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111 Cards in this Set

  • Front
  • Back
Work of the Heart
At rest, the heart extracts 70-80% of the O2 in the coronary flow. An increase in need for oxygen (due to increased work) can only be met by an increase in blood flow. The increase in blood flow occurs as a result of autoregulation of coronary vessel diameter and an increase in perfusion presure.
Ventricular work per beat correlates with O2 consumption. The work per beat is a product of stroke volume X mean arterial resistance (either pulmonary or aortic). The filling volume of the heart determines the length of stretch of ventricular muscle (the preload) and the arterial resistance determines the pressure (the afterload) at which the blood begins to move out of the ventricle. Reducing either the preload or the afterload reduces the work of the heart per beat and reduces the need for O2 by the working heart. However, they are not equally efficacious in reducing O2 need. Reducing afterload reduces O2 need much more than a similar reduction in preload would reduce O2 need (pressure work requires more O2 than volume work).
Relief of Anginal Symptoms
Angina pectoris is referred pain over the pectoral muscle resulting from myocardial ischemia. Essentially, the supply of O2 to the heart is inadequate to support the level of work being performed by the heart. There are two ways to relieve angina:
1. increase the blood flow (hence, O2 supply) of the heart
2. decrease the work (hence, O2 demand) of the heart
Nitrates (under some circumstances) are able to do both these things
MOA of Agents that Increase GMP
Nitrates, nitrites, and other nitrogen oxide generating compounds lead to formation of Nitric Oxide (NO) which activates guanylate cyclase increasing synthesis of cyclic GMP which leads to dephosphorylation of MLC and reduction in intracellular Ca++.
Organic nitrate metabolism allows release of nitrite of NO from the structure
-A hepatic enzyme can bring about this biotransformation and results in inactivation of nitrates. This inactivation is quite rapid and results in the difference in the effective sublingual vs. PO dose.
-Nitrates also undergo denitration by glutathione S-transferase in smooth muscle cells. This releases nitrite ion which is converted to NO by an uncharacterized pathway.
-Nitrates release NO directly when the mitochondrial enzyme aldehyde reductase is present. This enzyme is enriched in venous smooth muscle.
Nitrates in Typical Angina
-Low doses produce venodilation and minimal arteriolar dilation in the systemic circulation - leading to venous pooling (which reduces preload) with minimal effect on systemic BP - reducing preload reduces the stretch, hence force of contraction of the heart and this reduces O2 demand.
-may cause a favorable redistribution of blood in the heart without increasing coronary flow. It may cause a favorable redistribution of blood in the heart without increasing coronary flow. It dilates those vessels which can be dilated, and this would increase flow to ischemic areas (those served by the constricted vessels).
-blood flow is increase to subendocardial regions (which generally are most susceptible to ischemia because they are compressed most as the heart contracts).
-Higher doses of GTN have a more prominent effect on smooth muscle (including arteriolar), causing a decrease in systemic BP, leading to reflex tachycardia and increased force of contraction.
-this may override the beneficial effects of GTN and lead to angina
Nitrates in Vasospastic Angina
Vasospastic angina is also known as variant or Prinzmetal's angina. It is due to spasm of the coronary arteries.
-The smooth muscle relaxant effect of GTN would tend to relieve spasm and restore blood flow to the heart.
Nitrate Tolerance
-Repeated administration of sublingual nitroglycerin at frequent intervals or large doses of nitrates PO can result in tolerance.
-The mechanism of tolerance is not established but there is cross tolerance, including EDRF (NO).
-Withdrawal of the drug for a few hours or overnight resotres the response.
-A portion of this tolerance is due to decreases in tissue levels of thiol groups
-In addition, compensatory reflexes and retention of Na+ and water contribute to the tolerance seen with nitrates
Adverse Effects of Nitrates
-Headache due to dilation of cerebral vessels is common and may be severe with usual doses of nitrates
-Postural hypotension with dizziness, weakness, particularly while standing (alcohol, heat, exercise, and advanced age)
-Activation of baroreceptor reflexes leads to tachycardia
Other Uses of Nitrates
1. Unstable Angina (Unstable Coronary Syndrome)
2. Acute Congestive Heart Failure
3. Chronic Congestive Heart Failure
4. Ointment is used in adrenergic agonist extravasation
5. Nitrates for biliary spasm
How are nitrates used in unstable angina?
Unstable angina is also known as acute coronary syndrome.
Nitrates work through reduction in oxygen demand.
How are nitrates used in acute congestive heart failure?
They are venodilators, which are valuable since they reduce end-diastolic pressure. This reduces pulmonary pressure and also reduces stretch (preload) of the cardiac fibers. Arterial dilators reduce systemic resistance (afterload) thereby reducing the work of the heart and increasing cardiac output.
a. Nitrates - primarily venodilators
b. Hydralazine, Minoxidil - primarily arterial dilators
c. Nitroprusside, alpha-blockers, ACE-inhibitors - balanced arterial/venodilators
How are nitrates used in chronic congestive heart failure?
