2 independent receptor-mediated pathways

1. a₁ adrenergic - controls Ca channel activity via IP3; min to min regulation; small localized regions of control
2. angiotensin II - tightly coupled to Ca channel; backup system for abnormal conditions; systemic

• largely done by reduction in sympathetic tone
• local = prostacyclin, adenosine, pH
• systemic (coupled to EDRF) = bradykinin and ACh trigger NO release
• Dopamine D1/D2

1. Ca channel
2. Adrenergic receptors
3. Dec angiotensin II synthesis or block receptors
4. increase cellular NO

carotid sinuses

• stretch receptors in wall of carotids and aortic arch
• fall in BP increases sympathetic drive

1. HTN
2. decrease afterload, even preload --> heart failure
3. angina

• Prazosin - a₁ blockade; ORAL; T_1/2 3 hours
• Doxazosin - same but 20 hour half life, lowers blood lipids
• arterial system effects more pronounced
• syncope is common
• Useful for HTN, reduce afterload, and BPH

• PROTOTYPE: captopril
• prevent conversion of angiotensin I to II
• more pronounced on arteries
• reduces HTN, afterload
• "kidney-sparing"

Losartan

• about same anti-HTN as ACE inhibitors
• contraindicated in pregnancy

• renin inhibitor
• decreases angiotensin II levels
• similar efficacy to ACE or ARBs
• may have a "rebound" effect

prototypes: nifedipine, diltiazem, felodipine, verapamil

• minimize effects on heart while maintaining effects on vasculature
• treat HTN and angina due to coronary artery spasm
• all interact at different sites on L-type channel
• greater effect on arteries than veins
• Nifedipine and felodipine - cardio-sparing
• Verapamil - strong cardiac effects

nifedipine, diltiazem, felodipine, verapamil

• ORAL, long term therapy
• nifedipine: sustaine release or short term
• SE: headache and facial flushing, constipation, peripheral edema

metabolized and release NO in cells

• NO increases cGMP thus ↑dephosphorylation, ↑K+ efflux; ↓Ca channel activity

affects venous circulation: ↓VR,preload,CO

• quite labile (keep cool), large first pass effect
• given sublingual (acute angina), ointment, transdermal (prophylactic), and IV
• virtually immediate effects but only for 15 min

Uses: coronary insufficiency, acute angina

SE: headache, hypotension, flushing/burning sensation

• organic nitrate
• volatile liquid for INHALATION
• very rapid onset (30 sec)
• lasts 5 min
• Used to diagnose murmur and angina

• sugar nitrate
• stable, ORAL, lasts 2-4 hours
• given during nitrate-free holidays to ↓tolerance
• angina prophylaxis and CHF
• Mononitrate has longer half life but same effects

• organic nitrate
• ICU, emergencies to control arterial pressure, acute heart failure
• extremely potent vasodilator
• T_1/2 30 sec, immediate onset, quick reversal
• IV fusion
• Tox: hypotensive crisis, accumulation of thiocyanate leading to CNS abnormalities limits use to 48-72 hours --> B₁₂ reduces toxicity

Diazoxide, hydralazine, minoxidil

• dilation of arterioles by increasing K⁺ efflux (hyperpolarizes)), reduces sensitivity to ATP
• Baroreceptor reflex is adverse reaction
• control w/ b-blocker or diuretic

• arterial relaxant - opens K+ channels
• IV: potent arterial vasodilator, inc CO
• ORAL: blocks K+ secretion of insulin --> hyperglycemic effect
• SE: profound hypotension

• most used arterial relaxant
• ORAL: combo w/ b-blocker, diuretic, captopril
• treat HTN and CHF
• acetylated by liver adn kidney
• SE: lupus like syndrome

• frequently used arterial relaxant
• ORAL: activates K+ channels, ↑efflux
• SE: hypertrichosis
• used in combo with other drugs

• potent arterial vasodilator
• requires less drugs in combination to control blood pressure

Phosphodiesterase Type V inhibitor

• increased cGMP in corpus cavernosum
• ORAL, 40 min onset, lasts 3-4 hours
• Significant interaction w/ nitrates and a-adrenoceptor antagonists --> causes profound hypotension

• more selective phosphodiesterase type 5 inhibitor
• lasts for 36 hours