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Term 5 Flash Cards > Pharm Exam 1 Cardio > Flashcards

Pharm Exam 1 Cardio Flashcards

90
Q

Furosemide Torsemide

A
  • Loop diuretic. Act on thick ascending limb of Loop of Henle
  • Highest efficacy in removing Na+ & Cl- from body
  • Block NKCC2 Na+/Cl-/K+ cotransporter
  •  [Na+] & [Cl-] & [K+] in tubular fluid -> increase H2O excretion

USES
• Used primarily in patients who do not respond to thiazide therapy adequately
• Diuretics of choice for reducing acute pulmonary edema associated with heart failure and hepatic or renal disease
• Hypertension

ACTIONS
• Increased Ca2+ excretion
• Increased Mg2+ excretion
• Decreased renal vascular resistance
• Increased renal blood flow
• Increased prostaglandin synthesis

ADVERSE
• Ototoxicity
• Hyperuricemia
• Acute hypovolemia
• K+ depletion
• Hypomagnesemia
• Allergic reactions

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91
Q

HCTZ Chlorthalidone Metolazone

A
  • Ceiling diuretics. First-line agents. Effective in lowering BP by 10-15 mmHg.
  • Act on distal tubule – all have equal maximum effects
  • Act predominantly in distal convoluted tubule
  • Block NCCT Na+/Cl- cotransporter
  • Increased [Na+] & [Cl-] in tubular fluid

USES
• Long-term treatment = normal plasma volume but decreased peripheral resistance
• Counteract Na+ & H20 retention caused by other antihypertensive drugs -> useful in combination therapy
• Particularly useful in black & elderly (with normal renal & cardiac function)

ADVERSE
• Hypokalemia
• Hyperuricemia
• Hyperglycemia
• Hypomagnesemia
• Hypercholesterolemia

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92
Q

Spironolactone Eplerenone

A
  • K+ sparing aldosterone antagonist. Used alone when there is excess aldosterone.
  • Potassium levels must be closely monitored for hyperkalemia (more prominent in patients with chronic kidney disease or in patients taking concurrent ACEI, ARB or other K+-sparing diuretics)
  • Act mainly in collecting tubule

USES
• Can be used as part of first-line therapy in patients with hypertension & severe left ventricular dysfunction
• Heart failure (to treat refractory edema or as adjunct to standard therapy). + ACE inhibitors are shown to decrease morbidity & mortality in patients with severe heart failure
• Hypertension (adjunct to standard therapy)
• Primary hyperaldosteronism (diagnosis & treatment)
• Edema (associated with excessive aldosterone excretion)

ACTIONS
• Antagonize aldosterone at intracellular cytoplasmic receptor sites (prevents translocation of receptor complex -> nucleus)
• Na+ reabsorption &  K+ excretion
• Oral & strongly protein bound (t1/2 = 2-3 days)
• Spironolactone has an active metabolite (canrenone)

ADVERSE
• Gastric upset & peptic ulcers
• Endocrine effects (antiandrogen - gynecomastia, decreased libido, menstrual irregularities)
• Hyperkalemia
• CNS effects: nausea, lethargy, mental confusion (rare)

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93
Q

Amiloride Triamterene

A
  • Na+ channels inhibitors (decreased Na+/K+ exchange), K+ sparing
  • Do not rely on presence of aldosterone
  • Usually used in combination (not very efficacious)
  • Can prevent K+ loss associated with thiazides & furosemide
  • Act in collecting duct
  • Directly block epithelial sodium channel (ENaC) -> decreasing Na+/K+ exchange
  • Na+ reabsorption &  K+ excretion

ADVERSE
• Hyperkalemia
• Hyponatremia
• Leg cramps
• GI upset
• Dizziness, pruritus, headache & minor visual changes

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94
Q

Acetazolamide

A
  • Carbonic anhydrase inhibitor
  • Act mainly in proximal tubular epithelial cells
  • Less efficacious than other diuretics
  • Often used for other pharmacological properties

USES
• Glaucoma (reduce elevated intraocular pressure)
• Epilepsy (used alone or with other antiepileptics)
• Mountain sickness prophylaxis
• Metabolic alkalosis

ACTIONS
• Inhibits intracellular carbonic anhydrase
• Decreases ability to exchange Na+ for K+ (diuresis)
• HCO3- is retained in lumen (increasing urinary pH)