Venodilators (nitrates) improve exercise tolerance. ACE-inhibitors improve exercise tolerance and mortality.
Calcium Channel Blockers - Agents
There are three types of calcium channel blocking agents available for treatment of angina, arrhythmias, hypertension, and for other uses. These are:
Dihydropyridins - Nifedipine is the prototype
Phenylalylamines - Verapamil
Benzothiazepines - Diltiazem
Calcium Channel Blockers - MOA
These agents interfere with entry of calcium into cardiac and smooth muscle cells through voltage operated L-type calcium channels. Current evidence indicates that dihydropyridines bind to the transmembrane segments IIIS6 and IVS6 of the calcium channel; verapamil binds to the transmembrane segment IVS6. The site of binding of diltiazem is the cytoplasmic bridge between domains III and IV. The binding is state-dependent with binding occurring most readily in the depolarized state. The result is a decrease in the transmembrane flux of Ca++ and a reduction in force of contraction of heart and/or smooth muscle.
Actions of Nifedipine and other dihydropyridines
-have prominent vasodilatory effects on arterial smooth muscle; this lowers mean arterial pressure and triggers adrenergic reflexes
-the adrenergic reflexes tend to compensate for the direct depression of cardiac tissue produced by nifedipine and heart rate and cardiac output may increase modestly
-because of the decrease in mean arterial pressure, the heart works against a lower pressure gradient and there is a decrease in O2 need (thus relieving angina) in spite of the increase in heart rate and cardiac output
Absorption, Fate, and Excretion of Calcium Channel Blockers
-Dihydropyridines and others are well absorbed (~90%)
-All are subject to 1st pass metabolism
-Effects are evident 30-60 minutes after PO administration
-Half-life for nifedpine is ~1.8 hours, necessitating frequent dosing or sustained action dosage form
-Half-life for diltiazem is 3.5 hours and for verapamil is 5 hours. Each has at least weakly active metabolites.
Calcium Channel Blockers - Agents and Indications
-Nifedipine (Procardia, Adalat) indicated for hypertension and angina
-Nicardipine (Cardene) indicated for hypertension and angina (similar to nifedipine)
-Isradipine (Dynacirc) - indicated for hypertension only, it has a slow onset, it is a vasodilator without reflex tachycardia
-Felodipine (Plendil) - indicated for hypertension, has a slow onset, has great vascular selectivity, no negative inotropic effect therefore this is greater reflex tachycardia
-Amlodipine (Norvasc) - indicated for hypertension, chronic stable angina, and vasospastic angina; has a slow onset and a half-life of 35-50 hours, it has more stable blood levels therefore somewhat less reflex tachycardia
-Nimodipine (Nimotop) - used to prevent cerebral vasospasm following subarachnoid hemorrhage
Dihydropyridine Adverse Reactions
-increased risk for adverse cardiac events in hypertensives treated with short-acting preparations
-excessive vasodilation - dizziness, hypotension, headache, peripheral edema, pulmonary edema
-edema is said not to be due to expansion of ECF but rather due to reflex venule constriction resulting from arteriolar dilation
Verapamil and Diltiazem - MOA
-have more prominent negative inotropic and chronotropic effects than do dihydropyridines
-Therefore, when mean arterial pressure falls and adrenergic reflexes are activated, the direct cardiac effects balance the reflex effects and there is little effect on heart rate
-Cardiac output may still improve since afterload is reduced
-Effectiveness in angina is assured because of the reduction in pressure work
-Verapamil and diltiazem are more effective in angina because they produce more depression of force of contraction and rate than dihydropyridines
-Because of the direct negative inotropic effect of verapamil and diltiazem, they must be used cautiously in patients with CHF, especially IV verapamil
Adverse Effects of verapamil
-much lower incidence of excessive vasodilation
- constipation (8%)
- bradycardia (2%)
- increase in plasma levels of digoxin
- verapamil blocks P-glycoprotein
Uses of Calcium Channel Blockers
1. vasospastic angina
2. effort angina
3. unstable angina when due to vasospasm
4. antiarrhythmic
5. hypertension
Beta-Blockers in Angina
-Beta-blockers have negative chronotropic and inotropic effects on the heart and decrease blood pressure
-These actions lead to a net decrease in O2 consumption by the heart.
-Beta-blockers are useful in effort angina and probably better than Ca++ channel blockers
-NOT useful in vasospastic angina
-vasospastic angina may be worsened by blocking vasodilatory B-receptors and leaving unopposed in the coronary circulation the vasocontrictive effect of alpha receptors.
-Beta-blockers are so valuable in many types of cardiac disease that some authorities advocate they be used first if no contraindications exist
Agents Stabilizing Vascular Smooth Muscle Membrane Potential
Nicorandil
-opens K+ channels, stabilizing membrane potential CVS
-also appears to release NO, activation guanylyl cyclase
Newer Antianginal Drugs
Metabolic Inhibitors - Ranolazine
-partial inhibitor of faty acid metabolism (pFOX inhibitor)
-this shifts cardiac metabolism more to glucose which generates more ATP per unit of O2 than does FOX
-There may be a second MOA involving reduced Ca++ entry into the myocardial cells

Bradycardic drugs - ivabradine
-selective blockers of If (funny current)
-Na+ channel activated by hyperpolarization.
