Cardiac/Renal Pharm 3

86問 • 1年前

問題一覧

Pharmacokinetics of Digoxin

-Oral and injectable -Large Vd [muscle accumulation] -In acute situations—a loading dose is needed -Long 1⁄2 life—30 to 40° -Eliminated intact by the kidney -Dose adjustment is needed in renal disease

ADEs of Digoxin

-Has a very narrow therapeutic index -Anorexia, nausea, vomiting, blurred vision or yellowish vision suggests toxicity -If the Na+/K+ ATPase is markedly inhibited by this drug, the resting membrane becomes more excitable—increasing the risk of arrhythmias—low K+ makes the patient at risk -Substrate of P-gp and inhibits P-gp—Clarithromycin, Verapamil and Amiodarone can increase drug levels -Use with caution with other drugs that slow AV conduction—BB, Verapamil, Diltiazem

Dobutamine and Dopamine are the prototypes

Beta Adrenergic Agonists

-Positive inotropic effect and are vasodilators -These agents cause increased entry of Ca++ ions into the myocardial cells and enhance contraction -Both must be given IV—used short-term for acute HF in the acute care setting

Dobutamine and Dopamine

Milrinone is the prototype drug

Phosphodiesterase Inhibitors

Increases intracellular concentration of cAMP—this results in an increase of intracellular Ca++ and increase in cardiac contractility Given IV for short-term treatment of acute HF

Milrinone

Nesiritide [Natrecor] is the prototype

Recombinant B-Type Natriuretic Peptide

-Reduces preload and improves HF symptoms—such as dyspnea -Can be given when IV diuretics are not effective -It binds to natriuretic peptide receptors and decreases preload and improves HF symptoms (SOB) -Given IV as a bolus or an infusion; 1⁄2 life is 20 minutes -Cleared by renal filtration -ADEs—hypotension, dizziness, and can worsen renal function

Nesiritide

-_____ are the backbone of therapy and should be titrated to the maximum tolerated dose -After the patient is stabilized [from a volume perspective], a _____ should be added at a low dose—and slowly titrated -If symptoms remain—an ______is added and then hydralazine or BiDil if symptoms require it

-ACEI or ARB -Beta Blocker -Aldosterone blocker

-Work by blocking voltage sensitive Na+ channels (state dependent) -These agents show greater degree of specificity for tissues frequently depolarizing, and are. more effective when arrythmia is severe

Class I Antiarrhythmic Drugs

-Quinidine is the prototype drug, also includes Procainamide and Disopyramide -These drugs also have class III activity—they can precipitate VF

Class 1A Antiarrhythmic Drugs

MOA of Quinidine

-Binds to open & inactivated Na+ channels and prevents Na+ influx, inhibits K+ channels and blocks Ca++ channels -Slows conduction velocity and increases refractoriness -Has mild alpha blocking and anticholinergic actions

MOA of Procainamide

-Action similar to Quinidine -Less anticholinergic properties than Quinidine -No alpha blocking properties

MOA of Disopyramide

-Actions similar to Quinidine -More anticholinergic properties than Quinidine -No alpha blocking properties -Greater negative inotropic effect -Causes peripheral vasoconstriction

Atrial, AV junctional and ventricular tachyarrhythmias

Uses for Quinidine

Only available IV and used in acute atrial and ventricular arrhythmias (Wolf-Parkinson White)

Uses for Procainamide

-Used as an alternative for ventricular arrythmias -Used to rhythm control in AF or A-flutter

Uses for Disopyramide

Pharmacokinetics of Quinidine

-Well absorbed orally -Metabolized in liver by CYP450 3A4 and forms a metabolite

Pharmacokinetics of Procainamide

-Part of this drug is acetylated in liver to N-acetylprocainamide [NAPA]—which has actions and ADEs of a class III drug -NAPA eliminated in kidney, so renal dose needed in those with renal dysfunction

