Angina Flashcards
Where does most infarct-causing occlusions occur?
small-to-medium plaques (“active plaques”)
how doesmost infarct-causing occlusions occur?
thrombosis
what happens if the endothelium covering of the plaque or the cell layer enclosing the necrotic core of the plaque disrupt?
<ul><li>thrombogenic materials such as collagen are presented to the bloodstream</li><li>causing platelet adhesion</li><li>fibrin deposition</li><li>thrombus formation</li><li>closure of the blood vessel</li></ul>
What doesAtherosclerosis encompass?
<ul><li>increased lipid deposition in the subendothelial space (early plaque)</li><li>endothelial dysfunction with decreased production of NO</li><li>less vasodilation and increased risk of platelet adhesion</li><li>influx of lipid scavenger cells (mainly macrophages)</li><li>necrosis</li><li>sterile inflammation</li><li>proliferation of smooth muscle cells</li><li>calcification and narrowing of the blood vessel by increasing plaque formation<br></br></li></ul>
what are theTriggering factors of Ischemia?
<ul><li>acute inflammation (e.g., influenza)</li><li>blood pressure peaks during physical exercise or emotional stress</li></ul>
thrombus formation is the result of?
balance between thrombosis and thrombolysis by the fibrinolytic system (plasminogen)
What determines the infarct size?
<ul><li>degree and the duration of coronary obstruction</li><li>thereby of the ischemia of downstream myocardium (and its size)<br></br></li></ul>
What are the important factors that determine the progress of CAD?
<ul><li>concentration of lipids in the blood</li><li>endothelial function</li><li>blood pressure (as a mechanical factor predisposing to plaque rupture)</li><li>the activity of the inflammatory system</li><li>the reactivity of pro- and antithrombotic systems<br></br></li></ul>
What is theprimary symptom of ischemic heart disease?
Angina pectoris
Angina pectoris is caused by?
transient episodes of myocardial ischemia that are due to an imbalance in the myocardial oxygen supply-demand relationship
Imbalance in the myocardial oxygen supply-demand relationship is caused by?
<ul><li>increase in myocardial oxygen demand<br></br></li><li>decrease in myocardial oxygen supply<br></br></li></ul>
An increase in myocardial oxygen demand is determined by?
<ul><li>heart rate</li><li>ventricular contractility</li><li>ventricular wall tension<br></br></li></ul>
A decrease in myocardial oxygen supply is caused by?
<ul><li>primarily determined by coronary blood flow</li><li>occasionally modified by the oxygen-carrying capacity of the blood</li></ul>
which is the most prevalent form of angina pectoris?
typical or stable angina
coronary thrombosis occurs in which form of angina?
Unstable angina or ACS (Acute Coronary Syndrome)
localized vasospasm occurs in which form of angina?
Variant or Prinzmetal angina
In which angina, the pathological substrate is usually fixed atherosclerotic narrowing of an epicardial coronary artery, on which exertion or emotional stress superimposes an increase in myocardial O2 demand?
typical stable angina
In which angina, focal or diffuse coronary vasospasm episodically reduces coronary flow?
variant angina
In which angina, rupture of an atherosclerotic plaque, with consequent platelet adhesion and aggregation, decreases coronary blood flow?
unstable angina
Myocardial ischemia also may be {{c1::silent}}, with electrocardiographic, echocardiographic, or radionuclide evidence of ischemia appearing in the absence of symptoms.
silent
What is the principal therapeutic goal in ACSs with unstable angina?
<ul><li>prevent or reduce coronary thrombus formation</li><li>increase myocardial blood flow</li></ul>
The principal therapeutic aim in variant or Prinzmetal angina is to
prevent coronary vasospasm
In patients with typical exercise-induced angina on the basis of CAD, these antianginal agents improve the balance of myocardial O2 supply and O2 demand principally by
reducing myocardial O2 demand by <br></br><ul><li>decreasing heart rate</li><li>myocardial contractility</li><li>ventricular wall stress</li></ul>
What is the major effect of nitrovasodilators and Ca2+ channel blockers in variant angina?
Increased O2 supply by dilating the coronary vasculature
What medication is used routinely in patients with myocardial ischemia?
Aspirin
The optimal dose of Aspirin appears to be between {{c1::75}} and {{c1::150}} mg/d, although most large studies have been done with a {{c2::325}}-mg dose.
75<br></br>150<br></br>325
What medication is advised only as an alternative in patients with aspirin intolerance and advise against the routine use of dual platelet inhibition in patients with stable disease?
Clopidogrel
ACEIs or angiotensin receptor blockers are recommended for subgroups of patients with CAD with
<ul><li>reduced left ventricular systolic function</li><li>hypertension</li><li>diabetes</li><li>chronic kidney disease<br></br></li></ul>
{{c1::Statins}} reduce mortality in patients with CAD.
Statins
The organic nitrate agents are prodrugs that are sources of {{c1::NO}}
NO
NO activates the soluble isoform of {{c1::guanylyl cyclase}}, thereby {{c1::increasing}} intracellular levels of {{c1::cGMP}}
guanylyl cyclase<br></br>increasing<br></br>cGMP
cGMP promotes the {{c1::dephosphorylation}} of the {{c1::myosin light chain}} and the {{c1::reduction}} of {{c1::cytosolic Ca2+}} and leads to the {{c1::relaxation}}of {{c1::smooth muscle cells}}in a broad range of tissues
dephosphorylation<br></br>myosin light chain<br></br>reduction<br></br>cytosolic Ca2+<br></br>relaxation<br></br>smooth muscle cells
The NO-dependent relaxation of vascular smooth muscle leads to {{c1::vasodilation}}
vasodilation
NO-mediated guanylyl cyclase activation also {{c1::inhibits}} {{c2::platelet aggregation}} and {{c1::relaxes}} smooth muscle in the {{c2::bronchi and GIT}}.
inhibits <br></br>platelet aggregation<br></br>relaxes<br></br>bronchi and GIT
What are three distinct mammalian NOS isoforms?
nNOS, eNOS, and iNOS
What processes are the NOS isoforms involved in?
<ul><li>neurotransmission</li><li>vasomotion</li><li>immunomodulation</li></ul>
NO gas also may be administered by {{c1::inhalation}}
inhalation
The NO-stimulated elevation of cGMP {{c1::activates}} {{c3::PKG}} and modulates the activities of {{c2::cyclic nucleotide PDEs (PDEs 2, 3, and 5)}} in a variety of cell types.
activates <br></br>PKG <br></br>cyclic nucleotide PDEs (PDEs 2, 3, and 5)
{{c1::Reduced}} phosphorylation of myosin light chain is the result of {{c2::decreased}} myosin light-chain kinase activity and {{c2::increased}} myosin light-chain phosphatase activity and promotes {{c3::vasorelaxation}} and smooth muscle {{c3::relaxation}} in many tissues.
