Pharmacologic agents for Coronary Artery disease Flashcards
How much coronary blood flow per minute?
With intense exercise?
How much O2 extracted?
- Coronary blood flow is 70 ml/min/100g at rest
- 5% of the CO
- Coronary blood flow increases 2-4x with intense exercise
- 70% of the oxygen is extracted from the blood
What are the physiological factors that regulate coronary flow?
- Physical factors
- Vascular control by metabolites
- adenosine is released by myocardial cells in response to decreased PO2, causing coronary vasodilation
- Neural and humoral control
- sympathetic innervation
- large vessels- Alpha; vasoconstriction effects
- smaller vessels- Beta 2; dilator effects
What is the perfusion pressure to the left ventricle?
perfusion pressure to the left ventricle = DBP - LVEDP
Left ventricle only receives blood flow during diastole b/c systolic squeezing pressure closes arterioles and capillaries. This is not as much of an issue on the R side b/c the muscle mass is not as large
What factors increase myocardial demand?
- tachycardia
- high afterload
- high preload
- increased contractility
What factors increase myocardial supply?
- hgb concentration
- O2 saturation
- bradycardia (within reason)
- increased diastolic blood pressure
- low-normal preload
- decreased contractility
What is the treatment summary for stable angina?
(ABCDE)
- A: ASA, antianginals (nitrates, CCB, BB)
- B: Blood pressure (controlled)
- C: Cholesterol (statin), Cigarettes (stop)
- D: diet, diabetes
- E: education, exercise
How do nitrates help with CAD?
- Increase concentration of NO in smooth muscle cells
- Relax venous capacitance vessels and large coronary arteries to decrease preload and ventricular wall tension
- decrease demand and increase supply
Nitrate MOA?
- Nitrates release NO after they are metabolized
- NO activates soluble guanylate cyclase, increasing cGMP, which increases PKG
- This prevents Ca from entering the cell and the smooth muscle relaxes
What are the organic nitrate drugs?
- Nitroglycerin
- Isosorbide dinitrate
- DOA 6 hours
- Isosorbide mononitrate
What are the different ways nitroglycerin can be delivered?
- Sublingual- tablets or spray
- Oral- has a huge first pass liver metab, not often used
- Topical- ointment, patches
- Intravenous
Nitroglycerin
E1/2t
SE
- 90% degrated by the liver to inactive metabolites
- E1/2t of IV = 1.5 minutes
- SE
- HA
- postural hypotension
- methemoglobinemia- usually only with high doses or liver disease
Whats the deal with Nitrate tolerance?
- Nitrate-free intervals are necessary to prevent tolerance and/or adverse effects
- Usually nitrate-free intervals are done at night when the person is at rest
- removal of patch at night
- Oral Isosorbide mononitrate has a long E1/2t so it can provide high levels followed by low levels and can be administered once/day
How are Beta antagonists helpful in treating CAD?
- provide a more favorable O2 supply vs demand balance
- used to prevent stable or unstable angina
- decreases O2 demand by decreasing CO (more dramatic during activity than at rest)
- decrease HR, decrease contractility
- increase diastolic filling time (supply)
What kind of Beta antagonists are most used?
What should be avoided?
SE?
- Use primarily beta-1 selective agents
- metoprolol
- atenolol
- Improve survival in CAD
- Avoid:
- sudden d/c
- in variant angina- can worsen shoch symptoms after MI if given within 8 hours of STEMI
- SE
- depression
- insomnia
- mask hypoglycemic warning signs in DM
- exercise intolerance
- bronchospasms
What is the MOA of CCB?
Where do they have their effect?
- All bind to the alpha-1 subunit of the L-type calcium channel (at distinct sites)
- Dihydropyridines are more selective for Ca channels in vasculature (arterial)
- may cause reflex tachycardia
- Non-Dihydropyridines are more selective for Ca channels on the SA & AV nodes
- more at risk for heart block
- avoid with BBs
- Dihydropyridines are more selective for Ca channels in vasculature (arterial)
What are the dihydropyridines CCBs?
