Term
| What are 3 ways to modulate coronary blood flow volume (supply)? |
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Definition
1) Perfusion pressure (LV and aortic pressure)
2) Extrinsic compressive forces on artery
3) Intrinsic coronary artery resistance (coronary flow reserve) |
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Term
| What is coronary flow reserve and how does it determine treatments for supply-side ischemia? |
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Definition
1) Coronary flow reserve can be through of in terms of coronary resistance (R1- conductance vessels, R2- pre-capillary arterioles and R3- intramyocardial capillaries)
** major mediator at R2 is NO system (eNOS)
2) Exogenous nitrates will therefore treat supply side ischemia |
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Term
What are 3 ways to modulate coronary blood demand?
How do these factors relate to treatment options for ischemia? |
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Definition
Demand= HR * SBP
1) HR (decrease with beta blockers)
2) Contractility (decrease with calcium channel blockers or beta blockers)
3) Wall stress (ESP/after-load and LV volume. Treat pre-load or after-load issues) |
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Term
| How does myocardial contractility regulate myocardial oxygen demand (hint- think about CO)? |
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Definition
Remember, CO= HR X SV, and SV is modulated by myofibril contractility.
Myofibril contractility is determined by 1) loading conditions and 2) sympathetic tone. |
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Term
| What are the general strategies for treating the supply-demand mismatch in ischemia? |
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Definition
1) Supply
- Increase O2 carrying capacity (FiO2 and Hct)
- Increase Coronary blood flow (vasodilate and maintain BP)
2) Demand
- Decrease HR
- Decrease Contractility (Ca influx)
- Decrease Wall stress (pre-load and after-load) |
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Term
| What are the 3 major categories of anti-ischemia medications and how do they work? |
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Definition
1) Nitrates
- low-dose venodilation (reduce pre-load, wall tension and demand) and high-dose vasodilation (blood supply)
- increasing NO production through mitochondrial aldehyde DH)
2) Beta adrenergic receptor antagonists
- competitive inhibition of endogenous catecholamines
3) Calcium channel antagonists
- noncompetitive inhibition of L-type calcium channels in cardiac and smooth muscle
- decrease contractility (demand) and increase coronary and peripheral arterial vasodilation (supply) |
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Term
| How do Nitrates influence blood supply and demand? |
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Definition
Low-dose venodilation (pre-load and wall tension)
High-dose vasodilation (supply)
1) Supply (High dose)
- Decrease vascular resistance and extrinsic compression
- Increase collateral circulation
2) Demand (Low dose)
- Decrease preload (***) and after-load |
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Term
| What is the difference between short acting and long acting Nitrate preparations in terms of mechanism of action/use? |
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Definition
1) Short acting (Mucosal or Transdermal/Nitroglycerin)
- Bypasses enteral absorption and avoiding first pass in liver for rapid action and short (30-60 minute) duration
- Acute Angina or Prophylaxis in exercise
2) Long-acting (Oral or sustained-release transdermal)
- Isosorbide dinitrate goes through enteral absorption, rapid first pass metabolism and excreted renal (2 times per day).
- Isosorbide mononitrate DOES not undergoe first pass, and has great bioavailability (1 per day)
- |
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Term
| Why give Isosorbide mononitrate less often than dinitrate? |
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Definition
| Dinitrate undergoes substantial first-pass effects in liver while mononitrate does not! |
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Term
| What are the major side effects of taking nitrates? |
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Definition
1) Nitrate tolerance (tachyphylaxis)- prevent by adjusting dosing interval to provide 10-12 hour free interval at nigh
2) Headache/flushing
3) Hypotension
4) Hypoxemia
5) Tissue hypoxia (methemoglobinemia context)
6) Hypotension with sildenafil (viagra) |
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Term
What does each of the following mean in terms of Beta blocker activity?
1) Cardioselectivity
2) Intrinsic sympathomimetic activity (ISA)
3) Alpha-adrenoreceptor blocking activity |
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Definition
1) At low doses, drugs like Atenolol/Metoprolol will exert their effects to B1 (important if patient has peripheral vascular disease (a1) or mild asthma (B2)
2) Acebutolol (hydrophilic) (also cardio-selective) and Pindolol (lipophillic) have ISA, meaning they are "weak" agonists that block more potent agonists
** not first line, especially in CAD**
3) Labetolol and Carvedilol are non-beta-selective AND antagonist alpha receptors (prevent unopposed alpha activation, so good for HTN) |
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Term
| What kind of beta-blocker might you use in a patient with LV systolic dysfunction or HTN? |
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Definition
| Drugs like Carvedilol (lipophilic) or perhaps Labetolol (hydrophilic) also have alpha-antagonism, so they prevent unopposed peripheral vasoconstriction. |
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Term
What beta blockers might you give a patient with mild asthma?
Peripheral vascular disease? |
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Definition
Need beta-selective in BOTH cases.
