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Flashcards in Pharmacology of angina pectoris Deck (14):

Goal of angina Rx

-Angina due to O2 demand of heart exceeding the amount of O2 delivered
-Therefore the goal is to reduce the O2 demand of heart muscle since it is very difficult to increase O2 supply to heart
-The primary mechanism is to increase venodilation
-As veins dilate, blood pools in venous circulation and less blood is returned to the heart
-Lowering the EDV (preload) lowers stretch on the heart and thus decreases the amount of work the heart must do (lowers SV)
-As work (due to decreased preload, SV) is decreased the O2 demand is lowered


Nitrate drugs 1

-Nitrates are converted to NO, which activates GC converting GTP to cGMP and leads to dephosphorylation of myosin light chain in vascular SMCs
-When myosin light chain is dephosphorylated it cannot contract (phosphates needed for cross-bridged)
-This leads to vasodilation (primarily venodilation)
-NO also activates Ca-dependent K channel leading to hyperpolarization of cardiac cells and more relaxation


Nitrate drugs 2

-Additionally, NO relaxes coronary arteries to allow more O2 to get into the myocardium, and relieves vessel spasm
-But the primary mechanism is lowered venous return (via venodilation) leading to lower EDV-> lower SV-> less work
-Low doses of NO work on veins only, whereas higher doses work on arteries as well
-NO only dilates normal arteries (not plaque areas), but will dilate collateral arteries to bring blood to ischemic areas


Pharmacokinetics of nitrates

-Sublingual administrations have a rapid onset of action (2 min) and short duration (25min)
-PO onset is 30 in and duration is 4-8 hrs
-Transdermal patch has 30 min onset and duration of 8-14 hours


Side effects and tolerance of nitrates

-Most common: headache (due to dilation of meningeal vessels
-Other side effects: postural hypotension and tachycardia (due to cardiac reflex sensing drop in BP)
-Phosphodiesterase inhibitors (viagra) potentiate the activity of nitrates and can cause severe hypotension and death
-SMCs rapidly develop tolerance to nitrates via desensitization and leads to cessation of vasodilation
-Pts need drug free periods of time to allow for desensitization, typically 10-12 hrs without the drugs


Beta blockers (BB) 1

-BBs prevent NE from binding to beta-1 receptors in heart, thus lower HR and force of contraction
-These two together decrease the workload of the heart and reduce O2 demand
-Beta-1 selective drugs are used at low doses and do not have significant B2 activity
-BBs also increase EDV b/c of their effect of inducing bradycardia (allows for longer filling time during diastole and less blood ejected in systole due to reduced force of contraction)


Beta blockers (BB) 2

-2 main BBs used: metoprolo and atenolol (all BBs end in "olol" or "ilol"), both of which are B1 selective
-Carvedilol has B1/B2 and A1 blocking effects so on top of reducing HR and force of contraction, it also prevents vasoconstriction to decrease atrial filling and counteracts the B2 effect
-BBs also used with NO when pts don't respond to NO alone, and along w/ its effects the BB will prevent the cardiac reflex induced by NO thus potentiating NO's action
-BBs are more effective when symp tone is high (exercise)


Side effects of adrenergic blockers 1

-BBs that cross the BBB may cause depression
-Propanolol (both B1 and B2 equally) and metoprolol cross the BBB, but atenolol doesn't
-Use of BBs also causes up-regulation of B receptors, thus if the BB is stopped quickly the beta adrenergic stimulation is amplified due to high number of receptors
-This can cause angina or MI, so its important to slowly reduce BB dose when cutting it out


Side effects of adrenergic blockers 2

-BBs also affect insulin sensitivity (for diabetics)
-As blood glc falls there is epinephrine release which binds to beta receptors in the liver to stimulate glycogen breakdown and glc release
-However if the beta receptors are blocked the liver cannot respond to the drop in blood glc
-This means that when diabetics give insulin and blood glc falls, it won't be replenished by the liver and will remain depleted which can be life-threatening
-To avoid this simply lower insulin doses


Ca channel blockers

-Ca-blockers decrease O2 demand of heart by:
-Decreasing after load by arteriole dilation
-Depressing the SA node and slowing HR
-Slowing AV node conduction
-Acting as a negative inotrope in the heart
-Dilation of coronary arteries to increase O2 supply


Ca-blockers mechanism of action

-Ca enters the cell and binds to calmodulin, which activates myosin light chain kinase to phosphorylate myosin light chain
-This phosphorylation allows for actin and myosin to form cross-bridges and thus enables SM contraction (vasoconstriction)
-But blocking Ca from entering the cell prevents this and thus vasodilation occurs
-Ca-blockers also decrease cardiac contractility (negative inotropic), and suppress the SA and AV nodes (negative chronotropic)


Different types of Ca blockers

-Dihydropyridines: amlopidine, nicardipine, nifedipine all are good vasodilators but have little effect on nodes or cardiac contractility
-Diltiazem is good at suppressing contraction and nodes but little effect on peripheral vasoconstriction
-Verapamil is good at everything


Side effect of Ca blockers

-Primary side effect is hypotension (not postural)
-Since these drugs do not affect veins they do not cause postural hypotension
-Verapamil causes constipation



-New drug that reduces late Na current thats coupled to Ca entry into myocardial cell
-This reduces intercellular Ca and decreases contractility, thus decreasing O2 consumption