Cardiovascular Pharmacology Flashcards
Name the 3 major effects of Angiotensin II.
- arterial and venous vasoconstriction
- aldosterone and ADH secretion
- remodeling of the myocardium with hypertrophy of cardiac myocytes and growth of fibroblasts
How to ACE inhibitors affect bradykinin?
Elevated levels of bradykinin
To which receptor do ARBs bind?
angiotensin receptor (AT1)
Describe the activation of the renin-angiotensin system.
Hypovolemia –> renin release from kidney
Renin converts angiotensinogen from the liver –> angiotensin I
Angiotensin I activated by ACE in the kidney and lungs –> angiotensin II
Angiotensin II –> arterial and venous vasoconstriction + aldosterone and ADH secretion
Name the 2 classes of calcium channel blockers.
Bind to L-type calcium channels
1,4-Dihydropyridine - binds to Ca channel in inactive closed state
Non-Dihydropyridine - active open state
Metabolized by liver
What are the primary effects of DHP calcium channel blockers?
end in -dipine
Primarily PERIPHERAL arteriolar + some coronary vasodilation
Dec SVR and MAP
Increase coronary blood flow
Direct negative ionotrope + after load reduction –> reflex inc HR and maintain CO
What are the primary effects site of non-DHP calcium channel blockers?
Diltiazem and Verapamil
myocardium, conduction system and coronary arteries, with less effect on systemic arterioles
Both - depress contractility, HR, AV node conduction
Dilt - coronary vasodilator = angina tx
What are some common indications for Nimodipine and Nicardipine?
Nimodipine - cerebral vasospasm in ICH
Nicardipine - alternative to nitroprusside and fenoldopam for arteriolar vasospasm, Tx HTN after cardiac surgery
What are some common side effects from DHP calcium channel blockers?
Flushing, nausea, headache
Reflex tachycardia –> undesirable in its w/ CAD
What are some common side effects from non-DHP calcium channel blockers?
bradycardia and systole
, heart block, hypotension and heart failure.
What are the major determinants of myocardial oxygen demand?
HR
Contractility
Wall stress - ventricular afterload and radius
What determines coronary blood flow?
Diastolic filling time
Coronary profusion pressure (aortic diastolic pressure and LV diastolic pressure gradient)
What is the mechanism of action of hydralazine?
Inhibits release of intracellular calcium in arteriolar smooth muscle cells –> diminished contraction and vasodilation
Baroreceptor –> inc HR, contractility and CO
What are the primary cardiovascular effects of sodium nitroprusside?
Metabolized –> NO –> activates guanylyl cyclase, increasing [cGMP]
Increased intracellular cGMP inhibits entry of Ca into smooth muscle + may increase Ca uptake by the endoplasmic reticulum –> relaxation of smooth muscle
dilates both arterioles and venues –> decreased myocardial preload and afterload
Why is coronary artery steal less of a problem with nitroglycerin than with sodium nitroprusside?
Reduces coronary perfusion pressure –> shunting blood away from narrowed myocardium
What are the hemodynamic effects of nesiritide?
arterial and venous vasodilation by binding to A and B natriuretic peptide receptors on vascular smooth muscle –> increase in cGMP
reduction of preload and afterload, reduces preload, PVR
natriuresis
diuresis
suppression of the renin-angiotensin-aldosterone system
increases CO w/ little or no change in HR
Can worsen dyspnea in patients with pulmonary edema from congestive heart failure
Where is vasopressin synthesized?
hypothalamus - paraventricular nuclei
What are the most important stimuli for vasopressin release?
increased plasma osmolality
decreased arterial pressure
reduced cardiac filling
What is the normal plasma osmolality? Which receptors are responsible for its regulation? Where are they located?
285 and 295 mOsm/kg
peripheral Cosmo-receptors - near the portal vein
central receptors - near the third ventricle
What agents also stimulate vasopressin release?
acetylcholine histamine dopamine prostaglandins angiotensin II nicotine
hypoxia hyperthermia pain nausea hypercapnia - stimulating carotid body chemoreceptors
Name the vasopressin receptor subtypes
V1a
V1b
V2
Where are the V1a receptors mainly located in the body?
vascular smooth muscle - vasoconstriction in mesenteric, skin and skeletal tissues
platelets liver adrenal gland myometrium brain - inhibit SNS kidneys - constrict efferent arterioles --> inc GF, UOP
Where the the V2 receptors heavy distributed?
distal convoluted tubule and collecting duct –> increases water permeability
vascular endothelium –> arterial vasodilation.
Name three synthetic vasopressin analogs.
argipressin (AVP)
terlipressin (TP)
desmopressin (DDAVP).
What is the plasma half-life of exogenous vasopressin?
4-20 minutes - continuous infusion is necessary for maintenance
Name some of the common indications for vasopressin use.
- Vasodilated states - sepsis (w/ norepi)
- Refractory hypotension - can restore SNS response
- Cardiac arrest
- Bleeding esophageal varices
- central diabetes insipidus
What is terlipressin?
synthetic analogue of AVP - greater selectivity for the V1 receptor
What are some of the side effects of vasopressin?
Skin necrosis after extravasation
Anaphylaxis
bronchospasm
urticaria
ischemia of the GI tract
How does methylene blue (MB) work?
selective inhibitor of inducible nitric oxide synthase (iNOS) –> reduces the formation of NO
Inhibits guanylate cyclase in vascular smooth muscle –> vasoconstriction
- reverse hypotension in septic shock
- helpful in profound vasoplegia following cardiopulmonary bypass
Name some of the side effects of methylene blue.
contraindicated in severe renal insufficiency
cardiac arrhythmias (transient nodal rhythm and ventricular ectopy) angina pectoris coronary vasoconstriction decreased cardiac output decreased renal blood flow increased mesenteric vascular resistance
Which receptor is the target of the majority of cardiac inotropes?