Therapy of Angina
-Modify risk factors: smoking, hypertension, hyperlipidemia, obesity
-Antiplatelet drugs: clopidogrel, aspirin
-Lipid-lowering agents: statins
-Antianginal drugs (for normotensive use maintenance therapy with long-acting nitrate; for hypertensive use maintenance therapy with beta-blocker or calcium-blocker)
1. Exertional angina - combinations of 2 or all 3 types of antianginal therapies (although side effects increase considerably when 3 are employed)
2. Vasospastic angina - combination of calcium channel blockers and nitrates (NO Beta-blockers)
3 types of diuretics that work as antihypertensive agents
1. thiazides and related compounds (thiazides, chlorthalidone, metolozone)
2. loop diuretics
3. spironolactone
3 types of agents acting on the kidney that act as antihypertensive agents
1. renin inhibitors
2. ACE inhibitors
3. ARB's
4 types of Sympatholytic Agents that work as antihypertensive agents (give examples of each)
1. alpha-2 adrenergic agonists (methyldopa, clonidine, guanabenz, guanfacine)
2. ganglionic blocking agents (trimethaphan)
3. adrenergic neuron blocking agents (guanethidine, guanadrel, reserpine)
4. adrenergic receptor blocking agents (beta blockers - propranolol, alpha-1 blockers - prazosin)
2 types of vasodilators that work as antihypertensive agents
1. arterial dilators - hydralazine, minoxidil, calcium channel blocking agents
2. arterial and venous dilators - nitroprusside
MOA of Benzothiadiazines
This group includes "thiazides", indapamide, and chlorthalidone
-They produce a small but consistent reduction in ECF volume and Na+ content
-this mechanism is consistent with the Renal-Body Fluid mechanism
-also said to reduce peripheral resistance
Effects of Benzothiadiazines
-low doses (25 mg HCTZ) produce a saluresis and lower BP
-doses >50 mg HCTZ do not increase BP effect usually
-salt restriction potentiates the BP effect and combination with other antihypertensives potentiates the effects of both drugs
-usually, 2-4 weeks is required for full effect, but as much as 12 weeks may be needed
-usual reduction is 20/10
-for monotherapy, the maximum daily dose of HCTZ should not exceed 25 mg
Toxicity of Benzothiadiazine
-most toxicities are slowly developing, dose-related and patient-dependent
1. hyperuricemia - occasionally results in gout
2. Hyperglycemia - especially in patients with MO Diabetes, opens ATP sensitive K+ channel
3. Hyperlipidemia - 10% increase in LDL and VLDL, not in all patients, may not persist over 1 year
4. Hypokalemia - common, preventable, social problem. When thiazides combined with digitalis in which case hypokalemia may lead to arrhtyhmia; or when combined with drugs which cause torsades de pointes. may cause weakness and fatigue in others. May be able to prevent hypokalemia by dietary means but K-sparing diuretic, K-supplements, K-substitues for NaCl much more effective. Aldosterone antagonists are also effective.
5. Hypocalciuria - due to deposition of Ca++ in bone. 50 mg of HCTZ daily is associated with a lower incidence of hip fractures in older women than arelower doses or no thiazide.
6. Sexual impotence is the most common troublesome side effect of thiazides
Effects of Loop Diuretics
-less effective antihypertensives than thiazides because of short duration of action
-if given more often, they are often too effective with excessive side effects
-used only when hypertension is not controlled with thiazides or when edema accompanies hypertension
-cause same adverse effects as thiazides except Loops cause hypercalciuria
Effects and Adverse Effects of Spironolactone
-equal in efficacy to thiazides but higher incidence of side effects
Adverse Effects:
1. decrease HDL
2. hyperkalemia
3. amenorrhea; gynecomastia
4. annoying effects such as headache, abdominal pain, and lethargy
Alpha-2 Adrenergic Agonists Effects as Antihypertensives
Examples include methyldopa, clonidine, guanabenz, and guanfacine
-These agents stimulate presynaptic alpha-2 receptors in medullary autonomic centers for control of heart rate and blood pressure
-Stimulation of alpha-2 receptors decreases NE release centrally and decreases "outflow" of action potentials along SNS motor nerves
-baroreceptor activity is intact so there is little orthostatic hypotension
Adverse Effects of Alpha-2 Adrenergic Agents
1. CNS effects are in high percent of users - sedation, sleep disturbances, dizziness, nausea, impotence, depression
2. Xerostomia - dry mouth, nasal membranes, eyes; parotid swelling and pain
3. CVS - bradycardia, rare AV block; rebound hypertension if withdrawn abruptly
4. Methyldopa produces allergic hemolytic anemia in 1%; rarely, fatal hepatitis
5. rebound supersensitivity
6. retention of Na/H2O occasionally a problem
In what special case are alpha-2 agonists useful?
