – (Recombinant form of  Indications:  Prevention of stroke ischemic events
HIRUDIN) Can inactivate fibrin-bound o Patient with Heparin- in patients with atrial  Studies in stroke prevention in AF compared with
thrombin in thrombin Induced fibrillation ASA: prematurely stopped because of evidence of
3. BIVALIRUDIN – bivalent inhibitor of Thrombocytopenia increased efficacy in the APIXABAN arm
thrombin and also inhibits platelet (HIT) with or without
activation thrombosis IV. WARFARIN
 Pharmacokinetic: Rapid onset and o Coronary Angioplasty  Blocks the carboxylation of several Indications
short half-life in patients with HIT glutamate residues in:  For prophylaxis & treatment of
 Excretion: 20& Renal excretion,  Clearance: Dependent o Prothrombin and factors VII, IX, thrombotic diseases – INR 2-3
80% Metabolic on liver function and X  Artificial Heart Valves – INR of
 Indications: Percutaneous Coronary 5. MELAGATRAN o Endogenous anticoagulants protein 2.5-3.5
Angioplasty C&S Warfarin Resistance –
Oral Thrombin Inhibitors – Have predictable pharmacokinetics and o Resulting in incomplete molecules Progression or recurrence of a
bioavailability which allow fixed dosing and predictable anticoagulant that are biologically inactive in thrombotic event while in the
response (monitoring is unnecessary) coagulation therapeutic range
 Do not interact with P450 interacting drugs  Prevents the reductive metabolism of  Commonly seen in patients
 Rapid onset and offset of action allow for immediate anticoagulation w/o the inactive vit. K epoxide back to its with advanced cancers of GI
need of overlap with additional anticoagulants hydroquinone form (Vit. K origin
DABIGATRAN ETEXILATE MESYLATE Pharmacology: antagonism)  Recommendation: Increase the
 Approved for prevention of venous  Converted to DABIGATRAN Blocks the ability of Vitamin K to target INR (but with increased
thromboembolism in patients undergoing following oral administration carboxylate the Vitamin K dependent bleeding risk)
hip and knee replacement surgery  Bioavailability: 3-7% in clotting factors, thereby reducing their  Change to an alternative form
 First oral direct thrombin inhibitor normal volunteers coagulant activity. of anticoagulation – LMWH
approved by the FDA  Drug Interaction: Increase Toxicity
 Approved in 2010 to reduce the risk of effect with concomitant use  Hemorrhagic disorder in the fetus
stroke and systemic embolism with of KETOCONAZOLE,  Birth Defects – abnormal bone formation
nanvalvular atrial fibrillation and at least AMIODARONE, QUINIDINE,  Due to increased activity of protein C
one other defined risk factor dose of CLOPIDOGREL o Cutaneous necrosis
150mg bid was shown to be superior  Half Life: 12-17 hrs o Infarction of breast, fatty tissues, intestine, and extremities
warfarin with an INR target of 2-3  Excretion: Renal (Avoid in o Venous Thrombosis – Hemorrhagic Infarction
 Equivalent efficacy and safety with patients with severe renal  Monitoring: Prothrombin time with INR (International Normalized Ratio)
LMWH impairment)  Uses international reference thromboplastin made from human brain instead of the less
sensitive rabbit brain
 Dose: INR of 2-2.5
Drug Interactions
Pharmacokinetic: Pharmacodynamic:
FIBRINOLYTIC DRUGS
 Rapidly lyse thrombi by catalyzing the formation of the serine protease plasmin
 Enzyme induction 1. Synergism
from its precursor zymogen, plasminogen
 Enzyme inhibition 2. Competitive antagonism (Vit. K)
 Create a generalized lytic state when administered intravenously
 Reduced plasma 3. Altered physiologic control loop for Vit. K 1. STREPTOKINASE – protein synthesized by streptococci that combines with
protein binding the proactivator plasminogen that catalyzes the conversion of inactive
Increased Prothrombin Time Decreased Prothrombin Time plasminogen to active plasmin
Pharmacokinetic Pharmacodynamic Pharmacokinetic Pharmacodynamic 2. UROKINASE – human enzyme synthesized by the kidney that directly
