W10 Pharmacology of Ischemic Heart Disease

What are the four primary probable triggers that lead to endothelial dysfunction and atherosclerosis in IHD?

Hyperlipidemia, smoking, hypertension, and endothelial dysfunction

What is the pathophysiological progression from atherosclerosis to the clinical symptom of angina?

Atherosclerosis → reduced blood supply to the myocardium (ischemia) → Angina

What sequence of events leads to a Myocardial Infarction (MI)?

Plaque rupture → platelet aggregation → complete blockade of blood supply to the myocardium → Myocardial Infarction

How is Angina Pectoris clinically defined?

Chest pain or discomfort caused by ischemic heart disease, often radiating to the left shoulder, left arm, neck, or jaw

Why is myocardial ischemia considered the primary cause of angina?

Because ischemia represents a reduced blood supply that fails to meet the metabolic demands of the heart muscle and angina is a symptom of that

What metabolic change occurs in the myocardium when blood supply is reduced during ischemia?

The pH in the myocardium reduces (becomes more acidic). It is hypothesizes that this change in pH is sensed by acid sesing ion channels (ASICs) in the myocradium and transduces as pain

Besides pH changes, which two chemical mediators are believed to help mediate ischemic pain?

ATP and adenosine

What is the neurological mechanism behind referred pain in the left hand and neck during angina?

Convergence of afferent (pain-carrying) fibers from the heart and the skin/limbs to the same spinal segment, causing the brain to misinterpret the signal origin

What are the three major clinical types of Angina?

Stable Angina, Unstable Angina, and Vasospastic (Prinzmetal's/Variant) Angina

What are three alternative names for Stable Angina?

Atherosclerotic angina, Classic angina, and Exertional angina

What is the primary physical cause of Stable Angina?

Atherosclerotic plaques that narrow the coronary arteries

What are four common precipitants of Stable Angina pain?

Exercise, stress, strong emotion, or heavy meals. No pain or discomfort at rest

How is Unstable Angina defined in terms of predictability?

It is unpredictable chest pain that could happen at rest

What is the underlying pathology of Unstable Angina?

Plaque rupture leading to thrombus formation and platelet aggregation (incomplete blockade)

How does the intensity and duration of Unstable Angina compare to Stable Angina?

It is more intense and has a longer duration

Why is Unstable Angina considered a medical emergency?

Because the risk of MI and sudden death is significantly greater than with stable angina

What is the cause of Vasospastic (Prinzmetal's) Angina?

Intense focal coronary artery spasms that reduce blood flow to the heart, independent of atherosclerosis

When does the chest pain typically occur in Vasospastic Angina?

Sudden pain occurring even at rest

What are four major risk factors for Vasospastic Angina?

Smoking, hyperinsulinemia, insulin resistance, and stimulant drug use (specifically cocaine)

What are the two fundamental imbalances associated with Angina?

Reduced oxygen supply and increased oxygen demand

What are the two primary goals in the treatment of Angina?

1. Increase oxygen supply - Coronary vasodilates ; 2. Decrease oxygen demand - Vasodilators (reduce preload and afterload), Beta blockers (reduce heart rate and contractility)

What are the three main classes of drugs used to treat Angina?

Nitrates/Nitrites, Calcium Channel Blockers (CCBs), and beta-blockers

What are three examples of organic nitrates?

Nitroglycerine, Isosorbide dinitrate, and Isosorbide mononitrate

Why is sublingual Nitroglycerin used for acute attacks?

It provides a very fast onset of action (1–2 mins) and bypasses significant first-pass metabolism in the liver

What is the difference between Nitrates and Nitrites?

Nitrates - contain NO3- ion and are more stable ; Nitrites - contain NO2- ion

What are some examples of short acting Nitrates and Nitrites used for acute attacks?

"Nitroglycerin – sublingual (duration 10-30 min) ; Isosorbide dinitrate – sublingual (duration 10-60 min) ; Amyl nitrite – inhalant (duration 3-5 min)

"

What are the various long acting nitrates and nitrites used for prophylaxis?

Nitroglycerin - (Oral sustained-release, ointment, transdermal patch, and buccal slow-release) ; Isosorbide dinitrate (oral) ; Isosorbide mononitrate (oral)

What is the typical duration of action for long-acting Nitrates?

3–10 hours

Describe the molecular Mechanism of Action (MoA) of organic nitrates.

Converted to nitric oxide (NO) by nitrosothiols in the vascular smooth muscle cells → NO activates guanylate cyclase (GC) → increases cellular cGMP → vascular smooth muscle relaxation

How does elevated cGMP specifically lead to vascular smooth muscle relaxation?

It reduces intracellular calcium levels and leads to dephosphorylation of the myosin light chain

What is the effect of Nitrates and Nitrates on the peripheral arteries, veins and coronary arteires?

They dilate them, reducing preload,reduced after load (which decreases the workload and oxygen demand of the heart) and increasing oxygen supply to myocardium, thus balancing supply and demand

For which two types of Angina are Nitrates indicated?

