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M2 Cardio > 11/4 Angina Drugs - Ryazanov > Flashcards

11/4 Angina Drugs - Ryazanov Flashcards

1
Q

angina pectoris

3 types

A

episodes of ischemia (cardiac discomfort/pain) due to imbalance in cardial oxygen demand/supply

three types;

  1. typical: atherosclerotic narrowing of coronary artery
  2. atypical/variant (Prinzmetal’s): coronary vasospasm
  3. unstable: platelet aggregation secondary to plaque rupture
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2
Q

determinants of cardiac oxygen consumption

A
  1. HR (chronotropy)
  2. contractility (inotropy)
  3. ventricular wall stress
  • recall Law of Laplace: wall stress = (LV pressure * radius)/(2 * LV wall thickness)
    • intraventricular pressure
    • radius (heart size)
    • wall thickness
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3
Q

impact of vascular tone on ventricular wall pressure

A

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)
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4
Q

therapeutic goals of tx

goals

possible approaches

current tx in use

A
  1. suppress sx and freq of attacks
  2. 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:

  1. vasilators → decrease vasc smooth muscle tone
  2. beta-adrenergic blockers → suppress cardiac activity
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5
Q

mechanisms for relaxing arterial smooth muscle

A
  1. hyperpolarization (opening K-ATP channels) → decr L-type Ca channel opening
  2. blockade of L-type Ca channels
  3. incr cGMP (via NO)
  4. incr cAMP (via inhibition of PDE)
    • pentoxifylline
    • cilostazol
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6
Q

organic nitrates

A

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

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7
Q

CV effects of organic nitrates and nitrites

low doses

high does

overall effect

A

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
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8
Q

organic nitrates

PK

PD

A

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

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9
Q

nitrites

dosage forms, duration of action

A
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10
Q

Viagra and smooth muscle contraction

A
  • 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

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11
Q

Ca and smooth muscle contraction

type of contraction

sources of Ca in muscle

A

vascular smooth muscle contraction is tonic (not phasic)

  • tone is maintained by intracellular free Ca

sources of Ca

  1. sarcoplasmic reticulum : adrenergic/other receptor stimulated → IP3 mediates Ca release
  2. Ca-selective channels
    • ​voltage-gated
    • ligand-gated
  3. Ca/Na exchange channels
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12
Q

types of Ca channel

A

L-type channels are key for vascular resistance and myocardial cells

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13
Q

Ca channels and arterial smooth muscle tone

A

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
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14
Q

Ca channel blockers

mechanism

A

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!
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15
Q

net CV effects of nifedipine and verapamil at clinical doses

  • vasodilation
  • direct cardiac suppression
  • reflex cardiac activation
  • net balance
A

nifedipine : vasodilation with modest cardiac stim

verapamil : vasodilation with moderate cardiac suppression

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16
Q

nifedipine

A

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

17
Q

verapamil

A

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

18
Q

ranolazine

A

reduces intracellular Ca levels via inhibition of inward Na current in heart muscle → reduces tension in heart wall

19
Q

therapeutic advantages of Ca channel blockers

A
  1. no aggravation of diabetes, periph vascular disease, bronchospasm, lipid provile, glucose, or K
  2. no issues with tolerance!
20
Q

beta blockers

effects

A

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)
21
Q

specific props of beta blockers

A
  1. relative specificity for beta1 and beta2 receptors
  • beta1 > beta2 === cardioselective (due to decr effect on lung)
  • this distinction is not absolute
  1. varieties with partial agonist activity (intrinsic sympathomimetic activity) exist
    * potentially useful for patients who develop bradycardia/asthma with pure antagonists
  2. local anesthetic properties (membrane stabilizing activity)
    * undesirable when used topically on eye
  3. PK
  • well absorbed orally
  • usually hours-long duration of action
    • exception: esmolol (10 min halflife, IV, controlled)
22
Q

tx for typical angina

nitroglycerine

A

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

23
Q
A
24
Q

tx for typical angina

Ca channel blockers

A

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)
25
Q

tx for typical angina

beta blockers

A

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
26
Q

tx for variant angina

A

organic nitrates? effective

Ca channel blockers? effective

beta antagonists? NOT effective

M2 Cardio (22 decks)

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