What are the different mechanisms for relaxing arterial smooth muscle?
- Hyperpolarization (opening Katp channels) -> decrease opening of L channels
- Blockade of Ca2+ L channels
- Increasing cGMP via NO
- Increasing cAMP via inhbition of phosphodiesterase-Pentoxifylline, Cilostazol
What is the MOA for organic nitrates?
- Activates Guanylate Cyclase -> increasing cGMP
- Increasing cGMP activates cGMP-dependent protein kinase phosphorylation cascade->-> dephosphorylation of myosin light chain and muscle relaxation
What are the CV effects of organic nitrates and nitrites?
Low doses: Capacitance vessel effects-> venodilation; Systemic peripheral resistance maintained
-Decrease diastolic filling pressure
High doses: Resistance vessel effects, decrease in systemic peripheral resistance; reflex cardiac stimulation
Overall effects: Decreased heart size and wall tension during systole; * reflex cardiac stimulation
Pharmacokinetics of organic nitrates and nitrites
- 1st pass inactivation by nitrate reductase in liver
- Tolerance, physical dependence
Adverse effects of organic nitrates
- Hypotension esp when used with other vasodilators
- Headache, flushing, GI distress
- Sildenafil potentiaates actions of nitrates used for angina->severe hypotension and heart attacks
Calcium channel blockers MOA`
- Inhibit calcium selective channels carrying slow inward current during depolarization
- Nifedipine &DHPs bind to closed L-channels and decrease frequency of opening
- Verapamil binds to open channels, thus frequency of opening determines extent of blockade
Describe Nifedipine, Usage, Adverse effects, and metabolism
-Prototype dihydropyridine Ca2+ entry blocker
-@ clinical doses-> vasodilator -> systemic vasodilation of resistance but not capacitance vessels
-*** Coronary artery vasodilation & increased blood flow
Adverse effects: Flushing, headaches, hypotension, peripheral edema
Metabolism: Orally effective, undergo large first pass metabolism, half-life 2-5 hours
Describe Verapamil, Usage, Adverse effects, and metabolism
- Moderate vasodilation, cardiac suppression balance by reflex act.
-Contraindicated in severe CHF
Adverse effects: Flushing GI disturbances, left ventricular dysfunction
Metabolism: orally effective, large first pass in liver
What are the therapeutic advantages of Ca2+ entry blockers?
- ) No aggravation of diabetes, peripheral vascular disease, no bronchospasm, blood profiles of lipids, glucose or potassium
- ) Tolerance does not develop
Propanolol
- prototypical beta blocker agent
- No cardioselectivity
Beta blocker general effects
- )CV: decrease HR and myocardial contractility
- short term: decrease CO, incr peripheral resistance (B2 block)
- Long term: periph. resistance normalize, net effect: decrease myocardial O2 consumption - ) BP- no effect on normal, decrease HTN in hypertensives
- ) PUlmonary: B2 antagonism of bronchodilation- ** dangerous in COPD and asthma
- )Eye-> decreases aqu. humor production from ciliary epithelium
- ) Metabolic: blocks glucose mobilization (B2 antagonism of glycogenolysis)
b. ) slows lipolysis, increase in VLDL, lowers HDL
