Anti-anginals (drugs to treat angina)

Question 1

What is Stable Anginas symptoms?

Answer 1

pain during exercise or stress

Question 2

What is Stable Angina caused by?

Answer 2

• antherosclerosis of coronary artery
• thickened heart tissue

Question 3

What is Unstable Anginas symptoms?

Answer 3

anytime (at rest or during exercise)

Question 4

What is Unstable Angina caused by?

Answer 4

blood clots in atherosclerosis coronary arteries

Question 5

What is Vasospastic Angina (Prinzmetal) symptoms?

Answer 5

anytime (at rest or during exercise)

Question 6

What is Vasospastic Angina (Prinzmetal) caused by?

Answer 6

vasospasm induced vasoconstriction of coronary arteries

Question 7

What is it called when blood flow can not meet oxygen demand?

Answer 7

ISCHEMIA
- no permanent damage (like a heart attack)

Question 8

What is the physiology related to Angina (i.e. physiology of vessel contraction/dilation)?

Answer 8

1. L-type voltage gated Ca2+ channel releases Ca2+
2. Ca2+ activates myosin light chain kinase (MLCK)
   - phosphorylating enzyme that phosphorylates myosin
3. Myosin-P (now phosphylated) allows it to act with actin
4. CONTRACTION of vascular smooth muscle cell

OR

1. Nitric oxide (NO) (vasodilator - prod. naturally by endophial cells & other cells)
2. NO increases amount of cGMP

2a. Closes/inhibits VG Ca2+ channel

2b. MLC phosphatase activates MLCK (which DEphysophylates myosin)

3. DILATION of vascular smooth muscle cell

Question 9

What are cardiac preload and afterload?

Answer 9

• PRELOAD is the initial stretching of the cardiac muscle cells prior to contraction. It is related to ventricular filling, such as left ventricular end diastolic volume
  (i.e. input force on heart)
• AFTERLOAD is the force or load against which the heart has to contract to eject the blood.
  (i.e.force at which heart must pump against)

Question 10

What are drugs to treat Angina?

Answer 10

nitrates

Question 11

Nitrates are the…

Answer 11

most imp. class of drugs for angina

• Metabolized by esterases in vascular smooth muscle cells * Nitrates → nitrites → nitric oxide
• Esterases are more abundant in veins than arteries

Question 12

What is the mechanism of action for nitrates?

Answer 12

The PRELOAD to the heart is reduced due to venous system dilation.
* Decreases oxygen demand of the heart
* Coronary blood flow redistributes

Some arterial dilation, so AFTERLOAD is slightly decreased

(nitrates act on BV’s instead of heart)

Question 13

What are the different nitrate options?

Answer 13

• Nitroglycerin (sublingual, ointment, patch)
• main component in dynamite
• Isosorbide Dinitrate (sublingual or tablet)
• Isosorbide Mononitrate (extended release tablet)

Question 14

Prophylaxis or prophylactic drug =

Answer 14

preventation

Question 15

What are nitrates specific problems?

Answer 15

• **TOLERANCE
• 8-12 hrs of nitrate-free time needed daily (ex: at night)
• easy to get if they’re using it freq.
• can reverse quickly
• Reflex Tachycardia
• Nitrates have a synergistic effect with sildenafil (Viagra)
• beats faster (can be a problem)

Question 16

Describe Sildenafil (Viagra) to treat erectile dysfunction

Answer 16

• Release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation increases blood flow and causes erection of the penis
• Sildenafil prevents breakdown of cGMP by blocking phosphodiesterase 5
• The effects are enhanced by nitric oxide from nitrates - therefore if someone is taking Nitroglycerin for ex to treat angina then they’re increasing NO levels, therefore increasing cGMP. & if they’re also taking Sildenafil for ex that’s preventing breakdown of cGMP then now they have too much VASODILATION (b/c of NO) & can be fatal b/c of catastrophic HYPOtension

Question 17

What are Calcium Channel Blockers?

Answer 17

Binds to activated channels, preventing calcium influx

Question 18

What do Calcium Channel Blockers do?

Answer 18

Smooth muscle
* Arteries affected more than veins (b/c dilated artery)
* Lowers blood pressure

Cardiac muscle
* Slows heart rate (therefore, heart not working as hard; lower O2 demand - allows left ventricle to fill completely & lowers the heart workload)
* Reduces myocardial calcium and oxygen demand

Question 19

What are the 2 types of Calcium Channel Blockers?

Answer 19

1. Dihydropyridines
2. Non-dihydropyridines

Question 20

Dihydropyridine Calcium Channel Blockers:

Answer 20

• Least depressant of the heart
• Commonly used for vasospastic (Prinzmetal) angina (b/c act on SM)
• typically bind on Ca2+ channel blockers of ARTERIES (therefore don’t change HR as much as Non-dihydr.)

e.g. Nifedipine, Amlodipine

Question 21

Non-dihydropyridine Calcium Channel Blockers:

Answer 21

• Acts on heart and smooth muscle
• lowers HR & BP

e.g. Diltiazem, Verapamil

Question 22

What are Calcium Channel Blockers used for?

