Transcript beta blocker triglyceride

Coronary Artery Disease
Coronary Arteries
Coronary Artery Disease
• AKA Ischemic Heart Disease or Coronary Heart Disease
• 82.6 million American adults have CVD
– 16.3 million have CHD or CAD
• 7.9 million have had an AMI
– 7 million have had a stroke
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CHD caused 1 of 6 deaths in the US 2007
CHD is the single largest killer of US adults
Every 25 secs someone has a coronary event
Every minute someone will die from a coronary event
AHA stats 2011
Cause
• Ischemia - Imbalance between mycocardial
oxygen supply and demand results in hypoxia
• Mostly due to atherosclerotic plaques
Risk Factors
• Obesity/Inactivity
• Hyperlipidemia
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– LDL
Smoking
Hypertension (≥ 140/90 or on meds)
Low HDL (<40)
Diabetes mellitus
Type A personality (stress)
Age
– Men ≥ 45 or women ≥ 55
• Family history of CHD
– Before 55 for male or before 65 for female
New Problem?
Clinical Presentation
• Silent Ischemia
• Angina pectoris (chest pain)
– Description – heavy pressure
– Location – over the sternum, left arm, jaw
– Radiation – left shoulder, jaw
– Duration – 0.5-30 minutes
– Nitroglycerin relief
– Stable or Unstable
• Myocardial Infarction
Diagnosis
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Electrocardiogram (ECG)
Echocardiogram
Stress test
Angiogram
CT scan
Magnetic resonance
angiography (MRA)
• Bloodwork
– Cholesterol
– C-reactive protein
– MPO
Development of Atheroscleosis
Stages of Atherosclerosis
Intervention
• Many of these therapeutics can not reverse the
atherosclerotic scarring.
• Pharmacological and Lifestyle
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Treatment of Angina
Prevent thrombosis
Reduce further plaque formation/progression
Dissolve blood clots
• Invasive procedures
– Angioplasty
– Stent
– Bypass
Nature Medicine 17,1410–1422 (2011)
Established Therapies
Thrombolytics
Organic Nitrates
• Prodrugs – source of nitric oxide (NO)
– Nitroglycerine
– Isosorbide dinitrate, Isosorbide-5-mononitrate
– Taken during angina
attack
– Dose and freq
dependent
tolerance
Statins
• Competitive inhibitors of HMG-CoA reductase
– Decreased cholesterol synthesis
– Increased expression of the LDL receptor gene
• Reduce LDL levels
• Documented in reducing fatal and nonfatal
CHD events, strokes, and total mortality
– Adverse effects were similar in placebo and drug
groups
Statins
Zocor
Lipitor
Crestor
Effects on Triglycerides & Lipoprotein
Levels
• Decrease triglycerides in
hypertriglyceridemia
– 35-45%
• Increase HDL-C
– Normal patients: 5-10%
– Low patients: 15-20%
• Decrease LDL-C
– 20-55%
• Non-lipid lowering effects
– Endothelial function (Enhances
production of nitric oxide)
– Anti-inflammatory
– Reduce venous
thromboembolic events
• 43%
• Adverse Effects
– Hepatotoxicity
• Elevated hepatic transaminase
values
• One case of liver failure per
million person-years of use
– Myopathy
• One death per million
prescriptions caused by
rhabdomyolysis
Niacin (Nicotinic Acid)
• Inhibits the lipolysis by hormone-sensitive lipase
– Reduces transport of free fatty acids to the liver
– Decreases hepatic triglyceride synthesis
• May inhibit diacylglycerol acyltransferase-2
– Rate-limiting in triglyceride synthesis
– Reducing triglyceride synthesis reduces hepatic VLDL
production
• Raises HDL levels by decreasing the fractional
clearance of apoA-I in HDL
Effects on Lipoprotein Levels &
Adverse Effects
• Increases HDL: 30-40%
• Lowers triglycerides by
35-45%
• Reduces LDL: 20-30%
• Half-life: 60 minutes
– Requires 2-3 doses/day
• Therapeutic Use
– Hypertriglyceridemia
and low HDL levels
• Adverse Effects
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Flushing
Dyspepsia
Hepatotoxicity
Hyperglycemia
Renin Angiotensin Pathway Blockers
Beta Blockers
• Effects
– Reduce heart contractility and rate
– Reduce Renin secretion by kidneys
• Antihypertensive
Propranolol (Inderal)
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First β-blocker discovered
Nonselective
Prototypical drug
Competitive antagonist
Equal affinity for β1 and
β2
• Pure antagonist
• Pharmacokinetics
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Oral absorption: 95-98%
Metabolized by the liver
Renal excretion
Half-life: 3-6 hours
• Clinical Use
– Hypertension
– Angina
– Management of lifethreatening arrhythmias
– Prevention of myocardial
infarction, migraine and
anxiety disorders
• Adverse Effects
– Bradycardia
– Hypotension
Metoprolol (Lopressor)
• Second leading prescription
drug in 2007
• β1 selective
– First one
– Equipotent to propranolol in
inhibiting β1 but 50-100 fold
less potent at β2
• Pure antagonist
• Pharmacokinetics
– Oral absorption: 50%
– Metabolized by the liver
– Renal excretion
• Some in feces
– Half-life: 3-5 hours
• Clinical Use
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Hypertension
Angina
Tachycardia
Heart failure
Prevention of migraines
• Adverse Effects
– Hypotension
– Depression
– Vision problems
Calcium channel blockers
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Relax blood vessels
Increase the supply of blood and oxygen to the heart while
Reduce the heart's workload
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Norvasc (amlodipine)
Plendil (felodipine)
Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Diltia XT, Tiazac (diltiazem)
Calan, Calan SR, Covera-HS, Isoptin, Isoptin SR, Verelan, Verelan PM
(verapamil)
Adalat, Adalat CC, Procardia, Procardia XL (nifedipine)
Cardene, Cardene SR (nicardipine)
Sular (nisoldipine)
Vascor (bepridil)
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Caduet is a combination of a statin cholesterol drug and amlodipine (above).
Antiplatelet Drugs
Antiplatelet Drugs
Emerging Therapies
Nature Medicine 17,1410–1422 (2011)
Novel Experimental Strategies
Vaccines targeting LDL or and apoB
Novel Experimental Strategies