They are useful in kidney failure/dialysis patients because action doesn't involve kidney
Effects of Ganglionic Blocking Agents as Antihypertensives
-no longer used as antihypertensives except for very short term use such as dissecting aneurysm, surgical hypotension, and perhaps hypertensive emergencies
-trimethaphan camsylate (Arfonad) - many side effects due to blocking both SNS and PNS
Effects of Adrenergic Neuron Blocking Agents as Antihypertensives
-agents which depress the activity of the postganglionic, prejunctional sympathetic neurons
-their MOAs are complex and not fully clear
2 examples are guanethidine and reserpine
guanethidine
Adrenergic Neuron Blocking Agent
-is taken into the neuron by the NE uptake system, stored in synaptic vesicles
-inhibits release of NE by nerve impulses and depletes the neuron of NE because of a local anesthetic effect at nerve endings where the drug is concentrated
-these actions cause venodilation and decrease SNS stimulation of the heart (decreased cardiac output)
-does not enter the CNS
Adverse Effects of Adrenergic Blocking Agents
-orthostatic hypotension
-fluid retention
-congestive heart failure
-sexual dysfunction
-diarrhea
-rebound supersensitivity after abrupt discontinuation
only for reserpine:
-fluid retention and decreased cardiac output
-sedation, inability to concentrate; depression leading to suicide
-nasal stuffiness, peptic ulceration
reserpine
-enters SNS (or serotonin) neuron, binds to vesicle membrane transporter so that vesicle can no longer store transmitter; transmission fails
-acts in CNS and periphery
MOA of Beta Blockers
they are widely used and successful antihypertensives
-they decrease cardiac output (major effect)
-they decrease renin secretion (major effect)
-decrease SNS transmitter release
Adverse Effects of Beta Blockers
-bradycardia
-asthma
-PVD
-diabetes
Classes of Beta Blockers with examples of each
-nonspecific beta-blocker - propranolol (lipid solubility leads to CNS effects), nadolol, timolol
-specific beta-1 blocker (have less effect on bronchial smooth muscle, diabetes, and peripheral vascular disease) - metoprolol, atenolol, esmolol; less asthma
-nebivolol - more beta-1 selective and vasodilates through NO
-alpha and beta blocker (used in HT emergencies, blood pressure is decreased without altering HR or CO) - labetalol, carvedilol
-beta blocker with ISA (for patients with bradyarrhytmias or PVD) - pindolol, acebutolol
Alpha-1 Blocking Agents
-vasodilation is primary actions due to fluid retention
-small decreases in triglycerides and LDL; small increases in HDL
-"first-dose" effect - so initiate with small doses --> titrate upward and give at bedtime
-tachycardia
examples: prazosin, terazosin, doxazosin; tamsulosin is an alpha-1a-blocker which is relatively specific for the urinary tract
MOA of hydralazine (arterial dilator)
-direct arteriolar smooth muscle relaxation
-releases NO, which activates guanylate cyclase, increasing intracellular cyclic GMP, and leading to smooth muscle relaxation
-the reason that it is specific for arteries has not been determined
Adverse Effects of hydralazine
-little orthostatic hypotension but tachycardia and fluid retention a problem (leads to ischemia)
-subject to variations in rate of acetylation which determines bioavailability but not systemic elimination
-slow acetylators tend to develop a lupus-like syndrome (arthralgia, arthritis, fever, kidney impairment)
Uses of hydralazine
-third drug in antihypertensive regimens
-hypertensive emergencies in pregnant women
MOA of minoxidil (arterial dilator)
-the active metabolite increases cellular permeability to K+ (opens an ATP-modulated channel), thus causing hyperpolarization or membrane stabilization
Adverse Effects of minoxidil
-fluid/Na retention which leads to edema
-CVS - baroreceptor-mediated activation of SNS leads to tachycardia and increased force of contraction (angina in some)
-Hypertrichosis (thick hair) - face, back, arms, and legs
Uses of minoxidil
-should only be used as the third drug in combination and CVS/Renal adverse effects should be reduced by diuretic/Beta-blocker
MOA of diazoxide (arterial dilator)
a benzothiadiazine like thiazides
-activates an "ATP-sensitive K+ channel" leading to hyperpolarization of smooth muscle
-secondary agent in hypertensive emergencies
-available PO for treatment of hypoglycemia
Adverse Effects of diazoxide
-Na/fluid retention
-Reflex activation of SNS -->heart
-when used PO for hypertension toxicity is unacceptable (50% hyperglycemia, 20% hypertrichosis)
fenoldopam (arterial dilator)
-agonist at D1 receptors dilating arterioles, especially in renal and mesenteric circulation
Arterial and Venous Dilators
nitroprusside - releases NO when in contact with RBC's; given by continuous IV infusion, rapid action, protect from light for HT emergencies and severe heart failure
Agent for Orthostatic Hypotension
midodrine HCl (ProAmatine) which is an alpha-1 agonist
Digitalis and Congestive Heart Failure
The most common use of digitalis is in treatment of congestive heart failure. CHF affects 3 million people in the USA with 400,000 new cases annually. Signs and symptoms depend on how quickly CHF develops, whether it develops in left or right ventricle and whether it is diastolic or systolic failure.