Pharmacokinetics of Disopyramide

-Well absorbed orally -Metabolized in liver by CYP 3A4 to less active metabolite -1⁄2 of this drug is excreted unchanged in the kidney

ADEs of Quinidine

-Large doses can cause blurred vision, tinnitus, headache, disorientation and psychosis -Drug interactions are common—is an inhibitor of CYP 2D6 and P-glycoprotein -Use with caution with potent inhibitors of CYP 3A4

ADEs of Procainamide

-Long term use can cause Lupus (reversible) -IV administration can cause low BP

ADEs of Disopyramide

-Most anticholinergic effects—dry mouth, urinary retention, blurred vision and constipation -Use with caution with potent inhibitors of CYP 3A4

-The negative inotropic effects can worsen HF, so do not prescribe in those with CAD or HFrEF -These drugs also have class III activity—they can precipitate VF

Class 1A Antiarrhythmics

Lidocaine is the prototype and also includes Mexiletine

Class 1B Antiarrhythmics

Used to treat ventricular arrythmias—these drugs associate and dissociate from the Na+; actions are greatest when the cardiac cycle is depolarized or firing rapidly

Class 1B Antiarrhythmics

MOA of Class 1B Antiarrhythmics

Na+ channel blocker; decrease duration of action potential; neither is a negative inotrope

Uses for Lidocaine

• Can be used as an alternative to Amiodarone in VT and VF • Used with Amiodarone in VT storm • Dose not slow conduction, has little to no effect on atrial or AV junctional dysrhythmias

Uses for Mexiletine

Used for chronic treatment of ventricular arrhythmias, often with Amiodarone

Pharmacokinetics of Lidocaine

• Given IV • Extensive 1st pass transformation in the liver; drug broken down into 2 active metabolites by CYP 1A2 with a minor role from CYP 3A4 • Monitor closely in patients on other drugs affected by CYP isoenzymes

Pharmacokinetics of Mexiletine

• Absorbed well orally • Metabolized in liver by CYP2D6 • Excreted via the biliary tree

ADEs of Lidocaine

-Wide therapeutic index -Nystagmus,earlyindicatoroftoxicity • Drowsiness -Slurred speech -Paresthesias -Agitation -Confusion -Convulsions

ADEs of Mexiletine

• Narrow therapeutic index • Use caution when prescribing with inhibitors of CYP 2D6 • Nausea • Vomiting • Dyspepsia

Flecainide is the prototype and includes Propafenone

Class 1C Antiarrhythmic Drugs

These drugs slowly dissociate from resting Na+ channels and slow prominent effects, even at normal heart rates—negative inotropes and proarrhythmic effects—avoid use in those with structural heart disease [LVH, HF, CAD]

Class 1C Antiarrhythmic Drugs

MOA of Flecainide

• Markedly slows conduction in all cardiac fibers, with a minor effect on the action potential and refractoriness • Automaticity is reduced by an increase in threshold potential • Blocks K+ channels causing increased duration of the action potential

MOA of Propafenone

• Slows conduction in all cardiac tissues, but does not block K+ channels • Has weak BB properties

Uses for Flecainide

• Maintenance of NSR in AF or A-Flutter without structural heart disease • Refractory ventricular arrhythmias

Uses for Propafenone

• Restricted mostly to atrial arrhythmias—rhythm control of AF or A-Flutter • Paroxysmal SVT prophylaxis in those with AV re-entry tachycardias

Pharmacokinetics of Flecainide

• Well absorbed orally • Metabolized by CYP2D6 into multiple metabolites • Eliminated renally

Pharmacokinetics of Propafenone

• Metabolized into active metabolites by CYP 2D6 and by CYP 1A2 and CYP 3A4 • Metabolites excreted in urine and feces

ADEs of Flecainide

• Blurred vision • Dizziness • Nausea • Use with caution with potent inhibitors of CYP 2D6

ADEs of Propafenone

• SE similar to Flecainide,but can cause bronchospasm • Avoid in asthma patients • Inhibitor of P-glycoprotein • Use with caution with potent inhibitors of CYP 2D6

