Drugs to Treat Angina

what is angina?

Basically, angina is chest pain/discomfort caused by the heart muscle temporarily not getting enough oxygen-rich blood.

• Heart O₂ demand > Heart O₂ supply → ischemia → angina

explain how vessels contract?

↑ Ca²⁺ inside vascular smooth muscle → contraction

Here's the pathway:

L-type Ca²⁺ channel opens
→ Ca²⁺ enters the smooth muscle cell
→ Ca²⁺ activates myosin light-chain kinase (MLCK)
→ MLCK phosphorylates myosin → myosin-P
→ myosin-P interacts with actin
→ smooth muscle contracts → vessel constricts

Ca²⁺ → MLCK → phosphorylated myosin → CONTRACTION

explain how vessels dilate

Contraction vs Dilation chart

Contraction	Dilation
↑ Ca²⁺	↑ NO
↑ MLCK	↑ cGMP
Myosin gets phosphorylated	↑ MLC phosphatase
Myosin-P + actin	Myosin gets dephosphorylated
Contraction	Relaxation/dilation

what is cardiac preload

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

what is cardiac Afterload

is the force or load against which the heart has to contract to eject the blood

what are some Drugs to Treat Angina

Nitrates

What do nitrates do?

Nitrate drugs are converted inside vascular smooth muscle cells:

Once you produce NO:

Nitrate → NO → ↑ cGMP → dilation

how are nitrates metabolized in smooth muscle?

Metabolized by esterases in vascular smooth muscle cells

Nitrates → nitrites → nitric oxide

Why do nitrates affect veins more?

Esterases are more abundant in veins than arteries, so nitrates produce a stronger effect on the venous system

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

what are some nitrate specific problems (2)

1. Tolerance: 8-12 hrs of nitrate-free time needed daily

2. Nitrates have a synergistic effect with sildenafil (Viagra)

how does Sildenafil (Viagra) 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

Nitrates = ↑ cGMP production
Sildenafil = ↓ cGMP breakdown
Together = way too much cGMP → excessive vasodilation/hypotension

what do Calcium Channel Blockers do?

Binds to activated channels, preventing calcium influx

how do calcium channels work in normal vascular smooth muscle

Normally in vascular smooth muscle:

L-type Ca²⁺ channel opens → Ca²⁺ enters → activates MLCK → myosin phosphorylation → contraction

Calcium channel blockers interrupt this:

CCB → blocks L-type Ca²⁺ channel → ↓ Ca²⁺ entry → ↓ MLCK activity → ↓ smooth muscle contraction → VASODILATION

how calcium blockers diff than nitrates

Nitrates: ↑ NO/cGMP to cause relaxation
CCBs: ↓ Ca²⁺ entry to prevent contraction

Both ultimately produce vasodilation, but through different mechanisms.

how does CCBs affect arteries more than veins

CCBs → mainly arteries → arterial dilation → blood pressure decreases

When arteries dilate, the heart pumps against less resistance:

Arterial dilation → ↓ afterload → ↓ cardiac workload → ↓ myocardial O₂ demand

how can CCBs affect the heart

decreases heart rate
decreases myocardial Ca²⁺
→ decreases cardiac workload/O₂ demand

• slows down SA node

A slower heart doesn't have to work as hard, so it consumes less oxygen.

what does SA node do?

is the sinoatrial node which initates the heart beat with electrical impulses

• A slow heart rate allows the left ventricle to fill completely which lowers the heart workload

how can CCBs help angina in two major ways:

Blood vessels: arterial dilation → ↓ BP/afterload → ↓ O₂ demand
Heart: ↓ heart rate and myocardial Ca²⁺ → ↓ cardiac workload → ↓ O₂ demand

ex of Calcium channel blocker 3

1. Dihydropyridines- e.g. Nifedipine, Amlodipine

2. Non-dihydropyridines- e.g. Diltiazem, Verapamil

what are Dihydropyridines- e.g. Nifedipine, Amlodipine used for?

are calcium channel blockers mainly used for:

Vasodilation → ↓ blood pressure + ↓ afterload
• Commonly used for vasospastic (Prinzmetal) angina

what do Non-dihydropyridines- e.g. Diltiazem, Verapamil do?

are calcium channel blockers that act more on the heart.

They → ↓ heart rate + ↓ contractility + ↓ conduction → ↓ cardiac workload/O₂ demand.

• both non and dih are used to treat hypertension and cardiac arrythmias

ex Calcium Channel Blockers- 4

Metabolized by CYP3A4

• Grapefruit inhibits 3A4, increasing CCB activity

• Rifampin induces 3A4, decreasing CCB activity

What normally happens when β1 receptors are stimulated?

β1 receptors are found mainly in the heart. Your sympathetic nervous system releases norepinephrine/epinephrine, which stimulate these receptors

what does β1 stimulation causes:

↑ heart rate
↑ contractility = heart contracts more forcefully
↑ conduction = electrical impulses travel through the heart faster

how does that affect o2 and angina

β1 stimulation → heart works harder → ↑ myocardial O₂ demand

• That's a problem in angina because: - Angina occurs when heart O₂ demand exceeds the available O₂ supply.

So what does a beta blocker do?

A β-blocker blocks the β1 receptor, preventing/reducing the effects of norepinephrine and epinephrine.

explain the mechanism of beta blockers

β1 blocker → ↓ heart rate + ↓ contractility → ↓ cardiac workload → ↓ myocardial O₂ demand → helps prevent angina

how does B blockers help angina

β-blockers help angina primarily by reducing myocardial oxygen demand.

β1 vs β2 receptors: why selectivity matters

what is Ranolazine

A late sodium channel inhibitor

what does Ranolazine do?

Decrease oxygen demand by lowering calcium overload during contraction and decreasing myocardial tension.

• Exactly how it helps angina is unknown

• No significant impact on blood pressure or heart rate

how are ivabradine and ranolazine.metabolized?

Both are metabolized by CYP3A4

CYP3A4 is a liver enzyme that helps metabolize these drugs.

what would happen if something inhbits CYP3A4

So if something inhibits CYP3A4, the drugs aren't broken down as efficiently:

CYP3A4 inhibition → ↓ metabolism → ↑ drug levels/activity

what does grapefruit do?

Grapefruit inhibits CYP3A4 → ↑ ivabradine/ranolazine activity

what does rifampin do?

Rifampin induces CYP3A4 → ↓ ivabradine/ranolazine activity

why cant ivabradine and ranolazine 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 arrhythmia)

Adverse Effects

what is first line Treatment for angina (3)

Calcium channel blocker for prophylaxis OR
• Beta blocker for prophylaxis
• Nitrate (sublingual or spray) for fast relief of chest pain

what is 2nd line treatment for angina (3)

• Long acting nitrates
• Beta blocker + dihydropyridine CCB (like nifepidine)-
because verapamil also decrease heart rate
• Ranolazine or Ivabradine

Other drugs for Angina Patient

1. Anti-platelet agents - To prevent blood clots that can cause unstable angina

2. Statins - Cholesterol lowering drugs, To prevent further atherosclerosis