11 - Smooth Muscle Pharmacology Flashcards
What facilitates smooth muscle contraction? What causing contraction in vascular smooth muscle?
Electrochemical coupling operates through changes inc cell membrane potential.
Resting membrane potential = -40 to -70 mV.
K channels cause hyperpolarization while calcium channels cause depolarization.
What is pharmacological coupling of smooth muscle? What else can cause smooth muscle contraction?
Operates independent of cell membrane potential.
Involves receptors, intracellular signaling.
Nts, hormones, and paracrine factors.
What is the main mechanism of smooth muscle contraction? What causes relaxation?
Ca2+ channels allow calcium into cells and sarcoplasmic reticulum releases Ca2+.
Ca binds to calmodulin activating MLC kinase, which phosphorylated actin+MLC and causes contraction.
When RoA is bound to GDP it’s inactive and Rho kinase is inactive. As a result, myosin phosphatase is UN-phosphorylated and can remove a phosphate from MLC to cause muscle relaxation.
What are three mechanisms of smooth muscle relaxation?
Blocking calcium channels, blocking Galpha receptors, and blocking Rho kinase.
What are the different parts of the body that can be targeted by smooth muscle relaxation?
CV - vasodilators
Obstetrics - uterine relaxation
GI motility - contraction
Pulmonary - bronchodilators
What is preload? When is it increased?
The volume of blood in the ventricles at the end of diastole (end diastolic pressure).
Increased in hypervolemia and regurgitation of cardiac valves.
What is afterload? When is it increased?
Resistance that the left ventricle must overcome to circulate blood.
Increased in HTN and vasoconstriction.
Increased afterload = increased cardiac workload
What are five pharmacological actions of vasodilators?
- Nitric oxide
- Increase or decrease cell membrane channel activity (K+ or Ca2+ channels)
- Increase smooth muscle cell cAMP or cGMP levels
- Activate vasodilator receptors
- Inhibit vasoconstrictor pathways and receptors
What are the types of nitric oxide donors? How does their mechanism of action differ?
Organic Nitrates - indirectly increase through S-nitrosothiol
Sodium Nitroprusside - direct NO donor
Both work to increase cGMP and protein kinase G.
What drug is an organic nitrate that that acts on venous circulation? What is it used for and how is it given? What is the toxicity?
Nitroglycerin
Sublingual - works within 15-30 min. Treats angina/coronary artery disease.
Toxicity is hypotension and reflex tachycardia.
What drug is a NO donor that works on both arterial and venous circulation? When is it used? How is it given? What is the toxicity?
Nitroprusside - direct NO donor.
IV for HTN emergencies for rapid reduction in art pressure. Lasts 15-30 min.
Toxicity: hypotension, cyanide accumulation (needs monitoring).
What is a direct vasodilator that acts on arterial circulation and is used in heart failure and HTN? How is it given?
Hydralazine
Oral for long-term, combined with nitrates for heart failure.
What direct vasodilator works on arterial circulation and is a selective K+ ATP channels opener? What is it used for and how is it given? What is the side effect?
Minoxidil.
Used for heart failure and HTN.
Oral for long-term.
Hypertrichosis (hair growth–ROGAIN).
What direct vasodilator acts on arterial circulation and is a non-selective K+ channel opening? When is it used? How is it given? What is the toxicity?
Diazoxide.
Used in HTN emergencies.
Oral is long acting, IV for rapid decrease in vascular resistance and art BP.
Toxicity is hypotension.
What are the three types of membrane channel dilators (Ca2+ channel blockers)? What drugs fall into each category?
Phenylalkamines - verapamil
Benzothiazapines - diltiazem
Dihydropyridines - nifedipine, nicardipine, amlodipine
Where is the action of calcium channel blockers? Which ones are more vascular smooth muscle selective and which is cerebral vascular selective?
They are arterial dominant.
Vascular smooth muscle selective: dihydropyridines
Cerebral vascular selective: Nimodipine
What is the use of calcium channel blockers?
HTN, angina, cerebral and coronary vasospasm.
Which phosphodiesterases are present in vascular smooth muscle? What is the result of inhibiting each?
PDE5: inhibition causes increase in cGMP and causes vasodilation via PKG.
PDE3: inhibition causes an increase in cAMP and PKA, resulting in relaxation
Both of these cause smooth muscle relaxation.
Which phosphodiesterase is present in the heart? What is the result of inhibiting it?
PDE3: inhibition causes an increase in cAMP and enhances the contraction of the heart. Also decreases afterload.
Which phosphodiesterase inhibitors cause PDE3 inhibition? What effect do they have on the heart and vascular smooth muscle?
Milrinone and Inamrinone
Heart: causes increased force and velocity of contraction
Vascular smooth muscle: dilation of arterial side
Both work through an increase in cAMP.
What is the use of PDE3 inhibitors such as Milrinon and Inamrinone? How are they given?
Heart failure.
IV for short-term life-threatening heart failure.
Oral forms withdrawn due to sudden cardiac death.
Which drugs are PDE5 inhibitors? What is their action and use?
Sildenafil and tadalafil
PDE5 inhibition through an increase in cGMP.
Erectile dysfunction and pulmonary HTN.
What miscellaneous vasodilator acts as a dopamine D1 agonist? Where is it’s site of action? What is it used for?
Fenoldopam
Arterial dominant, natriuretic.
Used in HTN emergencies and post-operative HTN (IV).
What miscellaneous vasodilator is an alpha-adrenergic blocker? What is it’s site of action?
Prazosin
Arterial and venous circulation.
Used for HTN.
First dose phenomenon.