Good options are Atenolol (hydrophilic) and Metoprolol (Lipophilic). Neither have ISA or Alpha-receptor blockage. |
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Term
| How does lipid solubility of beta blockers influence metabolism? |
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Definition
1) Lipophillic beta blockers like Metoprolol (beta selective), Acebutolol (ISA) and Carvedilol (alpha antagonism) tend to be HEPATICALLY metabolized, with SHORTER half lives and CNS side effects
2) Hydrophillic drugs like Atenolol (beta selective), Acebutolol (ISA) and Labetolol (alpha antagonism) are RENAL excretion with LONGER half-lives and fewer CNS effects |
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Term
| How do beta blockers influence supply and demand of myocardial oxygen? |
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Definition
1) Supply
- Decrease HR and increase diastolic filling time
2) Demand
- Decrease HR and Myocardial contractility
**May slightly increase pre-load** |
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Term
| What side effects are of major concern when prescribing beta blockers? |
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Definition
WATCH out in bradycardia, conduction disease, peripheral vascular disease, LV dysfunction/CHF and Diabetes!
1) CNS for lipophilic drugs (fatigue, disruption in sleep, sexual and depression)
2) Conduction abnormalities (sinus bradycardia and AV nodal blockage
3) Exacerbate CHF in case of LV dysfunction ("start low and go slow")
4) Claudication in peripheral vascular disease (Raynaud's)
5) Hypoglycemia (beta-2 mediated glycogenolysis)- watch out in diabetes |
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Term
| What is the difference between Dihydropyridines, Benzothiazapines and Phenylalkylamines? |
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Definition
1) First Generation (Nifedipine) and Second Generation (all other "dipines"
- potent peripheral vasodilators (can cause reflex tachycardia)
- Second generation are more vasoselective.
2) Benzothiazapine (Diltiazem) and Phenylalkylamine (Verapamil)
- More potent effect on sinus and AV nodal calcium channel recovery (negative chronotropic and dromotropic effects)
- Can cause symptomatic bradycardia and AV nodal blockage. |
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Term
| Should you give Nifedipine, Verapamil or Diltiazem if a patient is already on beta blockers? |
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Definition
Diltiazem (Benzothiazapine)
Nifedipine will cause peripheral vasodilation and might cause reflex tachycardia.
Verapamil wis danger for complete heart block with AV-nodal blockage via beta blocker |
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Term
| What is the differential effect of each class of calcium channel blockers on myocardial supply and demand? |
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Definition
** ALL
supply- decreasing vascular resistance
demand- by decreasing after-load**
1) Dihydropyridines (Nefedipine)
Supply
- Decrease Extrinsic compression and increase collateral circulation
Demand
- Decrease pre-load and after-load, but may increase HR and/or contractility (reflex tachycardia)
2) Benzothiazapine (Diltiazem) and Phenylaklyamines (Veramapil)
Supply
- Increase diastolic filling time and collateral circulation, and decrease HR
Demand
- Decrease HR and Contractility |
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Term
| How are calcium channel blockers metabolized? |
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Definition
Most are hepatically
**Diltiazem is hepatically metabolized, but renal excreted.
** May influence and be influenced by other hepatically metabolized drugs** |
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Term
| What side effects are of major concern when prescribing calcium channel blockers? |
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Definition
1) Hypotension (dyhidropyridine)
2) CHF exacerbation (non-dyhidropyridine)
3) Conduction abnormalities
4) Edema
5) GI
6) Gingival hyperplasia (rare!)
7) CV mortality??? |
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Term
| What makes Ranolazine a unique drug for stable angina? |
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Definition
Doesn't alter HR, BP or contractility
Decreases wall tension by preventing calcium overload (so less demand).
1) In ischemic myocytes, delayed sodium currents increase intracellular sodium concentrations, decreasing the Na/Ca gradient for the pump, so more calcium sticks around inside the cell.
2) Ranolazine inhibits the delayed sodium currents and gets calcium out of there! |
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Term
| What side effects are of major concern when prescribing Ranolazine? |
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Definition
1) QT-prolongation (inhibits delayed K currents)
- can cause Torsades do pointes |
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Term
| How is Ranolazine metabolized? |
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Definition
1) CYP3a system in liver
** dont give to patients with CYP3a inhibition (Ketoconazole- anti-fungal or clarithromycin- macrolide) from other meds**
2) Increases Digoxin levels, so give with care |
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Term
| What is the general strategy to treating ischemic heart disease (1st, 2nd, 3rd line ect.) |
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Definition
1) Start with a NON-ISA beta blocker (maybe something Like Atenolol, which is cardioselective and hydrophilic)
2) Try long-acting nitrates (isosorbide mononitrate) if angina persists
3) try non-dihydropyrimidines if there are beta-blocker contraindications
4) TRIPLE therapy and novel agents are used for refractory syndromes. |
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