-Metoprolol is the prototype and most widely used for arrhythmias -They diminish phase 4 depolarization, depress automaticity, prolong -AV conduction, decrease HR and contractility -Used in tachyarrhythmias caused by increased sympathetic activity -Also used for AF, A-Flutter, AV nodal re-entry tachycardia -Prevent life-threatening ventricular arrhythmias after MI

Class 2 Antiarrhythmic Drugs

Pharmacokinetics of Metoprolol

Extensively metabolized by CYP 2D6 and has CNS penetration

-Is a short and fast acting BB used IV in acute arrhythmia management during surgery or emergent situations -Rapidly metabolized by esterase's in RBCs—so no drug interactions

Esmolol

Amiodarone is the prototype and includes, Dronedarone, Sotalol, Dofetilide, and Ibutilide

Class 3 Antiarrhythmic Drug

• Block K+ channels, and diminish the outward current during repolarization • They prolong the effective refractory period and increase refractoriness • All of these agents have the potential to induce arrythmias

Class 3 Antiarrhythmic Drugs

MOA of Amiodarone

• Contains iodine and structurally like thyroxine • Has Class I, II, III and IV actions • Has BB activity • Prolongs the action potential duration and the refractory period by blocking K+ channels

Uses for Amiodarone

• Severe refractory SVT and ventricular tachyarrhythmias • Back bone of therapy for AF and A- Flutter • Thought to be less proarrhythmic of the class I and class III drugs

Pharmacokinetics of Amiodarone

• Incompletely absorbed after oral intake • Long 1⁄2 life of several weeks • Distribut esextensively in the tissues • Full effects may not be seen for months after drug is started [unless a loading dose is used]

ADEs of Amiodarone

• Pulmonary fibrosis • Neuropathy • Hepatotoxicity • Corneal deposits • Optic neuritis • Blue-gray skin discoloration • Hypo or Hyperthyroidism • Metabolized by CYP3A4 • Inhibitor of CYP1A2, CYP2C9, CYP2D6 and P-glycoprotein

• Benzofuran Amiodarone derivative, that is less lipophilic and has a shorter 1⁄2 life • Does not have iodine properties, so no thyroid effects [like seen in Amiodarone] • Has Class I, II, III and IV actions • Better ADE profile than Amiodarone, but can still cause liver failure • Contraindicated in symptomatic HF or permanent AF—increased risk of death • Used to maintain NSR in AF or A-Flutter, less effective than Amiodarone

Dronedarone

• Nonselective BB with some Class III antiarrhythmic actions • Blocks rapid outward K+ current prolonging the refractory period • Used to maintain NSR in those with AF, A-Flutter, refractory paroxysmal SVT and in ventricular arrhythmias • Used for patients with LVH or CAD • ADEs—similar to other BBs, but have low ADEs compared to other antiarrhythmics • Eliminated in the urine so dose interval must be lengthened for CKD • Should be given in the hosptial due to the risk for arrythmias

Sotalol

• Pure K+ channel blocker • 1s line in those with persistent AF and HF [or those with CAD] • Initiated inpatient for risk of arrhythmia • 1⁄2 life is 10 hours • Excreted unchanged in the urine • Drugs that inhibit active tubular secretion are contraindicated with this agent

Dofetilide

• K+ channel blocker that also activates the inward Na+ current • DOC for chemical cardioversion of A-Flutter • Undergoes extensive 1st pass metabolism and is not used orally • Initiation is done in the inpatient setting

Ibutilide

Verapamil and Diltiazem

Class 4 Antiarrhythmic Drugs

• Nondihydropyridine CCBs • Major effect of this class is on vascular smooth muscle and the heart • Both drugs effect the heart more than the smooth muscle, but more with Verapamil • In the myocardium—these drugs bind only to open depolarized voltage sensitive channels, decreasing the inward current carried by Ca+

