Angina

Question 1

• discuss the cause, pathophysiology and presentation of angina.

Answer 1

• angina is chest pain caused by an imbalance between oxygen supply to/demand of the cardiac tissue.
  
  • an increase in O2 demand can be caused by an increase in:
    
    • HR, contractility, ventricular wall tension
  • a decrease in O2 supply can be caused by:
    
    • an increase in coronary artery diameter, perfusion pressure, collateral blood flow
    • a decrease in HR

Question 2

how does perfusion pressure effect myocardial oxygen supply?

what cardiac events might effect perfusion pressure?

Answer 2

• myocardial O2 supply is contingent upon an adequate perfusion pressure.
  
  • in this case, perfusion pressure = the pressure gradient from the aorta down to the coronary arteries, which branch from it.
  • an increase in LV end-diastolic pressure can decrease this gradient, slowing O2 supply to the heart
    
    • (the coronary arteries fill during diastole, and the aorta must overcome the pressure the heart puts on them)

Question 3

how does heart rate effect myocardial O2 supply?

Answer 3

• HR is inversely related to myocardial O2 supply.
  
  • the coronary arteries fill during diastole. a faster HR slows down diastole, thus slowing the time for the coronary arteries to fill and perfuse to heart tissue

Question 4

what characterizes stable angina?

Answer 4

• stable angina is due a to a fixed atherosclerotic lesion that causes narrowing of the major coronary arteries.
  
  • this plaque does NOT rupture or embolize
  • stable angina tends to present during exertion/stress.

Question 5

what characterizes unstable angina?

Answer 5

• unstable angina is due to plaque rupture/clot formation in the major coronary arteries. the pain often presents during rest

Question 6

what characterizes variant angina?

Answer 6

• variant angina is caused by a transient vasospasm (spasm of coronary vessel muscles) in the large coronary arteries rather than a fixed atherosclerotic lesion.
  
  • it presents during rest

Question 7

what characterizes microvascular angina?

Answer 7

• microvascular angina is caused by a transient vasospasm in the small coronary arteries
  
  • like with variant angina, there is no atherosclerotic lesion involved.
  • presents during rest

Question 8

what is the general phamaceutical approaches to managing angina?

Answer 8

• treat angina be either
  
  • 1. reducing oxygen demand
       * lower HR, BP (afterload, preload) and contractility
  • 2. increasing O2 supply

Question 9

nitrate esters

• MOA
• pharmokinetics
• what drugs are included in this class?

Answer 9

• drugs:
  
  • nitroglycerine
  • isosorbide dinitrate
  • isosorbide mononitrate
• MOA:
  
  • nitrate esters are vasorelaxants.
    
    • they are all prodrugs.
      
      • ​in the liver, dinitrates are broken down to mononitrates.
      • in smooth muscle mitrochondria, mononitrates are converted to NO2 by aldehyde dehyrogenase 2 (ALDH2)
      • in the cytosol, NO2 is converted to NO (active drug) by P540 reductase
        
        • ​NO2 activates guanylyl cyclase –> active guanylyl cyclase cleaves GTP to cGMP –> cGMP phosphorylates an activates MLC phsophotase –> dephosphorylates and inactivates myosin light chain kinase –> relaxation

Question 10

what is ALDH2*2 and what is its clinical significance?

Answer 10

• a mutated version of the aldehyde dehydrogenase 2 enzyme (results from a single nucleotide polymorphism).
• clinical:
  
  • ALDH2*2 is seen in 30-50% of Asians
  • results in less NO production from nitrate esters. thus, nitrates are less effective vasorelaxer in these patients.
  • ALDH2 is also involved in ethanol metabolism, and patients with this mutation will experience facial flushing when drinking (a way to identify pts with mutation)

Question 11

what are the primary effects of nitrates

Answer 11

venous dilation. this ultimately lowers the end diastolic wall pressure (lowering O2 demand) while increasing O2 supply.

Question 12

which nitrate is immediate release? what are its indications and other characteristics?

Answer 12

• nitroglycerine in the form of sublingual/buccal oral spray​
  
  • has a rapid onset of action and short duration
  • used to treat an acute angina attack (all four types)

Question 13

which nitrates are long-acting? what are their indications and characteristics?

Answer 13

• nitroglycerine in transdermal patch/ointment form
• isosorbided mono-nitrate
• isosorbide dinatates
• indications:
  
  • prevention of stable, unstable, and variant angina
  • treatment of stable angina:
    
    • ​used as an alternative to beta blockers
    • or combined w/ a beta blocker or calcium channel blocker

Question 14

what are the acute and chronic adverse effects of nitrates?

