What are the physiologic responses to activation of B1 and B2 adrenergic receptors?

B1 Cardiac cells: increased heart rate adn contraction strength juxtaglomerular cells (kidney): increase blood pressure B2 Vasculat: dilate vessels Bronchial: dilate bronchial tubes to open the airway B-receptor agonists are commonly used to treat patients suffering from diseases that close the airway, namely asthma & COPD (chronic obstructive pulmonary disease)

Antiarrhythmic Agents II Flashcards by Katherine E Nordstrom

Describe the effect of beta-adrenergic stiumlation of the atria & ventricles?

stimulation of the SA & AV nodes?

Atria & ventricles (stronger)
- B stimulation of I_Ca-Lvia
  - cAMP –> PKA –> phosphorylation of Ca_L-type channels
  - increases the size of the action potential & plateau phase is lager b/c more calcium coming in
SA & AV nodes (faster)
- B stimulatin of I_f & I_Ca-L
  - via CAMP –> PKA –> phosphorylation of funny & Ca_L-typechannels
  - action potential becomes more frequent, the interval between the action potentials becomes more shorter, its easier to generate an action potential & the action potential is steeper

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What is the general response of B-adrenergic receptor blockers in the AV node & the atria and venricles?

Slow AP conduction through AV node
- SA & AV node: reduce B-stimulation of I_f to decrease HR
- reduce B-stimulation of I_Ca_-L to increase AP threshold in AV node
Reduce B-stimulation of cardiac contraction
- reduce B-stimulation of I_Ca-L (phase 2) to reduce cardiac contraction
Other cardiac benefits
- normalized Ca²⁺ handling, reduced SERCA phosphorylation to reduce Ca²⁺_i overload
** shown to reduce mortality in HF patients !!

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What are the Antiarrhythmic Class I drugs?

Esmolol (IV only)
Metoprolol
Atenolol
Propranolol

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What is is the mechism of action of beta-blockers?

Cardiac effect
- Inhibit B-adrenergic receptor stimulation by SNS
This results in:
- reduced I_f to slow SA node AP rate (HR)
- reduced I_Ca-Lto slow AV conduction velocity
- suuppression of automaticity - suppress EADs (early after depolarizations)

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What are the clinical uses for beta blockers?

Uses: most commonly prescribed drug class for CV disease
- sinus tachycardia
- supraventricular and ventricular tachyarrhythmias
- atrial fibrillation: rate control
- stable angina, hypertension, heart failure
- reduces mortality following acute MI in HF
All patients with either HF or post MI will be on a B-blocker, if they can tolerate it

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What are the physiologic responses to activation of B₁ and B₂ adrenergic receptors?

B₁
- Cardiac cells: increased heart rate adn contraction strength
- juxtaglomerular cells (kidney): increase blood pressure
B₂
- Vasculat: dilate vessels
- Bronchial: dilate bronchial tubes to open the airway
B-receptor agonists are commonly used to treat patients suffering from diseases that close the airway, namely asthma & COPD (chronic obstructive pulmonary disease)

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What are the nonselective B-blockers?

What are the cardioselective B-blockers? What receptor are they selective for?

Nonselective B-blockers
- both B₁ and B₂-adrenergic receptors
  - propranolol
Cardioselective B-blockers
- more selective for B₁-adrenergic receptors
  - Atenolol
  - Metoprolol
  - Esmolol

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What are the common adverse effects of B-blockers?

Both cardioselective & nonselective
- CV: bradycardia, heart block, hypotension, exercise intolerance
More common nonselective due to B₂-blockers
- Pulmonary: bronchospasm
- Vascular: cold extremities, Raynaud’s phenomenon, claudication, and erectile dysfunction
- Metabolic: excerbation of hypoglycemia in patients taking oral hypoglycemic agents or insulin, new onset diabetes

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What type of drug is Propranolol?

Phamacokinetics?

Adverse effects?

Propranolol (nonselective B-blocker)

Pharmacokinetics
- stron 1st pass metaboism, CYP2D6
- Propranolol levels strongly increased by CYP2D6 blockers (e.g. quinidine, terbinafine)
- Lipophilic: enters the bran well
Adverse effects: (additional)
- CNS: nightmares, fatigue, depression
- Pulmonary: bronchospasm (B₂-receptor block)
- Contraindicated in asthma & COPD patients

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What type of drug is Metoprolol?

Phamacokinetics?

Adverse effects?