Reduced<br></br>decreased<br></br>increased<br></br>vasorelaxation<br></br>relaxation
{{c1::cGMP}} is a substrate for {{c2::PDE 5}}, whose {{c3::inhibition}} by {{c3::sildenafil}} and related compounds potentiates the action of nitrovasodilators
cGMP<br></br>PDE 5<br></br>inhibition<br></br>sildenafil
what happens at low doses of Nitrates?
<ul><li>dilate veins and conductance arteries </li><li>leave the tone of the small-to-medium arterioles (that regulate resistance) unaffected</li></ul>
What happens at low-to-medium doses of nitrates?
<ul><li>venodilation decreases venous return</li><li>leading to a fall in left and right ventricular chamber size and end-diastolic pressures</li><li>reduced wall stress</li><li>thereby reduced cardiac O2 demand</li></ul>
{{c1::Systemic vascular resistance}} and {{c1::arterial pressure}} are not or only mildly decreased, leaving coronary perfusion pressure unaffected.
Systemic vascular resistance<br></br>arterial pressure
Heart rate remains {{c1::unchanged}} or may {{c1::increase}} slightly in response to a decrease in blood pressure.
unchanged <br></br>increase
What remains unchanged or may increase slightly in response to a decrease in blood pressure?
Heart rate
Doses of nitroglycerine that do not alter systemic arterial pressure may still produce {{c1::arteriolar dilation}} in the face and neck, resulting in a facial flush, or dilation of meningeal arterial vessels, causing headache.
arteriolar dilation
Doses of GTN (Nitroglycerine) that do not alter systemic arterial pressure may still produce arteriolar dilation in the face and neck, results in?
<ul><li>facial flush</li><li>dilation of meningeal arterial vessels</li><li>causing headache</li></ul>
What does Higher doses of organic nitrates cause?
<ul><li>venous pooling </li><li>decrease arteriolar resistance</li><li>decrease systolic and diastolic blood pressure<br></br></li><li>pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes<br></br></li></ul>
Higher doses of organic nitrates can compromise what?
coronary flow
In Higher doses of organic nitrates,the sympathetic increase in myocardial O2 demand leads to?
ischemia
Sublingual nitroglycerin administration may produce {{c1::bradycardia}} and {{c1::hypotension}}, probably owing to activation of the Bezold-Jarisch reflex.
bradycardia<br></br>hypotension
What causes Bezold-Jarisch reflex?
sublingual nitroglycerin administration
What is tolerance?
Frequently repeated or continuous exposure to high doses of nitrovasodilators lead to tolerance, that is, marked attenuation in the magnitude of most of their pharmacological effects.
Monday disease occurs due to
prolonged exposure with nitrates
Due to Monday disease, there is an increase in the incidence of ACSs during the {{c1::24}} to {{c1::72}} h periods away from the work environment.
24<br></br>72
Due to Monday disease, workers may experience
<ul><li>severe headaches</li><li>dizziness</li><li>postural weakness</li></ul>
High doses of nitrates should be avoided and therapy interrupted for {{c1::8–12}} h daily, which allows the return of efficacy.
8–12
In patients with {{c1::exertional angina}}, it is usually most convenient to omit dosing at {{c1::night}} either by adjusting dosing intervals of oral or buccal preparations or by removing cutaneous GTN
exertional angina<br></br>night
Patients whose anginal pattern suggests its precipitation by increased left ventricular filling pressures (e.g., in association with orthopnea or paroxysmal nocturnal dyspnea) may benefit from continuing nitrates at {{c1::night}} and omitting them during a quiet period of the {{c1::day}}.
night<br></br>day
TOXICITY OF NITRATES
<ul><li>Headache<br></br></li><li>dizziness</li><li>weakness</li><li>postural hypotension<br></br></li><li>occasionally progress to loss of consciousness<br></br></li><li>seen in patients with autonomic dysfunction<br></br></li></ul>
Coomon drugs for Erectile dysfunction
sildenafil and other PDE5 inhibitors with organic nitrate vasodilators
In Erectile dysfunction, antianginal therapy can cause
extreme hypotension
Cells in the {{c1::corpus cavernosum}} produce NO during sexual arousal in response to nonadrenergic, noncholinergic neurotransmission
corpus cavernosum
What drugs inhibit PDE5 and have been demonstrated to improve erectile function in patients with erectile dysfunction?
<ul><li>Sildenafil</li><li>Tadalafil</li><li>Vardenafil</li></ul>
PDE5 inhibitors are contraindicated for patients taking {{c1::organic nitrate vasodilators}}, and the PDE5 inhibitors should be used with caution in patients taking {{c2::α- or β blockers}}.
organic nitrate vasodilators<br></br>α- or β blockers
PDE5 inhibitors and nitrates act synergistically to cause profound {{c1::increases}} in cGMP and dramatic {{c2::reductions}} in blood pressure ({{c2::>25}} mm Hg)
increases<br></br>reductions<br></br>(>25 mm Hg)
PDE5 inhibitor should NOT be used in the {{c1::24}} h prior to initiating nitrate therapy
24
Sildenafil, tadalafil, and vardenafil are metabolized via {{c1::CYP3A4}}
CYP3A4
Short-Acting Nitrates
<ul><li>GTN/NITROGLYCERINE (onset of action is within 1–2 min)</li><li>ISDN (onset of action: 3–4 min)<br></br></li></ul>
FIRST CHOICE OF DRUG against anginal episodes in patients who have more than occasional angina
β blockers
DRUGS FOR Variant (Prinzmetal) Angina
<ol><li>Ca2+ channel blockers (1st line drugs)<br></br></li><li>Long-acting nitrates<br></br></li></ol>
In which angina, Nitrates are considered assecond-line drugs?
Unstable Angina Pectoris
DRUGS FOR Unstable Angina
Ca2+ channel blockers
TYPE OF Voltage-gated Ca2+ channels mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes and SA and AV nodal cells in response to electrical depolarization.
L-type or slow channels
In vascular smooth muscle, {{c1::INHIBTION}} of {{c1::CALCIUM INFLUX}} leads to {{c1::relaxation}}, especially in arterial beds, in cardiac myocytes to {{c2::negative}} inotropic effects.
INHIBTION<br></br>CALCIUM INFLUX<br></br>relaxation<br></br>negative
Ca2+ channel blockers DRUGS
phenylalkylamine: verapamil
benzothiazepine: diltiazem
dihydropyridines:amlodipin,clevidipine,
felodipine, isradipine, lercanidine
Ca2+ is a trigger for
contraction
In contrast to cardiac muscle, smooth muscles typically contract {{c1::tonically}}
tonically
The Ca2+ channel blockers produce their effects by binding to the {{c1::α1}} subunit of the L-type voltage-gated Ca2+ channels and reducing Ca2+ flux through the channel.
