Angina Pharm Flashcards
What is angina?
lack of sufficient oxygen (ischemia) to the heart that causes pain
Why does angina occur?
coronary artery obstruction limits blood supply to part of the myocardium
What is exertional angina? What is the cause?
coronary circulation can meet oxygen demands of the myocardium at rest, but not when the heart work increases by exercise (due to atheroma/fixed coronary vascular obstruction)
What is Prinzmetal’s angina? What is it also called? Prognosis?
Variant angina. Occurs when vasospasm blocks blood flow. Excellent prognosis.
What is unstable angina? What is its cause?
Recurrent angina associated with minimal exertion. Caused by atherosclerosis and thrombosis (formed by platelet aggregation after fissuring of plaques) that blocks blood flow
Heart work “demand” is determined by what?
HR
Cardiac contractility
Wall tension (afterload)
Heart (O2) “supply” is determined by what?
coronary vascular resistance
perfusion pressure
collateral blood flow
HR and mechanics
What type of angina has a high correlation with MI?
unstable angina
What type of angina will have normal coronary angiograms?
Prinzmetal’s (variant) angina
What are the 3 major approaches for treating angina?
1) Increase coronary blood flow
2) Reduce myocardial oxygen consumption
3) Prevent platelet deposition/aggregation
What are the 3 ways to reduce myocardial oxygen consumption?
1) Negative chronotropic effect (decrease HR)
2) Negative inotropic effect (decrease contractility)
3) Decrease ventricular workload (reduce preload or afterload)
What is the effect of venodilation?
reduced preload
What is the effect of vasodilation?
reduced afterload
When does the heart receive greatest perfusion? How do we exploit this to get relief of angina?
During diastole, because blood vessels are allowed to relax and serve the subendocardium. You want to increase the amount of time the heart is in diastole (use beta blockers/calcium channel blockers)
What are the two major effects of nitrate treatment for angina? How do these help?
1) Venodilation (decrease in preload and increase in subendocardial blood flow)
2) Coronary vasodilation (reperfuse ischemic areas, prevent/reverse coronary vasospasm)
What are the hemodynamic effects of nitrate therapy?
1) BP unchanged or slightly decreased
2) HR unchanged or slightly decreased
3) Pulmonary vascular resistance decreased
4) Slight reduction in CO
What is the cellular mechanism of nitrate action?
Nitrovasodilators undergo denitration to release NO. This activates guanylate cyclase to elevate intracellular cGMP that works through PKG to cause relaxation of vascular SM that leads to venodilation and coronary vasodilation.
How does the nitrate vasoreactant pathway change over time?
it decreases with age
What are the ROAs of nitrate drugs? List the drugs by group
1) Mucosal (spray, sublingual): Nitrostat, Nitrogard
2) Oral: Isordil, Ismo, Nitro-SR
3) Transdermal: Nitrol ointment
4) IV: Tridil
What is the most common adverse effect of nitrates? Why does this occur?
Headache. Due to vasodilation of meningeal arteries (vasomotor headache) that is transient and can be treated with aspirin or Tylenol
What adverse effect is commonly seen with higher doses of nitrates? Why? Compensatory responses?
Hypotension from arterial vasodilation. This may trigger reflex sympathetic stimulation of the heart (tachycardia, decreased coronary perfusion, etc.) that may worsen angina.
What adverse effects of nitrates are commonly seen in patients who are sensitive to reductions in preload (they are volume depleted, have a valvular heart disease, or HCM)?
Dizziness, orthostatic hypotension, syncope
What adverse effect is seen with long acting nitrates or cutaneous nitrates?
drug rash
What drugs are ABSOLUTELY contraindicated with nitrates? Why?
Sildenifil (Viagra) and other Type V PDE inhibitors that increase levels of cGMP by preventing its breakdown (this compounds the effect of nitrates and can lead to profound hypotension and MI)
What is the major problem with continuous nitrate therapy?
Tolerance- frequently repeated or continuous exposure to high doses of organic nitrates leads to a marked attenuation of their biological effects. Worse problem with high doses or oral, transdermal or IV.
How do you get around the problem of nitrate tolerance?
have 8-12 hours of “nitrate free” intervals each day (usually at night) OR (for IV) titrate dose upward until effect is seen so that you are using the minimal required dose
What is the most important mechanism of nitrate tolerance?
depletion of tissue cysteine stores (so that the nitrate can no longer form NO)
What is anginal rebound?
Sudden interruption of IV nitroglycerin in unstable angina leads to coronary vasospasm. This is why you MUST overlap with transdermal or oral form when you are withdrawing someone from nitrates
What are the 3 major uses of CCBs?
1) Angina
2) HTN
3) Supraventricular arrhythmias
What are the three chemical classes of CCBs?
1) Phenylalkylamines
2) Benzothiazepines
3) Dihydropyridines
List the phenylalkylamine used for angina treatment.
Verapamil
List the benzothiazepine used for angina treatment.
diltiazem
List the dihydropyridines used for angina treatment.
Nifedipine Amlodipine Felodipine Nicardipine Isradipine
What is the major role of intracellular calcium?
induce contraction of muscle cells
How does calcium affect the heart?
Binds to troponin C and reduces the inhibition of actin-myosin cross bridges
1) contraction (of atria and ventricle)
2) upstroke of AP in slow response cells (AV node and SA node)
How does calcium affect vascular smooth muscle?
binding to calmodulin activates MLCK which phosphorylates myosin and triggers contraction (graded, slow, and sustained)
What is the level of cytoplasmic Ca2+ at rest? At stimulation? How does it get to that level?
1 uM due to release of calcium from ER (intracellular stores) and capacitive entry of extracellular Ca2+
What do CCBs act upon?
