Vasodilators

Case Study Examples

• Patient Profile: A 52-year-old male experiencing chest pain induced by exercise, sometimes radiating to the lower jaw, but subsiding with rest.
• Vital Statistics: Cholesterol 245 mg/dL, LDL 160 mg/dL, Blood Pressure (BP) 145/90 mm Hg, Heart Rate (HR) 80 bpm.
• Family History: Father died of a "heart attack" at age 55.
• Diagnosis: Stable effort angina.
• Treatment Options: Sublingual or sprayed nitroglycerin; beta-blocker (metoprolol) or a medium-to-long-acting calcium channel blocker (verapamil, diltiazem, or amlodipine); low-dose daily aspirin; treatment for high cholesterol.

Angina

• Definition: Angina is a chest pain caused by inadequate coronary oxygen supply (from the Latin word angere, to choke), often described as pectoris (chest).
• Prevalence: 6 million US citizens experience various angina forms.
• Frequency: Angina attacks occur approximately 1,000 times per minute in the US.
• Hospitalizations: 8 million ER visits annually related to chest pain, 3 million discharged, 2.5 million are non-cardiac, 1 million diagnosed with AMI, 1.2 million unstable angina cases, 0.3 million deaths.

Types of Angina

• Atherosclerotic Angina: A form of angina characterized by the presence of lipid plaques partially obstructing one or more coronary arteries, most common (90%). Exercise, cold, or stress-induced emotional stimuli can trigger ischemic changes in the arteries, producing pain.
• Vasospastic Angina (Prinzmetal's): Angina occurring at rest and is also known as variant or Prinzmetal's angina. It's caused by spontaneous spasm in atherosclerotic arteries. This type of angina can happen while sleeping. It sometimes transitions into unstable angina.
• Unstable Angina: A serious form, known as crescendo angina. Characterized by unpredictable and high frequency attacks; a precursor to a myocardial infarction (MI). This type of angina is caused by a combination of underlying pathologies, including atherosclerotic plaques, platelet aggregation at affected plaques, and vasospasm in the affected artery.

Myron Prinzmetal

• Physician and Pharmacist: Held degrees in medicine and pharmacy (from UCSF).
• Angina Researcher: First to describe a variant angina form.

Drugs Used to Treat Angina

• Vasodilators (for atherosclerotic angina): Nitrates, Calcium Channel Blockers
• Cardiac Depressants (for all types): Calcium Channel Blockers, Beta-Blockers

Therapeutic Strategies

• Goal: Treat the underlying cause of angina, focusing on inadequate coronary oxygen supply, either increasing the amount of oxygen delivered or decreasing the amount of oxygen required.
• Approaches: Increase oxygen delivery to the heart, reduce oxygen requirement in the heart.
• Nitrate use: Reduce oxygen requirements in atherosclerotic angina.
• Calcium Channel Blockers & Beta-Blocker use Reduce oxygen requirements for all types.
• Special Cases (Unstable Angina): Revascularization techniques (bypass grafting, angioplasty) along with antiplatelet medications may be required.

How Drugs Relax Vascular Smooth Muscle

• Nitroprusside, Nitrates, Nitroglycerin, NO: Increase intracellular cGMP levels by inhibiting phosphorylation of myosin.
• Calcium Channel Blockers, Beta Blockers: Decrease intracellular Ca2+ preventing myosin light chain kinase activity. Decreases calcium levels that cause smooth muscle contraction.
• Minoxidil: Opens potassium channels, hyperpolarizes cells, leading to relaxation.
• Beta-2 agonists: Increases cAMP for myosin light chain kinase inactivation. Usually not used for angina treatment due to excessive heart stimulation.

Nitrates

• Forms: Available in various forms with varying durations of action. (inhaled (3-5 min), sublingual (10-30 min), oral (4-6 h), transdermal (8-10 h)).
• Drug Examples: Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.