α1
Only the {{c1::L-type}} channel is sensitive to the dihydropyridine Ca2+ channel blockers.
L-type
Voltage-gated Ca2+ channels subtypes are?
<ul><li>L</li><li>N</li><li>T</li></ul>
IN CARDIAC CELLS,Ca2+ channel blockers {{c1::reduce}} the peak size of the systolic Ca2+ transient and thereby produce a {{c1::negative}} inotropic effect
reduce<br></br>negative
the greater degree of peripheral vasodilation seen with the {{c1::dihydropyridines}} is accompanied by a baroreceptor reflex–mediated increase in sympathetic tone sufficient to overcome the negative inotropic effect.
dihydropyridines
WHAT DRUG reduces the slow inward current in a dose-dependent manner, it does not affect the rate of recovery of the slow Ca2+ channel?
Nifedipine
nifedipine has clear {{c1::negative}} chronotropic effects in isolated preparations
negative
WHAT DRUG stimulates the heart indirectly by eliciting reflex sympathetic activation in response to a lowering of blood pressure?
Nifedipine
WHAT DRUG reduces the magnitude of the Ca2+ current through the slow channel, also decreases the rate of recovery of the channel?
Verapamil
WHAT DRUG inhibits fast Na+ and repolarizing K+ currents?
Verapamil
{{c1::Verapamil}} and {{c1::diltiazem}} depress the rate of the sinus node pacemaker and slow AV conduction
Verapamil<br></br>diltiazem
WHICH DRUG shows a phenomenon known as frequency dependence or use dependence (channel blockade is enhanced as the frequency of stimulation increases)?
Verapamil
Ca2+ channel blockers show {{c1::first-pass metabolism}}by {{c1::CYP3A4}} enzymes in the intestinal epithelium and the liver.
first-pass metabolism<br></br>CYP3A4
What is a common side effect of verapamil?
Constipation
TOXICITY OF CA CHANNEL BLOCKERS
<ul><li>PULMONARY EDEMA</li><li>gastroesophageal reflux<br></br></li><li>Constipation: Verapamil<br></br></li><li>Urinary retention: rare<br></br></li><li>rash and elevations of liver enzymes: uncommon<br></br></li><li>headache, flushing, and dizziness: Nifedipine<br></br></li></ul>
verapamil and diltiazem are used as antiarrhythmic agents in
supraventricular tachyarrhythmias
Ca2+ channel blockers are contraindicated in patients with
heart failure with reduced ejection fraction
which drugimproves left ventricular outflow obstruction and symptoms in patients with HCM (Hypertrophic Cardiomyopathy)?
Verapamil
WHICH DRUG is used in patients with neurological deficits secondary to cerebral vasospasm after the rupture of a congenital intracranial aneurysm?
Nimodipine
Nimodipine has been approved for use in patients with {{c1::neurological deficits}} secondary to {{c1::cerebral vasospasm}} after the rupture of a {{c2::congenital intracranial aneurysm}}
neurological deficits<br></br>cerebral vasospasm<br></br>congenital intracranial aneurysm
DRUGS used in Raynaud disease
<ul><li>Nifedipine</li><li>diltiazem</li><li>amlodipine</li><li>felodipine</li></ul>
WHAT DRUG causes relaxation of the myometrium in vitro?
Nifedipine
DRUG used in reducing preterm uterine contractions in preterm labor
Nifedipine
only drug class that is effective in reducing the severity and frequency of attacks of exertional angina and in improving survival in patients who have had an MI
β blockers
firstline treatment of patients with stable CAD andunstable angina/ACS
β blockers
DRUG showing reverse steal or Robin Hood phenomenon
β blockers
What is reverse steal or Robin Hood phenomenon?
An increased blood flow toward ischemic regions by increasing coronary collateral resistance and preventing blood from being shunted away from the ischemic myocardium during maximal coronary vasodilation
WHAT DRUG shows steal phenomenon?
Nitrates
What is steal phenomenon?
Dilating the relatively constricted arterioles of the healthy myocardium, leading to redistribution of blood flow away from the ischemic myocardium
the net effect of β blockade usually is to
decrease myocardial O2 consumption
Standard drugs for the treatment of angina are
<ul><li>β1 -selective</li><li>those without intrinsic sympathomimetic activity</li></ul>
β1 -selective drugs are
<ul><li>atenolol</li><li>bisoprolol</li><li>metoprolol</li></ul>
The decrease in myocardial O2 consumption is due to a {{c1::negative}} chronotropic effect (particularly during exercise), a {{c1::negative}}inotropic effect, and a {{c1::reduction}} in arterial blood pressure (particularly systolic pressure) during exercise.
negative<br></br>negative<br></br>reduction
DRUGS represent the cornerstone of therapy for ACS
Antiplatelet agents
Which drug inhibits platelet aggregation by irreversibly inactivating the thromboxane-synthesizing COX-1 in platelets, thereby reducing production of TxA2?
Aspirin
Antiplatelet agents interfere either which two signaling pathways?
<ol><li>TxA2 </li><li>ADP</li></ol>
Antiplatelet agents interfere either with two signaling pathways (TxA2 and ADP) that cooperatively {{c1::promote}} platelet aggregation in an auto- and paracrine manner or with a major common pathway of platelet aggregation, the {{c1::GpIIb/IIIa}} fibrinogen receptor.
promote<br></br>GpIIb/IIIa
Drugs which are ADP receptor (P2Y12 receptor) antagonists that block the proaggregatory effect of ADP
thienopyridines
Nonemergency major noncardiac surgeries should therefore be postponed for {{c1::5}} ({{c2::ticagrelor, clopidogrel}}) or {{c1::7}} days ({{c2::prasugrel, aspirin}}) after intake of the last dose ofAntiplatelet agents
5 or 7 days<br></br>ticagrelor, clopidogrel<br></br>prasugrel, aspirin
What drugs directed against the platelet integrin GPIIb/IIIa (including abciximab, tirofiban, and eptifibatide) are highly effective by blocking the final effector pathway of platelet aggregation?