L-type Ca2+ channels (specific because these are only really locate in the CV system)
What effect do CCBs have on neurons?
they don’t! Neurons use N-type and P-type calcium channels for neurotransmitter release that are not affected by CCBs
Which CCBs work to slow the recovery of the calcium channel?
Verapamil
Diltiazem
What effects do CCBs have on venous smooth muscle?
they do not really have any effect (reduce afterload but NOT preload)
What CCBs reduce inotropy and slow AV conduction/ pacemaker firing?
non-DHPs:
Verapamil
Diltiazem
How do DHPs and non-DHPs differ in their effects of CV cells?
- DHPs are selective vasodilators (both peripheral and coronary) that have the potential to cause reflex increase in HR, contractility, and O2 demand.
- Non-DHPs are equipotent for cardiac tissue and vasculature (decrease HR, peripheral and coronary vasodilation, reduced inotropy)
What CCBs use use-dependent binding? What is this?
Diltiazem and Verapamil use use-dependent binding that targets cardiac cells (bind to channels that are constantly opening and closing because they are more likely to find a channel in the proper conformaiton)
What CCBs use voltage-dependent binding? What is this?
DHPs like Nifedipine use voltage-dependent binding that targets SM cells (bind to channels at a certain voltage, and smooth muscle voltage changes VERY slowly, so these are targeted).
What are 2 common hemodynamic effects of all CCBs?
coronary vasodilation, suppress SA Node (not as much in DHPs)
Which CCB does NOT suppress cardiac contractility?
Nicardipine
Which CCBs do NOT suppress AV node?
DHPs
Where are CCBs abosorbed?
GI tract
Do CCBs undergo first pass metabolism?
YES- extensive first-pass hepatic metabolism reduces bioavailability
What are the adverse effects of bolus CCB?
tachycardia, headache, coronary steal
What CCBs are metabolized by and inhibit CYP3A4?
Verapamil and (to lesser extent) Diltiazem
What CCBs have a longer halflife?
Isradipine, Felodipine
What is the benefit of SR CCBs?
lower side effects (absense of bolus effect)
What are the adverse effects of Dihydropyridines?
- Excessive vasodilation (dizziness, hypotension, HA)
- GI irritation (nausea)
- Peripheral edema
- Coronary steal (not problem with SR forms)
What is coronary steal?
profound vasodilation during MI or anginal event stealing perfusion away from myocardium that exacerbates angina
Verapamil and Diltiazem should not be combined with what drug type? Why?
Never combine with a beta blocker (can really slow heart conduction and lead to AV block)
When are verapamil and diltiazem contraindicated?
CHF (because of negative inotropic effect)
Pregnancy category C (crosses placenta/breast milk)
Hypotension
(AV conduction defects and sinus bradycardia for Verapamil as well)
What unique AA does Verapamil cause? List others.
constipation
hypotension, headache, edema
What are the AAs of diltiazen?
Hypotension
Edema
What situations favor use of DHP CCBs?
- Combine with beta-blocker to reduce afterload (coronary vasodilation)
- Sinus bradycardia/ SA/AV block
- Valvular insufficiency to reduce afterload
What situations favor Diltiazen or Verapamil?
- Patients who cannot tolerate beta blockers (asthma/COPD)
- Severe PVD with pain at rest
- Labile insulin dependent diabetes
CCBs are best to treat what types of angina?
1) Exertional
2) Vasospastic
What is considered a drug of 1st choice in angina?
beta-blockers
How do beta blockers treat angina?
1) Blunt heart rate and inotropic response to exercise
2) Reduce afterload (CNS)
Why would you want to combine a beta blocker with a nitrate?
Beta blockers do NOT reduce preload: need to reduce LVEDP, LV volume, dilates coronary arteries
Why would you want to combine a beta blocker with a DHP CCB?
Beta blockers to not prevent coronary vasospasm: combine to prevent coronary vasospasm, reduce systemic vascular resistance
Beta blockers are best to treat what type of angina?
unstable (with nitrates)
exertional
What type of angina do beta blockers not help? Why?
vasospastic angina (because they block beta2 receptors that help vasodilate)
What is the effect of beta blockers on MI?
- Reduce chest pain, ST elevation, cardiac enzyme elevation
- Reduce ventricular ectopy and v fib
- REduce reinfarction and ischemic episodes
- Reduse 2-3 year mortality in MI
What are the recommendaitons concerning beta blocker use in angina?
Give beta-blocker IV in acute MI/unstable angina following PO therapy provided no CHF, hypotension, or sinus bradycardia/heart block
What is ranolazine?
novel metabolic modulator with unknown MOA
How might ranolazine work?
- Partial fatty acid oxidase inhibitor–increase glucose oxidation and efficacy of O2 utilization in the heart.
- Late sodium current inhibitor
What are the effects ranolazine?
Reduces metabolic demand on the heart
no effect on HR and BP, no relief of acute angina attacks
When would you give a patient ranolazine?
If other things like beta blockers, nitrates, and CCBs do not control chronic stable angina and are NOT candidates for revascularization (but very expensive for very little effect)
What are the major DDIs with ranolazine?
1) Digoxin concentrations increase 40-60% through p-glycoprotein inhibition.
2) CYP3A4 inhibitors
3) Tricyclic antidepressants
4) Class Ia/III antiarrhythmics
What are the adverse effects of ranolazine?
- Dizziness
- Headache
- Constipation
- Nausea
- Reversible elevation in serum creatinine and BUN
- Syncope and asthenia (rare)
What are the contraindications of ranolazine?
any hepatic impairment
mild renal impairment (caution)
What drugs are known to reduce CHD events/death?
ASPIRIN (especially after MI)
beta blockers
CCBs variable
Nitrates do NOT
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