PH402 Nitric Oxide and Angina

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PH402 Nitric Oxide and Angina

• Chris Hague, PhD
• chague_at_u.washington.edu
• Technical Advisor Seth Goldenberg, PhD

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References

• Brodys Human Pharmacology, 4th Edition
• Guyton Human Physiology
• http//www.nhlbi.nih.gov/health/dci/Diseases/Angin
  a/Angina_WhatIs.html
• http//www.americanheart.org/presenter.jhtml?ident
  ifier4472
• http//www.nlm.nih.gov/medlineplus/tutorials/angin
  a/htm/_no_50_no_0.htm

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Outline

• 1. Angina
• 2. Coronary artery disease/Atherosclerosis
• 3. Nitrovasodilators
• 4. Beta-adrenergic receptor antagonists
• 5. Ca2 channel antagonists
• 6. New Therapies

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What is Angina?

• ankhon strangling pectus chest
• chest pain that is experienced as squeezing or
  pressure
• also localized to shoulders, neck, jaw or back
• a symptom of coronary artery disease (CAD)
• secondary to atherosclerosis

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Types of Angina

• 3 types
• Stable
• most common
• has common pattern
• occurs during exercise
• decreases at rest
• treatable
• Unstable
• no pattern
• not relieved by rest/medicine
• preclude to heart attack
• Variant (or Prinzmetals)
• rare
• occurs at rest between midnight and early morning
• relieved by medicine

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Angina Statistics

• 15.8 million have experienced angina in US
  (8.5 male, 7.2 female)
• 8.9 million currently affected
• 400k new cases/year
• caucasian (9.4/6)
  african-american (7.1/7.8)
  hispanic (5.6/5.3)

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Risk Factors

• hypertensive patients
• high blood cholesterol
• obesity
• smoking
• diabetes

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Oxygen supply to the heart

• oxygen and nutrients supplied by coronary
  arteries
• branch from aorta
• left CA supplies anterior/lateral LV
• right CA supplies RV/ posterior LV
• main arteries on surface of heart
• smaller arteries penetrate cardiac muscle

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Anatomy of an artery

• multiple layers
• tunica adventitia macrophages, monocytes,
  fibroblasts
• tunica media smooth muscle cells
• endothelium
• single layer of cells
• source of NO

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Coronary artery disease (CAD)

• CAs become hardened and narrowed
• increased plaque formation
• decreased nutrient/oxygen supply to cardiac
  muscle
• also causes acute coronary occlusion
• collateral vessels can develop

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Atherosclerosis

• buildup of plaque in arteries over time
• narrows luminal diameter
• cholesterol deposited below endothelium
• inflammatory response
• invaded by fibrous tissue and become calcified

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Treatment of Angina

• Goals
• increase CA blood flow
• vasodilators (NO donors, Ca2 channel
  antagonists)
• decrease demand on heart
• ß-adrenergic receptor antagonists
• treat CAD
• decrease cholesterol statins
• surgical procedures (stents, angioplasty)
• lifestyle changes

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Contraction of vascular smooth muscle

• GPCRs expressed on smooth muscle cells
  (a1-adrenergic, angiotensin II, serotonin)
• stimulates phospholipase C, cleaves PIP2 into
  IP3/DAG
• increases intracellular Ca2/calmodulin

• activates myosin light chain kinase
• phosphorylates myosin, interacts with actin
• contraction

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NO production in Endothelium

• GPCRs expressed on endothelium (muscarinic,
  histamine, bradykinin)
• activation increases Ca2/calmodulin

• activates nitric oxide synthase (NOS)
• converts arginine to citrulline NO
• NO diffuses into smooth muscle cells in media
  tunica

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NO causes vasodilation

• NO activates soluble guanylyl cyclase in smooth
  muscle cells
• soluble guanylyl cyclase increases cGMP production

• cGMP activates cGMP protein kinase
• phosphorylates ion channels
• decrease Ca2 channel activation
• vasodilation

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Organic Nitrates

• earliest known therapy (100 years old)
• quick onset (1-2 min)
• nitroglycerin (TNT)
• delivered in all forms
• sublingual (cheap, prophylactic)
• isosorbide dinitrate
• longer duration of action
  (active metabolite 5-isosorbide
  mononitrate)
• tetranitrates
• differ in onset and duration of actions