Anti-integrin agents
Anti-integrin agents directed against the platelet integrin {{c1::GPIIb/IIIa}} (including abciximab, tirofiban, and eptifibatide) are highly effective by {{c1::blocking}}the final effector pathway of platelet aggregation
GPIIb/IIIa<br></br>blocking
Heparin is a/an
Antithrombotic agent
a heparinoid pentasaccharide, antithrombin III-dependent Factor Xa inhibitor has the best efficacy-safety profile of all anticoagulants and is therefore currently first choice
Fondaparinux
first choice of anticoagulant drugs
Fondaparinux
Thrombin inhibitors
<ul><li>hirudin</li><li>bivalirudin</li></ul>
Thrombolytic agents
rTPA
second-line agent for the treatment of chronic angina
Ranolazine
Ranolazine reduces {{c1::cardiac fatty acid oxidation}} and stimulates {{c1::glucose metabolism}} without inhibiting carnitine palmityl transferase 1
cardiac fatty acid oxidation<br></br>glucose metabolism
Preferential inhibition of late INa
Ranolazine
Ranolazine is metabolized mainly by
CYP3A4
Which drug is approved for treating stable angina and heart failure in patients in whom β blockers are not tolerated or are insufficiently effective in reducing heart rate and FDA-approved only for the treatment of heart failure?
Ivabradine
Funny channels
Ivabradine
selective blocker of hyperpolarization-activated HCN ion channels involved in the generation of automaticity in the SA node
Ivabradine
nitrate ester of nicotinamide is used for the treatment of stable angina
Nicorandil
Which drug has nitrate-like (cGMP-dependent) properties and acts as an agonist at ATPsensitive potassium (KATP) channels
Nicorandil
Properties of Nicorandil
<ul><li>nitrate-like (cGMP-dependent) properties</li><li>agonist at ATPsensitive potassium (KATP) channels</li></ul>
Nicorandil’svasodilating action is potentiated by {{c1::PDE5 inhibitors}} and only partially blocked by inhibitors of {{c2::KATP channels}}, such as {{c2::glibenclamide}}
PDE5 inhibitors<br></br>KATP channels<br></br>glibenclamide
Nicorandil {{c1::dilates}} both arterial and venous vascular beds, leading to {{c1::decreases}} in afterload and preload of the heart.
dilates<br></br>decreases
Adverse Effects of Nicorandil
nitrate-like headache and hypotension<br></br>GI ulcerations,perforations
Which drug is ussed in the partial shift from FFA to glucose oxidation in the heart, which provides less ATP but requires less O2 and may therefore be beneficial in ischemia?
Trimetazidine
Adverse effects ofTrimetazidine
<ul><li>GI upset</li><li>nausea</li><li>vomiting</li><li>rarely</li><ul><li>thrombocytopenia</li><li>agranulocytosis</li><li>liver dysfunction</li></ul></ul>
CONTRAINDICATIONS OF Trimetazidine
Parkinson disease<br></br>patients with decreased kidney function
considered first-line treatment of chronic angina relief
β blockers
Drugs considered in patients who do not tolerate β blockers
Dihydropyridines
In case of persistent angina, a combination of a {{c1::dihydropyridine}} and a {{c1::β blocker}} should be considered.
dihydropyridine <br></br>β blocker
Second-Line Treatment ofangina
<ul><li>Longer-acting organic nitrates</li><li>ranolazine<br></br></li><li>ivabradine</li><li>trimetazidine</li><li>nicorandil</li></ul>
Drugs which have a direct effect on the myocardium and likely act independently of hemodynamic effects.
<ul><li>Ranolazine</li><li>trimetazidine</li></ul>
In severe exertional or vasospastic angina, what drugs are used
<ul><li>Ca2+ Channel Blockers</li><li>Nitrates</li></ul>
{{c1::Nitrates}} primarily reduce {{c2::preload}}, whereas {{c1::Ca2+ channel blockers}} reduce {{c2::afterload}}
Nitrates<br></br>preload<br></br>Ca2+ channel blockers<br></br>afterload
unstable angina pectoris is resistant to
nitrates
Most patients with peripheral vascular disease have
CAD
In the cerebral circulation, arterial disease may be manifest as {{c1::stroke}} or {{c1::transient ischemic attacks}}
stroke or transient ischemic attacks
peripheral arterial disease in the lower extremities is called
claudication
Drugs used specifically in the treatment of lower extremity claudication
<ol><li>pentoxifylline</li><li>cilostazol<br></br></li></ol>
A methylxanthine derivative that is called a rheologic modifier for its effects on increasing the deformability of red blood cells
Pentoxifylline
an inhibitor of PDE3 and promotes accumulation of intracellular cAMP in many cells, including blood platelets.
Cilostazol
Which anti-claudication drug is labeled as being contraindicated in patients with heart failure?
Cilostazol
Atherosclerotic angina
Atherosclerotic angina is also known as angina of effort or classic angina. crushing, strangling chest pain that is precipitated by exertion and relieved by rest
Which type of plaques are associated with classic angina?
associated with atheromatous plaques that partially occlude one or more coronary arteries. When cardiac work increases (eg, in exercise), the obstruction of flow and inadequate oxygen delivery result in the accumulation of metabolites, eg, lactic acid, and ischemic changes that stimulate myocardial pain endings. Rest, by reducing cardiac work, usually leads to complete relief of the pain within 15 min
This type of angina is associated with 90%of all cases
atherosclerotic angina
Vasospastic angina
Vasospastic angina, also known as rest angina, variant angina, or Prinzmetal’s angina, is responsible for less than 10% of angina cases. It involves reversible spasm of coronaries, usually at the site of an atherosclerotic plaque. Spasm may occur at any time, even during sleep. Vasospastic angina may deteriorate into unstable angina
Unstable angina
The third type of angina—unstable or crescendo angina, one manifestation of acute coronary syndrome—is characterized by the increased frequency and severity of attacks that result from a combination of atherosclerotic plaques, platelet aggregation at fractured plaques, and vasospasm.
“Monday disease
Industrial disease caused by chronic exposure to vasodilating concentrations of organic nitrates in the workplace; characterized by headache, dizziness, and tachycardia on return to work after 2 days absence
Nitrate tolerance, tachyphylaxis
Loss of effect of a nitrate vasodilator when exposure is prolonged beyond 10–12 h
Preload
Filling pressure of the heart, dependent on venous tone and blood volume; determines end-diastolic fiber length and tension
Afterload
Impedance to the ejection of stroke volume; determined by vascular resistance (arterial blood pressure) and arterial stiffness; determines systolic fiber tension
Intramyocardial fiber tension
Force exerted by myocardial fibers, especially ventricular fibers at any given time; a primary determinant of myocardial O2 requirement
Double product
The product of heart rate and systolic blood pressure; an estimate of cardiac work
Myocardial revascularization
Mechanical intervention to improve O2 delivery to the myocardium by angioplasty or bypass grafting
A major determinant of Cardiac oxygen requirement
myocardial fiber tension (the higher the tension, the greater the oxygen requirement)
Diastolic factors that increase O2 requirement
Blood volume and Venous Tone
Systolic factors that increase O2 requirement
TPR, HR, Heart force, Ejection time
. Heart rate and systolic blood pressure may be multiplied to yield
double product, a measure of cardiac work and therefore of oxygen requirement. As intensity of exercise (eg, running on a treadmill) increases, demand for cardiac output increases, so the double product also increases
In patients with atherosclerotic angina, effective drugs reduce the
double product by reducing cardiac work without reducing exercise capacity.
