CVS pharm

• Ischaemic heart disease includes

  • Angina: Stable & Unstable
  • Myocardial infarction
  • Heart failure
  • Arrhythmia
• Peak incidence of symptomatic IHD is age 50-60 (men) and 60-70 (women)
• Atherosclerosis


  Progressive inflammatory disorder of the arterial wall characterized by focal lipid rich deposits of atheroma
• Atherosclerosis


  • Remain clinically asymptomatic until large enough to impair tissue perfusion, Ulceration and disruption of the lesion result in thrombotic occlusion, Distal embolization of the vessel
  • Clinical manifestations depend upon the site of the lesion and the vulnerability of the organ supplied
• Atherosclerosis starts with


  1. Abnormal endothelial function

  2. Inflammatory cells, predominantly monocytes, bind to receptors expressed by endothelial cells, Migrate into the intima, Take up oxidized low-density lipoprotein (LDL) particles, Become lipid-laden macrophages or foam cells

  3. As Foam cells dies, it releases its lipid pool in intimal space with cytokines and growth factor
• Atherosclerosis progression


  1. Smooth muscle cells migrate from the media of the arterial wall into the intima

  2. Lipid core will be covered by smooth muscle cells and matrix

  3. Forms stable atherosclerotic plaque that will remain asymptomatic until it becomes large enough to obstruct arterial flow
• In the heart, atherosclerosis results in ischemia usually leading to pain and eventually death (infarction) of the myocardium if not treated as an emergency
• Risk factors of atherosclerosis

  • Age
  • Male sex
  • Positive family history
  • Smoking
  • Hypertension
  • Hypercholesterolaemia
  • Diabetes mellitus
  • Haemostatic factors
  • Physical activity
  • Obesity
  • Alcohol
  • Other dietary factors
• Angina pectoris


  Occurs when there is an imbalance between O2 requirements of the heart cells (myocardial O2 demand) and O2 available to it (myocardial O2 supply), usually due to coronary artery disease (CAD)
• Types of angina


  • Stable
  • Unstable
  • Variant Angina (Prinzmetal)
• Stable angina


  • Attacks are provoked by exertion/exercise or excitement, when the heart has to work harder than normal and myocardial O2 requirement increases without a proportional increase in coronary blood flow
  • The attack ceases when the increased energy demand is withdrawn
  • The underlying pathology is usually chronic coronary artery disease
  • Typical symptoms: retrosternal chest pain, tightness or discomfort radiating to left(± right) shoulder/arm/ neck/jaw, Brief duration, lasting <10-15 min, associated with diaphoresis, nausea, anxiety
• Variant angina/Atypical angina


  • Occurs when the increase in myocardial O2 demand is due to reversible spasms of the coronary arteries as in coronary artery stenosis
  • Occurs spontaneously with no relationship to activity, usually happens when resting, unrelated to exercise, relieved by nitrates
  • The coronary arteries can spasm as a result of: Exposure to cold, emotional stress, medicines that tighten or narrow blood vessels, smoking, and cocaine use
• Unstable angina


  • Due to spasm and partial obstruction of coronaries
  • It occurs with lesser exertion or at rest and unpredictable, unlike stable angina
  • Characterized by increasing severity, frequency and duration of chest pain in patients with previously stable angina
  • Is usually more severe and lasts longer than stable angina, may be as long as 30 minutes
  • Usually Interferes with patient lifestyle
  • May not disappear with rest or use of angina medication
  • May lead to complete occlusion of vessel causing MI
• Symptoms of angina


  • Pain in your arms, neck, jaw, shoulder or back accompanying chest pain
  • Nausea
  • Fatigue
  • Shortness of breath
  • Anxiety
  • Sweating
  • Chest pain or discomfort is usually felt as pressure, heaviness, tightening, squeezing
• Pharmacological intervention for angina

  • Decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure, and contractility)
  • In some patients, the nitrates and calcium channel blockers may cause a redistribution of coronary flow and increase oxygen delivery to ischemic tissue
  • In variant angina, these two drugs also increase myocardial oxygen delivery by reversing coronary artery spasm
• Drugs used for treating or preventing attacks of angina


  • Organic nitrates
  • Ca2+ channel antagonists
  • β adrenoceptor antagonist
  • K+ channel activators
  • Newer drugs, represented by ranolazine, ivabradine, and trimetazidine
• Pharmacological agents used in unstable angina


  • Antiplatelet drugs such as low dose aspirin and other such as clopidogrel,ticlopidine and dipyridamole
  • Antithrombotic agents or anticoagulants such as heparin, warfarin and heparin derivatives (e.g Enoxaparin)
  • Lipid lowering drugs e.g the statins
• Organic nitrates


  • They are the mainstay of therapy for the immediate relief of angina
  • Nitric oxide is thought to be enzymatically released from nitroglycerine
  • It then reacts with and activates guanylyl cyclase to increase intracellular cGMP levels, which in turn dephosphorylates myosin light chain kinase, causes calcium extrusion, and suppresses smooth muscle tone
• Organic nitrates


  • They relieve coronary arterial spasms in variant angina and any vascular spasms that may occur in stable or unstable angina
  • Tolerance (Tachyphylaxis) may develop in part from a decrease in available sulfhydryl groups(avoided by a 6–8-hour nitrate-free period)
  • Autonomic receptors are not involved in the primary response of nitroglycerine, but compensatory mechanisms may counter the primary actions
  • They cause improvement in blood flow through the coronary vessels and hence improvement of perfusion to ischemic areas (improved subendocardial perfusion)
• Glyceryl Trinitrate (GTN)


