Drugs to treat angina

Organic nitrates examples

Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate

Advantages of nitrates being prodrugs?

Active metabolites have longer half lives than the parent drug

MOA of nitrates

1. nitrate compound is de-nitrated by mitochondrial aldehyde dehydrogenase (mtALDH— which is present at higher concentration in veins)

2. this forms NO (nitric oxide)

3. NO stimulates guanylyl cyclase

4. guanylyl cyclase increases cGMP levels

5. cGMP activates protein kinase G

6. this leads to decreased Ca influx into vascular smooth muscle, and increased calcium efflux from VSM, via controlling calcium voltage gated channels and myosin-LC

7. decreased Ca levels lead to relaxation of VSM

Veins >> arteries (at therapeutic doses)

Pharmacological effects of nitrates

Relaxes all segments of vascular smooth muscle, both arteries and veins, but venous dilation predominates arterial dilation

• venodilation → decrease venous return → decrease preload

• some arteriolar dilation → mild decrease in afterload

• coronary artery dilation → increase O2 supply

• does not significantly effect HR/contractility

What metabolizes nitrates?

glutathione-organic nitrate reductase from the liver

Do nitrates have high or low first pass metabolism?

high, leads to low oral bioavailability

Sublingual forms of nitrates

• rapid onset, short duration

• avoids first pass metabolism

• used to relieve acute angina

Oral and transdermal forms of nitrates

• slower onset and longer duration

• patches, ointments, oral

• use for prophylaxis of angina

Clinical uses for nitrates

• stable angina: decrease o2 demand via venodilation

• variant angina: increase o2 supply via coronary vasodilation

• unstable angina (adjunct): relieve chest pain via decreasing demand and increasing supply

What is nitrate tolerance and why does it happen?

• with prolonged use, nitroglycerin oxidized mtALDH enzyme, decreasing NO formation and decreasing vasodilation

• causes tachyphylaxis - acute tolerance where there is a loss of efficacy

• e.g. a patch can provide stable blood levels for 24 hours, but efficacy is less than 8-10 hours

What do we do to prevent nitrate tolerance?

• implement a nitrate-free interval of 8-12 hours daily

  • may remove the patch at bedtime

Adverse effects of nitrates

At high concentrations, there is excessive venous and arteriolar dilation

• orthostatic hypotension and dizziness (from venodilation)

• reflex tachycardia, increasing o2 demand (from arteriolar dilation)

• throbbing headache due to dilation of meningeal arteries

• facial flushing and warmth, due to dilation of facial and skin arteries

Contraindications for nitrates

PDE-5 inhibitors (-afils)

• massive increase in cGMP → profound vasodilation → severe hypotension that can increase risk of syncope, MI, or death

How long apart should we dose nitrates and sildenafil/vardenafil?

nitrates should not be given within 24 hours of sildenafil/vardenafil administration

How long after taking tadalafil can we administer nitrates?

48 hours

DHP CCBs examples

Amlodipine, nifedipine, felodipine

Non-DHP CCBs

verapamil, diltiazem

MOA of CCBs

Block voltage gated L type Ca channels in VSM and cardiac muscle → decreasing Ca concentrations intracellularly → vasodilation and/or cardiac suppression

• vascular effects (all CCBs)

  • arteriolar vasodilation → decrease TPR → decrease demand

    • minimal effect on veins (preload)

  • DHPs are more potent vasodilators

• Cardiac effects (mainly non DHP CCBs)

  • decrease ca influx in SA and AV nodes and myocardium → decrease HR, AV node conduction + contractility → decrease demand

  • Non DHPs are more potent cardiac depressants

DHP CCBs clinical uses

• stable angina: artery dilation, decreasing demand

• vasospastic angina (FIRST LINE): coronary vasodilation, increase supply

• NOT preferred in unstable angina due to reflex tachycardia

Non-DHP CCBs clinical uses

• Stable and unstable angina (SECOND LINE): decreased HR + contractility decreases demand, mild artery dilation decreases O2 demand

• only used if beta blockers are contraindicated or ineffective

DHP CCBs adverse effects

• reflex tachycardia

  • use extended release products to help with this

• peripheral edema (ankle swelling) due to arteriolar dilation causing capillary pressure and fluid leakage***

• flushing and headache due to cutaneous and cerebral vasodilation

Non-DHP CCBs adverse effects

• bradycardia, AV block, decreased cardiac contractility

• constipation (mainly verapamil)