This defect (lack of O2 supply)can be corrected—at present—in 2 ways
increasing oxygen delivery and by reducing oxygen requirement
What are the traditional pharmacologic therapies useful for inadequate coronary oxygen delivery?
Nitrates, CCBs and Beta-blocker
the newer strategies to improve oxygen delivery
increase the efficiency of oxygen utilization by shifting the energy substrate preference of the heart from fatty acids to glucose. Drugs that may act by this mechanism are termed partial fatty acid oxidation inhibitors (pFOX inhibitors) and include ranolazine and trimetazidine
a new group of antianginal drugs selectively reduces heart rate (and O2 requirement) with no other detectable hemodynamic effects
These drugs (ivabradine is the prototype) act by inhibition of the sinoatrial pacemaker current, If
drugs that reduce the cardiac oxygen requirement in atherosclerotic angina
nitrates, calcium blockers, and β blockers
Drugs that also increase oxygen delivery by reducing spasms in vasospastic angina
Nitrates and calcium channel blockers (but not β blockers)
Myocardial revascularization
corrects coronary obstruction either by bypass grafting or by angioplasty (enlargement of the coronary lumen by means of a special catheter)
How does unstable angina therapy differ from regular (stable) angina
Therapy of unstable angina differs from that of stable angina in that urgent angioplasty is the treatment of choice in most patients and platelet clotting is the major target of drug therapy. A variety of platelet inhibitors are used in this condition (see Chapter 34). Intravenous nitroglycerin is sometimes of value in unstable angina.
Drugs that are platelet inhibitors
Anticoagulants, Thrombolytics Antiplateletdrugs
Anticoagulants
Heparins, Direct thrombin inhibitors, Direct factor Xa inhibitors, Warfarin
Thrombolytics
t-Pa derivatives, Streptokinase
Anti-platelet drugs
Aspirin, GP 2b/3a inhibitors, ADP inhibitors (Clopidogrel)PDE/adenosine uptake inhibitors
NITRATES
Nitroglycerin (the active ingredient in dynamite) is the most important of the therapeutic nitrates and is available in forms that provide a range of durations of action from 10–20 min (sublingual for relief of acute attacks) to 8–10 h (transdermal for prophylaxis)
Nitroglycerin (glyceryl trinitrate)
rapidly denitrated in the liver and in smooth muscle—first to the 2 dinitrates (glyceryl dinitrate), which retain a significant vasodilating effect; and more slowly to the mononitrates, which are much less active. Because of the high enzyme activity in the liver, the first-pass effect for nitroglycerin is about 90%. The efficacy of oral (swallowed) nitroglycerin probably results from the high levels of glyceryl dinitrate in the blood
why are sublingual and transdermal administrations of nitroglycerin better than oral?
they can bypass FPM
Isosorbide dinitrate
commonly used nitrate; it is available in sublingual and oral forms. Isosorbide dinitrate is rapidly denitrated in the liver and smooth muscle to isosorbide mononitrate, which is also active. Isosorbide mononitrate is available as a separate drug for oral use.
pentaerythritol tetranitrate
Like the oral nitroglycerin preparation, these oral organic nitrates have an intermediate duration of action (4–6 h)
Amyl nitrite
is a volatile and rapid-acting vasodilator that was used for angina by the inhalational route but is now rarely prescribed
MOA of Nitrates
Nitrates release nitric oxide (NO) within smooth muscle cells, probably through the action of the mitochondrial enzyme aldehyde dehydrogenase-2 (ALDH2). NO stimulates soluble (cytoplasmic) guanylyl cyclase and causes an increase of the second messenger cGMP (cyclic guanosine monophosphate); the latter results in smooth muscle relaxation by stimulating the dephosphorylation of myosin light-chain phosphate. Note that this mechanism is identical to that of nitroprusside
Cardiovascular effects of Nitrates
Smooth muscle relaxation by nitrates leads to an important degree of vasodilation, which results in reduced cardiac size and cardiac output through reduced preload. Relaxation of arterial smooth muscle may increase flow through partially occluded epicardial coronary vessels. Reduced afterload, from arteriolar dilation of resistance vessels, may contribute to an increase in ejection and a further decrease in cardiac size
Venodilation leads to
decreased diastolic heart size and fiber tension.
Arteriolar dilation leads to
reduced peripheral resistance and blood pressure. These changes contribute to an overall reduction in myocardial fiber tension, oxygen consumption, and the double product.
the primary mechanism of the therapeutic benefit of nitrates in atherosclerotic angina is
reduction of the oxygen requirement. A secondary mechanism—namely, an increase in coronary flow via collateral vessels in ischemic areas—may also contribute. In vasospastic angina, reversal of coronary spasm and increased flow can be demonstrated.
Nitrates have no direct effects on the cardiac muscle, but
significant reflex tachycardia and increased force of contraction are common results when nitroglycerin reduces the blood pressure. These compensatory effects result from the baroreceptor mechanism
Nitrates effect on Other organs
Nitrates relax the smooth muscle of the bronchi, gastrointestinal tract, and genitourinary tract, but these effects are too small to be clinically significant. Intravenous nitroglycerin (sometimes used in unstable angina) reduces platelet aggregation. There are no clinically useful effects on other tissues
The standard form for treatment of acute anginal pain is the
sublingual tablet or spray, which has a duration of action of 10–20 min. Sublingual isosorbide dinitrate is similar with a duration of 30 min.
Oral (swallowed) normal-release formulations of nitroglycerin and isosorbide dinitrate have durations of action of
4-6 hours
Transdermal formulations (ointment or patch)
maintain nitrate blood levels for up to 24 h. However, tolerance develops after 8–10 h, with rapidly diminishing effectiveness thereafter. It is therefore recommended that nitroglycerin patches be removed after 10–12 h. A new patch can be applied after 12 h of patch-free recovery.