Answer 14

• acute AEs
  
  • headache
  • flushing
  • syncope
  • orthostatic hypotension
  • reflex tachycardia
• chronic AEs
  
  • development of tolerance to nitrates (in long acting nitrates)
  • methemoglobinemia - a lack of oxygenation to systemic tissues
    
    • seen only at high doses

Question 15

how do we prevent development of tolerance to nitrates?

Answer 15

by mandating a 8-10 hour drug-free period every 24 hrs while using long acting nitrates

Question 16

potential drug drug interactions of nitrates

Answer 16

• PDE5 inhibitors (-“fils”: sildenafil, taladafil) - the additive effects can cause extreme vasodilation
• CYP-3A4 inhibitors/inducers
• dapsone - poses a risk of methemobloginemia

Question 17

contraindications of nitrates

Answer 17

• hypotension
• PDE inhibitors (- “fls”)
• soluble guanylyl cyclase inhibitors
• elevated intracranial pressure

Question 18

use of beta blockers to treat angina

• what is their MOA
• what are their indications?
• when are they NOT to be used?

Answer 18

• MOA: decrease O2 demand by decreasing contractility and heart rate
• indications: first line treatment of stable & unstable angina
  
  • decrease the frequency and severity of ischemic events
  • prevention of nitrate induced reflex tachycardia in these types of angina
• NOT used for variant angina!! (vasospasm of large coronary arteries)

Question 19

what are the non-selective and cardioselective beta blockers?

Answer 19

• non-selective: propanolol, nadolol
• cardioselective: atenolol, metoprolol

Question 20

adverse effects of beta blockers (indicate which AE correponds to which receptor blockade)

Answer 20

• B1 blockage
  
  • bradycardia
  • AV block
  • reduced exercise tolerance
• B2 blockage (propanolol, nadolol)
  
  • bronchospasm
  • cold extremities
  • claudication
  • erectile dysfunction
  • hypoglycemia
• lipophilic beta blockers (propanolol)
  
  • CNS effects: nightmares, fatigue, depression
• all beta blockers:
  
  • long term use can cause compensatory upregulation of beta blockers after cessation of use

Question 21

drug drug interactions of beta blockers in the treatment of angina?

Answer 21

• non-DHP CCBs (verapamil, diltiazem): these further reduce HR/contractility
• digoxin: further reduces HR (can cause bradycardia)

Question 22

contraindications of beta blockers

Answer 22

• for non-selective blockers (propanolol, nadolol)
  
  • asthma
  • COPD
• for all
  
  • severe bradycardia
  • AV block

Question 23

calcium channel blockers (CCPs)

• what are the two subsets within this class?
• what are their MOAs in the treatment of angina?

Answer 23

• calcium channel blockers promote smooth muscle relaxation. there are two classes
  
  • DHPs: “-dipines”
    
    • reduce myocardiac O2 demand by relaxing cardiac muscle, which reduces HR and contractility
  • non-DHPs: verapamil, diltiazem
    
    • ​reduce myocardial O2 demand AND increase O2 supply by relaxation vascular muscle. this dilates arteries, which 1. increases coronary blood flow to cardiac tissue and 2. reduces afterload against the heart

Question 24

specific indications of calcium channel blockers (DHP vs non-DHP)

Answer 24

• stable angina: both non-DHPs (veramapil, diatiazem) & DHPs (dipines):
  
  • ​like long-acting nitates, they are used as an alternative to/in combination with a beta blocker
• arrythmias: non-DHPs only
• FIRST LINE treatment for variant angina: DHPs only
• HTN: DHPs only
• Reynaud’s phenomenom: DHPs only

Question 25

AEs of CCBs (DHP vs non-DHP)

Answer 25

* both non-DHPs and DHPs: * peripheral edema * headache * flushing * short acting DHPs (rarely used) * reflex tachycardia * MI risk * dizziness * non-DHPs * cardiac related AEs * bradycardia * AV block * cardiac depression * gingiva hyperplasia * nausea * constipation (verapamil only\*\*)

Question 26

drug drug interactions of CCBs

Answer 26

* both DHPs and non-DHPs: CYP-3A4 inhibitors * non-DHPs only: * B-blockers - can cause bradycardia * digoxin - can cause bradycardia * P-glycoprotein inhibitors

Question 27

contraindications of CCBs

Answer 27

* both DHPs and non-DHPs * hypotension * aortic stenosis * non-DHPs only: * bradycardia * AV block

Question 28

which drugs are non-DHP CCBs? what are the indications, AEs, and contraindications of non-DHPs that are _not shared_ by DHPs?

