Anti-anginals (drugs to treat angina) Flashcards
What is Stable Anginas symptoms?
pain during exercise or stress
What is Stable Angina caused by?
- antherosclerosis of coronary artery
- thickened heart tissue
What is Unstable Anginas symptoms?
anytime (at rest or during exercise)
What is Unstable Angina caused by?
blood clots in atherosclerosis coronary arteries
What is Vasospastic Angina (Prinzmetal) symptoms?
anytime (at rest or during exercise)
What is Vasospastic Angina (Prinzmetal) caused by?
vasospasm induced vasoconstriction of coronary arteries
What is it called when blood flow can not meet oxygen demand?
ISCHEMIA
- no permanent damage (like a heart attack)
What is the physiology related to Angina (i.e. physiology of vessel contraction/dilation)?
- L-type voltage gated Ca2+ channel releases Ca2+
- Ca2+ activates myosin light chain kinase (MLCK)
- phosphorylating enzyme that phosphorylates myosin - Myosin-P (now phosphylated) allows it to act with actin
- CONTRACTION of vascular smooth muscle cell
OR
- Nitric oxide (NO) (vasodilator - prod. naturally by endophial cells & other cells)
- NO increases amount of cGMP
2a. Closes/inhibits VG Ca2+ channel
2b. MLC phosphatase activates MLCK (which DEphysophylates myosin)
- DILATION of vascular smooth muscle cell
What are cardiac preload and afterload?
- 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)
What are drugs to treat Angina?
nitrates
Nitrates are the…
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
What is the mechanism of action for nitrates?
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)
What are the different nitrate options?
- Nitroglycerin (sublingual, ointment, patch)
- main component in dynamite
- Isosorbide Dinitrate (sublingual or tablet)
- Isosorbide Mononitrate (extended release tablet)
Prophylaxis or prophylactic drug =
preventation
What are nitrates specific problems?
- **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)
Describe Sildenafil (Viagra) to treat erectile dysfunction
- 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
What are Calcium Channel Blockers?
Binds to activated channels, preventing calcium influx
What do Calcium Channel Blockers do?
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
What are the 2 types of Calcium Channel Blockers?
- Dihydropyridines
- Non-dihydropyridines
Dihydropyridine Calcium Channel Blockers:
- 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
Non-dihydropyridine Calcium Channel Blockers:
- Acts on heart and smooth muscle
- lowers HR & BP
e.g. Diltiazem, Verapamil
What are Calcium Channel Blockers used for?
- 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)
What are Calcium Channel Blockers metabolized by?
Metabolized by CYP3A4
What is unique about CYP3A4?
easily inhibited/induced by things
- Grapefruit inhibits 3A4, increasing CCB activity
- Rifampin induces 3A4, decreasing CCB activity
What are Beta Blockers? What is their mechanism of action?
Blocks B1 & B2 adrenergic receptors that GPCRs activated on many cells as part of the sympathetic nervous system
Why are Beta Blockers useful to treat angina?
- DECREASED CONTRACTILITY, CO, HR & BP
- REDUCE O2 DEMAND on the heart
- SLOW CONDUCTION through the AV node, slow the ventricular response
Beta Blockers are the…
1st line for angina prophylaxis (take it daily to try prevent chest pain)
Where are Beta Blockers contraindicated in?
vasospastic angina
- b/c will make it more freq. for them
What are examples of Beta Blockers?
- Propranolol
- Problem for asthma (b/c it’ll cause bronchoconstriction)
- Metoprolol, Atenolol
- Cardioselective (β1)
What are the 2 new drugs now available in Canada?
Ivabradine & Ranolazine
Describe Ivabradine
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
Describe Ranolazine
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
What is Ivabradine & Ranolazine metabolized by?
CYP3A4
* Grapefruit inhibits 3A4, increasing CCB activity
* Rifampin induces 3A4, decreasing CCB activity
Where is Ivabradine & Ranolazine contraindicated in?
liver disease
- b/c metabolized in liver
What can Ivabradine & Ranolazine not be taken with?
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
What are the adverse effects of Nitrates?
- headache
- flushing
- hypotension
What are the adverse effects of Calcium Channel Blockers?
- headache
- flushing
- hypotension
- bradycardia
What are the adverse effects of Beta Blockers?
- headache
- hypotension
- bradycardia
- bronchospasms
What are the adverse effects of Ranolazine?
- headache
- Minimal impact on BP (hypotension)
- Minimal impact on HR (bradycardia)
What are the adverse effects of Ivabradine?
- headache
- minimal impact on BP (hypotension)
- Bradycardia
What is the treatment regimen for angina?
*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
What are other drugs for Angina Patients?
Anti-platelet agents
* To prevent blood clots that can cause unstable angina
Statins
* Cholesterol lowering drugs
* To prevent further atherosclerosis
What is stable angina?
caused by atherosclerosis (usually)
(heart isn’t getting enough blood)
What is unstable angina?
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)
What is Prinzmetal angina?
caused by spasms of coronary artery