Verapamil and Diltiazem

• Are use dependent—they prevent repolarization until the drug dissociates from the channel— decreased rate of spontaneous depolarization • Slow conduction in tissues that are dependent on Ca++ currents— the AV and SA nodes • Most effective against atrial arrythmias—used to treat re-entry SVT, and in decreasing the ventricular rate in AF and A-flutter

Verapamil and Ditilizem

ADEs of Class 4 Antiarrhythmic Drugs

Bradycardia, hypotension, and peripheral edema

Pharmacokinetics of Class 4 Antiarrhythmic Drugs

• Metabolized in the liver by CYP 3A4 and have drugs interactions with inhibitors of CYP 3A4 and substrates and inhibitors of P-glycoprotein • Dose adjust in liver dysfunction

• Inhibits Na+/K+ ATPase pump shortening the refractory period in atrial and ventricular myocardial cells, while prolonging the refractory period and decreasing conduction velocity at the AV node • Used to control ventricular response in AF and A-flutter • Toxicity can cause PVCs that can result in VT or VF • Serum trough levels of 1.0 are desirable for AF or A-Flutter, and levels of .5 - .8 are desired for systolic HF

Digoxin

• Naturally occurring nucleoside, but at high doses decreases the conduction velocity, prolongs the refractory period and decreases automaticity in the AV node • IV form is the DOC for converting acute SVT • Low toxicity, but causes flushing, CP and low BP • Short duration of action—10 to 15 seconds—due to the rapid uptake by the RBCs and endothelial cells

Adenosine

• Needed for transport of Na+, Ca++ and K+ across cell membranes • Slows the rate of SAS node impulse formation and prolongs conduction time along the myocardial tissue • IV it is used to treat arrythmias—not effective orally • DOC for treating Torsades de Pointes and Digoxin induced arrhythmias

Magnesium Sulfate

• Antianginal drug with antiarrhythmic properties like Amiodarone • Main effect is shortening of repolarization and decrease action potential duration [similar to Mexiletine] • Used to treat refractory atrial and ventricular arrhythmias • Well tolerated—dizziness and constipation are most common ADEs • Extensive metabolism in liver by CYP 3A4 and CYP 2D6 • Renally excreted • Contraindicated for use if patient already on a strong CYP 3A inducer or inhibitor

Ranolazine

• Short-acting, burning, heavy or squeezing sensation • Atypical symptoms - fatigue, nausea or sweating; while others may have no symptoms—more common in women, diabetics and older adults • Caused by ↓ perfusion from a fixed obstruction of a coronary artery from a plaque • Activity may cause chest pain that is relieved by rest or NTG

Stable Angina

• CP that happens with increased frequency and intensity without activity • Angina at rest that last longer than 20 minutes with or without SOB • The symptoms are not relieved by rest or NTG

Unstable Angina

• Uncommon; episodic angina that occurs at rest and it from decreased blood flow to the myocardium from spasm of the coronary arteries • Patients have Hx of significant CAD • The angina attacks are NOT related to activity, HR or BP • This type of angina responds to coronary vasodilators, such as NTG and CCBs

Prinzmetal Angina

• Emergency—commonly from rupture of a plaque and partial or complete thrombosis of a coronary artery • If the thrombus occludes most of the vessel, and it is not treated— necrosis of the myocardium may occur—an MI

Acute Coronary Syndrome

What are the four families of drugs used to treat chest pain?

BBs, CCBCs, organic nitrates and Na+ channel blockers— Ranolazine

• Decrease the O2 demand of myocardium by blocking B1 receptors, caused reduced HR, contractility, CO and BP • O2 demand is lowered during exertion and at rest—so they reduce angina • Can be used to increase exercise duration and tolerance in those with effort induce chest pain • 1st line in angina management, except in Pritzmetal angina [not effective and may worsen symptoms] and in the severe asthmatic