  • Oral & well absorbed
  • t1/2 = 3-6 h.
  • Increase urine pH

ADVERSE
• Metabolic acidosis
• Hyponatremia
• Hypokalemia
• Crystalluria
• Malaise, fatigue, depression, headache, GI disturbances, drowsiness, paresthesia

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95
Q

Mannitol

A
  • Raises osmotic pressure of the plasma thus draws H20 out of body tissues & produces osmotic diuresis
  • Does not effect Na+ excretion. Works everywhere in tubule

USES
• Increase urine flow in patients with acute renal failure
• Reduce increased intracranial pressure & treatment of cerebral edema
• Promote excretion of toxic substances

ADVERSE
• Extracellular water expansion (can lead to hyponatremia)
• Tissue dehydration

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96
Q

Conivaptan

A
  • ADH antagonist. ADH controls permeability of collecting tubule to H20
  • Conivaptan is antagonist V1 and V2 receptors
  • In the absence of ADH, tubule is H20 impermeable -> dilute urine

USES
• Euvolemic and hypervolemic hyponatremia
• SIADH (syndrome of inappropriate ADH secretion)
• Heart failure (only when benefits outweigh risks –
safety not established)

PK
• IV only
• Metabolized by & potent inhibitor of CYP 3A4

ADVERSE
• Infusion site reactions
• Thirst
• Atrial fibrillation
• GI & electrolyte disturbances
• Nephrogenic diabetes insipidus

CONTRAINDICATIONS
• Hypovolemic hyponatremia
• Renal failure

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97
Q

Lines of treatment for hypertension

A

First-line agents
• ACE-inhibitors, ARBs, calcium channel blockers,
thiazide diuretics

Second-line agents
• B-blockers, aldosterone antagonists

Other agents
• Loop diuretics, B-blockers, direct vasodilators, central a2-agonists, renin inhibitors

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98
Q

Captopril Enalapril Lisinopril

A
  • ACE inhibitors. First-line agents for HTN. Agents of choice for HF
  • Decrease BP by decreasing peripheral vascular resistance -> increased CO (decreased afterload)
  • DECREASE Na+ & H20 retention (decreased preload)
  • Decrease long-term remodeling of the heart
  • INCREASE BRADYKININ levels
  • DO NOT reflexively increase cardiac output, rate or contractility

USES
• Hypertension (most effective in white, young patients) + diuretic = effectiveness similar in white and black
• Preserve renal function in patients with either diabetic or non-diabetic nephropathy
• Effective in treatment of chronic HF
• Standard of care for patients following MI (started 24h after end of infarction)

ADVERSE
• Hyperkalemia
• Hypotension
• Dry cough
• Angioedema (rare but life-threatening)
• Acute renal failure (patients with bilateral renal artery stenosis)
• Rash, fever, altered taste
• Teratogenic

CONTRAINDICATIONS
• Pregnancy - During 1st trimester due to risk of congenital malformations and during 2nd and 3rd trimesters because of risk of fetal hypotension, anuria & renal failure
• Patients with bilateral renal artery stenosis

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99
Q

Lorsartan Valsartan

A
  • Angiotension receptor blockers (ARB’s). Alternatives to ACEI’s
  • Block angiotensin-2 type 1 receptors
  • Decrease BP by causing arteriolar & venous dilation
  • Block aldosterone secretion -> decrease Na+ & H20 retention
  • Decreased diabetic nephrotoxicity
  • DO NOT INCREASE BRADYKININ levels

ADVERSE
• Similar to those of ACE inhibitors
• Dry cough does not occur (due to no effect on
bradykinin levels)
• Angioedema risk is significantly lower than with ACEI’s

CONTRAINDICATIONS
• Pregnancy
• Patients with bilateral renal artery stenosis

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100
Q

Aliskiren

A
  • Renin inhibitor. Alternative agent in the treatment of hypertension
  • Inhibits enzyme activity of renin and prevents conversion of angiotensinogen into angiotensin I

End result:
• Inhibits production of both angiotensin II and aldosterone

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101
Q

Verapamil

A
  • Diphenylalkylamine. Ca2+ blocker
  • Least selective of any Ca2+-blocker
  • Significant effects in cardiac & vascular smooth muscle
  • Used to treat angina, supraventricular tachyarrythmias & migraine
 ADVERSE
 Constipation (~7 %), should be avoided in patients with congestive HF (-ve inotropic effects)
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102
Q

