• Has the same positive outcomes as cardiac stenting in terms or morbidity and mortality over a 5 year course

1. Decrease M.I. likelihood

• These were the drugs mentioned in the previous DSA

1. Control angina symptoms 

• This is the material covered by DSA 8

• Statins:  These prevent/"reverse" plaque buildup 
• Aspirin
• ADP agents ("grel") 
• Anticoagulants

-The major goals of aspirin, ADP agents, and anticoagulants is to decrease the formation of  thombi 

• Organic nitrates (nitroglycerin)
• Beta-blockers 
• Ca-channel blockers that are cardio/vascular-selective

• It is a painful clinical syndrome that is due to:

-An imbalance between myocardial O2 supply and deman

-CAD is usually the underlying cause  

• Typical agina:  This is stable angina. Angina due to exersion 
• Atypical angina:  This is angina that occurs even at rest

-Atypical angina (unstable) is going to have 3 variants:

1. Variant
2. Vasospastic 
3. Prinzmetal 

 Unstable angina is any change in frequency of anginal attacks.  This is related to a high mortality probability

1. What is typical angina caused by usually?
2. What is going to aggrevate/relieve this angina?
3. How long are the attacks?
4. What are you giong to see on an angiogram during an attack?

1. Atherosclerotic plaque
2. Aggrevate = exeercise; Relieve = rest 
3. Does not last longer than 30 minutes w/5-15 episodes/week 
4. ST-segment depression 

IMPORTANT to know that the initial attack of even stable angina/typical angina is considered atypical/unstable angina because it is a change in the frequency of anginal pain 

1. What is prinzmetal angina?
2. What is the underlying cause? 
3. What are you going to see on ECG? 

• It is a type of atypical (rest) angina
• Vasospams are going to cause angina at rest
• Transient ST-segment elevation during angina 

1. How do you define unstable angina?
2. What is unstable angina usually caused by?
3. What is the history of the patient with this?
4. What does unstable angina allude to?

1. It is the progression from stable to more frequent angina (this includes the first attack)
2. Ofen results from thrombus
3. Resting angina, usually at least 2 attacks/24 hours 
4. MI is imminent 

• O2 supply available to the heart is decreased significantly 
• O2 demands are not met 
• Autoregulatory mechanisms usually fail to mitigate the imbalance 

• It is ONLY in in the large vessels 
• At rest, the small vessels can dilate enough to maintain the blood blow however with higher O2 demands, it cannot dilate enough

• Pain occurs b/c blood flow is limited 

• It is angina that is induced by SPASM
• Etiology is unclear 
• Spasm is NOT a consequence of increased sympathetic activity 

• ADDITIONAL artery block from usual the already reduced and usual pattern of blood flow
• This is goiing to be caused by:

-Clot forming to a thrombus

-Plaque rupture

-Spasm  

1. Acute prophylaxis: Anticipiate angina-inducing situations
2. Treat attack in prgoress (select rapidly-acting drug) 
3. Chronic prophylaxis which you are going to use:

-"Statins" as and cholesterol/triglyceride lowering drugs

-Anti-platelets 

-Anti-coagulation

1. Increase oxygen supply (but this is difficult w/atherosclerotic plaque and this is why this is usually nota viable strategy)
2. Decrease oxygen demand for:

• Exertional angina
• Unstable angina

1. Relax (dilation) the vasculature

• This is effective in prinzmetal angina 

• Oxygen demand that is determined by:

-Heart rate

-Myocardial contractility

-Systolic blood pressure (afterload)

-LV volume (preload) 

• During angina, the extraction rate is at threshold 
• It is important to note that pharmacologic intervention does NOT change extraction threshold 
• Pharmacoligic intervention decreases the amount of work the heart performs for ANY given level of exercise, which allows patients to reach a higher level of exercise than w/o treatment 

Organic nitrates

(nitroglycerin)

Pharmacodynamic effects?

What can this be used in?

• Relax vascular smooth muscle 
• Mainly there is relaxation of large veins → decreases venous return → decreases preload → decreases O2 demand (this is the major effect) 
• Smaller decrease in afterload which reduces heart work

This can be use to treat

• Angina
• Effective in prevention/relaxation of coronary vasospasm (this is why these are useful for prinzmetal)

• Peripheral vascular venodilation 

-This reduces the pre-load which reduces the work of the heart

• In healthy subject, NO dilates the coronary artereis and leads to increaesd flow in the coronary arteries 
• But this is NOT the case in patients that have angina because their coronary arteries are maximally dilated and this means that the effect is NOT on the heart directly
• Direct infusion of NtG into the heart of an anginal patient does not reliieve angina, but sublingual NTG DOES  

• Nitrates or endothelial cells → cause the release of NO → cause activation of guanylyl cyclase → causes GTP to cGMP 
• Activated myosin light chain kinase (MLCK) → causes myosin-LC to become myosin-LC-PO4 + actin → contraction
• cGMP + myosin-LC-PO4 → Myosin-LC → relaxation 

***phosphodiesterase inactivates cGMP***

1. Angina (of ALL types)
2. Congestive heart failure:  By venodilating  and shifting fluid from the central to the peripheral compartment, improve pulmonary edema 
3. After MI: ↓ work of the heart and ↓ platelet aggregation
4. Raynaud's disease 

• Headache + dizziness b/c of excessive vasodilation
• Orthostatic hypotension
• Tolerance

               Dose/frequency depdendent 

               Maintain patients nitrate free for at least 8-hr/day 

               Taking a drug "holiday" can alleviate 

• Drugs for erectile dysfunction ("afil" class drugs)

               -Inhibit phosphodiesterase-5 enzyme to prolong cGMP

               -Leads to a reduced  breakdown of cGMP 

               -Causes severe enhance vascular effects

               -Causes severe hypotension 

• "afils" (erectile dysfucntion) drugs are going to be contraindicated 

• NTG
• Amyl nitrate
• Lsosorbide dinitrate 

NTG

ROA?

