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Anti-Ischemic Drugs: A compilation from Levis lecture, baby Katzung, and some Lilly/Costanzo.

(Not all of ischemic heart disease though.) If you understand this slide and know where the different drugs fit in, you are in decent shape.

3 types of ANGINA (chest pain due to oxygen shortage in the heart) Classic (effort, stress, atherosclerotic) Variant (at rest, angiospastic, -- Prinzmetal) Unstable (thrombotic) use antipatelet therapy too Determinants of Cardiac Oxygen demand: Different sources describe the oxygen demand/supply problem in different terms, but the main determinants are the same. Katzung describes it as a function of fiber tension. (kind of weird)

Preload: blood volume. Sympathetic activity increases preload due to increased venous tone Afterload: arterial blood pressure due to sympathetic outflow Inc Heart Rate increases demand and reduces supply: 1) at fast HR, fibers spend more time (proportionally) at systolic tension levels. 2) Less diastole = less time for coronary blood flow.

Contractility: increased ejection time = increased oxygen requirement

Costanzo describes it as cardiac work, and notes two categories: volume work and pressure work. Pressure work is MUCH more costly in terms of myocardial oxygen demand than, say, exercise. (think chronic hypertension, aortic stenosis.) Lillys notes 3 main contributors to myocardial O2 demand: (closest to Levi)

Increased wall stress (systolic and diastolic)

--Diastolic depends on preload (look at the chart, what physiologically alters preload? Venous capacitance) function of blood volume and venous tone --Systolic depends on afterload (what alters this? Peripheral resistance, heart rate, heart force, ejection time. Think of: Hypertension, aortic stenosis)

Heart rate see Katzung

Contractilitity see Katzung above

These determinants of myocardial O2 demand/supply will frame the pharmacologic strategy! Two main strategies: Vasodilate (increase Os delivery) or Cardiac Depress(reduce demand) Vasodilators include: Nitrates and Calcium Channel blockers Cardiac depressants include Calcium Channel blockers and Beta Blockers ** which calcium channel blocker depends on which class they vary! Surgical strategy: Revascularization (stents, CABG) In unstable angina, use urgent angioplasty, main focus is on anti-platelet therapy to prevent clotting but that is outside the scope of this lecture/chapter. Levis 3 types of Anti-anginal Drugs Nitrites and Nitrates Ca2+-channel Blockers -Blockers Nitrites and Nitrates PK Nitrates have: Poor <20% oral bioavailability by first pass metabolism (hepatic organic nitrate reductase denitrates it) Admin sublingual, bypass first pass and achieve fast therapeutic plasma levels Duration of Action: short, 15-30 min Sublingual doe limited by adverse efx such as: syncope, headache May give buccal/transdermal preparation for longer duration of action Nitrites are esters of nitrous acid Nitrates are esters of nitric acid They both release NO in vascular smooth muscle cells

Half life: un-denitrated is 2-8 min Hepatic metabolite is up to 3 h Excretion by kidney The efx are dose dependent. Sm dose venule dilation (desireable) Med dose arteries (do not want) High dose artioles and capillary sphincters (do not want) Effective for vasospasm!

MOA: denitration of nitrates in VSM cells by mito ALDH (aldehyde) causes release of nitric oxide (NO) NO stims sol GC Intracellular efx of cGMP are PI hydrolysis, Ca seq, dec Ca sensitivity Effect is vasorelaxation by dephosphorylation of myosin light chain phosphatase. Identical to nitroprusside MOA. End result is VSM relaxation. Note: people w/ ALDH -/- suffer no ill efx of NO OD!

Organ system Efx of NO: Cardiovascular:

peripheral venodilation reduced cardiac size, reduced CO through reduced preload arteriolar dilation reduced afterload

main effect is reduced O2 demand!!! Increased coronary flow may play a role, but is thought to be secondary. It DOES relax SMC of epicardial cor art and reduce vasospasm in var angina

Other organs: Relxes sm muscle of bronchi, GI, GU tracts, no other sig efx. Toxicities: tachycardia from baroreceptor reflex, orthostatic hypotension and syncope from venodilation, throbbing headache from meningeal artery vasodilation. NitrItes may also cause methemoglobinemia at high blood concentrations (cyanide antidote) NitrAtes do not cause methemoglobinemia., but do cause tolerance headaches (Monday disease.)