Diltiazem

A
  • Benzothiazepine Ca2+ channel blocker. Effects in both cardiac & vascular smooth muscle (less pronounced effect on heart than verapamil)
  • Good side-effect profile
  • Used to treat angina & supraventricular tachyarrythmias

ADVERSE
Hypotension, dizziness, headache, fatigue, peripheral edema (esp. feet & ankles), bradycardia, heart block, reflex tachycardia can occur, especially in short-acting preparations

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103
Q

Amlodipine Nifedipine

A
  • Dihydropyridine Ca2+ blockers. 1st generation: nifedipine. 2nd generation: amlodipine
  • Greater affinity for vascular Ca2+-channels than for cardiac Ca2+-channels
  • Reduce Ca2+ entry into smooth muscles to cause coronary & peripheral vasodilatation & lower BP
  • Most useful in treating hypertension. ONLY CA2+ BLOCKERS NOT USED FOR TREATING CARDIAC ARRHYTHMIAS

PK
• High-doses of short-acting dihydropyridine Ca2+- channel blockers can increase risk of MI (excessive vasodilation & reflex cardiac stimulation)
• Sustained release preparations are preferred

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104
Q

B-blockers in HTN

A
  • Propranolol, Metoprolol, Atenolol, Pindolol
  • Used only as add-on therapy to first line agents in primary prevention patients
  • First-line therapy only for patients with coronary artery disease or left ventricular dysfunction

• May take several weeks to develop full effects

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105
Q

Hydralazine Minoxidil

A
  • Direct vasodilators. Not used as first-line antihypertensives
  • Direct acting smooth muscle relaxants
  • Produce reflex tachycardia, increase plasma renin -> Na+ & H20 retention
  • Major side effects can be blocked if combine with diuretic & B-blocker

HYDRALAZINE
• Can be given oral or IV
• Acts mainly on arterioles
• Used to treat pregnancy induced hypertension / pre- eclampsia
• Used in management of hypertension as last-line therapy

ADVERSE
• Fluid retention & reflex tachycardia are common
• Reversible lupus-like syndrome
• Headache, nausea, sweating, flushing
• Usually administered with B-blocker & thiazide

MINOXIDIL
• Causes direct peripheral vasodilatation of arterioles
• Oral treatment for severe-malignant hypertension (refractory to other treatments)

ADVERSE
• Reflex tachycardia & fluid retention may be severe (combine with loop diuretic & B-blocker)
• Causes hypertrichosis (also used topically to treat male pattern baldness)

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106
Q

Bosentan

A

• Used for pulm HTN
• Nonselective endothelin receptor blocker
• Blocks both the initial transient depressor (ETA) and the
prolonged pressor (ETB) responses to IV endothelin
• Pregnancy category X

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107
Q

Hypertensive emergency treatments

A
  • Sodium nitroprusside
  • Labetalol
  • Fenoldopam
  • Nicardipine
  • Nitroglycerin
  • Diazoxide
  • Phentolamine
  • Esmolol
  • Hydralazine

Phentolamine
Drug of choice for patients with catecholamine- related emergencies

Esmolol
Often used for aortic dissection or postoperative hypertension

Hydralazine
Drug of choice in treating hypertensive emergencies in pregnancy related to eclampsia

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108
Q

Sodium nitroprusside

A
  • Drug of choice for hypertensive emergencies
  • Always given IV (poisonous if given orally)
  • t1/2 = 1-2 min -> requires continuous infusion
  • Prompt vasodilation & reflex tachycardia
  • Equal effect on arterial & venous smooth muscle

ADVERSE
• Hypotension (overdose), goose bumps, abdominal cramping, nausea, vomiting, headache
• Cyanide toxicity (rare)
nitroprusside metabolism -> cyanide ion
Can be treated with sodium thiosulfate infusion -> nontoxic thiocyanate

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109
Q

Fenoldopam

A
  • Peripheral dopamine-1 (D1) receptor agonist
  • Evokes arteriolar dilation
  • IV infusion for hypertensive emergency
  • t1/2 = 30 min
  • Maintains or increases renal perfusion as lowers BP
  • Promotes naturesis
  • Safe to use in all hypertensive emergencies (particularly beneficial in patients with renal insufficiency)

CONTRAINDICATIONS
• Glaucoma

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110
Q

Nicardipine

A
  • Calcium-channel blocker
  • IV infusion for hypertensive emergency
  • t1/2 = 30 min
  • Evokes reflex tachycardia
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111
Q

