11/4 Angina Drugs - Ryazanov Flashcards
angina pectoris
3 types
episodes of ischemia (cardiac discomfort/pain) due to imbalance in cardial oxygen demand/supply
three types;
- typical: atherosclerotic narrowing of coronary artery
- atypical/variant (Prinzmetal’s): coronary vasospasm
- unstable: platelet aggregation secondary to plaque rupture
determinants of cardiac oxygen consumption
- HR (chronotropy)
- contractility (inotropy)
- ventricular wall stress
- recall Law of Laplace: wall stress = (LV pressure * radius)/(2 * LV wall thickness)
- intraventricular pressure
- radius (heart size)
- wall thickness
impact of vascular tone on ventricular wall pressure
arterial tone determines peripheral vascular resistance → arterial bp
- increased arterial tone = increased afterload = increased LV pressure
- decreased arterial tone = decreased afterload = decreased LV pressure
- *changes in myocardial work affect oxygen demand
venous tone determines capacitance of venous circ → diastolic bp
- increased venous tone → increased end diastolic volume → increased ventricular wall tension (pressure and radius both affected)
therapeutic goals of tx
goals
possible approaches
current tx in use
- suppress sx and freq of attacks
- improve exercise tolerance
approaches:
CANNOT incrase oxygen extraction from blood (not poss), so targets are:
- incr myocardial perfusion and oxygenation
- decrease work of heart (and oxygen demand of heart)
- stimulate angiogenesis (investigational stage)
current effective therapies are:
- vasilators → decrease vasc smooth muscle tone
- beta-adrenergic blockers → suppress cardiac activity
mechanisms for relaxing arterial smooth muscle
- hyperpolarization (opening K-ATP channels) → decr L-type Ca channel opening
- blockade of L-type Ca channels
- incr cGMP (via NO)
- incr cAMP (via inhibition of PDE)
- pentoxifylline
- cilostazol
organic nitrates
release NO in smooth muscle cells
mechanism:
- NO activates guanyl cyclase → incr cGMP
- cGMP activates cGMP-dep protein kinase phosphorylation cascade →→→ dephosphorylation of myosin light chain → muscle relaxation
also
decr phosphoinositol turnover and internal Ca release
CV effects of organic nitrates and nitrites
low doses
high does
overall effect
low doses : capacitance vessel effects
- venodilation, venous pooling → decr diastolic filling pressure
- decr pulmo vessel resistance
- systemic peripheral resistance maintained
- side effects: flushign, headache, orthostatic hypotension, coronary vasodil
high doses : resistance vessel effects
- decr systemic peripheral resistance
- reflex cardiac stimulation
overall effects
- decreased heart size and wall tension during systole
- reflex cardiac stimulation
organic nitrates
PK
PD
metabolism:
- first pass inactivation: nitrate reductase (liver)
- denitration can occur in tissues (diff levels in diff tissues) → release of nitric oxide
- more resistant → less potent, so can be used in larger dose with longer halflife
adverse effects:
- hypotension (esp combined with other vasodilators)
- headache, flushing, GI distress
tolerance/phys dependence are issues
nitrites
dosage forms, duration of action
Viagra and smooth muscle contraction
- NO mediates normal erectile fx by relaxing smooth muscle in corpora cavernosa
- PDE5 is a PDE that mediates cGMP breakdown in this tissue
- sildenafil inhibits PDE5 → incr [cGMP] → enhanced erection in males who innervation and NO synth is intact
ISSUE: sildenafil potentiates nitrate activity →→→ severe hypotension, some heart attacks
Ca and smooth muscle contraction
type of contraction
sources of Ca in muscle
vascular smooth muscle contraction is tonic (not phasic)
- tone is maintained by intracellular free Ca
sources of Ca
- sarcoplasmic reticulum : adrenergic/other receptor stimulated → IP3 mediates Ca release
-
Ca-selective channels
- voltage-gated
- ligand-gated
- Ca/Na exchange channels
types of Ca channel
L-type channels are key for vascular resistance and myocardial cells
Ca channels and arterial smooth muscle tone
Ca enters via voltage-dep L-type Ca channels
- opening probability increases with:
- activation of alpha1a receptor activation
- increase in membrane potential
what affects membrane potential?