Etiology of Congestive Heart Failure
Systolic Failure develops as a result of decreased contractility of the heart. A normal heart is able to pump sufficient blood to supply O2 and nutrients to the tissues and still have considerable reserve pumping capacity. Over many years, the ability of the heart to generate force proportional to the stretch on the cardiac fibers decreases (failing curve). A point will be reached (in such a heart) at which the heart cannot pump forcefully enough to expel all the blood that comes to it and end-systole volume (and pressure) will start to increase and stretch or dilate the chambers of the heart. These changes ultimately decreaes ejections fraction below 40% and result in heart failure due to "left ventricular systolic dysfunction." Some of the more obvious symptoms of CHF result from this increase in end-systole volume and pressure. Pulmonary edema develops when the left side of the heart fails. When the left side fails, blood "backs-up" into the pulmonary veins, increasing pressure in the pulmonary capillaries and causing transudation. Peripheral edema usually follows right heart failure. In right heart failure, the blood would accumulate in the venous circulation, venous pressure would rise and fluid would pass from peripheral capillaries into tissue.
Other signs of Systolic Failure
In addition to edema, other signs of systolic failure include elevated heart and respiratory rates and rales (abnormal lung sounds described as "cracking leaves"). Symptoms of systolic failure include breathlessness (particularly when lying down), fatigue, confusion, nocturia, and hemoptysis.
Other Causes of Heart Failure
In addition to LVSD, heart failure may be due to left ventricular diastolic dysfunction. In this circumstance, the problem is usually a decrease in compliance of the left ventricle leading to a decrease filling of the ventricle. These patients have signs and symptoms of heart failure and an ejection fraction of 40% or more (normal is 60%).
Compensation to Help Systolic Failure
When the heart is not able to pump sufficient blood to supply tissues, compensatory mechanisms are activated in an attempt to increase tissue blood flow. These mechanisms are effective temporarily, but over a long period, they increase the work of the heart and are detrimental to the heart. Included in the compensatory mechanisms are:
1. myocardial hypertrophy
2. increased secretion of catecholamines
3. increased secretion of renin
Result of Increased Catecholamine Secretion
Increase in catecholamine secretion results in increases in force of contraction and increase in heart rate. This would temporarily displace the Starling Curve upward, but increase work by the failing heart and probably increase afterload (arterolar constriction) and preload (venoconstriction) and the heart would eventually fail again.
Result of Increased Renin Secretion
Renin secretion results in formation of angiotensin-II, with increased retention of fluid and expansion of ECF and vasoconstriction (increasing afterload and preload). Angiotensin-II would also contribute to edema formation. Thus, these compensations might be beneficial over a short period but all are detrimental over a long period.
General Actions of Digoxin
Digoxin improves the CVS function in CHF by producing a positive inotropic effect ithout an increase in heart rate (usually produces slowing) and without an increase in afterload (usually produces a decrease in arterial pressure). This upward displacement of the Starling curve improves blood flow to the kidney and increases urine formation, thereby eliminating edema fluids and lowering blood pressure. The improved blood flow also reduces compensatory mechanisms, including reducing catecholamine secretion (slowing the heart) and reducing renin secretion (reducing vasoconstriction and fluid retention and reducing afterload).
Digitalis produces a dose-related increase in force of contraction in both normal and failing hearts. It is much more obvious and easily observed in an individual with a failing heart. In addition to the increase in force, digitalis also produces an increase in rate of development of force in the heart.
MOA of Digoxin
Digitalis binds to Na/K-ATPase in the cell membrane and inhibits this active transport system. This slows exchange of intracellular Na+ for extracellular K+ which normally exchanges extracellular Na+ for intracellular Ca+++. This leads to an increase in intracellular Ca+++ and increase storage of the Ca+++ in the sarcoplasmic reticulum and increase release of SR Ca++ by each action potential. Intracellular Ca++ determines the extent of interaction of actin and myosin and therefore the strengt of contraction of the cardiac cell. There are other actions of digitalis that may be involved in increasing force of contraction. There is a proposed increase in the inward curre nt of Ca++ ("trigger Ca++) associated with the AP. There is a proposed "sharpening" of the Ca++ signal (more rapid influx to a higher peak, followed by a more rapid reuptake of Ca++ into SR, mitochondria, and transport out of the cell). The relative importance of these effects is not established
Dosage and Administration of Digoxin
All Digitalis used in the US is in the form of Digoxin. Dosing with digoxin may employ a loading ("digitalizing") dose (if need for the effect is urgent) or may be initiated with a maintenance dose (no loading dose) if the situation is not urgent. Before digitalization begins, great care should be taken to ensure that the patient has not previously received digitalis. An "average" digitalizing dose of digoxin will be 1.0 mg given over 24 hours by a variety of dosing schedules. Dosage should be adjusted no more often than weekly.