Nitroglycerin

A
  • Arterial and venous vasodilator
  • Drug of choice for hypertensive emergencies in patients with cardiac ischemia or angina, or after cardiac bypass surgery
  • t1/2 = 2-5 min
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112
Q

Diazoxide

A
  • Arteriolar dilator
  • Prevents vascular smooth muscle contraction by opening K+ channels and stabilizing membrane potential • t1/2 = ~24h

ADVERSE
• Hypotension, reflex tachycardia, Na+ & H20 retention
• Inhibits insulin release and can be used to treat hypoglycemia secondary to insulinoma

113
Q

Candesartan Valsartan

A
  • ARBs HF. NO LOSARTAN
  • Potent competitive antagonists of angiotensin I receptor
  • DO NOT affect bradykinin levels

Clinical Application In HF
• Substitute for patients who can’t tolerate ACE inhibitors (severe cough or angioedema)

ADVERSE
• Similar to ACE inhibitors (no cough) Teratogenic

114
Q

Hydralazine Isosorbide dinitrate

A
  • Direct vasodilators. Used in HF
  • Increased vasodilation -> decreased preload
  • Increased arterial dilation -> decreased TPR and afterload

• Concurrent use of two oral vasodilators: hydralazine & isosorbide dinitrate can produce sustained improvement in LVEF
• Concurrent use of hydralazine & isosorbide dinitrate recommended for use in patients:
1) who cannot tolerate ACEI or ARB
OR
2) in black patients with advanced heart failure as an adjunct to standard therapy

ADVERSE
Hydralazine & isosorbide dinitrate
Headache, dizziness

Hydralazine
Tachycardia, peripheral neuritis, lupus-like syndrome

115
Q

Carvedilol Metoprolol

A
  • B-blockers for HF. Reverse cardiac remodeling & reduction in mortality & hospitalization
  • Decrease HR (negative inotropic effect) & inhibit renin release (B1 receptors)
  • Prevent deleterious effects of norepinephrine on cardiac muscle fibers -> decreased remodeling, hypertrophy etc
  • Can get initial exacerbation of symptoms (start at low dose & gradually increase over several weeks)

Recommended in addition to an ACEI for patients with:

  • Symptomatic heart failure
  • Asymptomatic patients with a decreased LVEF or history of MI

ADVERSE
• Same as all B-blockers
• Use cautiously in asthmatics and patients with severe
bradycardia
• Fluid retention (upon initial treatment) – an increasing dose of concurrent diuretic may help

116
Q

Digoxin

A
  • Cardiac glycoside
  • Used in HF with atrial fibrillation (main application)
  • Can be used (in addition to ACEI & B-blocker) to decrease symptoms, increase exercise tolerance & decrease rate of hospitalization
  • Derived from digitalis (foxglove) plant
  • Digoxin can decrease the symptoms of heart failure, increase exercise tolerance and decrease rate of hospitalization, but does not increase survival

• Digitalis inhibits Na+/K+ exchange by Na+/K+-ATPase
• Ca2+ is retained intracellularly -> increased [Ca2+]i
that enhances contractility of cardiac muscle and -> increases cardiac output
• Also, reduced sympathetic activity (RAAS and AV velocity), reduced peripheral resistance -> decreased HR
• Enhanced vagal tone

117
Q

Digoxin adverse effects

A

ADVERSE
• Cardiac effects: arrhythmias, characterized by slowing of
AV conduction (atrial arrhythmias)
• GI effects: anorexia, nausea & vomiting
• CNS effects: headache, fatigue, confusion, blurred vision, alteration of color perception, halos on dark objects

Factors predisposing to digoxin toxicity
• Quinidine, verapamil & amiodarone can cause digoxin toxicity by displacement from tissue protein-binding sites & competition for renal excretion ([digoxin] can increase by 70-100%)

Precipitating factors for adverse effects
• Hypokalemia
• Drug accumulation / relative overdose
• Hypomagnesemia or hypercalcemia
• Hyperthyreosis
• Abnormal renal function
• Respiratory disease
• Acid-base imbalances
• …. age above 65, low body weight, fever etc

Factors predisposing to digoxin toxicity
• K+-depleting diuretics
• Corticosteroids
• Hypothyroidism
• Hypoxia
• Renal failure
• Myocarditis