  • A short acting smooth muscle relaxant with widespread vasodilator activity
  • It is extensively metabolized in the liver and has almost 0% bioavailability when administered orally
  • It is either administered sublingually or transdermally as a patch or paste
  • It is also rapidly eliminated from the body with elimination t1/2 of about 2 min
• Side effects of organic nitrates

  • Headache, flushing, dizziness, postural hypotension, syncope etc
  • The symptoms of the adverse effects can be terminated by swallowing the tablet or spitting it out
  • With a patch or paste, the effect could be terminated by removing the patch
• Mechanism of action of nitrates

  • Decrease venous return to the heart and the resulting reduction of intra-cardiac volume are important beneficial hemodynamic effects of nitrates
  • Decrease intraventricular pressure and LV volume and hence decrease myocardial oxygen requirement
  • Systemic administered nitrates may decrease overall coronary blood flow (and myocardial oxygen consumption) if cardiac output is reduced due to decreased venous return
  • The reduction in oxygen consumption is the major mechanism for the relief of stable angina
• Nitrates in variant and unstable angina

  • In Variant angina, nitrates relax the smooth muscles of the epicardial coronary arteries and relieves coronary artery spasm
  • In unstable angina, nitrates may relieve the angina pain by either dilating the epicardial coronary arteries or by reducing myocardial oxygen demand or both
  • Nitroglycerine decreases platelet aggregation by increasing the level of cGMP and this may be beneficial in unstable angina
• Potassium channel activators


  • Arterial and venous dilating properties but do not exhibit the tolerance seen with nitrates
  • Nicorandil (10–30mg 12-hourly orally) - only drug in this class currently available for clinical use
  • It is a nicotinamide nitrate ester that has vasodilating properties in normal coronary arteries but more complex effects in patient with angina
  • It has been shown to provide some myocardial protection via preconditioning by activation of cardiac KATP channels
• Beta blockers in angina

  • Reduce myocardial O2 consumption by: Reducing an increase in heart rate associated with exercise and anxiety, Reducing the force of myocardial contraction
  • They also improve myocardial perfusion by increasing the duration of diastole and the time available for coronary circulation
  • The preferred beta blockers are those selective for beta-1 receptors or those with vasodilating properties (i.e α1, antagonists effects) - Atenolol, Bisoprolol, Metoprolol, Labetalol & Carvedilol
• Beta blockers reduces the rate of mortality in patients with myocardial infarction and reduces re-infarction following a previous myocardial infarction
• Calcium channel blockers used for angina

  • Verapamil & Diltiazem for both stable & Unstable angina
  • Dihydropyridine for variant angina
  • Short acting Nifedipine may increase the risk of sudden death in unstable angina, via reflex tachycardia
• Ivabradine


  • The first of the so-called bradycadic drugs because they induce bradycardia by modulating ion channels in the sinus node
  • It reduces cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the SA node
  • It appears to reduce angina attacks with an efficacy similar to the beta blockers and Ca channel blockers
  • Comparatively, does not have other cardiovascular effects (No effect on myocardial contraction, relaxation or ventricular repolarization)
  • Safe to use in patients with heart failure
• Ranolazine


  • A newer antianginal drug that acts by reducing late sodium current (INa) that facilitated calcium entry via sodium-calcium exchanger
  • The resulting reduction in intracellular calcium concentration reduces cardiac contractility and work
• Trimetazidine


  • A Metabolic modulators, a pFOX inhibitor
  • It partially inhibits the fatty acid oxidation pathway in myocardium
  • In an ischemic myocardium, metabolism shifts to oxidation of fatty acids increasing the oxygen requirement per unit of ATP produced
  • A partial inhibition of the enzyme required for fatty acid oxidation appears to improve the metabolic status of ischemic tissues
• Revascularisation options if drug therapy fails

  • Coronary artery bypass grafting (CABG)
  • Percutaneous Coronary Intervention (PCI)
• Myocardial infarction


  • Refers to the death of myocardial muscle cells that occurs when a substantial decrease or complete disruption of blood flow through a coronary artery deprives the downstream tissue of oxygen for an extended period
  • In an MI, an area of the myocardium is permanently destroyed
  • Infarctions is death of part of the myocardium from deprivation of blood & oxygen
• MI occurs when a coronary vessel becomes blocked as a result of thrombosis
• MI is the commonest cause of sudden deaths (Heart attack) in many parts of the world
• The heart cells rely on aerobic metabolism and hence if the supply of oxygen via coronary circulation is poor, sequence of events leading to cell death by necrosis ensues
• Prevention of ischaemic damage following coronary thrombosis is an important therapeutic aim in the management of Ischaemic heart diseases
• Symptoms of myocardial infarction

  • Severe pain similar to pain in angina pectoris
  • Palpitation
  • Cough
  • Light-headedness
• Coronary artery bypass grafting (CABG)


  Procedure to treat myocardial infarction when drug therapy fails
• Percutaneous Coronary Intervention (PCI)


  Procedure to treat myocardial infarction when drug therapy fails
• Myocardial infarction (MI)


  Death of myocardial muscle cells due to deprivation of blood and oxygen