Amiodarone Drugs Barbituate Drugs converts plasminogen to active plasmin
Cimetidine Aspirin (high doses) Cholestyramine Diuretics 3. ANISTREPLASE (Anisoylated plasminogen streptokinase activator comples
Disulfiram Cephalosporins 3rd Rifampin Vitamin K – APSAC) – consists of a complex of human plasminogen and bacterial
Metronidazone Generation Body Factors streptokinase that has been acylated to protect the enzyme’s active site. When
Fluconazole Heparin Hereditary administered, the acyl group spontaneously hydrolyzes, freeing the activated
Phenylbutarazone Body Factors Resistance streptokinase-proactivator complex
Sulfinpyrazone Hepatic Disease Hypothyroidism 4. TISSUE PLASMINOGEN ACTIVATORS (T-PA) – preferentially activate
Trimethoprim- Hyperthyroidism plasminogen that is bound to fibrin w/c confines fibrinolysis to the formed
sulfamethoxazole thrombus and avoids systemic activation
No Effect: 5. ALTEPLASE – human t-PA manufactured by recombinant DNA technology
 Ethanol  Opioids 6. RETEPLASE – human recombinant t-PA from which several amoni acid
 Phenothiazines  Indomethacin sequences have been deleted; less fibrin-specific than TPA
 Benzidiazepines  Most antibiotics 7. TENECTEPLASE – mutant form of t-PA, has longer half-life, slightly more
 Acetaminophen fibrin specific than t-PA
Warfarin: Reversal of Effect General Indications: Indications for thrombolytic therapy in
1. Pulmonary embolism with MI
 Stop the drug  Prothrombin Complex Concentrates hemodynamic instability 1. Chest pain suggestive of MI
 Administer Vit. K1 (PHYTONADIONE) (PCC) – Bebulin and Proplex T 2. Severe deep thrombosis (ie. Superior 2. ST Segment elevation >0.1mV
 Fresh Frozen Plasma  Recombinant factor VIIa (rFVIIa) vena caval syndrome) (1mm) in 2 or more contiguous
3. Ascending thrombophlebitis of the ilio- ECG limb leads or chest leads or
femoral vein with severe lower new or presumably new LBBB,
extremity edema strngly suspicious for injury (BBB
4. Peripheral vascular disease obscuring ST segment analysis)
5. Acute STEMI 3. Symptom onset <12hrs (Class I) or
6. Acute Ischemic stroke within 3 hrs of 12-24hrs with continuing pain
symptom onset (recombinant t-PA) (Class IIa)
Absolute Cautions
Contraindications 1. Severe uncontrolled HPN on presentation (BP
1. Previous hemorrhagic 180/110mmHg); history of severe chronic HPN
stroke 2. Current use of anticoagulants (INR>2.5); known
2. Other stroke or CVA bleeding disorder
within 1 year 3. Recent trauma (w/in 2-4 wks), including head
3. Active internal and traumatic CPR or major surgery (<3wks)
bleeding (menses 4. Recent (2-4wks) internal bleeding; active peptic
excluded) ulcer
4. Suspected aortic 5. Pregnancy
dissection 6. For Streptokinase: allergy or prior exposure (esp
5 days to 2 years) to anticoagulant drugs

AGENTS USED IN DYSLIPIDEMIA
Drug Therapy for Dietary Management for
Hyperlipidemia Hyperlipoproteinemia
 Decision to treat is based General Recommendations
on specific metabolic  Limit total calories from fat to 20-25%
defect and its potential for of daily intake
causing atherosclerosis or  Saturated fats to less than 8%
pancreatitis  Cholesterol to less than 200mg/day
 Diet is necessary adjunct to Elevated LDL
drug therapy  Restrict cholesterol, saturated, and
 Avoid drug treatment to trans-fat
women likely to become  Provide sufficient calories to maintain
pregnant ideal body weight
 Drug treatment is rarely  Use complex carbohydrates and fiber
indicated before age 18  Monounsaturated fat within the fat
allowance
Elevated Triglycerides
 Fat, alcohol, and calorie restriction
 Omega-3 fatty acids in fish oils –
induce profound lowering of
triglycerides
 Avoid alcohol
REDUCTASE INHIBITORS
Mechanism of Action
 Structural analog of HMG-
CoA intermediate that is
formed by HMG-CoA
reeducates in the synthesis
of mevalonate thus causing
partial inhibition of the
enzyme
 Decrease LDL by inducing
an increase in high affinity
LDL receptors resulting to
increased fractional
catabolic rate of LDL and
liver excretion of VLDL