What are the non-dihydropyridines?
- Dihydropyridines:
- Nifedipine
- Amlodipine
- Nicardipine
- Non-dihydropyridine
- Verapamil
- Diltiazem
How is ASA used to treat CAD?
- Antiplatelet activity of ASA prevents thrombus formation
- Irreversible cox inhibition- lasts duration of platelet life (8-10 days)
- 80 mg
What drugs are used to treat unstable angina or nonST elevation MI (partial occlusion)?
ST elevation MI (total occlusion)?
- partial occlusion:
- antianginal drugs
- heparin, ASA
- GPIIb/IIIa antagonists (eptifibatide)
- Clopidogrel (plavix)
- total occlusion
- surgery
- thrombolytics (streptokinase, tPA)
Clopidogrel (plavix)
class
use
risks
- Antiplatelet agent- irreversible platelet ADP-receptor antagonist
- All acute coronary syndrome patients with ASA allergy take this
- reduces coronary events
- Risks:
- combination with ASA or GPIIb/IIIa inhibitor increases risk of major bleeding
GPIIb/IIIa inhibitors
names
use
- Abciximab (ReoPro)
- eptifibatide (Integrilin)
- tirofiban (Aggrastat)
- Reduce risk of MI in pts with unstable angina
- reduce risk of recurrent MI and urgent revascularization in pts with NSTEMI
What do you use to treat stable angina?
Unstable angina?
variant angina?
- Stable angina:
- Nitrates
- BBs
- CCBs
- Unstable angina:
- Nitrates
- BBs
- CCBs
- Aspirin/clopidogrel
- Heparin/thrombolytics
- Glycoprotein IIb/IIIa receptor inhibitor
- Variant angina
- Nitrates
- CCBs
What is the viscious cycle of heart failure?
(pic)
What are the different ventricular dysfunctions?
What causes them?
- Systolic dysfunction (EF<40%)
- Coronary artery disease
- nonischemic cardiomyopathy
- hypertension
- valvular disease
- alcohol
- thyroid disease
- cardiotoxic drugs
- Diastolic dysfunction (impaired filling)
- cardiomyopathies
- incomplete relaxation of the LV during ischemia
What are the major manifestations of HF?
- Dyspnea
- on exertion
- orthopnea
- paroxysmal nocturnal dyspnea
- fatigue
- fluid retention
What are the physiologic goals of drug therapy for heart failure?
- reduce preload
- diuretics
- aldosterone antagonists
- venodilators
- Reduce afterload
- ACEIs
- BBs
- Vasodilators
- Increase inotropu
- cardiac glycosides
- sympathomimetic amines
- phosphodiesterase inhibitors
What are the hemodynamic goals of CHF?
(table)
How are diuretics used to treat HF?
most common diuretics used?
- Alleviate congestive symptoms
- use with caution, consider preload status (ideally it will remain normal)
- No evidence of mortality benefit with thiazide or loop diuretics
- Loop diuretics most commonly used
- Furosemide, bumetanid, torsemide
- Inhibit Na/K/Cl pump in loop on henle, promoting excretion of Na, K, H2O
Which diuretics work on the distal tubule?
how much do they increase Na excretion?
- Thiazides
- Metolazone (thiazide-like)
- K sparing (spirinolactone)
- These diuretics lose effectiveness when creatinine clearance < 30 ml/min
- Increase Na excretion 5-10%
How much do loop diuretics increase Na excretion?
20-25%
What is the aldosterone antagonist?
MOA?
What is RALES?
Can you with with ACEI?
- Spirinolactone
- K sparing diuretic that acts as a competative antagonist at aldosterone receptor
- Decreases K/Na exchange in distal tubule and collecting duct of nephron
- RALES study showed a 30% reduction in mortality of pts with HF treated with spironolactone
- Must monitor K levels if given with an ACEI b/c both decrease K excretion
What are some side effects of spironolactone?
Why?
What about Eplerenone?