INTERACTIONS
K+
Digoxin & K+ inhibit each others binding to Na+/K+ ATPase
• Hyperkalemia reduces digoxin activity
• Hypokalemia facilitates digoxin activity

Ca2+
Accelerates overloading of Ca2+ stores
• Facilitates toxic actions of digoxin, esp.
arrhythmias

Mg2+
• Opposite to Ca2+ (Mg2+ antagonizes effects of Ca2+)

Treatment of digoxin toxicity
• Withdraw drug for some days and/or reduce dose
• Monitor plasma digoxin and K+ levels, ECG
• Adjust electrolyte status (K+ supplements)
• Ventricular tachyarrhythmia: lidocaine, magnesium, adjust K+ to high normal

Severe digoxin intoxication
• Bradyarrhythmias, suppressed automaticity

118
Q

Inamrinone Milrinone

A
  • PDE III inhibitors. Inhibit myocardial cAMP PDE activity -> increased cAMP levels (+ve inotropic effect and increased cardiac output)
  • Possess systemic & pulmonary vasodilator effects (reduce both preload and afterload)
  • Shown to increase AV conduction slightly
  • Used for short-term therapy in patients with intractable heart failure (acute HF)
119
Q

Dopamine

A

Stimulates both adrenergic & dopaminergic receptors

  • Lower doses = mainly dopaminergic stimulating (produce renal and mesenteric vasodilation)
  • Higher doses = both dopaminergic & B1 stimulating (produce cardiac stimulation & renal vasodilation)
  • Large doses = stimulate a receptors (vasoconstriction)

• Used in the treatment of shock (eg, MI, open heart surgery, renal failure, cardiac decompensation) which persists after adequate fluid volume replacement. Dopamine also promotes diuresis.
63

120
Q

Glucagon

A

Stimulates adenylyl cyclase to produce increased cAMP (by binding to GPCR), leading to potent inotropic and chronotropic effects
• Produces similar effect to B-agonists, WITHOUT requiring functioning B-receptors
• Used as a cardiac stimulant in management of severe cases of B-blocker overdosage

121
Q

Treatment of diastolic HF

A

Diuretics
• Can be used to treat any resulting pulmonary edema; must be used cautiously (do not want stroke volume to decrease)

Calcium-channel blockers
• In diastolic failure inotropy can be normal so Ca2+- channel blockers do not impair stroke volume. Shown to be beneficial in improving ventricular relaxation and reducing heart rate

B-blockers
• Similar beneficial effects to Ca2+-channel blockers

Agents NOT used
• Positive inotropes (increasing inotropy can lead to increased outflow obstruction)

122
Q

Classification of anti-arrhythmic drugs

A

Class I - fast channel blockers (Na+)
• (IA) Quinidine, procainamide, disopyramide
• (IB) Lidocaine, mexiletine, tocainide
• (IC) Flecainide, propafenone

Class II - B-blockers (Ca2+)
• Propranolol, metoprolol, esmolol

Class III - inhibitors of repolarization (K+)
• Amiodarone, sotalol, dofetilide

Class IV - calcium channel blockers (Ca2+)
• Verapamil, diltiazem

Miscellaneous
• Digoxin, adenosine, magnesium, atropine

123
Q

Class I antiarrhythmics

A

• Block fast inward Na+ channels
• Decreased Na+ entry slows rate of rise of Phase 0
depolarization
• Cause in excitability and conduction velocity
• Different properties depending on their affinity for Na+ channel
• Use / state-dependent

124
Q

Class IA antiarrhythmics

A

Quinidine, Procainide, Disopyramide

• Slow rate of change of phase 0
• Slowing conduction, prolonging action potential &
increasing ventricular effective refractory period
• Prolong phase 3 by an inhibiting K+ channels
• Intermediate speed of association with activated / inactivated Na+ channels & intermediate rate of dissociation

125
Q

Quinidine

A
  • Class IA anti-arrhythmic. Concomitant Class III activity (block K+ channels)
  • Due to toxicity is being replaced by Ca2+ antagonists

USES
• Conversion and prevention of relapse into atrial fibrillation +/or flutter
• Suppression of ventricular arrhythmias

MOA/PK
• Prevents Na+ influx
• Slows Phase 0
• Decreases slope of Phase 4
• Inhibits K+ channels
• Quinidine sulfate = rapid oral absorption
• Forms active metabolites (CYP 3A4)
• Inhibits CYP 2D6, 3A4 & P-glycoprotein

