Pharmacology of angina pectoris Flashcards
1
Q
Goal of angina Rx
A
- 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
2
Q
Nitrate drugs 1
A
- 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
3
Q
Nitrate drugs 2
A
- 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
4
Q
Pharmacokinetics of nitrates
A
- 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
5
Q
Side effects and tolerance of nitrates
A
- 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
6
Q
Beta blockers (BB) 1
A
- 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)
7
Q
Beta blockers (BB) 2
A
- 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)
8
Q
Side effects of adrenergic blockers 1
A
- 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
9
Q
Side effects of adrenergic blockers 2
A
- 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
10
Q
Ca channel blockers
A
- 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
11
Q
Ca-blockers mechanism of action
A
- 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)
12
Q
Different types of Ca blockers
A
- 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
13
Q
Side effect of Ca blockers
A
- Primary side effect is hypotension (not postural)
- Since these drugs do not affect veins they do not cause postural hypotension
- Verapamil causes constipation
14
Q
Ranolazine
A
- 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