Toxicity of Nitrates and Nitrites
The most common adverse effects of nitrates are the responses evoked by vasodilation. These include tachycardia (from the baroreceptor reflex), orthostatic hypotension (a direct extension of the venodilator effect), and throbbing headache from meningeal artery vasodilation
Nitrates interact with sildenafil and similar drugs
hese agents inhibit a phosphodiesterase isoform (PDE5) that metabolizes cGMP in smooth muscle (Figure 12–4). The increased cGMP in erectile smooth muscle relaxes it, allowing for greater inflow of blood and more effective and prolonged erection. This relaxation also occurs in vascular smooth muscle. As a result, the combination of nitrates (through increased production of cGMP) and a PDE5 inhibitor (through the decreased breakdown of cGMP) causes a synergistic relaxation of vascular smooth muscle with potentially dangerous hypotension and inadequate perfusion of critical organs
Nitrites toxicity
are of significant toxicologic importance because they cause methemoglobinemia at high blood concentrations. This same effect has a potential antidotal action in cyanide poisoning (see later discussion). The nitrates do not cause methemoglobinemia
Nitrites in the Treatment of Cyanide Poisoning
Cyanide ion rapidly complexes with the iron in cytochrome oxidase, resulting in a block of oxidative metabolism and cell death. Fortunately, the iron in methemoglobin has a higher affinity for cyanide than does the iron in cytochrome oxidase. Nitrites convert the ferrous iron in hemoglobin to the ferric form, yielding methemoglobin. Therefore, cyanide poisoning can be treated
3 steps to treat CN poisoning
(1) immediate inhalation of amyl nitrite, followed by (2) intravenous administration of sodium nitrite, which rapidly increases the methemoglobin level to the degree necessary to remove a significant amount of cyanide from cytochrome oxidase. This is followed by (3) intravenous sodium thiosulfate, which converts cyanomethemoglobin resulting from step 2 to thiocyanate and methemoglobin. Thiocyanate is much less toxic than cyanide and is excreted by the kidney.
hydroxocobalamin,
an alternative to nitrate, a B12 analogue, is preferred for CN
CALCIUM CHANNEL-BLOCKING DRUGS
Several types of calcium channel blockers are approved for use in angina; these drugs are typified by nifedipine, a dihydropyridine,several other dihydropyridines, and the nondihydropyridines diltiazemand verapamil. Although calcium channel blockers differ markedly in structure, all are orally active and most have half-lives of 3–6 h
Mechanism of Action of CCBs
Calcium channel blockers block voltage-gated L-type calcium channels, the calcium channels most important in cardiac and smooth muscle, and reduce intracellular calcium concentration and muscle contractility (Figure 12–3). None of these channel blockers interferes with calcium-dependent neurotransmission or hormone release because these processes use different calcium channels that are not blocked by L-channel blockers. Nerve ending calcium channels are of the N-, P-, and R-types. Secretory cells use L-type channels, but these channels are less sensitive to the calcium blockers than are cardiac and smooth muscle L-type channels
Effects and Clinical Use of CCbs
Calcium blockers relax blood vessels and, to a lesser extent, the uterus, bronchi, and gut. The rate and contractility of the heart are reduced by diltiazem and verapamil. Because they block calcium-dependent conduction in the atrioventricular (AV) node, verapamil and diltiazem may be used to treat AV nodal arrhythmias Nifedipine and other dihydropyridines evoke greater vasodilation, and the resulting sympathetic reflex prevents bradycardia and may actually increase heart rate. All the calcium channel blockers insufficient dosage reduce blood pressure and reduce the double product in patients with angina
Calcium blockers are effective as prophylactic therapy in
effort and vasospastic angina;
nifedipine
used to abort acute anginal attacks but the use of the prompt-release form is contraindicated (see Skill Keeper)
A pair of studies during the 1990s suggested that the use of nifedipine was associated with an increased risk of myocardial infarction. What effects of nifedipine might lead to this result?
Several studies have suggested that patients receiving prompt-release nifedipine may have an increased risk of myocardial infarction. Slow-release formulations do not seem to impose this risk. These observations have been explained as follows: Rapid-acting vasodilators—such as nifedipine in its prompt-release formulation—cause a significant and sudden reduction in blood pressure. The drop in blood pressure evokes increased sympathetic outflow to the cardiovascular system and increases heart rate and force of contraction. These changes can markedly increase cardiac oxygen requirement. If the coronary blood flow does not increase sufficiently to match the increased requirement, ischemia and infarction can result.
In severe atherosclerotic angina, CCBs are
particularly valuable when combined with nitrates In addition to well-established uses in angina, hypertension, and supraventricular tachycardia, some of these agents are used in migraine, preterm labor, stroke, and Raynaud’s phenomenon
Toxicity if CCBs
The calcium channel blockers may cause constipation, pretibial edema, nausea, flushing, and dizziness. More serious adverse effects include heart failure, AV blockade, and sinus node depression; these are most common with verapamil and least common with dihydropyridines.
BETA-BLOCKING DRUGS
Actions include both beneficial antianginal effects (decreased heart rate, cardiac force, blood pressure) and detrimental effects (increased heart size, longer ejection period) Like nitrates and calcium channel blockers, β blockers reduce cardiac work, the double product, and oxygen demand.
Are b-blockers helpful in Acute anginal attacks?
Beta-blockers are used only for the prophylactic therapy of angina; they are of no value in an acute attack
Beta blockers are effective in ___________ and ineffective in _____________
effective in preventing exercise-induced anginaineffective in- Vasospastic angina
The combination of β blockers and nitrates is useful because
adverse undesirable compensatory effects evoked by the nitrates (tachycardia and increased cardiac force) are prevented or reduced by β blockade
Nitrates Alone
HR: Reflex increase (undesirable)Arterial P: DecreaseEnd-dia P.- DecreaseContractility- Reflex increase (undesirable)Ejection time- Reflex decreaseNet Myocardial O2 req: Decrease
Beta Blockers or Calcium Channel Blockers Alone
HR; DecArt.P: DecEDP: inc (undesireable)EJT: increase (und)Contractility: DecreaseMO2 req: Decrease
Combined Nitrates and a Blockers or Calcium Channel Blockers
HR, AP, EDP, Net O2 req:- DecreaseCon, ET- decrease
Ranolazine
appears to act mainly by reducing a late, prolonged sodium current in myocardial cells. The decrease in intracellular sodium causes an increase in calcium expulsion via the Na/Ca transporter (see Chapter 13) and a reduction in cardiac force and work. As noted previously, it may also alter cardiac metabolism. Ranolazine is moderately effective in angina prophylaxis.
Ivabradine
a drug used in heart failure inhibits the Ifsodium current in the sinoatrial node. The reduction in this hyperpolarization-induced inward pacemaker current results in decreased heart rate and consequently decreased cardiac work. Ivabradine is used off-label with β blockers as prophylaxis in angina.
NONPHARMACOLOGIC THERAPY
Myocardial revascularization by coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are extremely important in the treatment of severe angina. These are the only methods capable of consistently increasing coronary flow in atherosclerotic angina and increasing the double product.