remnants
 Modest decrease in plasma
Triglycerides
 Small increase in HDL
 Decrease oxidative stress
& vascular inflammation
 Increase stability of
atherosclerotic lesions
 Reduces the availability of
isoprenyl groups from the
HMG-CoA pathway
resulting in reduced
prenylation of Rho & Rab
proteins resulting in
reduced activation of Rho
kinase
Pharmacokinetics
 LOVASTATIN and SIMVASTATIN –
inactive lactone prodrugs, hydrolyzed in
the GIT to active -hydroxyl derivatives
 PRAVASTATIN – has an open, active
lactone ring
 ATORVASTATIN / FLUVASTATIN /
ROSUVASTATIN – Fluorine-containing
congeners, active as given
 Absorption: 40-75%, except
FLUVASTATIN (completely absorbed)
o All have high 1st pass extraction by
the liver
 Excretion: Most in bile, 5-20% in urine
 Plasma half-life: 1-3 hrs, except
ATORVASTATIN (14hrs) &
ROSUVASTATIN (19hrs)
 Absorption enhanced with food
 ROSUVASTATIN – most efficacious
agent for severe hypercholesterolemia
Toxicity
 Elevation of serum aminotransferase
activity
 Patients with hepatotoxicity may
present w/ precipitous decreases in LDL,
malaise, and anorexia
 Minor increase in creatinine kinase
activity
 Myopathy in monotherapy and when
used with AMIODARONE & VERAPAMIL
Drug Interactions of Reductase Inhibitors NIACIN
Cytochrome P450 3A4 Inhibit or compete with 3A4  Water soluble vitamin (Vit. B3) Therapeutic Uses
LOVASTATIN  Macrolides  Inhibits VLDL secretion, in turn  Normalize levels of LDL in patients
SIMVASTATIN  Cyclosporin decreasing production of LDL with heterozygous familial
ATORVASTATIN  Ketoconazole  Decreases production of VLDL hypercholesterolemia in
 HIV Protease Inhibitors apolipoproteins combination with a bile acid-binding
 Nefazodome  Increases clearance of VLDL resin or a reductase inhibitor
 Fibrates via the lipoprotein lipase  Nephrosis
 Tacrolimus pathway thus contributing to  Severe lipidemia not completely
 Grapefruit Juice the reduction of TGC responsive to dietary measures
Increase expression of CYP3A4  Increases excretion of neutral Toxicity
 Phenytoin sterols in the stool  Cutaneous vasodilation –
 Griseofulvin  Decreases the catabolic rate prostaglandin-mediated side effect
 Barbituates of HDL thus mitigated by 81-325mg of ASA
 Rifampin  Reduces fibrinogen levels and Ibuprofen
 Thiazolidinediones  Increases levels of tissue  Pruritus, rashes, dry skin and
CYP 2C9 Inhibitors of CYP 3A4 plasminogen activator mucuous membranes, Acanthosis
FLUVASTATIN  Ketokonazole  Inhibits intracellular lipase of nigricans
ROSUVASTATIN  Metronidazole adipose tissues via receptor  Nausea, Abdominal discomfort
 Sulfinpyrazone mediated signaling thus  Elevations in levels of
 Amiodarone reducing VLDL production by aminotransferases; true
 Cimetidine reducing the flux of free fatty hepatotoxicity – rare
Pravastatin - sulfation acids to the liver  Carbohydrate intolerance
 Hyperuricemia
Reductase Inhibitors
 Grapefruit or grapefruit juice  Atrial Arrthymias
 Reversible toxic amblyopia
 Elevate levels of LOVASTATIN, SIMVASTATIN, and ATORVASTATIN
 May potentiate the action of anti-
 Creatibibe Kinase should be measured frequently in patients receiving
HPN agents
potentially interacting drug combinations
 Birth defects (animals)
 Should be discontinued temporarily in the event of serious illness,
trauma, or major surgery
 FIBRIC ACID DERIVATIVES BILE ACID BINDING RESIN
 CLOFIBRATE Chemistry & Pharmacokinetics
 GERNFIBROZIL  GERNFIBROZIL – absorbed from the intestine, tightly
 FENOFIBRATE bound to plasma proteins, undergoes enterohepatic
 BEZAFIBRATE circulation, readily crosses the placenta
- T½: 1.5hrs
- Excretion: Renal 75%
 FENOFIBRATE – isopropyl ester hydrolyzed completely
in the intestine
- T½: 20hrs
- Excretion: 70% renal as glucuronide and 25% feces
Functions primarily as a ligand for the nuclear transcription regulator,
peroxisome proliferator-activated receptor-alpha (PPAR-a)
- Thus it transcriptionally upregulate LPL, apo-AI and apo-AII, and
down-regulate apoCIII which is an inhibitor of lipolysis