Therapeutic Uses of Digoxin
Obviously, CHF is a primary use of digoxin. In addition to (or in place of) digoxin, other modalities of therapy in CHF are: rest, restriction of salt, a diuretic, vasodilators, and an ACE inhibitor. An important point is that digoxin is not essential in management of CHF. Since there is significant risk of toxicity with digoxin, its use will probably decline in the future. Note that digoxin has not been shown to prolong the lives of patients with heart failure. Digoxin has been shown to improve symptoms and exercise tolerance.
Atrial flutter and and atrial fibrillation are the other indications for use of digoxin. Again, the intent of therapy is to reduce the number of impulses passing through the AV node, thus protecting the ventricles from the excesive atrial rate.
Digoxin used with Diuretics
Diuretics in particular have been used in combination with digoxin. There are two problems associated with their use:
1. Diuretics (thiazide or loop) cause potassium loss by the kidney. Low ECF K+ increases binding of digoxin to Na,K-ATPase and may convert a therapeutic concentration of digoxin to a toxic one.
2. Diuretics with high max effect (loop) may cause such a rapid and large decrease in ECF that ventricular filling is compromised to the extent of reducing cardiac output
Digoxin Toxicity - General
Digoxin is a toxic drug. It has a low therapeutic index, and its toxicities can be severe and lethal. It is estimated that 25% of patients taking digoxin have some sign of toxicity and perhaps as many as 33% will be hospitalized at some point due to toxicity.
Other toxicity:
1. GI Tract - anorexia is very common, nausea, vomiting, diarrhea also common; GI pain
2. Vision - blurred vision; white borders around objects; yellow or green vision
3. Neurological - weakness and fatigue; neuralgic pain simulating trigeminal neuralgia
4. Gynecomastia
Digoxin Effects on the Heart
Digoxin is one of the most common causes of cardiac arrhythmias, most commonly disturbances of AV conduction. Digoxin is administered to patients with diseased hearts and it is often difficult to determine whether an arrhythmia is due to progression of the disease or to toxic effects of digoxin. Generally, if the arrhthmia disappears rapidly after discontinuation of the drug, this is considered evidence that digoxin was the cause of the arrhythmia.
Catecholamines as Inotropic Agents
NE, Epi, and isoproterenol; improve contractility but may have vascular effects that adversely affect the heart; also, downregulation occurs and effects are lost
Dopamine as an Inotropic Agent
Dopamine, while a catecholamine, is more useful.
-At low concentrations, it combines with specific dopamine receptors and increases renal and mesenteric blood flow
-higher doses stimulate B-1 receptors and have a positive inotropic effect
-still higher concentrations stimulate alpha-1 receptors producing vasoconstriction and increased blood pressure
Dobutamine as an Inotropic Agent
Dobutamine is a relatively selective Beta-1 stimulant and produces greater inotropic than chronotropic effect; at therapeutic levels, it also dilates the aorta and resistance vessels and reduces afterload. At higher doses, selectivity may be lost; the DOA is limited by tolerance, but the effects usually persist several days. Outpatient use is on an intermittent basis.
Bipyridines as Inotropic Agents
inamrinone and milrinone - these agents are relatively selective inhibitors of phosphodiesterase III thus increasing cAMP without affecting cGMP
a. increased cAMP in the heart leads to positive inotropic effect
b. increased cAMP in smooth muscle leads to vasodilation (also beneficial in CHF)
These have been used on inpatient and outpatient basis, but studies indicate an increase in mortality rather than a decrease with chronic use of the bipyridines. Therefore they are used intermittently.
Inamrinone causes a 10% incidence of thrombocytopenia, therefore it is little used.