ADVERSE
• Arrhythmias (torsades de pointes)
• SA & AV block or asystole
• Nausea, vomiting & diarrhea (30-50%)
• Thrombocytopenic purpura
• Toxic doses – ventricular tachycardia (exacerbated by hyperkalemia)
• Cinchonism (blurred vision, tinnitus, headache, psychosis)
• Mixed a-adrenergic block & antimuscarinic properties
• Can increase [digoxin] by decreasing renal clearance

CONTRAINDICATIONS
Do not use in patients with:
• Complete heart block

Use with extreme caution in patients with:
• Prolonged QT interval
• History of Torsades de Pointes
• Incomplete heart block
• Uncompensated heart failure
• Myocarditis
• Severe myocardial damage

126
Q

Procainide

A
  • Class IA anti-arrhythmic. Derivative of local anesthetic procaine
  • Similar actions to quinidine
  • Blockade of Na+ channels in activated state
  • Blockade of K+ channels
  • Antimuscarinic properties

Clinical Applications
• Ventricular arrhythmias
• Due to proarrhythmic effects use should be reserved for life-threatening arrhythmias

PK
• Oral
• Metabolized by CYP 2D6
• Partly acetylated to N-acetylprocainamide (NAPA) which prolongs duration of action potential (class III)

ADVERSE
Chronic use = high incidence of AE
• Reversible lupus-like syndrome (25-30%)
• Toxic doses: asystole, induction of ventricular arrhythmias
• CNS effects (depression, hallucination, psychosis)
• Weak anticholingeric effects
• Hypotension

CONTRAINDICATIONS
• Hypersensitivity
• Complete heart block
• 2nd degree AV block
• Systemic lupus erythematosus (SLE)
• Torsades de Pointes
• Heart failure & hypertension (use with caution)

127
Q

Disopyramide

A
  • Class IA anti-arrhythmic. Strong negative inotropic effect (> quinidine & procainamide)
  • Strong antimuscarinic properties
  • Causes peripheral vasoconstriction • Blocks K+ channels

Clinical Applications
• Supraventricular and ventricular arrhythmias

ADVERSE
• Pronounced negative inotropic effects
• Severe antimuscarinic effects (dry-mouth, urinary
retention, blurred vision, constipation)
• May induce hypotension & cardiac failure without pre- existing myocardial dysfunction

128
Q

Class IB antiarrhythmics

A

Lidocaine Mexiletine Tocainide

  • Slows Phase 0 & decreases slope of Phase 4
  • Shortens Phase 3 repolarization
  • Little effect on depolarization phase of action potential in normal cells
  • Decrease duration of action potential by shortening repolarization
  • Rapidly associate and dissociate with Na+ channels
129
Q

Lidocaine

A

• Class IB anti-arrhythmic. Local anesthetic.
• Rapidly associates & dissociates from Na+ channels
• More effect on ischemic or diseased tissue
• Particularly useful in treating ventricular arrhythmias
• LITTLE EFFECT on K+ channels
Pharmacokinetics
• IV only (extensive first-pass metabolism)

USES
• Drug of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia
• Little effect on atrial or AV junction arrhythmias

ADVERSE
• Wide toxic-therapeutic ratio
• CNS effects (drowsiness, slurred speech, agitation etc.) • Little impairment of left ventricular function
• NO negative inotropic effect
• Cardiac arrhythmias (
• Toxic doses: convulsions, coma

130
Q

Mexiletine

A
  • Class IB anti-arrhythmic. Orally active derivative of lidocaine
  • Can be used both orally and IV

USES
• Management of severe ventricular arrhythmias

ADVERSE
Mainly CNS & GI

131
Q

Class IC antiarrhythmics

A

Flecainide Propafenone

• Markedly depress Phase 0 of action potential
-> marked slowing of conduction of action potential but, little effect on duration or ventricular effective refractory period
• Associate and re-associate slowly with Na+ channels
• Show prominent effects even at normal heart rates

132
Q

Flecainide

A
  • Class IC antiarrhythmic
  • Decreases rate of rise of Phase 0 depolarization without affecting duration of action potential
  • Causes slight prolongation of refractory periods
  • Automaticity reduced by an increase in threshold potential of ventricle rather than decrease in slope of Phase 4