Effects: Therapeutic Uses:  COLESTIPOL Mechanism of Action
 Major effect: increase in  Useful in hypertriglyceridemias in which  CHOLESTYRAMINE  Tenfold increased excretion of bile acids
oxidation of fatty acids in VLDL predominate  Increased clearance results in enhanced
 COLESEVELAM
liver & striated muscle  Dysbetalipoproteinemia conversion of cholesterol to bile acids via 7-
 Bind bile acids in the hydroxylation which is normally controlled by
 Increase lipolysis of  Hypertriglyceridemias resulting from use intestinal lumen and negative feedback by bile acids
lipoprotein TGC via of viral protease inhibitors prevent their  Decreased activation of the FXR receptor by bile
lipoprotein lipase Toxicity: reabsorption acids may result in modest increase in TGC but
 Decrease intracellular  Skin rashes  Useful in can also improve glucose metabolism in diabetics
lipolysis in adipose tissue  GIT symptoms hyperlipoproteinemias  Upregulation of LDL receptors in cell membrane
 Decrease VLDL in plasma  Myopathy involving isolated esp. liver resulting in increased uptake of LDL and
due to decreased  Arrythmias increases in LDL IDL
secretion from the liver  Hypokalemias Therapeutic Uses Toxicity
 Decrease TGC in plasma  High levels of transferases and alkaline  Only for isolated increases in LDL  Constipation
 Moderately increase HDL phosphatase  Primary hypercholesterolemia  Heartburn and diarrhea
cholesterol level  Decrease in white blood count or  In combination with other anti-  Malabsorption of Vit. K
 Moderately decrease LDL hematocrit lipid drugs  Dry flaking skin
 Relief of pruritus in patients with
o But in those with  Potentiate the action of coumarin and  Impairs absorption of digitalis,
cholestasis and bile salt
combined indanedione anticoagulants thiazides, warfarin, tetracycline,
accumulation
hyperlipidemia, LDL  Rhabdomyolysis – rare thyroxine, iron salts, prevastatine,
 Digitalis toxicity – resins bind
often increases fluvastatine, folic acid,
 Avoid in patients with hepatic and renal digitalis glycosides, increasing their phenylbutazone, aspirin, ascorbic acid
dysfunction rate of removal from the GIT
 Modest increase in cholesterol gallstones
– due to increase in cholesterol content
of bile
 INHIBITORS OF INTESTINAL STEROL ABSORPTION
EZETIMIBE
 Selective inhibitor of intestinal absorption of
cholesterol and phytosterols through the transport
protein NPC1L1
o Inhibits reabsorption of cholesterol excreted in
the bile
o Synergistic with reductase inhibitors in
decreasing LDL as great as 25%
 Absorbed and conjugated in the intestine to an
active glucuronide reaching peak blood vessels in
12-14 hrs
 Undergoes enterohepatic circulation – T½: 22hrs
 80% excreted in the feces
 No interaction with WARFARIN & DIGOXIN
DRUG COMBINATIONS
Toxicity  Useful when:
 Not a substrate for o VLDL levels are significantly increased during treatment of
cytochrome P450 hypercholesterolemia with a bile acid binding resin
 Small increase in o LDL & VLDL levels are both elevated initially
impaired hepatic o LDL and VLDL levels are not notmalized with a single agent
function when o Elevated levels of Lp(a) or HDL deficiency coexist with other
given with statins – hyperlipidemias
liver function tests Fibric Acid Derivatives & Bile Acid- HMG-CoA Reductase Inhibitor &
should be done Binding Resin Bile Acid Binding Resin
before starting the
 Useful in familial combined  Familial Hyperholesterolemia
drug then every 2-
hyperlipidemia intolerant of  Reductase Inhibitors should be
4 months
niacin given 1 hour before or 4 hours
 May increase risk of cholelithiasis after resin
Niacin & Bile Acid Binding Resin Niacin & Reductase Inhibitors
 Effectively controls VLDL levels  In hypercholesterolemia: more
during resin therapy of familial effective than either agent alone
combined hyperlipidemia  Indication: Familial combined
involving both increased VLDL & hyperlipoproteinemia
LDL levels Reductase Inhibitors & Ezetimibe