- Inhibits both androgen and mineralcorticoid receptors
- Causing gynecomastia and impotence
- Eplerenone is more selective and has fewer SE
How does NTG work to improve HF?
- Increases venous capacitance which reduces venous return to heart
- decreases myocardial O2 demand
- alleviates ischemia which improves diastolic relaxation
- improved LV compliance in addition to preload reduction
- Use with caution; don’t want to decrease preload too much, these pts need an adequate preload
How do ACEIs treat HF?
- Reverse vasoconstriction and volume retention that is caused by RAAS
- Reduces afterload which increases SV
- increases GFR, which increases natriuresis and diuresis
- Reversal of aldosterone-related volume retention decreases preload
- Statistically significant mortality benefit seen in multiple clinical trials
How are ARBS used to treat HF?
- Hemodynamic profile similar to ACEIs
- lack of bradykinin related vasodilation means less of a preload reduction
- Mortality benefit seen in studies
- may be additive with ACEI
How are Beta blockers used to treat HF?
- **a little counterintuitife in CHF
- Benefits are related to:
- inhibition of Renin release
- attenuation of cytotoxic and signaling effects of circulating catecholamines
- prevention of ACS (acute coronary syndromes??)
- Do not use in acute decompensated HF
How are hydralazine and Isosorbide dinitrate used to treat HF?
- Vasodilators
- used when pt does not tolerate ACEIs
- mortality benefit seen in african-american patients
-
use both agents together
- hydralazine- pure arterial dilator
- isosorbide dinitrate- venodilator
How does digoxin work to treat HF?
- Digoxin is an Na-K adenosine triphosphatase inhibitor
- In vagal afferent fibers, it sensitizes cardiac baoreceptors to decrease sympathetic outflow
- increases parasympathetic outflow
- decreased conduction velocity; increased AV refractory period
- decreases HR, preload and afterload
- Increases intracellular calcium
- decreased renal tubular absorption of Na
What are the therapeutic levels of digoxin?
onset
half life
steady state?
metab?
SE?
- Therapeutic levels 0.5-1.2 ng/ml
- onset: 30-60 min
- Half life 36 hours
- steady state takes 7 days
- 90% renally excreted
- SE
- hypokalemia
- AV block
- ventricular ectopy
What is the antidote for digoxin toxicity?
digoxin immune Fab
What are the pharmacodynamic interaction of Digoxin?
pharmacokinetic interactions?
- Pharmacodynamic interactions:
- increased risk of AV block with BBs
- BBs and CCBs decrease contractility
- Pharmacokinetic interactions
- antibiotics increase absorption
- verapamil, quinidine, amiodarone increase digoxin levels by affecting VD and/or renal clearance
What other inotropic agent is used to treat HF?
- Dobutamine
- stimulation of B1 increases cardiac contractility
- stimulation of vascular B2 causes arerial vasodilation and reduced afterload
How do phosphodiesterase inhibitors work to treat HF?
- Inhibit degredation of cAMP and cGMP in cardiac myocytes and vascular smooth muscle
- “inodilators”
- increased contractility (d/t increased intracellular Ca)
- minimal increase in myocardial O2 demand
- good choice for BB overdose
- arterial and venous dilation decreases afterload and preload
- mild bronchodilation
- improved diastolic relaxation by increasing Ca removal from mycoplasm after action potential
Amrinone
class?
effects?
SE?
- Class: phosphodiesterase inhibitor
- effects:
- increased CO and LV EF
- decreased LVEDP, pulmonary wedge pressures
- slight increase in HR and slight decrease in BP
- SE:
- hypotension
- thrombocytopenia
- arrhythmias d/t increased intracellular Ca
Milrinone
class?
effects?
- phosphodiesterase inhibitor
- effects: (similar to Amrinone)
- increased CO and LV EF
- decreased LVEDP and pulmonary wedge pressure
- HR slightly increased, BP slightly decreased
- long term use not proven to improve M&M
- helpful in treating pulmonary hypertension