USES
• Severe symptomatic ventricular arrhythmias (life- threatening only), premature ventricular contraction or ventricular tachycardia resistant to other therapy
• Severe symptomatic supraventricular arrhythmias & prevention of paroxysmal atrial fibrillation

ADVERSE
• Aggravates CHF (negative inotropic effect)
• CNS effects: dizziness, blurred vision, headache
• GI effects: nausea, vomiting, diarrhea
• Life-threatening arrhythmias & ventricular tachycardia

133
Q

Propafenone

A
  • Class IC antiarrhythmic
  • Decreases rate of rise of Phase 0 depolarization without affecting duration of action potential
  • Prolongs conduction & refractoriness in all areas of the myocardium
  • Prolongs effective refractory period & reduces spontaneous automaticity

USES
• Used for treatment of life-threatening ventricular arrhythmias and the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation

134
Q

Class II antiarrhythmics

A

Propranolol, Metoprolol
• Reduce incidence of sudden arrhythmic death after MI
• Control of supraventricular tachycardias (atrial
fibrillation & flutter, AV nodal re-entrant tachycardias)
• Ventricular tachycardias (catecholamine-induced arrhythmias, digoxin toxicity

Esmolol
• Short-acting B1-selective antagonist
• t1/2 =~9min
• Used IV for treatment of acute arrhythmias occurring during surgery or in emergency situations

ADVERSE - Propranolol, Metoprolol, Esmolol
• Bradycardia, hypotension, CNS effects etc.
• Contraindicated in CHF, severe bradycardia or heart block and severe hyperactive airway disease

135
Q

Class III antiarrhythmics

A

• Block repolarizing K+ channels
• Prolong action potential (and QT interval) without
altering Phase 0 or resting membrane potential
• Prolong effective refractory period
• All have potential to induce arrhythmias

136
Q

Amiodarone

A

• Class III antiarrhythmic
• Related structurally to thyroxine (contains iodine)
• Complex MOA showing Class I, II and III (& some IV)
effects
• Dominant effect = K+ channel blockade.
• Decreases AV conduction & sinus node function.
• Blocks mostly inactivated Na+ channels
• Weak Ca2+ channel blocker
• Inhibits adrenergic stimulation (a & B-blocking properties)
• Antianginal & antiarrhythmic activity

USES
• One of most commonly employed antiarrhythmics (despite side-effect profile)
• Used in the management of ventricular & supraventricular arrhythmias
• Low doses for maintaining normal sinus rhythm in patients with atrial fibrillation

PK
• Oral (very well absorbed)
• t1/2 = several weeks (extensively distributed in adipose tissue), loading dose required
• Full clinical effects (& adverse effects) may take 6 weeks to achieve

ADVERSE
• Long term use = > 50% patients show adverse effects severe enough for discontinuation
• Many are dose-related and reversible on decreasing dose eg, interstital pulmonary fibrosis, GI intolerance, tremor, ataxia, dizziness, hyper- or hypothyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, hypotension, bradycardia, AV block, arrhythmias
• Blue skin discoloration (iodine accumulation)
• Despite prolonging the QT interval, has low incidence of Torsades de Pointes.

CONTRAINDICATIONS
Patients taking:
• Digoxin, theophylline, warfarin, quinidine

Patients with:
• Bradycardia
• SA or AV block
• Severe hypotension
• Severe respiratory failure

137
Q

Sotalol

A
  • Class III antiarrhythmic. Potent non-selective B-blocker
  • Inhibits rapid outward K+ current
  • Prolongs repolarization & duration of action potential • Lengthens refractory period

USES
• Treatment of life-threatening ventricular arrhythmias
• Maintenance of sinus rhythm in patients with atrial
fibrillation & flutter who are currently in sinus rhythm
• Due to pro-arrhythmic effects – do not use for asymptomatic arrhythmias

ADVERSE
• As for B-blockers
• Lowest rate (of antiarrhythmics) of acute or long-term
adverse effects
• Torsades de pointes (prolongs QT interval)
• Use with caution in patients with renal impairment

138
Q

Dofetilide

A

• Class III antiarrhythmic. Potent and pure K+ channel blocker

USES
• Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation / flutter of longer than one week duration who have been converted to normal sinus rhythm
• Conversion of atrial fibrillation / flutter to normal sinus rhythm

PK
• Excreted in urine (~80 % unchanged) -> if kidney fxn falls, must adjust dose to prevent toxicity