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Pharmacokinetics

• high lipid solubility
• sublingual
• absorbed across skin
• rapidly absorbed from anywhere
• extensive 1st pass metabolism
• older forms shorter T 1/2
• newer tetranitrites have longer T 1/2

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Side Effects

• headache
• orthostatic hypotension
• faint when stand-up
• decreased venous return
• tachycardia
• baroreceptor reflex
• conversion to nitrites at high concentrations
• oxidizes ferrous iron
• converts hemoglobin to methemoglobin
• reduces O2 supply

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cGMP phosphodiesterase inhibitors

• cGMP phosphodiesterases convert cGMP to GMP
• numerous subtypes of cGMP PDEs discovered
• PDE5 prevalent in vascular smooth muscle
• PDE5 inhibitors inhibit breakdown of cGMP
• increase cGMP, vasodilation
• Sildenafil (Viagra)
• Tadalafil (Cialis)
• Vardenafil (Levitra)

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Pharmacokinetics/Side Effects

• active orally
• fairly quick onset (30 minutes)
• long duration (4-48 hours)
• metabolized to inactive metabolites in liver by
  p450 enzymes
• cause vision problems, hypotension, GERD, CNS
  effects
• optimal for treatment of angina in combination
  with erectile dysfunction

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ß-blockers

• antagonize ß1-adrenergic receptors expressed on
  cardiac myocytes
• decrease heart rate (decrease CO)
• decrease preload/afterload
• net effect decrease myocardial O2 demand
• used prophylactically, not used to treat acute
  angina
• increases exercise tolerance of patient, reduces
  frequency of attacks
• Atenolol, Acebutolol, Metoprolol, Propranolol

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Pharmacokinetics/Side Effects

• taken orally
• long T 1/2 (4-20 hours)
• cheap!
• few side effects in healthy individuals
• many potential side effects secondary to
  underlying diseases
• include cardiac failure, fatigue, hypoglycemia,
  impotence
• contraindicated in asthma

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Ca2 channel antagonists

• inhibits Ca2 influx through voltage-gated L-type
  Ca2 channels
• relax arterial smooth muscle, not venous
• increase blood flow to the heart

• inhibit myocyte contractility
• decrease CO
• given prophylactically, do not reverse acute
  angina

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Verapamil

• first selective Ca2 channel inhibitor
• relaxes coronary arteries
• potent negative inotropic actions
• depresses AV nodal rate and conduction
• Tradenames Calan, Isoptin

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Pharmacokinetics/Side Effects

• extensive 1st pass metabolism in liver
• norverapamil is active metabolite (20-30
  activity)
• T 1/2 5 hours
• contraindicated with ß-blocker
• Side Effects dizziness, headache, constipation,
  flushing, fatigue, bradycardia, indigestion

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Diltiazem

• relaxes coronary arteries
• potent negative inotropic actions
• depresses AV nodal rate and conduction, but with
  lesser effectiveness then verapamil
• Tradenames Cardizem, Dilacor, Diltia

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Pharmacokinetics/Side Effects

• also extensive 1st pass metabolism in liver
• CYP3A4
• desacetyl diltiazem is active metabolite (20-50
  activity)
• T 1/2 3.5 hours
• contraindicated with ß-blocker
• Side Effects same as with verapamil, yellowing
  of skin/eyes, fever, rash

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Dihydropyridines

• selective arterial vasodilators
• reduce peripheral resistance, cardiac afterload
• no effect on AV nodal rate and conduction
• Nicardipine (Cardene)
• Felodopine (Plendil)
• used for angina at low doses
• relax CA without causing myocardial depression

Felodipine
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Pharmacokinetics/Side Effects

• 1st pass metabolism in liver, CYP3A4
• grapefruit juice! (bergamottin)
• inducers barbiturates, phenytoin, rifampicin
• inhibitors azoles (antifungals), SSRI,
  macrolides, cimetidine
• T 1/2 differs amongst formulations
• longer T 1/2 preferred

• Side Effects
• dizziness
• tachycardia
• vasodilation
• heart failure with underlying disease

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Emerging Therapies

• Aspirin
• prevent thrombi
• Statins
• lower blood cholesterol
• prevent plaque formation
• prevent CAD
• Ranolazine (Ranexa)
• activates pyruvate dehydrogenase
• modulates L-type Ca2 channels
• late Na current modulator ???
• enhances O2 metabolism from carbohydrates