Answer 28

**= verapamil, diltiazem** * unique indications: **​** * **_arrythmias_** * unique AES: * cardiac AEs: bradycardia, AV block, cardiac depression * gingival hyperplasia * constipation (_verapamil_ only) * unique drug-drug interactions: * B-clockers * digoxin * p-glycoprotein inhibitors

Question 29

which drugs are DHP CCBs? what are their clinical uses, AEs and contraindications that _they do not share_ with non-DHPs?

Answer 29

= **"dipines"** * **unique clinical uses:** * ​_variant angina_ * hypertension * raynaud's dynrome * don't have AEs/contraindications that don't also apply to non-DHPs.

Question 30

which angina drug has constipation as a side effect?

Answer 30

verapamil (non-DHP CCB)

Question 31

which drugs are the first line treatment for stable and unstable angina?

Answer 31

beta blockers

Question 32

which drugs are first line treatment for variant angina?

Answer 32

DHP calcium channel blockers (- dipines)

Question 33

what is the **_late phase sodium current_** and what is its _physiological role_ in cardiac muscle relaxation?

Answer 33

* in cardiac myocytes, the late phase of sodium current is point of the action potential during which intracellular Na+ is low * this **low intracellular Na+** favors creates a favorable gradient for Na+ influx, which will drive the **Na-Ca exchanger (NCX**) to bring in Na+ in **exchange for Ca++** * the consequent decrease in intracellular calcium allows for **muscle relaxation**

Question 34

how does the late phase sodium channel play a role in **cardiac ischemia**?

Answer 34

* in pathological circumstances, is a **higher intracellular [Na+]** during the late phase *than there should be.* * this high intracellular Na+ **reverses the NCX** channel, which drives Na+ out and pulls Ca++ in the **high intracellular [Ca++]** causes **myocyte contraction,** which will increase _workload_ on the heart * --\> **myocardial ischemia**

Question 35

what is the MOA of ranolazine?

Answer 35

* inhibits late phase sodium current * this lowers intracellular [Na+] * this drives Na+ in and Ca+ out * --\> relaxation

Question 36

what are the effects of ranolazine?

Answer 36

* increases O2 demand and decreases O2 supply * does **NOT affect HR or blood pressure** (only angina drug that does not effect BP)

Question 37

clinical uses of ranolazine:

Answer 37

* **second-line** agent for the treatment of chronic **stable angina** * **​**(beta blockers are 1st line for stable angina) * typically used for: * as an alternative pts who cannot tolerate B-blockers/CCBs * as an add-onn for pts who cannot reach therapuetic goal with B-blockers/CCBs/nitrates * _who have hypotension:_ works because ranolazine *does NOT lower BP*

Question 38

AEs of ranolazine

Answer 38

* **serious: increased QT interval via block of IKr** * others: * dizziness * headache * constipation

Question 39

what are the main drug drug interactions of ranolzine & how to manage minimize the effects from these interactions?

Answer 39

(ranolzine interacts with substrate of CYP-3A4 and p-glycoprotein) * AVOID giving ranolazine it pt taking: * strong CYP-3A4 inhibitors/inducers * drugs that decrease QT interval * lower ranolazine dose if patient taking: * moderate CYP-3A4 inhibitors

Question 40

contraindications of ranolazine

Answer 40

* stong CYP-3A4 inhibitors/inducers * pts with long QT interval * pts with hepatic dysfunction

Question 41

summarize the unique uses of each class of angina drugs

Answer 41

* nitrates: * rapid relase are for acute symptom release * long acting: for prevention * B-receptor blockers: * **first line prevention** of _stable/unstable_ angina * **reduce morality after MI** * ranolazine: * treatment of _stable angina_ if other tx inadequate or **hypotensive patients** * CCBs: * prevention of stable/_variant angina_ * anti-platelets: * for _unstable angina_ * antihyperlipidemic agents: * decreased incidence of **ischemia/adverse CV events**

Question 42

what key angina drugs are to prevent _stable_ angina?

Answer 42

* b-blockers (1st line) * CCBs: both DHPs (dipines) and non-DHPs (diltiazem, verapamil) * long-acting nitrates * *ranolazine* *(only treats unstable)* * lipid-lowering medications *B-blockers/non-DHPs reduce O2 use, long acting nitrates/ DHPs increase O2 supply, ranolzine does both*

Question 43

what drugs are used to prevent _unstable_ angina attacks

Answer 43

* B-blockers: first line * long-acting nitrates * lipid lowering agents * *_anti-platelets/anti-coagulants_* (only treats unstable)

Question 44

what drugs are used to prevent _variant and microvascular_ angina?

Answer 44

* **DHPs (-dipines): first line** * **+** long acting nitrates