Using Beta Blockers for Chest Pain

• They reduce risk of death and MI in those who have had an MI • Improve mortality in those with HFrEF • Avoid in those with severe bradycardia • Must be tapered over 2-3 weeks if they are discontinued [to prevent hypertensive crisis, rebound angina and MI]

Using Beta Blockers for Chest Pain

• Agents with intrinsic sympathomimetic activity [ISA]—such as Pindolol, should be avoided in those with angina or previous MI • Cardioselectives are preferred and can be used in those with DM, PAOD, COPD • Noncardioselectives should be avoided in asthma patients

Using Calcium Channel Blockers for Chest Pain

• Protect the tissue by inhibiting the entrance of Ca+ into cardiac and smooth muscle cells of the coronary and systemic arterial beds • All are arteriolar vasodilators that cause a decrease in smoot muscle tone and vascular resistance • They primary affect the resistance of peripheral and coronary arteriolar smooth muscles • In effort induced angina, they decrease myocardial O2 consumption by decreasing peripheral resistance, decreasing afterload • Efficacy in vasospastic angina is due to relaxation of the coronary arteries

Using Calcium Channel Blockers for Chest Pain

Calcium Channel Blockers for Chest Pain

Verapamil, Diltiazem, and Amlodipine

• Minimally effects on cardiac conduction and works mainly as arteriolar vasodilator—this vasodilatory effect makes it useful in treating variant angina caused by spontaneous coronary spasm • Short acting forms of this class should not be used in CAD—they have been associated with increased mortality after an MI and increased MI risk in the patient who is hypertensive

Dihydropyridine CCBs for Chest Pain

• Slows AV conduction directly and decreases HR, contractility, BP and O2 demand • Has more of a negative inotropic effect than does Amlodipine, but it is a weaker vasodilator • Contraindicated in those with preexisting depressed cardiac function or AV conduction abnormalities

Verapamil for Chest Pain

• Slows AV conduction, decreases rate of firing of SA node pacemaker • It is a coronary artery vasodilator • It can relieve coronary artery spasm—used in Pritzmetal angina

Diltiazem for Chest Pain

• Contraindicated in those with preexisting depressed cardiac function or AV conduction abnormalities • Can worsen HF from their negative inotropic effects

Nondihydropyridine CCBs for Chest Pain

• Reduce myocardial O2 demand, relieving symptoms of CP • Effective in stable, unstable and variant angina

Nitrates for Chest Pain

MOA of Nitrates

• Relax vascular smooth muscle by intracellular conversion to nitrite ions and then to NO, which activates and increases cGMP—elevated cGMP causes vascular smooth muscle relaxation • Dilate the large veins—reducing preload and work of the heart • Dilate the coronary vessels, increasing blood supply

Pharmacokinetics of Nitrates

• Differ in onset and rate of elimination • NTG onset is 1 min • Isosorbide Mononitrate onset is 30 hours • SL NTG is available in tablet or spray—DOC for prompt relief of CP from exertion or stress • 1st pass in the liver—thus it is given SL or transdermal • Oral Isosorbide Mononitrate has improved bioavailability and longer duration of action • Oral Isosorbide Dinitrate undergoes conversion into 2 mononitrates—both of which prevent angina

Pharmacokinetics of Nitrates

ADEs of Nitrates

• Headache • High doses can cause postural low BP, facial flushing and tachycardia • PDE5 inhibitors, such as Sildenafil, potentiate the action—the combination is contraindicated

Ranolazine is the prototype drug

Sodium Channel Blockers for Chest Pain

• Inhibits the late phase of the Na+ current—improving O2 supply and demand, and reduces intracellular Na+ and Ca++ overload— improving diastolic function • Often used in those who have failed other antianginal therapy • Antianginal effects are less in women • Metabolized in liver, by CYP 3A and CYP 2D6; it is also a substrate of P-glycoprotein • It can prolong QT interval— Avoid: Clarithromycin, Azoles, Quinolones, Dilantin, Tegretol, St. John’s Wort, Citalopram, Quetiapine, many others

Sodium Channel Blockers for Chest Pain

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