Short-acting nitrates
Nitroglycerin, (sublingual), Isosorbide nitrate (longer acting- 20-30 min)
Mechanism of Action of SAN
Releases nitric oxide (NO), increases cGMP (cyclic guanosine monophosphate), and relaxes vascular smooth musle
Clinical Applications of SAN
Acute angina pectoris • acute coronary syndrome
Pharmacokinetics SAN
Rapid onset (1 min) • short duration (15 min)
Toxicities, Interactions SAN
Tachycardia, orthostatic hypotension, headache
Intermediate-acting nitrates
Nitroglycerin, oral; Isosorbide dinitrate and mononitrate, oral Pentaerythritol tetranitrate and other oral nitrates
MOA IAN
Like nitroglycerin SL • active metabolite dinitroglycerin
CA of IAN
Prophylaxis of angina
Pharmacokinetics IAN
Slow onset • Duration: 2–4 h
Toxicities, Interactions of IAN
Tachycardia, orthostatic hypotension, headache
Long-acting nitrate
Transdermal nitroglycerin
MOA of LAN
active metabolite dinitroglycerin
LAN Applications
Prophylaxis of Angina
Pharmacokinetics of LAN
Slow onset • long duration of absorption: 24 h • duration of effect: 10 h (tachyphylaxis)
Toxicities, interactions
Tachycardia, orthostatic hypotension, headacheloss of response is common after 10–12 h exposure to drug
Ultrashort-acting nitrite
Amyl nitrite
MOA of UsAN
Releases nitric oxide (NO), increases cGMP (cyclic guanosine monophosphate), and relaxes vascular smooth muscle
CA of UsAN
Obsolete for angina • some recreational use
PK of UsAN
Volatile liquid, vapors are inhaled • onset seconds Duration: 1–5 min
TOxicities of UsAN
Tachycardia, orthostatic hypotension, headache
CCBs that are indicated in Raynauds
Felodipine, Nifedipine, Diltiazem
This drug is claimed to be particularly selective for cerebral blood vessels.
Nimodipine, appears to reduce morbidity after a subarachnoid hemorrhage. Nimodipine was approved for use in patients who have had a hemorrhagic stroke. Verapamil is better indicated despite its lack of vasoselectivity in treating strokes
This drug is a selective T-type calcium channel blocker that was introduced for antiarrhythmic use but has been withdrawn.
Mibefradil
Many vasodilators can be shown to increase coronary flow in theabsence of atherosclerotic disease. These include
dipyridamoleand adenosine. In fact, dipyridamole is an extremely effective coronary dilator, but it is not effective in angina becauseof coronary steal
What is FFR and Which drug helps in measuring Fractional flow reserve (FFR)
FFR is the ratio between maximum blood flow in a diseased coronary artery and theoretical maximum flow in that artery. FFR of 1.0 is considered normal. FFR any lower than 0.75-0.8 is considered as MI.Adenosine, acting on A2A receptors causes a very brief but marked dilationof the coronary resistance vessels and has been used as a drugto measure maximum coronary flow (“fractional flow reserve,”FFR) in patients with coronary disease. The drug also markedlyslows or blocks atrioventricular (AV) conduction in the heartand is used to convert AV nodal tachycardias to normal sinusrhythm
Regadenoson
a selective A2A agonistand has been developed for use in stress testing in suspectedcoronary artery disease and for imaging the coronary circulation.It appears to have a better benefit-to-risk ratio than adenosine in these applications. Similar A2A agonists (binodenoson, apadenoson)
Coronary steal
the term is given to the action of nonselective coronary arteriolar dilators in patients with partial obstruction ofa portion of the coronary vasculature. It results from the fact thatin the absence of drugs, arterioles in ischemic areas of the myocardium are usually maximally dilated as a result of local control factors, whereas the resistance vessels in well-perfused regions are capable of further dilation in response to exercise
In patients with unstable angina, transient coronary steal mayprecipitate a
myocardial infarction. Adenosine and regadenoson are labeled with warnings of this effect.
This oxytocin antagonist is better indicated in preterm labor than Nifedipine
. Nifedipine has some efficacy in preterm labor but is moretoxic and not as effective as atosiban, an investigational oxytocinantagonist
Why is a combination of verapamil and diltiazem worse than Nifedipine on Ventricular depression
Nifedipinedoes not decrease atrioventricular conduction and therefore canbe used more safely than verapamil or diltiazem in the presence ofatrioventricular conduction abnormalities. A combination of verapamil or diltiazem with β blockers may produce atrioventricularblock and depression of ventricular function. In the presence ofovert heart failure, all calcium channel blockers can cause furtherworsening of failure as a result of their negative inotropic effect
This drug does not increase mortality in patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in HF patient
amlodipine
Why is a combination of verapamil and diltiazem better than Nifedipine (dihydropyridine) on people with hypotension
dihydropyridinescan cause further deleterious lowering of pressure. Verapamil anddiltiazem appear to produce less hypotension and may be bettertolerated in these circumstances. In patients with a history of atrialtachycardia, flutter, and fibrillation, verapamil and diltiazem provide a distinct advantage because of their antiarrhythmic effects.In the patient receiving digitalis, verapamil should be used withcaution, because it may increase digoxin blood levels through apharmacokinetic interaction
Ranolazine
appears to act by reducing a late sodium current (INa) that facilitates calcium entry via the sodium-calciumexchanger (see Chapter 13). The reduction in intracellular calcium concentration that results from ranolazine reduces diastolictension, cardiac contractility, and work. Ranolazine is approvedfor use in angina in the USA. Several studies demonstrate itseffectiveness in stable angina, but it does not reduce the incidenceof death in acute coronary syndromes
ECG changes in Ranolazine
prolongs theQT interval in patients with coronary artery disease (but shortensit in patients with long QT syndrome, LQT3). It has not beenassociated with torsades de pointes arrhythmia and may inhibitthe metabolism of digoxin and simvastatin
trimetazidine
pFOX inhibitors because they partially inhibit the fatty acidoxidation pathway in myocardium. Because metabolism shifts tooxidation of fatty acids in ischemic myocardium, the oxygenrequirement per unit of ATP produced increases. Partial inhibition of the enzyme required for fatty acid oxidation (long-chain3-ketoacyl thiolase, LC-3KAT) appears to improve the metabolic status of ischemic tissue
New drugs or drug groups underinvestigation for use in angina.
AmilorideCapsaicinDirect bradycardic agents, eg, ivabradineInhibitors of slowly inactivating sodium current, eg, ranolazineMetabolic modulators, eg, trimetazidineNitric oxide donors, eg, L-argininePotassium channel activators, eg, nicorandilProtein kinase G facilitators, eg, detanonoateRho-kinase inhibitors, eg, fasudilSulfonylureas, eg, glibenclamideThiazolidinedionesVasopeptidase inhibitorsXanthine oxidase inhibitors, eg, allopurinol
Perhexiline
found to benefit some patients with anginadecades ago but was abandoned because of reports of hepatotoxicity and peripheral neuropathy. However, pharmacokinetic studiessuggested that toxicity was due to variable clearance of the drug,with extremely high plasma concentrations in patients with deficient CYP2D6 activity. This drug may shift myocardial metabolism from fatty acid oxidation to more efficient glucose oxidation(compared with trimetazidine). Because it does not involve vasodilation, it may be useful in patients refractory to ordinary medicaltherapy if plasma concentration is carefully controlled.