Stable angina and Prinzmetal's (Vasospastic) angina

What is the clinical term for the loss of drug effect during continuous nitrate exposure?

Nitrate tolerance (or resistance)

What is the hypothesized mechanism for developing nitrate resistance?

Depletion of nitrosothiols due to continuous exposure (Nitrosothiols and P450 reductase convert organic nitrates and nirtrites to NO)

How is nitrate tolerance typically avoided in patients?

By providing a nitrate-free interval (usually 8–12 hours, often at night)

What is onset of action and half life of Nitroglycerine?

Very fast onset of action (1-2 min) and it has a short half life

What happens to Nitroglycerin if it is swallowed rather than taken sublingually?

It undergoes nearly 90% first-pass metabolism in the liver, making it ineffective

Why can Isosorbide mononitrate be given as an oral tablet compared to Nitroglycerin?

It does not undergo significant first-pass metabolism and has a longer half-life

What is the onset time for Isosorbide mononitrate?

Approximately 15 minutes

What are the primary ADRs of Nitrates related to vasodilation?

Orthostatic hypotension (due to venodilation), headache (meningeal artery pulsation), and reflex tachycardia, reflex vasoconstriction

Why do Nitrates cause reflex tachycardia?

Arterial dilation triggers baroreceptors, causing a sympathetic discharge by baroreceptors and homonal mechanisms to increase heart rate

What hematologic ADR is associated with Nitrates/Nitrites?

Methemoglobinemia (hemoglobin oxidized to methemoglobin)

Which drug class is strictly contraindicated with Nitrates due to the risk of a life-threatening drop in blood pressure?

PDE-5 inhibitors (e.g., Sildenafil/Viagra)

Why is Amyl nitrite abused as a 'popper'?

It causes euphoria, lightheadedness, and increased sexual potency through rapid vasodilation >>> cause alveolar damage, hypotension

What is the Mechanism of Action of Calcium Channel Blockers (CCBs) in Angina?

Bind to L-type calcium channels → reduce calcium influx → relax vascular smooth muscle reduce myocardial contractility, and reduce frequency of opening in response to depolarization. Some of them also have affinity towards T-type

What does the reduction of transmembrane Ca2+ influx caused by CCBs cause?

Relaxtion in vascular smooth muscles (DHP) and reduced contractily in myocardium (Non-DHP)

What effect do CCBs have on the SA and AV nodes?

They reduce the pacemaker rate in the SA node and reduce conduction velocity in the AV node

For which type of angina are CCBs considered the drug of choice?

Prinzmetal's (Vasospastic) angina - directly relax coronary arteries and prevent spasms - non DHP are also used for stable but most important is variant

Which two drug classes are considered first-line anti-anginal agents for Stable Angina?

CCBs or beta-blockers

What are the key pharmacological properties of calcium channel blockers regarding tissue selectivity and metabolism?

Varying affinity for vascular smooth muscle vs myocardial cells from one drug to another; limited or no effect on other smooth + skeletal muscle; no adverse effect on lipid or glucose metabolism (unlike beta blockers)

How is a CCB overdose typically treated?

Using intravenous calcium solutions and positive inotropes

What are the three chemical classifications of CCBs?

Dihydropyridines, Benzothiazepines, and Phenylalkylamines

Name two examples of Dihydropyridine CCBs.

Amlodipine and Nifedipine - they cause vasodilation of the arteries with minimal effect on the heart rate - useful in stable and variable angina so they work on periphery

Name an example of a Benzothiazepine CCB.

Diltiazem

Name an example of a Phenylalkylamine CCB.

Verapamil

How do CCBs specifically reduce oxygen demand?

Act on the periohery but Non DHP also reduce myocardial contractility (negative inotropy) and working directly on the heart - hence DHPs best for angina with tachycardias and unstable angina - hence decrease demand by lowering preload and increase supply

What is a common ADR specific to Dihydropyridine CCBs?

Peripheral edema (ankle edema) more common with DHPs. With non- DHPs there is a reduction in cardiac output, conduction block with verapamil and diltiazem. Other general ADRs also include: Constipation, vertigo, headache, fatigue, hypotension

Name three examples of non-selective beta-blockers (beta-1 + beta-2).

Propranolol, Timolol, and Nadolol

Name three examples of selective beta-1 (cardioselective) blockers.

Atenolol, Metoprolol, and Penbutolol

Which beta-blockers also possess alpha-1 antagonistic activity?

Carvedilol and Labetalol (Pregnant women give labetalol - safe but non specific. Reduce BP well but not HR very well)

Which beta-blocker is unique for augmenting nitric oxide (NO) activity?

Nebivolol (BB and vasodilator)

Whivh beta-blockers have intrinsic sympathetic activity

Acebutolol, Pindolol (Good for HTN + bradycardia)

What is meant by Intrinsic Sympathomimetic Activity (ISA) in beta-blockers like Pindolol?

They provide a mild beta-stimulation at rest but block more potent stimulation during exercise

What is the primary antianginal mechanism of beta-blockers?