 Heterozygous Familial  Primary hypercholesterolemia
Hypercholesterolemia  Homozygous
 May be taken together because hypercholesterolemia who have
niacin do not bind to resin some receptor function
 Niacin & Reductase Inhibitor: Reductase Inhibitors and
Familial Hypercholesterolemia Fenolfibrate
 Ternary combination of Resin,  Fenofibrate with Rosuvastatin –
Niacin, and Reductase Inhibitor: familial combined
Severe disorders involving hyperlipoproteinemia and other
elevated LDL levels conditions involving elevation in
both LDL & VLDL
Ternary Combinations of Resins, Ezetimibe, Niacin, and Reductase
Inhibitors
 Act in a complimentary fashion to normalize cholesterol in patients
with severe disorders involving elevated LDL
 Effective doses of individual drugs may be lower than when each is
used alone
Case Discussion 8 – ANTIANGINAL DRUGS / ANTICOAGULANTS /  Emergency Room
AGENTS USED IN DYSLIPIDEMIA o Nitroglycerine Drip
TibbsNotes – MGC o ASA 325mg
o Streptokinase (1.5 units) per IV infusion in 60 minutes
A 50-year old hypertensive, obese male came into the emergency room  2d Echo (2 days after)
complaining of severe precordial chest pain, compressing in character o Severe hypokinesia of anterior wall - infarction
and radiating to the jaw which used to be relieved by 1 dose of sublingual o Interventricular septum with suspicious apical thrombus
NITROGLYCERINE in the past 2 weeks. 2 hours prior to consult, the pain 2. What are the goals of treatment?
recurred and persisted for 30 mins. despite 3 doses of sublingual Treatment Goals:
NITROGLYCERINE. He was diaphoretic, with BP of 180/110 and HR=110  Control of Discomfort
(regular). The breath sounds were normal but his heart sounds were faint  Limitation of Infarct size and further progression of STEMI –
and there was an audible S4 component. Other PE findings were normal. restoration of coronary reperfusion, reduce O2 demand, prevent
12 lead EKG showed 3 mm ST-segment elevation in V1-V5 suggestive of noxious stimuli
acute anterior wall myocardial infarction. Troponin was positive. At the  Maintain patency of the infarct-related artery
emergency room, NITROGLYCERINE drip was started. He was also given
 Reduce recurrence of thrombosis in coronary artery
ASA 325mg chewed as well as 1.5 million units of streptokinase per IV
 Treat apical thrombus
infusion in 60 mins. A 2d echo done 2 days later showed severe
hypokinesia of the anterior wall & interventricular septum with suspicious  Treat HPN
apical thrombus.  Treat Obesity
1. What is the problem of the patient? 3. What is NITROGLYCERINE? Why was it given sublingually? What
 General Data:  Physical Exam: are the other preparations and what are its indications?
o 50-year old, male o General: Diaphoretic  Nitroglycerine is an Nitrate that ultimately increases cGMP, which
o Hypertensive (increased sweating) – in turn leads to downstream effects leading to smooth muscle
o Obese sympathetic response relaxation (vasodilatation)
 CC: Chest Pain o CV: o MoA: Releases nitrite which is converted to Nitric Oxide,
o Severe  BP: 180/110 (HPN) which then combines with the heme group of guanylyl
o Compressing  HR: 110 (regular) cyclase
o Precordial radiating to the  Faint Heart sound o It also contibutes to the production of PGE & PGI2
jaw (Upon Admission)  S4 heart sound (atrial valve o It also protects against thrombosis and atherogenesis
 History: closure) – Ventricular o Due to Vasodilatation, it also induces reflex tachycardia & salt & water
o 2wks PTC - Admission: failure retention. It also relaxes other sm, inhibits plalet aggregation, and
Relieved by 1 dose sublingual o Respiratory produces methemoglobin
Nitroglycerin  Normal Breath sounds  It has very low oral bioavailability (<10-20%) due to extensive hepatic 1st
o 2hrs PTC: recurrence of pain,  ECG: pass effect because of the organic nitrate reductase in the liver that
persistence for 30mins. o 3mm ST Segment Elevation removes nitrate groups. Thus, we give it sublingually to bypass this.
