Cardiovascular Pharmacology Flashcards by Jon Johnson

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

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How to ACE inhibitors affect bradykinin?

Elevated levels of bradykinin

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To which receptor do ARBs bind?

angiotensin receptor (AT1)

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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

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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

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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

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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

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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

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What are some common side effects from DHP calcium channel blockers?

Flushing, nausea, headache

Reflex tachycardia –> undesirable in its w/ CAD

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What are some common side effects from non-DHP calcium channel blockers?

bradycardia and systole

, heart block, hypotension and heart failure.

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What are the major determinants of myocardial oxygen demand?

Contractility

Wall stress - ventricular afterload and radius

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What determines coronary blood flow?

Diastolic filling time

Coronary profusion pressure (aortic diastolic pressure and LV diastolic pressure gradient)

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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

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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

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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

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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

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Where is vasopressin synthesized?

hypothalamus - paraventricular nuclei

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What are the most important stimuli for vasopressin release?

increased plasma osmolality
decreased arterial pressure
reduced cardiac filling

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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

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What agents also stimulate vasopressin release?

acetylcholine
histamine
dopamine
prostaglandins
angiotensin II
nicotine

hypoxia
hyperthermia
pain
nausea
hypercapnia - stimulating carotid body chemoreceptors

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Name the vasopressin receptor subtypes

V1a
V1b
V2

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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

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Where the the V2 receptors heavy distributed?

distal convoluted tubule and collecting duct –> increases water permeability

vascular endothelium –> arterial vasodilation.

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Name three synthetic vasopressin analogs.

argipressin (AVP)
terlipressin (TP)
desmopressin (DDAVP).

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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.

1. Vasodilated states - sepsis (w/ norepi) 2. Refractory hypotension - can restore SNS response 3. Cardiac arrest 4. Bleeding esophageal varices 5. 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: 1. HTN w/ normal LV fxn 2. Vasoplegia 3. Pulm HTN 4. 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?

1. Slow response - cell w/ automaticity 2. 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