Decreasing heart rate and contractility→ decreasing myocardial oxygen demand

How do beta-blockers improve myocardial perfusion indirectly?

By reducing heart rate, they increase diastolic perfusion time, allowing more blood to reach the myocardium

Why are beta-blockers not useful in Prinzmetal's (Vasospastic) angina?

Blocking beta-2 receptors allows unopposed alpha-mediated vasoconstriction, which can worsen coronary spasm (also not useful in acute attacks better to use faster acting nitrates).

When are beta-blockers NOT recommended for long-term use in Chronic Coronary Disease?

In the absence of a previous MI, or if the Left Ventricle Ejection Fraction (LVEF) is >50%, or another primary indication for beta blocker therpay

What happens if a patient suddenly withdraws from beta-blocker therapy?

"Exacerbated angina or Myocardial Infarction due to up-regulation of beta-receptors.Treatment of the withdrawal syndrome is by reintroduction of β-blockade. Best therapy is to avoid this condition by gradual withdrawal.

"

Why are beta-blockers used with caution in diabetic patients?

They can mask the symptoms of hypoglycemia (tachycardia/tremor not profuse sweating) for diabetics on antidiabetic drugs

What are the common ADRs of Beta blockers?

"Hypotension, Bradycardia, Sexual dysfunction

Fatigue, Insomnia, Lethargy - CNS effects"

How do beta-blockers affect lipid and glucose metabolism?

They can disturb lipid levels and glucose metabolism

What are two examples of second-line new anti-ischemic agents?

Ranolazine (Ranexa) and Nicorandil (Nicomax)

What is the MoA of Ranolazine?

Inhibits the late sodium current in cardiac cells, reducing intracellular Na+ conc and thereby reducing Ca2+ influx influx via the Na+/Ca2+ exchanger > reduced intracellular Ca2+ > reducing ventricular tension and oxygen demand. Ranolazine reduces myocardial oxygen demand (helps symptoms) BUT it does NOT affect disease progression or long-term outcomes

What are the indications for Ranolazine use?

Useful for treating chronic stable angina in pateints who cannot take beta blockers

What is the benefit of Ranolazine regarding hemodynamics?

It does not significantly reduce heart rate or blood pressure

What the ADRs associated with Ranolazine?

Dizziness, nausea, headache

What is a major contraindication for Ranolazine?

Patients with QT prolongation or hepatic/renal dysfunction

Whar are the DIs associated with Ranolazine?

Inhibitor of CYP3A and CYP2D6, so affects levels of several drugs

What is the dual mechanism of Nicorandil?

1. Potassium channel opener (vasodilation/reduced afterload) that relaxes vascular smooth muscle through membrane hyperpolarization via increased transmembrane potassium condutance > arterial vasodilation > reduced afterload ; 2. Nitrate-like NO donor > activation of guanylate cyclase > increased cGMP> venodilation/reduced preload

What are the indications for Nicorandil use?

For symptomatic treatment of stable angina pectoris that is adequately controlled, or in patients who have a contraindication or intolerance to fire-line anti-anginal therpaies. May be useful in prevention of coronary vasospam (Prinzmetal's). Not useful in treating acute angina attacks

What are the ADRs associated with Nicrorandil use?

Lethargy, back pain,m chest pain, infection, feeling of weakness, ulceration

When is Nicorandil contraindicated?

In patients with hypotension or taking drugs that can cause hypotension

What is a DI associated with Nicorandil use?

PDE-5 inhibitors (e.g., Sildenafil/Viagra)

Which drug is used for the treatment of pain and anxiety associated with a Myocardial Infarction?

Morphine Sulfate (Opioid agonist) - sometimes used in anginal pain if nitrates do not relieve chest discomfort

Why must clinicians be careful when giving Morphine to an MI patient?

It can exacerbate hypotension

In a patient with heart failure, why is Verapamil contraindicated?

Because it is a potent negative inotrope and will further decrease cardiac contractility

For a patient on Metoprolol who still gets exertional chest pain and has HF, which drug is a safe add-on for prophylaxis?

Isosorbide mononitrate (nitrates are safe in HF; adding another beta-blocker or certain CCBs is not) (long-acting nitrate) — used for chronic prophylaxis; avoid verapamil in HF (↓ contractility) and avoid adding another β-blocker

Why is sublingual Nitroglycerin inappropriate for long-term prophylaxis?

It has a very short duration and is intended for the immediate relief of acute attacks

In a patient with asthma and stable angina, why is Propranolol contraindicated?

It is a non-selective beta-blocker that blocks beta-2 receptors in the lungs, potentially causing bronchospasm switch to CCBs

In the case of a patient developing nitrate resistance, what is the best strategy?

Switching to a different drug class, such as a Calcium Channel Blocker (e.g., Nifedipine)

Why is around-the-clock Nitroglycerin patch use a mistake in clinical practice?

It leads to the rapid development of nitrate tolerance/resistance

Which drug is used for acute relief of chest pain in stable angina?

Sublingual nitroglycerin (NG SL) — rapid onset for acute attacks; oral nitrates and β-blockers are for chronic management