Onset? 

Duration? 

Half-life?

Additional information?

• ROA = sublingual
• Onset = short
• Duration = short-acting b/c short half-life

**there is a LARGE first pass effect so that is why sublingual**

Amyl Nitrite 

ROA?

Onset?

Important Note

• ROA:  Inhalation (poppers/snappers-has abuse potential)
• Onset:  Most rapid onset

-There isn't much of difference from the onset or duration than NTG

Isosoribide dinitrate

ROA?

Onset?

Important Notes

• ROA:  Oral
• Onset:  Slower + less potent than NTG

-Can develop tolerance if used extensively for prophylaxis of angina

Nitrate therapy in chornic stable angina

1. How are they used as short-acting drugs?
2. How are they used as long-acting drugs?
3. What are there limitations?

• Short acting:  1)  Relief during acute episodes 2)  Prophylaxis of acute episodes

• Long acting:  1)  Monotherapy for mild angina 2)  Adjuntive for severe angina 

• Limitations:  1)  SE  2)  Tolerance 

• ↓HR (major effect) 
• ↓Contractility (lesser effect)
• ↓Cardiac Work → ↓O2 demand
• ↓Peripheral resistance by blocking renin release → which in the long run ↓oxygen demand 

***This has NO EFFECT on the O2 supply***

• Systolic BP * HR = Cardiac output
• Cardiac output = Pressure-Rate Product 

**It will do NOTHING to the final CO**

• Angina will still occur at the same CO
• Beta-blockers decrease the HR and contractility 

Indications:

• Mono-therapy for mild-moderate angina of effort 
• These cannot be used for prinzmetal angina
• Can be used after an MI

• Bradyarrhythmias
• Congestive HRT failure
• Extra-cardiac effects 

What are the non-selective beta-blockers?

What are the beta-1 selective blockers?

Non-selective:

• Propranolol 
• Nadolol 
• Timolol

Beta-1 selective:

•  Metoprolol
• Atenolol 

Ca++ channel blockers in angina

What is the MOA of Ca++ blockers?

• Block Ca++ entry though L-type channels → causes relaxation of the arterioloar smooth muscle → ↓afterload → ↓O2 demand 
• Also increase the supply of blood to the heart by causing dilation of the coronaries

Intracellular Ca++ increases via 3 ways:

1. Voltaged gated channels (L, N, and T)
2. Receptor mediated activation of internal stores (alpha-1) 
3. Receptor mediated influx of Ca++ 

**All of these mechanisms cause an increase in cell contraction**

1. Myosin-LC + activated myosin light-chain kinase → myosin-LC-PO4 + actin → contraction
2. Ca++ activates calmodulin → calmodulin binds to myosin light chain kinase → activation of myosin light chain kinase

1. What are the classes of Ca-Channel Blockers?
2. What are the drugs in each class

Predominately vascular:

• "Pines" 
• Dihydropyridine drugs 

Predominately cardiac:

• Verapamil
• Diltiazem 

1. Decrease left ventricular wall tension (decreases effort)
2. Decreases excitability of vascular smooth muscle and can decrease arterial spasms (helpful in Prinzmetal) 
3. Decreases tone of vascular smooth muscle (decreases afterload and so helps with anginal effort)

In addition to vascular effects, verapamil and diltiazem are going to:

• Decrease SA and AV node fucntion (decrease HR)
• Much more effective at decreasing contractility than "pine" drugs

Both of these are going to cause a decrease in cardiac work and so they are useful in angina related to effort

Goal is to relax the vasculature so you are going to use:

• Nitrates
• Ca++ channel blockers 

Verapamil:

• AV-node and SA-node bradyarrhythmia 
• CHF (++)
• Hypotension (++)

Diltiazem:

• AV-node and SA-node bradyarrhythmia
• CHF (+)
• Hypotension (+)

Nifedipine:  Hypotension (+++) and reflex trachycardia (++)

Non-cardiac SE w/Ca++ blockers?

Verapamil:

• Headache/ postural dizziness/ flushing/ peripheral edema (+)
• Constipation (+++)

Diltiazem:

• Headache/ postural dizziness/ flushing/ peripheral edema/ constipation (+)

Nifedpine:

• Headache (++); postural dizziness (+++); flushing (+++); peripheral edema (+++); constipation (+)

• Prinzmetal angina
• Patients w/sinus bradycardia or AV dysfunction do NOT use verapamil/diltiazem, use "ipine" Ca-blocker
• Atrial fib/flutter
• Patients that are resistant/tolerant to nitrates or Beta-Blockers; use them (either the vascular or cardiac) as ADDITIONAL agents 

• Ca++ channel blocker w/ a beta-blocker

-This combination is more effective than giving either alone for angina of effort 

-Clopidogrel in place of aspirin b/c it does NOT effect PG

-Is preferred over aspirin when:

• If loop diuretic is being used
• If there is kidney disease 

**Clopidogrel is particularly useful in unstable angina**

NTG 

Onset: 1-3 minutes

Duration:  20 minutes 

Beta-blockers 

Ca-blockers

Long duration nitrates 

Combination

NTG

Onset:  1-3 minutes

Duration:  20 minutes 

Drugs that decrease afterload/pre-load only are NOT effective against angina that is caused by effort

• Alpha-blockers 
• ACE-I
• ARBs
• Hydralazine (they actually WORSENS angina by causing "coronary steal")

Hydralazine 

Causes "coronary steal" syndrome