Other Agents used for Heart Failure (classes and examples)
Vasodilators
1. ACE inhibitors
2. Hydralazine-Isosorbide Dinitrate
3. Sodium Nitroprusside
4. Calcium Channel Blocking Agents
5. Beta-adrenergic Antagonists (metoprolol, carvedilol)
Vasodilators and Heart Failure
CHF activates mechanisms for maintenance of organ perfusion - increased catecholamines, increased renin, and increased vasopressin are all bad for the failing heart
ACE Inhibitors used in Heart Failure
a. they decrease preload and afterload, increase efficacy of the heart; they reduce aldosterone release causing decreased water and Na+ retention
b. increased stroke volume with decreased work and decreased O2 consumption, blood distribution
c. significant increase in exercise tolerance and decrease in mortality
d. prolongs life after MI due to prevention of left ventricular dilation
Hydralazine-Isosorbide Dinitrate use in Heart Failure
combination that dilates both arteries and veins, proven efficacy
Sodium Nitroprusside used in Heart Failure
reduces preload and afterload, improves ventricular compliance; titratable dosage, short duration
Calcium Channel Blocking Agents used in Heart Failure
reduce afterload, may increase mortality in systolic dysfunction
Beta-Adrenergic Antagonists used in Heart Failure
block excessive compensatory SNS activation, but also depress ventricular contractility; used cautiously but used in virtually everyone
-metoprolol - most clinical studies
-carvedilol - nonselective beta-blocker and vasodilator; FDA approved
Arrhythmias Due to Abnormalities of Impulse Generation - Altered Normal Automaticity
i. Sinus Node - altered by ANS or disease
ii. Purkinje Fibers - common cause of arrhythmias; SNS augments firing rate
Arrhythmias Due to Abnormalities of Impulse Generation - Abnormal Generation of Impulses
i. Abnormal Automaticity - spontaneous diastolic depolarizations that occur at a very low (relatively positive) value of Vm in a cell that normally has a much higher value of Vm in diastole - Purkinje fibers, atrial and ventricular muscle can all exhibit spontaneous depolarization at resting Vm of -60
ii. Triggered Activity - generation of impulses by afterdepolarizations that reach threshold - these are dependent on the prior depolarization and therefore are not self initiated; they can be self-sustaining. Results in:
Early afterdepolarizations - secondary depolarizations that occur before repolarization is complete, especially if the AP duration is prolonged (drugs, low K+)
Delayed Afterdepolarizations - secondary depolarization that occurs soon after full repolarization - often due to catecholamines, digitalis, low K+, high Ca++. May result in a single extrasystole or a "run" of tachycardia
Arrhythmias Due to Abnormalities of Impulse Conduction
Reentry - reciculation activation; requires one-way transient block of conducation to establish a circuit; one-way block is usually due to marked slowing of conduction in abnormal tissue or shortened refractoriness or both
Classification of Antiarrhythmic Actions
Antiarrhythmic actions (drugs) have been classified according to many schemes, the most widely accepted being that of Vaughn Williams. These classes are:
I. Sodium Channel Blockade
a. moderate phase 0 depression
b. minial phase 0 depression
c. marked phase 0 depression
II. Beta-adrenergic blockade
III. Prolong repoalrization (usually K+ channel blockade)
IV. Calcium Channel Blockade
Actions of Sodium Channel Blocking Agents (as Antiarrhythmics)
The actions of Sodium Channel Blocking agents is best ezplained by the Modulated Receptor Hypothesis. The essential features are that:
a. the receptor for these agents is part of (or at least very close to) the proteins forming the Na+ channel
b. in the course of its normal function (as membrane potential changes), the channel changes conformation and the proteins obviously also change conformation. Three conformations are possible and are designated as R (resting), O (open), and I (inactivated).
c. since the proteins change conformation, the receptor (being part of the proteins) also must change conformation;
d. changes in conformation of receptor are associated with changes (modulations) in the affinity of drugs for the receptor, with some conformations having higher affinity than other conformations (generally, affinity of drug for receptor is I > O >> R).
e. when drug is bound to the receptor, the channel is blocked and it undergoes transition to the next conformation very slowly or not at all; 1/2 time of binding drugs to the receptor is measured in msec.
f. since drugs bind primarily to the I state, they prevent transition from I to R; since the channel can open only from the R state, binding of drugs to the I-state does 2 things:
i. prolongs refractoriness (prolong time spent in I state, delays R state)
ii. slows conduction (less than 100% of channels in R state at tine of AP)
g. abnormal automaticity should resolve due to prolongation of refractoriness
h. reentry should resolve due to slowing of conduction
Time Constant for Recovery of Sodium Channel Blocking Agents
A. Quinidine (6000 msec)
Procainamide (2300 msec)
B. Lidocaine (180 msec)
Mexiletine (360 msec)
Tocainamide (550 msec)
C. Encainide
Flecainide (20000 msec)
Propafenone
Indecanide
Beta-1 Adrenergic Blockade (as Antiarrhythmics)
Stimulation of adrenergic receptors increases automaticity (increases the slope of phase-4 depolarization). This is accomplished by (1) quicker closing of K+ channels in pacemaker tissue and (2) increased opening of L-type Ca++ channels. This may result in abnormal automaticity (ectopic pacemakers). Treatment with beta-1 blockers prevents these effects and prolongs the refractory period of pacemaker tissue (AV node much more sensitive than SA node).
Agents: propranolol, acebutolol, esmolol
Drugs that cause Prolongation of Repolarization and their MOA
Blockade of the K+ current during the plateua phase of the AP is considered to be the mechanism by which drugs prolong the repolarization period. There are several potassium currents or channels during the AP, the most important being:
a. Ito - the "Transient Outward" current responsible for phse 1 repolarization
b. IK - the "Delayed Rectifier" current responsible for phse 3 repolarization
c. IK1 - the "Background" current responsible for maintaining resting potential in non-pacemaker cells
An agent that prolongs the repolarization period would reduce the number of impulses which could be transmitted per unit time.
