Angina: Imbalance between O2 supply and demand

4 types of drugs: B-Blockers, nitrites/nitrates, Ca channel blockers, Ranolazine; Can be combined b/c each has a different site of action

Classic/Stable/Exertional angina: Predictable pain that goes away with rest; ST depression; Atherosclerosis; Damaged endothelium leads to inappropriate vasoconstriciton b/c not enough NO is released for relaxation; Ischemia->bradykinin->protects heart, but causes pain

Unstable angina: random, instense, not relieved by rest or vasodilator like nitroglycerin; Ruptured plaque->an emergency; Treat with platelet aggregation inhibitor 1st, like aspirin

Variant angina: ST elevation and acute vasospasm of large epicardial vessels; most often at rest; healthy people

O2 supply: CBF (coronary blood flow)=aortic pressure/resistance of coronary vessels; Heart gets maximally perfused during diastole, but you can't make the heart excract more oxygen b/c it's already excracting its maximum, but time spent in diastole can be extended

Endocardium is most vulnerable to ischemia, drugs can redistribute blood flow across all layers

O2 Demand: HR, contractile force, and Wall tension determine it; Drugs work here, except ranolazine which has no effect on CV system

Wall tenion: (Afterload x preload)/wall thickness; highest during systole; We can reduce it by reducing arteriolar resistance to bring down afterload (CCB) or adjusting preload (nitrates)-decreasing preload gives heart less blood, but EF increases to empty heart more completely

Vascular contraction: Ca brought into cell by L-type voltage dependent Ca channel->Ca combines w/ calmodulin to activate MLC-Kinase->Phosphorylates MLC->contraction

Vascular Relaxation: Ca channel blockers; Stimulating B2 receptors (activates ATP->increased cAMP->activates PKA->Phosphorylates MLCK->OFF); Nitrates (NO->increased cGMP->PKG->activates MLC-phosphatase->dephosphorylates MLC->OFF); K+ channel acivation (hyperpolarization->harder to depolarize; nicorandil: not available in US)

"Nit=right" (preload)

Nitroglycerine=prototype, rapidly metabolized into 2 inactive metabolites

Isosorbide dinitrate and it's metabolite, isosorbide-5-Mononitrate, dont unergo 1st pass elimination, t1/2 longer than oral nitrates

Isosorbide Dinitrate: Comined w/ hydralazine (arteriole dilator and anti-oxidant),no tolerance develops

Sublingual (quick onset, short t1/2), Spray (slightly faster onset than sublingual, same t1/2), buccal (quick onset, longer t1/2=3 hours), ointment (chest, t1/2=6-8 hours), Patch (longest lasting, 1x/day), Oral (High dose needed b/c of 1st pass effect), IV (for patient w/ MI to relieve pain)

Tolerance: Patch must be taken off at night; From 1) depletion of thiol groups 2)neurohumoral system activates baroreceptor reflex, RAAS, and renal mechanisms, or 3) generation of free radicals; Leads to angina rebound (increased angina upon removal)

Large vessels most responsive, w/ large dose arteries and arterioles afected

Selective for venous smooth muscle; venodilation->decreased preload->decreased blood volume in ventricles->decreased wall tension

Converted to NO by Mitochondria Aldehyde Deydrogenase (MAD) that requires a cofactor w/ thiol groups

Cause a redistribution of blood flow (not an increase) by increasing collateral blood flow (unlike dypiramidole that decreases collateral blood flow-b/c "dypriamidole wants you to die during angina")

Lusitropy: nitrate increases heart's ability to relax; requires ATP, so interrupted by ischemia

Decreaed ejection time due to decreaed preload, decreased arterial pressure, vasodilation of epicardial coronary arteries in variant angina

Barcoreceptor relex->tachycardia and increased contractility->decreased diastolic perfusion time: mitigated by adding B-blockers

SE: Headache, Orthostatic HTN, Interaction w/ PDE inhibitors (Sildeafil, causes excessive relaxation and hypotension)

Used for: Unstable angina (1st choice, plus aspirin), Angina, MI (plus B blocker), variant angina (2nd line)

L-type Ca channel blockers->relaxation

Selective for arterioles->NO orthostatic hypotension

NO Tolerance

Dose related effects

Affect arterioles AND heart

Antiarrhythmic

Can NOT use in combo with B blockers (Non DHP is not acceptable w/ B-blocker)

Diltiazem or Verapamil=drugs

Monotherapy is equally effective as B-antagonist

Slow HR (chronotropic), Slow conduction through AV node (dromotropic), decrease contractile force (inotropic)

Slowing HR->decreased O2 demand->anti-angina

Decreased contractile force->decreased O2 demand->decreased atrial arrhythmias

Use for: Chronic stable angina w/ A-Fib/flutter, variant angina (1st line), Unstable angina if patient can't tolerate B-Blocker

Ineffective in MI

SE: peripheral edema, hypotension (not orthostatic)

Arterioles only

NO antiarrhythmic effect

CAN use in combo w/ B-Blockers

Amodipine and Nifedipine=drugs (AN DHP)

Less effective than B-Antagonist

Amlodipine: Most prescribed, t1/2=48 hours, ramps up then comes down slowly->minimal reflex sympathetic response ("A" for being the best)

Nifedipin: Shorter t1/2, stronger sympathetic response

Use for: Stable Angina

All Drugs in the class have the same efficacy: =Nitrate and non-DHP strength, >DHP 

Use for: Angina (1st line), MI; Decrease morbidity and mortality by decreasing MI incidence and arrhythmias; NOT for Varient angina

Decreased HR and contractility->decreased O2 demand, esp during exercise

Decreased HR and contractile force->decreased stroke volume->greater EDV->increased ventricle size and wall tension...outweighed by + effects

Nitrates decrease ventricular volume and size->good combo w/ B-blockers to minimize - effects

Contra: HF, Asthma, Diabetes

The non lipid soluble ones have fewer SE's

Drugs (alphabetical order):

Atenolol: Cardioselective for B1, Not lipid soluble, Long t1/2 (1x/day), Widely used (Gets an "A" for being all good)

Metoprolol: Cardioselective for B1, Lipid soluble, short t1/2, widely used

Nebivolol: Cardioselective for B1-the most, Not lipid soluble, very long t1/2, safe for asthmatics, causes endothelial cell to release NO (Neville the asthmatic can use it)

Propanolol: Not cardioselective, Lipid soluble, short t1/2, cheap (all the bad stuff)

Inhibits late Na current in heart (late Na current increases calcium and prolongs AP in ischemia)->more O2 supplied to the heart because decreasing AP allows relaxation (lusotropic) and diastolic filling

Only works in ischemic hearts, doesn't affect cardiovascular functions

SE: CYP3A4 interactions, QT prolongation->torsades de pointes

Use for: Exertional angina

Step 1: Aspirin + B-Blocker

Step 2: Add Ca channel blocker or long acting nitrate if angina occurs 2-3x/week

Step 3: Add a 3rd drug if patient still has angina