Beta-1
inc Ca –> excitation-contraction coupling
+ lusitropy (relaxation)
+ chronotropy (HR)
+ dromotropy (conduction velocity)
High dose dopamine primarily effects which receptor?
alpha receptors at >10ug/kg/min
What is the effect of milrinone on SVR?
PDE-III inhibitor
Systemic vasodilation –> DEC SVR
Inc HR and CO
How does digoxin increase inotropy?
inhibits Na+/K+-ATPase in cardiac myocytes –> increases intracellular Na+, –> so more Na+ can exit through the Na+/Ca+ exchanger –> increasing intracellular Ca2+ –> augmenting excitation-contraction coupling
Digoxin toxicity is more likely in which disease state?
Renal insufficiency Hypokalemia loop and thiazide diuretics amiodarone advanced age.
What is the digitalis effect on EKG?
classic (nonischemic) downward slope of the ECG ST-segment
What is the pathognomonic ECG finding in digitalis toxicity?
paroxysmal atrial tachycardia with 2:1 atrioventricular (AV) block
What are two limiting side effects of dobutamine?
Tachycardia
Hypotension
What are the main actions of PDE-III inhibitors on the myocardium?
Inc SV, CO,HR, contractility
Dec SVR, PVR, MvO2, Preload
Can you use milrinone in renal insufficiency?
Cautiously - may –> hypotension as effects may persist long after d/c
List two differences between milrinone and amrinone.
Amrinone = thrombocytopenia
Milrinone - shorter half-time
Milrinone is best used to treat which of the following:
- HTN w/ normal LV fxn
- Vasoplegia
- Pulm HTN
- Biventricular HF
4 - Biventricular HF –> dec filling pressures = “off-loading” the heart and inc stroke work
Also beneficial in low cardiac index, high SVR patients
2 = methylene blue
What are the primary ions involved in the cardiac action potential?
Na
Ca
K
What are the two different types of action potentials?
- Slow response
- cell w/ automaticity - Fast response
- muscle and purkinjie fibbers
True or False: The resting membrane potential for cells with automaticity is more negative than cells without automaticity.
False - slow response = automaticity = less negative
What are the primary etiologies of arrhythmias?
reentrant phenomena and enhanced automaticity.
Describe the phases and ion movements in myocyte and pacemaker cells
Phase zero: sodium in
Phase one: potassium out
Phase two: calcium in
Phase three: potassium out
Phase four: if slow response fiber, then sodium leaks in to the cell - regulated by ANS
Describe the 4 classes of antiarrhythmics
Class I - Na channel blockers
Class II - beta-blockers
Class III - K channel blockers
Class IV - Ca channel blockers.
What is the objective and main mechanism of antiarrhythmics?
changing action potential duration
changing properties of automaticity
What is a unique side effect of procainamide?
Lupus-like syndrome
What is the effect of the potassium channel blockers on APD (action potential duration) and ERP (effective refractory period)?
Ex: amiodarone, sotalol, ibutilide, dofetilide, and bretylium
lengthen the APD, and the ERP
Class II antiarrhythmics effect what phase of the action potential?
Beta-blockers –> Phase 4 of the slow response AP
Class 1 antiarrhythmics are most likely to effect which phase(s) of the action potential?
Phase 0 and 4
What are some side effects of amiodarone?
Pulmonary toxicity
Hypo or hyperthyroidism
Which phases of the standard cardiac myocyte action potential are caused by outflow of potassium into the extracellular space?
Repolarization
- myocyte = phases 1 through 3
- pacemaker cells = phase 3
List the progression of EKG changes that occur with progressive hyperkalemia.
6-7 --> peaked T-waves Prolonged PR Widened QRS Dec P-wave amplitude and disappearance Shortened ST VF or asystole
List the EKG changes seen with hypokalemia.
Inc amplitude and width of P-wave Prolonged PR T-wave flattening or inversion ST depression Prominent U-waves (precordial leads) SVT, AF, Aflutter, VT, VF
Describe the major effect Ca2+ has on global myocardial function.
excitation-contraction coupling
changes in Ca2+ movement or binding can affect both inotropy (contractility) and lusitropy (relaxation).
How does hypocalcemia affect the cardiovascular system?
Dec ionotropy
Hypotension d/t dec tone
QT prolongation
What EKG changes occur in hypercalcemia?
Short QT
Short PR
Osborn (J-waves)
VF
How does Mg2+ regulate cardiovascular smooth muscle function?
Ca antagonist and regulates entry into cell –> normal vascular tone, prevention of vasospasm, prevention of Ca overload
What are three major cardiovascular consequences of hypomagnesemia?
Torsades de Pointes –> VT
Dilated cardiomyopathy
Ionotrope requirement
What are the major effects of hypermagnesemia on the vasculature?
Vasodilation - direct SM relaxation, enhanced NO release, inhibits catecholamine release
Bradycardia
Hypotension
5-10mg/dl –> AV block, prolonged QT –> cardiac arrest
What primary role does phosphorus play in the function of cardiac myocytes?
ATP - stores and releases energy via high-energy PO43- bonds.
What are the major consequences of hypo- and hyperphosphatemia?
Hypo - if severe –> muscle weakness, cardiomyopathy and arrhythmias
Hyper - hypoCa –> dec ionotropy, heart block