Agents: amiodarone, bretylium, sotalol, quinidine, procainamide
Calcium Channel Blockers (as Antiarrhythmics)
Agents blocking calcium channels act by the MRH to reduce the number of impulses the AV Node is capable of transmitting.
Agents: verapamil, diltiazem (not nifedipine)
Miscellaneous drugs used as Antiarrhythmics
digoxin, adenosine
Cautions with Regard to Antiarrhythmic Drugs
1. All have a primary mode of action, hence Vaughn Williams class
2. Virtually all have a secondary mode of action
3. Many have active metabolites; the active metabolites (and quantity of each) are subject to variation from patient to patient based on the genotype of the patient.
4. The active metabolites commonly have different mode of action compared to the parent drugs.
5. The drugs may be stereoisomers whose enantiomers may have different actions
Class 1A Antiarrhythmic Agents
quinidine, procainamide, disopyramide
Actions of Quinidine
Quinidine has the effects of a 1A Na+ channel blocking agent, but its action is complicated by a number of other effects, all of which influence it CVS actions. Quinidine posesses antimuscarinic activity, alpha-adrenergic blocking activity and probably K+ channel blocking activity
Absorption, Distribution, and Excretion of Quinidine
Usually administered PO; IM route possible but painful and increases adverse effects
Adverse Effects of Quinidine
About 1/3 of patients DC quinidine almost immediately because of diarrhea; other than that, almost all toxicity is cardiac toxicity. Many types of cardiac arrhythmias appear when quinidine accumulates or quinidine poisoning occurs. These are referred to collectively as "proarrhythmic" effects of quinidine (and other antiarrhythmics).
-torsades de pointes (polymorphic ventricular tachycardia) is especially significant and associated with "quinidine syncope"
-paradoxical increase in ventricular rate while treating atrial fibrillation (block AV node first)
-SA block or arrest; AV block; asystole
-significant hypotension (due to alpha-blocking effect)
-emboli after conversion of atrial fibrillation
Absorption, Distribution, and Excretion of Procainamide
Well absorbed after PO administeration; short half-life makes SR products very useful; has an important metabolite N-acetyl-procainamide (NAPA); formation of NAPA is under genetic control and it is an active metabolite, although its actions are somewhat different from procainamide (NAPA appears to be a Class III agent); much of administered dose of procainamide is excreted in urine and it accumulates in renal impairment and also subject to changes in excretion if urine pH changes
Adverse Effects of Procainamide
Essentially the same as quinidine; GI disorders less common; also associated with an autoimmune reaction resembling SLE
Group 1B Antiarrhythmic Agents
lidocaine, phenytoin
Actions of Lidocaine
suppresses activity of ectopic pacemakers; minimal effect on slowing conduction
Absorption, Distribution, and Excretion of Lidocaine
Well absorbed after PO administration but extensively metabolized on first pass and associated with many GI side effects, thus not suitable for PO administration; usually administered IV
Adverse Effects of Lidocaine
Not as serious as clas 1A drugs; CNS effects include drowsiness, paresthesias, dissociation
Adverse Effects of Class 1C Antiarrhythmics
All 1C agents produce an 8-15% incidence of proarrhythmic events in patients with malignant ventricular arrhythmias and are reported to increase the incidence of sudden death and cardiac arrest in patients with asymptomatic ventricular arrhythmias; all can aggravate sinus node dysfunction and CHF; all-in-all a toxic group
Class 3 Antiarrhythmic Agents
amiodarone, bretylium, sotalol
Actions of Amiodarone as an Antiarrhythmic
Blocks K+ channels, Na+ channels, Ca++ channels and has a noncompetitive adrenergic blocking action. Inhibits abnormal automaticity, prolongs APD and slows conduction. Useful in recurrent ventricular tachycardia or fibrillation resistant to other therapy.
Absorption, Distribution, and Excretion of Amiodarone
Long half-life (months?), loading dose for several weeks and then maintenance dose
Adverse Effects of Amiodarone
Hypotension, pulmonary fibrosis, corneal deposits, hepatic dysfunction, peripheral neuropathy, discoloration of skin
Class 4 Antiarrhythmic Agents and Actions
Calcium channels blockers have their action on the node; nifedipine is ineffective
Class 5 Antiarrhythmic Agents
adenosine, digoxin
Actions and Dosing of Adenosine as an Antiarrhythmic
Adenosine activates some K+ channels, shortening AP duration, causing hyperpolarization and slowing spontaneous depolarization. It also inhibits the effect of cAMP, resulting in a decrease in Ca++ entry into the cell
Rapid administration of a bolus dose. Duration is very short, thus very few adverse effects.
Digoxin as an Antiarrhythmic
The use of digitalis is in treatment of atrial tachyarrhythmias. The primary objective in these arrhythmias is control of ventricular rate by reducing the number of impulses passing through the AV node. Restoring normal sinus rhythm is a secondary objective.