(Despite 3 doses of sublingual (Acute anterior wall  Other Preparations:
Nitroglycerin) myocardial infarction) – o It also has a transdermal patch preparation, also to avoid first
medical emergency pass effect
o (+) Troponin – MI (Acute?)
 o Isosorbide Mononitrate has increased bioavailability
(100%)
o Isosorbide Dinitrate releases 2 nitrite ions, which produces
greater effects
o Topical/Oral Nitrates used only when pain is resolved
o Nitroglycerine Drip is used at the ER. Given when sublingual
dose does not address pain after 3 doses, 5 mins. apart
 In STEMI, IV Nitroglycerine is indicated for immediate relief of
chest discomfort. Additionally, it decreases myocardial oxygen
demand (by powering preload) and increases oxygen supply by
dilating coronary vessels or collateral vessels)
4. What is streptokinase? Why was it given in the emergency
room? What is the pathophysiology in Acute MI that warrants
its use?
 Streptokinase is an anticoagulant, specifically a fibrinolytic drugs,
which lyses thrombi by catalyzing plasmin production from
binding to plasminogen. It is synthesized from streptococci
 The use of fibrinolytics is indicated in a certain diagnosis of
thrombus formation within the coronary arteries. Its goal is to re-
establish reperfusion in the affected area, thereby limiting the
infarct area. However, primary PCI is more preferred if diagnosis
is in doubt.
 It should be started within 30 mins. of therapy when there are no
contraindications
 It is also warranted to prevent further thrombosis and recurrence
of thrombosis of the affected artery
5. What is ASA? Why was it given? If the patient has asthma or
history of Peptic Ulcer Disease, what alternative drugs can be
given?
 ASA (Aspirin) is an antiplatelet drug which inhibits Thromboxane
A2 production by irreversible acetylation (inhibition) of COX-1
 It is used to maintain coronary artery patency, adjunct to the
fibrinolytic drugs.
 It also reduces coronary re-occlusion and recurrent events after
fibrinolytic therapy in patients (It is also absorbed more quickly
when chewed hours after MI).
 Alternatives would include ADP-Inhibitors (Clopidogrel,
Prasugrel, Ticagrelor) and Glycoprotein IIB/IIIA Inhibitors
(Abciximab, Eptifibatide, Tirofiban)
 Heparin is shown to be an effective agent; however, it can induce
gastric ulcerations
6. What is heparin? Why was it given? What take home
medication can be given to prevent a thromboembolic event?
How will treatment be monitored?
 Heparin is an anticoagulant and is the standard anticoagulant
agent used in clinical practice
o It exerts its effect by tightly binding to antithrombin, which
then exposes its active site for more rapid interaction with
proteases (agonist for antithrombin). UFH has high affinity for
antithrombin while LMWH inhibits activated factor X and has
low affinity for antithrombin
 Like ASA, it was given to prevent re-occlusion of the coronary
artery and maintains its patency
 Oral ASA can be given at home to prevent thromboembolic
events.
 UFH is monitored through aPTT (Prothrombin Time), protamine
titration, and antiXa units (should have 2-2.5x control). LMWH is
only monitored through anti-Xa
7. What are the drugs that will decrease myocardial oxygen
demand? Give the MoA.
 -blockers – Decrease HR, BP, and Contractility
 Calcium Channel Blockers (Non-dihydropyridine) – Bind to L-type
channel calcium channels, exerting long-lasting muscle relaxation
through closure of channels.
o This decreases oxygen requirement (through decreased
contractility, decreased HR, and decreased arteriolar tone and
systemic vascular resistance
o This also provides relief & prevention of focal coronary spasm and
increases myocardial oxygen supply
o This also decreases AV nodal conduction (effective for terminating
supraventricular reentrant tachycardia; decreases ventricular
response in atrial fibrillation and flutter)
 Nitrates & Nitrites – increases cGMP which then relaxes sm muscles
(vasodilation). This decreases preload. This also increases O2 supply by
dilating coronary artery
 If Sodium Channel Blockers – (IVABRADINE) selective If sodium channel
blocker w/c reduced cardiac rate by inhibiting hyperpolarization-
associated sodium-channel in the sino-atrial node
8. What is the role of ACEI and ARBs in this patient?
 Reduces mortality and CHF associated with MI
o Prevent adverse LV remodelling
o Delay progression of HF
o Decrease sudden death and recurrent MI
 Administered after 6hours after MI
9. If the LDL is 200mg/dL, and the Triglycerides is 100mg/dL, what
drug must be given?
 HMG-CoA Reductase Inhibitors