ADVERSE
• Headache, chest pain, dizziness, ventricular tachycardia • Torsade de Pointes (prolongs QT interval)

139
Q

Class IV antiarrhythmics

A

• Ca2+ channel blockers
• Decrease inward Ca2+ current leads to decreased rate
of Phase 4 spontaneous depolarization
• Slow conduction in tissues dependent on Ca2+ current (SA & AV nodes)
• Major effects on both vascular smooth muscle & heart

Verapamil (phenylalkylamine class) = relatively selective for the myocardium and is less effective as a systemic vasodilator drug

Diltiazem (benzothiazepine class) = intermediate selectivity for the myocardium between verapamil and the dihydropyridines

Major Effects:
• Decrease contractility (negative inotropy)
• Decrease heart rate (negative chronotropy)

  • Inhibit voltage-sensitive Ca2+ channels -> decrease in slow inward current that triggers cardiac contraction
  • Bind only to open, depolarized channels, preventing repolarization before drug dissociates
  • Use/state-dependent
  • Slow conduction & prolong effective refractory period
  • Decrease conduction velocity (negative dromotropy)

USES
• More effective against atrial than ventricular arrhythmias • Supraventricular tachycardia is major arrhythmia
indication
• Reduction of ventricular rate in atrial fibrillation & flutter

ADVERSE
• Negative inotropes
• Transient decrease in BP
• CNS effects (headache, fatigue, dizziness) • GI effects (constipation, nausea)

CONTRAINDICATIONS
• Verapamil can increase the concentrations of other cardiovascular drugs such as digoxin, dofetilide, simvastatin, & lovastatin
• Hypertension, angina

140
Q

Digoxin - antiarrhythmic

A
  • Shortens refractory period in atrial & ventricular myocardial cells
  • Prolongs effective refractory period & diminishes conduction velocity in AV node

USES
• Control of ventricular response rate in atrial fibrillation & flutter with impaired left ventricular function or heart failure

MOA
Heart Failure
• Positive inotrope (increases intracellular [Ca2+]i)

Arrhythmias
• Direct AV node blocking effects & vagomimetic
properties:
1) Inhibition of Ca2+ currents in AV node
2) Activation of Ach-mediated K+ currents in atrium

Major indirect actions
• Hyperpolarization
• Shortening of atrial action potentials
• Increases in AV nodal refractoriness

(1) Slows AV conduction,
and
(2) Prolongs effective refractory period of the AV node
thereby decreasing the fraction of atrial impulses that are conducted through the node
-> useful in treating atrial flutter / fibrillations (by controlling ventricular rate)

ADVERSE
• Ectopic ventricular beats -> ventricular tachycardia & fibrillation

141
Q

Adenosine

A
  • Antiarrhythmic. Naturally occurring nucleoside (P1 receptor agonist)
  • High doses = decreases conduction velocity & prolongs refractory period as well as decreasing automaticity in AV node
  • Very short t1/2 (15 s)

• Enhances K+ conductance
• Inhibits cAMP-mediated Ca2+ influx
• Leads to hyperpolarization esp. in AV node
Clinical Applications
• IV adenosine = drug of choice for abolishing acute supraventricular tachycardia

ADVERSE
Low toxicity
• Flushing
• Burning
• Chest pain
• Hypotension
• Bronchoconstriction in asthmatics (may persist up to 30 min)

142
Q

Mg2+ - antiarrhythmic

A

• Functional Ca2+ antagonist

Used for treatment of:
• Torsades de pointes
• Digitalis-induced arrhythmia
• Prophylaxis of arrhythmia in acute MI

143
Q

Atropine - antiarrhythmic

A

• Used in bradyarrhythmias to decrease vagal tone

144
Q

Arrhythmias - rate and rhythm control drugs

A
  1. Rate control (slowing of ventricular rate) - negative dromotropic agents
    • Ca2+ channel blockers
    • B-blockers
    • Digoxin (only first-line if HF is present)
  2. Rhythm control (induction / maintenance of sinus rhythm)
    • Class IC antiarrhythmics, (flecainide, propafenone)
    • Class III antiarrhythmics, (amiodarone, dofetilide)

• Heparin (IV)
Unstable patients who require immediate cardioversion
• Warfarin (oral)
In stable patients cardioversion should be delayed for 3- 4 weeks until adequate anticoagulation has been achieved

145
Q
A

Term 5 Flash Cards (16 decks)

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