Answer 22

• Also used to treat hypertension and cardiac arrythmias
• Prophylactic treatment for angina (i.e. take it everyday for rest of life (& also carry a nitrate in case)

Question 23

What are Calcium Channel Blockers metabolized by?

Answer 23

Metabolized by CYP3A4

Question 24

What is unique about CYP3A4?

Answer 24

easily inhibited/induced by things

• Grapefruit inhibits 3A4, increasing CCB activity
• Rifampin induces 3A4, decreasing CCB activity

Question 25

What are Beta Blockers? What is their mechanism of action?

Answer 25

Blocks B1 & B2 adrenergic receptors that GPCRs activated on many cells as part of the sympathetic nervous system

Question 26

Why are Beta Blockers useful to treat angina?

Answer 26

- DECREASED CONTRACTILITY, CO, HR & BP - REDUCE O2 DEMAND on the heart - SLOW CONDUCTION through the AV node, slow the ventricular response

Question 27

Beta Blockers are the...

Answer 27

1st line for angina prophylaxis (take it daily to try prevent chest pain)

Question 28

Where are Beta Blockers contraindicated in?

Answer 28

vasospastic angina - b/c will make it more freq. for them

Question 29

What are examples of Beta Blockers?

Answer 29

* Propranolol * Problem for asthma (b/c it'll cause bronchoconstriction) * Metoprolol, Atenolol * Cardioselective (β1)

Question 30

What are the 2 new drugs now available in Canada?

Answer 30

Ivabradine & Ranolazine

Question 31

Describe Ivabradine

Answer 31

selective sinus node inhibitor - prophylactic treatment - take it long term Specifically targets the pacemaker current by blocking hyperpolarization-activated cyclic- nucleotide gated channel (HCN) * Activated at hyperpolarized potentials and conducts Na+ and K+ to depolarize the pace-making cells * This triggers an action potential in the rest of the heart * Slows heart rate * REDUCES myocardial calcium and oxygen demand

Question 32

Describe Ranolazine

Answer 32

A late sodium channel inhibitor - when heart is contracting (when in late in contraction cycle) * Exactly how it helps angina is unknown * Decrease oxygen demand by lowering calcium overload during contraction and decreasing myocardial tension * No significant impact on blood pressure or heart rate! - more about heart rhythm - changes how heart is contracting

Question 33

What is Ivabradine & Ranolazine metabolized by?

Answer 33

CYP3A4 * Grapefruit inhibits 3A4, increasing CCB activity * Rifampin induces 3A4, decreasing CCB activity

Question 34

Where is Ivabradine & Ranolazine contraindicated in?

Answer 34

liver disease - b/c metabolized in liver

Question 35

What can Ivabradine & Ranolazine not be taken with?

Answer 35

Can not be taken with non-dihydropyridine calcium channel blocker (i.e. diltiazem) * These drugs all affect electrical signals of the heart (potential synergistic effect to cause - b/c can have bad synergistic effects to cause arrhythmias

Question 36

What are the adverse effects of Nitrates?

Answer 36

- headache - flushing - hypotension

Question 37

What are the adverse effects of Calcium Channel Blockers?

Answer 37

- headache - flushing - hypotension - bradycardia

Question 38

What are the adverse effects of Beta Blockers?

Answer 38

- headache - hypotension - bradycardia - bronchospasms

Question 39

What are the adverse effects of Ranolazine?

Answer 39

- headache - Minimal impact on BP (hypotension) - Minimal impact on HR (bradycardia)

Question 40

What are the adverse effects of Ivabradine?

Answer 40

- headache - minimal impact on BP (hypotension) - Bradycardia

Question 41

What is the treatment regimen for angina?

Answer 41

*1st line * Calcium channel blocker for prophylaxis OR * Beta blocker for prophylaxis * Nitrate (sublingual or spray) for fast relief of chest pain - ex: at dentist * 2nd line * Long acting nitrates * Beta blocker + dihydropyridine CCB (like nifepidine)- because verapamil also decrease heart rate (too much if they took a B-blocker & verapamil together) * Ranolazine or Ivabradine

Question 42

What are other drugs for Angina Patients?

Answer 42

Anti-platelet agents * To prevent blood clots that can cause unstable angina Statins * Cholesterol lowering drugs * To prevent further atherosclerosis

Question 43

What is stable angina?

Answer 43

caused by atherosclerosis (usually) (heart isn't getting enough blood)

Question 44

What is unstable angina?

Answer 44

already have stable but then a blood clot forms & that further ischemia cannot be alleviated by their nitrates (should go to ER b/c may have unstable)

Question 45

What is Prinzmetal angina?

Answer 45

caused by spasms of coronary artery