, ivabradine
bradycardic drugs, relatively selective If sodium channel blockers (eg, ivabradine), reduce the cardiac rate by inhibiting thea hyperpolarization-activated sodium channel in the sinoatrial node.No other significant hemodynamic effects have been reported.Ivabradine appears to reduce anginal attacks with an efficacy similar to that of calcium channel blockers and β blockers. The lack of effect on the gastrointestinal and bronchial smooth muscle is an advantage of ivabradine, and it is approved for use in angina and heartfailure outside the USA
Rho kinases (ROCK)
family of enzymes thatinhibit vascular relaxation and diverse functions of several othercell types. Excessive activity of these enzymes has been implicatedin coronary spasm, pulmonary hypertension, apoptosis, and otherconditions. Drugs targeting the enzyme have therefore been soughtfor possible clinical applications
. Fasudil
an inhibitor of smoothmuscle Rho kinase and reduces coronary vasospasm in experimental animals. In clinical trials in patients with CAD, it has improvedperformance in stress tests. It is investigational in angina.
Allopurinol
Studies suggest that high-dose allopurinol (eg, 600 mg/d)prolongs exercise time in patients with atherosclerotic angina.The mechanism is uncertain, but the drug appears to improveendothelium-dependent vasodilation. Allopurinol is not currentlyapproved for use in angina
Refractory angina and acute coronary syndromes are best treated with
physical revascularization, ie, percutaneous coronary intervention(PCI), with insertion of stents, or coronary artery bypass grafting(CABG).
First-line therapy of CAD depends on
modification of risk factors such as hypertension, hyperlipidemia, obesity, smoking, and clinical depression. Inaddition, antiplatelet drugs are very important.
Specific pharmacologic therapy to prevent myocardial infarctionand death consists of
antiplatelet agents (aspirin, ADP receptorblockers, and lipid-lowering agents, especially statins. Aggressive therapy with statins has been shown toreduce the incidence and severity of ischemia in patients duringexercise testing and the incidence of cardiac events (including infarction and death) in a clinical trial
Inpatients with unstable angina and non-ST-segment elevation myocardial infarction, aggressive therapy consisting of
coronary stenting, anti-lipid drugs, heparin, and antiplatelet agents are recommended
therapeutics Angina of Effort
Many studies have demonstrated that nitrates, calcium channelblockers and β blockers increase the time to onset of angina andST depression during treadmill tests in patients with angina ofeffort. Although exercise tolerance increases, thereis usually no change in the angina threshold, ie, the rate-pressureproduct at which symptoms occur.
maintenance therapy of chronic stable angina
β blockers,calcium channel-blocking agents, or long-acting nitrates may bechosen; the drug of choice depends on the individual patient’sresponse.
In hypertensive patients
monotherapy with either slow release or long-acting calcium channel blockers or β blockers maybe adequate
In normotensive patients,
long-acting nitrates may besuitable. The combination of a β blocker with a calcium channelblocker (eg, propranolol with nifedipine) or two different calciumchannel blockers (eg, nifedipine and verapamil) has been shown tobe more effective than individual drugs used alone. If a dihydropyridine is used, a longer-acting agent should be chosen (amlodipine or felodipine)
Some patients may require therapy with all threedrug groups, which include the_____________
Ranolazine or ivabradine (off-label), combined with βblockers, may be effective in some patients refractory to traditionaldrugs. Most experts recommend coronary angiography and revascularization (if not contraindicated) in patients with stable chronicangina refractory to three-drug medical treatment. In the future,agents such as allopurinol or perhexiline may be useful in patientswho are not candidates for revascularization.
Vasospastic Angina therapy
Nitrates and the calcium channel blockers, but not β blockers,are effective drugs for relieving and preventing ischemic episodesin patients with variant angina. In approximately 70% of patientstreated with nitrates plus calcium channel blockers, angina attacksare completely abolished; in another 20%, marked reduction offrequency of anginal episodes is observed.
Surgical revascularization and angioplasty are notindicated in patients with
variant angina
Unstable Angina & Acute CoronarySyndromes
In patients with unstable angina with recurrent ischemic episodesat rest, recurrent platelet-rich nonocclusive thrombus formationis the principal mechanism. Aggressive antiplatelet therapy with acombination of aspirin and clopidogrel is indicated. Intravenousheparin or subcutaneous low-molecular-weight heparin is alsoindicated in most patients.
If percutaneous coronary interventionwith stenting is required
glycoprotein IIb/IIIa inhibitors such as abciximab should be added. In addition, therapy with nitroglycerin and βblockers should be considered; calcium channel blockers should beadded in refractory cases for relief of myocardial ischemia. Primarylipid-lowering and ACE-inhibitor therapy should also be initiated
TREATMENT OF PERIPHERALARTERY DISEASE & INTERMITTENTCLAUDICATION
Atherosclerosis can result in ischemia of peripheral muscles justas coronary artery disease causes cardiac ischemia. Pain (claudication) occurs in skeletal muscles, especially in the legs, duringexercise and disappears with rest. Although claudication is notimmediately life-threatening, peripheral artery disease (PAD) isassociated with increased mortality, can severely limit exercisetolerance, and may be associated with chronic ischemic ulcers,susceptibility to infection, and the need for amputation
Conventional vasodilators are of no benefit because
vessels distal to the obstructive lesions are usually alreadydilated at rest. Antiplatelet drugs such as aspirin or clopidogrel(see Chapter 34) are often used to prevent clotting in the regionof plaques and have documented benefits in reducing the risk ofmyocardial infarction, stroke, and vascular death even thoughthey have little or no effect on claudication
Two drugs are usedalmost exclusively for PAD
Cilostazol, a phosphodiesterase type3 (PDE3) inhibitor, may have selective antiplatelet and vasodilating effects. This drug has been shown to increase exercisetolerance in patients with severe claudication. Pentoxifylline, axanthine derivative, is widely promoted for use in this conditionbut is not recommended. It is thought to act by reducing theviscosity of blood and perhaps increasing the deformability of redblood cells, allowing blood to flow more easily through partiallyobstructed areas.
Naftidrofuryl
5-HT2 antagonist, is availableoutside the USA and appears to have benefits similar to those ofcilostazol. Percutaneous angioplasty with stenting may be effective in patients with medically intractable signs and symptoms oflower limb ischemia.