Nitrate Drug Interactions: with sildenafil (Viagra.) Nitrates increase production of cGMP, and sildenafil blocks PDE5 (which degrades cGMP) combo eft is dangerous hypoperfusion of organs from too much VSM relaxation!

Random facts from Levi lecture on PDE inhibitors:

1/2 Lives: sildenafil and vardenafil ~4 hr; tadalafil ~17.5 hr. Mild Vasodilators, minimal effect on BP Contraindicated with nitrate use Contraindicated with -blocker use Safe with antihypertensive medications

Other uses of PDE inhibition include: pulmonary hypertension In pulmonary hypertension, you have:

Decreased endothelial NO production decreased PA vasodilation, decreased PA remodeling Increased PDE5 activity in SMC and PDE3 in RV reduced PA vasodilation, rediced RV ionotropy

Calcium channel blockers Mech of action

Block L type calcium channels only, so does not interfere with hormonal release or neurotransmission, which employ other ca channels. Decrease intracellular calcium --> decrease muscle contractility. The effect may be either to vasodilator or to reduce cardiac contractility. Diff agents have diff spectrum of efx.

3 classes of calcium channel blockers Phenylalkylamine (verapamil) Benzothiazepine (diltiazem) Dihydroperidine (nifedipine)

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Effective for both stable and unstable angina.

For stable angina, the main MOA is to reduce O2 demand. Increases exercise tolerance and delays onset. For unstable angina, the main MOA is to increase O2 delivery, but also reduce demand and vasospasm For variant angina, the eft is to reduce vasospasm Also used in hypertension, supra ventricular tachycardia, migraine, preterm labor, stroke, and raynauds.

Dose dependent response: the clinical range is at the vasodilation dose. w/ inc dose you incur reduced heart contractility and reduced SAN. Specifically: Toxicities Constipation, edema, nausea, flushing, dizziness. More serious include congestive heart failure, av block, sa node depression. More common in verapamil Ethan dihydropyridines. Bepridil may induce torsade de points. Beta blockers must know: (propranolol, metoprolol, carvedilol) Competitive -- antagonize the -effects of catecholamines on heart, vessels, bronchi etc. Selective -- B2 v B1 v alpha (B1 is cardio-selective) need to fill this in for your 3 drugs Specifice -- don t antagonize cardiac stimulation and vasodilatation elicited by agents other than agonists SAR of -Blockers Goals in creating a -blocker: a) keep affinity for R, b) abolish intrinsic activity (as agonist, you want an antagonist) Thus, keep side chain, but substitute ring. Moa decrease cAmp decrease PKA activity, phosphorylate what? --? Decrease Ca intracellular concentration PROPRANOLOL At 50-100 ng/ml in humans propranolol will: 4. Lower plasma renin activity 3. Display anti-arrhythmic effects 2. Inhibit exercise tachycardia 1. Alleviate angina symptoms Summary of Effects Beneficial: decreased heart rate, cardiac force, blood pressure. Detrimental efx: increased heart size, longer ejection period. Asthma! (b/c of non-selectivity)

Clinical use Prophylactic tx of angina only. useful in acute setting. Ineffective against vasospasm but useful in exertional angina. Useful in combo w nitrates bc it prevents tachycardia and increased cardiac force induced by nitrates. Specific types: BETA-BLOCKER GENERATIONS 1st: Blanket or non-selective (1- + 2-blockers)(propranolol etc.) 2nd: Cardio-selective (1-blockers)(atenolol, metoprolol etc.) 3rd: Vasodilating properties (pindolol, carvedilol etc.) Mixed - and -blockers (labetalol) T1/2: 9 min (esmolol) to ~24 hr (nadolol) Lipid/water solubility influences route of elimination

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Nice Summary of all 3 classes of anti-Ischemics MOA:

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