- stretch increases potential from -70 to -45 → correlates with extent of Ca channel opening
Ca channel blockers
mechanism
inhibit Ca selective channels carrying slow inward current during depol in a state-dependent way (i.e. depends on whether channel is open or closed)
closed channels
- nifedipine and DHPs (dihydropyridines) → decrease freq of channel opening
open channels
-
verapamil → blocks open channels
- effect affected by freq of opening!
net CV effects of nifedipine and verapamil at clinical doses
- vasodilation
- direct cardiac suppression
- reflex cardiac activation
- net balance
nifedipine : vasodilation with modest cardiac stim
verapamil : vasodilation with moderate cardiac suppression
nifedipine
prototypical dihydropyridine Ca channel blocker
- blocks entry of Ca into cell
effects: VASODILATION
- systemic vasodil of resistance (not capacitance) vessels
- coronary artery vasodil → increased blood flow
- cardiosuppressive effects largely balanced by reflex activation
adverse effects: flushing, headache, hypotension, periph edema
PK: orally effective (but large first-pass metabolism), 2-5hr halflife
verapamil
effects:
- moderate vasodilation
- cardiac suppression largely balanced by reflex activation → CO/HR only modestly decr
- some alpha adrenergic blockade
adverse effects: flushing, GI issues, LV dysfx
PK: orally effective, large first-pass metabolism, 3-7h halflife
diltiazem is similar, but has less suppressive heart effects
ranolazine
reduces intracellular Ca levels via inhibition of inward Na current in heart muscle → reduces tension in heart wall
therapeutic advantages of Ca channel blockers
- no aggravation of diabetes, periph vascular disease, bronchospasm, lipid provile, glucose, or K
- no issues with tolerance!
beta blockers
effects
1. CARDIOVASCULAR: neg inotropy, neg chronotropy
- short term: decr CO, incr periph resistance (beta2 blocade)
- long term: peripheral resistance normalizes
- net effect: decreased myocardial oxygen consumption
2. blood pressure
- normal bp: no effect
- HTN: decrease in bp
3. pulmonary
- beta2 antagonism → bronchodilation interrupted
- ***dangerous in COPD and asthma
4. eye
- decr aqueous humor production from ciliary epithelium
5. metabolic
- blocks glucose mobilization (beta2 antagonism → glycogenolysis interrupted)
- slows lipolysis, increases VLDL, lowers HDL (not sure how)
specific props of beta blockers
- relative specificity for beta1 and beta2 receptors
- beta1 > beta2 === cardioselective (due to decr effect on lung)
- this distinction is not absolute
- varieties with partial agonist activity (intrinsic sympathomimetic activity) exist
* potentially useful for patients who develop bradycardia/asthma with pure antagonists - local anesthetic properties (membrane stabilizing activity)
* undesirable when used topically on eye - PK
- well absorbed orally
- usually hours-long duration of action
- exception: esmolol (10 min halflife, IV, controlled)
tx for typical angina
nitroglycerine
NITROGLYCERINE
- effects on PERFUSION
- no overall incr in coronary bloodflow
- some redistribution frim epicardial → endocardial ischemic regions
- preferential dilation at occluded sites
- effect on MYOCARDIAL WORKLOAD
- venodilation (lots)
- arteriolar dilation (some)
- reflex cardiac stimulation (ino/chronotropy)
utility for typical angina: lowering heart’s workload, good for supressing acute attacks
tx for typical angina
Ca channel blockers
CA CHANNEL BLOCKERS
- effects on PERFUSION
- incr in coronary bloodflow
- effect on MYOCARDIAL WORKLOAD
- resistance vessel dilation
- decreased cardiac workload
- reflex cardiac stim varies with diff agents
utility for typical angina:
- reduce freq of attacks
- reduce nitrate req
- incr exercise performance
- no reduction in incidence of MI
- used when nitrates or beta blockers poorly tolerated (ex. bronchospastic disorder, periph vascular disease, insulin dep diabetes, severe hypertriglyceridemia)
tx for typical angina
beta blockers
BETA BLOCKERS
- effect on MYOCARDIAL WORKLOAD
- block beta receptors in heart → suppression of activity
- prolong diastole
- lower oxygen consumption
utility for typical angina: most effective agents currently available for reduction of cardiac ischemia
- reduces freq and severity of attacks
- no tolerance
- useful for suppression recurrent MI
adverse effects:
- possible aggravation of peripheral insufficiency, increased airway resistance
- possible rebound angina or MI on withdrawal
tx for variant angina
organic nitrates? effective
Ca channel blockers? effective
beta antagonists? NOT effective