Nitroglycerin

• Discovery: Discovered by Ascanio Sobrero, used initially for explosives.
• Mechanism of Action: NG, within smooth muscle, becomes denitrated, releasing nitric oxide (NO) to increase cGMP, thereby dephosphorylating myosin light chains to relax muscle and dilate blood vessels.
• Alternative Drug for Patients with First-Pass Liver Metabolism Issues: Isosorbide dinitrate.
• Adverse effects: Tolerance develops after 8-10 hours (Monday Disease), so patches may be removed after this timeframe. Other possible side effects include tachycardia from baroreceptor reflex, orthostatic hypotension, and severe throbbing headaches caused by meningeal arterial vasodilation.
• Combinations: Sildenafil (Viagra) enhances cGMP effects.

Cardiac Oxygen Requirements

• Physiologic Factors: Myocardial oxygen requirements are governed by muscle fiber tension. This tension is impacted by variables like preload (diastolic filling), afterload (systolic determinant), heart rate, and contractility.

Variables That Determine Fiber Tension

• Preload: Determined by blood volume and venous tone, which reflects the sympathetic outflow.
• Afterload: Systolic determinant controlled by arterial blood pressure.
• Heart Rate: Faster rates lead to lower coronary artery blood flow and less diastolic time.

Terms

• Angina: from L. angere, to choke.
• Pectoral: pertains to the chest

Calcium Channel Blockers (CCBs)

• Activity: Oral absorption is active, with half-lives ranging between 3 and 6 hours.
• Treatment Indications: Widely employed in angina therapy. Many products are FDA approved.
• Mechanism of action: Block the influx of calcium into cardiac smooth muscle. Inhibit the activation of the calcium-calmodulin complex, preventing myosin light chain kinase phosphorylation which prevents actin-myosin cross-bridge formation. This directly relaxes smooth muscle and dilates blood vessels.
• Drugs: Nifedipine, dihydropyridine ,diltiazem, verapamil

CCB Adverse Reactions

• Common: Constipation, nausea, pretibial edema, flushing, and dizziness.

Peripheral Artery Disease (PAD)

• Cause: Atherosclerosis, reducing blood flow.
• Symptoms: Intermittent claudication (pain with exercise relieved with rest)
• Consequences: Chronic ischemic ulcers, infection risk.

Drugs to Treat PAD

• Cilostazol: Phosphodiesterase 3 form inhibitor, leading to increased cAMP, vasodilation, and enhanced blood flow.
• Sildenafil (Viagra): Also has a similar mechanism but inhibits PDE 5 (rather than PDE 3.)

Beta-Blockers

• Treatment Role: Used frequently in angina prophylaxis;
• Use for acute attack: No effectiveness for acute treatment.
• Protection from vasospastic angina: Not effective in preventing attacks.

Summary of All Drugs (effects on various cardiac factors)

• Nitrates: Increase heart rate, decrease arterial pressure, decrease diastolic pressure, increase contractility (r increase), Decrease ejection time (r decrease)
• Beta Blockers or CCBs: Decrease heart rate, decrease arterial pressure, increase diastolic pressure, decrease contractility, increase ejection time

Summary of Drug Mechanisms

• Nitrates: Reduce cGMP which blocks muscle contraction
• CCBs: Block in-flow of calcium.
• Beta Blockers: Increase cAMP to speed up activation of MLCK enzyme.

Vasodilator Mechanisms

• Actions: Dilation of blood vessels are caused by direct action on smooth muscle through methods: Release NO, Hyperpolarization through potassium channels, block calcium channels, and activating dopamine D1 receptors

Other Vasodilators

• Hydralazine: Releases NO; toxic at higher doses (tachycardia, salt retention). Less toxic at less than 200 mg/day
• Minoxidil: Opens potassium channels, leading to hyperpolarization and muscle relaxation.

Nitroprusside

• Action: Releases NO to cause vasodilation; Used intravenously in emergencies to reduce blood pressure.

Fenoldopam

• Action: Dopamine D1 receptor agonist; Causes arterial vasodilation, administered intravenously, used in emergencies to address hypertensive crises.

Other Noteworthy Topics

• Unstable Angina: This is a more serious form requiring revascularization (bypasses or angioplasty); antiplatelet medications are also used.
• Cyanide and Nitrite Toxicity: These substances are metabolized through various processes to cause poisoning..
• Methemoglobinemia (MHb): A condition where hemoglobin iron is in a ferric (rather than ferrous) form and cannot adequately carry oxygen, leading to hypoxia.