STEPTRACKERPHARMACOLOGY | CARDIOVASCULAR | HIGH-YIELD REVIEW

Antianginals & Vasodilators

Angina is an oxygen supply-demand problem: every antianginal lowers demand (HR, contractility, wall stress) or raises supply — and some do opposite things to heart rate.

FOCUS ON
Myocardial O₂ demand rises with HR, contractility, preload (end-diastolic volume) and afterload. Nitrates (nitroglycerin, isosorbide mononitrate/dinitrate): release NO → ↑ cGMP → venodilation (↓ preload) > arteriolar; dilate coronaries in vasospasm. Adverse: headache, flushing, reflex tachycardia, orthostasis, tolerance (nitrate-free interval), "Monday disease" in industrial exposure. Never with PDE5 inhibitors (severe hypotension). β-blockers ↓ HR and contractility; combining with nitrates blocks reflex tachycardia. CCBs: nondihydropyridines ↓ HR; dihydropyridines dilate arterioles; drug of choice for vasospastic (Prinzmetal) angina. Ranolazine blocks late Na⁺ current → ↓ Ca²⁺ overload, prolongs QT. Secondary prevention: aspirin, high-intensity statin. Pulmonary hypertension: endothelin antagonists (bosentan), PDE5 inhibitors (sildenafil), prostacyclins (epoprostenol), riociguat.
DRUG · CLASS
MECHANISM
EFFECT ON DEMAND
ADVERSE · NOTES
Nitroglycerin
sublingual, IV, patch
NO → guanylyl cyclase → ↑ cGMP → myosin light-chain dephosphorylation
↓ Preload (venous) → ↓ wall stress
Headache, reflex tachycardia, hypotension
Isosorbide mono/dinitrate
Oral long-acting nitrates
Chronic angina prophylaxis
Tolerance → 10–12 h nitrate-free interval
β-blockers
↓ HR, contractility
↓ Demand; longer diastole ↑ perfusion
Avoid in vasospastic angina
Verapamil · diltiazem
Cardiac L-type Ca²⁺ block
↓ HR, ↓ contractility, ↓ afterload
Bradycardia, constipation; don't combine with β-blocker freely
Dihydropyridines
Vascular L-type Ca²⁺ block
↓ Afterload, coronary dilation
Reflex tachycardia (short-acting nifedipine avoid)
Ranolazine
Inhibits late Na⁺ current
↓ Diastolic wall tension; no HR/BP change
QT prolongation, constipation, dizziness · CYP3A4 substrate
Ivabradine
If channel block
↓ HR only
Phosphenes
PDE5 inhibitors
sildenafil, tadalafil
↑ cGMP (blocks breakdown)
Erectile dysfunction, pulmonary HTN, BPH (tadalafil)
Hypotension with nitrates, blue-tinted vision (sildenafil), headache
Bosentan · ambrisentan · macitentan
Endothelin-receptor antagonists
Pulmonary arterial hypertension
Hepatotoxicity (bosentan), teratogenic, edema
Epoprostenol · iloprost · treprostinil
Prostacyclin (PGI₂) analogs → vasodilation, ↓ platelet aggregation
Pulmonary arterial hypertension
Flushing, jaw pain, continuous infusion
Riociguat
Stimulates soluble guanylyl cyclase
PAH, chronic thromboembolic pulmonary HTN
Not with PDE5 inhibitors or nitrates
Cilostazol
PDE3 inhibitor → vasodilation, ↓ platelet aggregation
Intermittent claudication
Contraindicated in HF

Mechanism — the NO-cGMP pathway

Nitrate → NO
→
Soluble guanylyl cyclase(riociguat stimulates)
→
↑ cGMP(PDE5 breaks down; sildenafil blocks)
→
Smooth muscle relaxes

Nitrates plus sildenafil stack cGMP from both ends → profound hypotension.

Combined effects on demand

EFFECT
NITRATE
β-BLOCKER
BOTH
HR
↑ reflex
↓
No change / ↓
Contractility
↑ reflex
↓
Little change
EDV
↓
↑
No change / ↓
Ejection time
↓
↑
Little change

How it's tested

COMMON CONFUSIONNitrates mainly dilate veins (↓ preload); hydralazine dilates arterioles (↓ afterload); nitroprusside does both.
THE TRAPNitrates in an inferior MI with right ventricular infarction drop preload and cause collapse; also contraindicated after PDE5 inhibitors (24–48 h).
YOUR APPROACHAsk what each drug does to HR, contractility, preload and afterload — then pick combinations that cancel each other's reflexes.

If you see… think…

Headache on a weekday, gone on weekends, factory worker → nitrate tolerance and withdrawal
Chest pain at rest, early morning, transient ST elevation → vasospastic angina → CCB, nitrate
Syncope after nitroglycerin, recent sildenafil → cGMP-mediated hypotension
Antianginal with no HR or BP effect, prolongs QT → ranolazine
Blue-tinged vision → sildenafil (PDE6 cross-reactivity)
Pulmonary hypertension drug with liver toxicity → bosentan
Claudication drug contraindicated in HF → cilostazol
Hypotension after nitrate in inferior MI → RV infarction (preload dependent)
Combining β-blocker with nitrate → blunts reflex tachycardia
Nitrate's main site → veins (↓ preload)