Metoprolol

Cardioselective - B₁- adrenergic receptors

Pharmacokinetics
- Metabolized by CYP2D6
- plasma levels increase by CYP2D6 blockers (e.g. quinidine)
- less lipophilic than propranolol
Adverse effects
- less pulmonary effects due to low B₂-receptors block
- less metabolic & vascular effects dur to low B₂-block
- less CNS effects due to lower CNS penetration
- Cardiac adverse effects due to bock of B₁-receptors block
  - bradycardia, heart block, hypotension, exercise intoerance

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What type of drug is Atenolol?

Phamacokinetics?

Adverse effects?

Atenolol

(cardioselective - B₁-adrenergic receptors)

Pharmacokinetics
- excreted by the kidney unchanged
- less potential drug-drug interaction than metoprolol
- Plasma levels increased in patients with renal disease
- Hydrophilic - little or no CNS penetration
Adverse effects
- less pulmonary effects due to low B₂-receptors block
- less metabolic & vascular effects due to low B₂-block
- No CNS effects due to poor CNS penetration
- Cardiac adverse effects due to block of B₁-receptors block
  - bradycardia, heart block, hypotension, exercise intolerance

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What type of drug is Esmolol?

Phamacokinetics?

Adverse effects?

Esmolol (IV only)

Cardioselective - B₁-adrenergic receptors

Use:
- intraoperative arrhythmias, constant infusion
pharmacokinetics
- very short plasma lifetime T1/2 = 10 minutes
- metabolized by plasma esterases
adverse effects
- cardiac: hypotension

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How do Class III anti-arrhythmia drugs work?

Block K⁺ currents during repolarization (phase 3)
- longer action potential which generates the longer effective refractory period
this prolongs refractoriness (ERP) by prolonging AP duration
Amiodarone also inhibits I_Na, I_Ca and B-receptors
trying to maintain the heart in sinus rhythm

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What are the antiarrhythmic class III drugs?

Amiodarone
Dronedarone
Dofetilide
Ibutilide (IV only)
Sotalol

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What are the common uses of Class III: Potassium Channel Blockers?

Drug-drug interactions?

Common effect
- All block I_Kr
Uses
- Convert an arrhythmia back to sinus rhythm (IV) Or maintain the heart in sinus rhythm (oral)
  - ventricular tachycardia
  - supraventricular tachycardia - Rhythm control
Drug-drug interactions
- avoid prescribing other drugs that block I_Kr
  - Macrolides (clarithromycin, erythromycin)
  - fluoroquinolones (levofloxacin, moxifloxacin)
  - lefamulin
  - telavancin

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What type of drug is Amiodarone?

Phamacokinetics?

Adverse effects?

Drug-drug interactions?

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Amiodarone

most commonly used class III agent- Potassium channel blocker

Also blocks I_Na, I_Ca, and B-adrenergic receptors

Uses
- IV: convert arrhythmia back to sinus rhythm
  - termination of ventricular tachycardia
  - termination of supraventricular tachycardia
- oral: maintain sinus rhythm
  - supraventricular tachyarrhythmias
    - atrial fibrillation - rhythm control
  - ventricular tachyarrhythmias
  - redue shock frequency in patients with ICD
- _Safe in patients with structural heart disease (_MI)
Pharmacokinetics
- active metabolite, desethylamiodarone
- hepatic metabolism: CYP3A4
- Inhibitor of CYP3A4, CYP2C9, and P-glycoprotein (not potent)
- T1/2 40-55 days - Hepatic excretion
  - several weeks in required to reach full effect
  - loading dose (400-1200 mg/day) for 10-20 days
    - Taper to maintenance dose (typically 200 mg/day)
Adverse effects
- Hepatic - liver function - test before & monitor during
- GI: Stomach upset, constipation
- CV: LQT, but low risk of Torsades de Pointes
  - also block I_Na, I_Ca, and B-receptors (mechanism you get Torsades)
- Pulmonary fibrosis - not used with lung disease
  - potentially fatal
- Thyroid dysfunction (either hypo or hyper)
- Tissue deposition
- Skin reactions - photodermatitis
Drug-drug interactions
- moderate inhibitor of
  - CYP2C9: most NSAIDs, Celecoxib, ARBs
  - CYP3A4: statins, calcium channel blockers
- inhibits P-glycoprotein - digoxin transport

What type of drug is Dronedarone?

uses?

Phamacokinetics?

Adverse effects?

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Dronedarone- amiodarone analog w/o iodine

potassium channel blocker

Uses
- atrial flutter/fibrillation after conversion
Pharmacokinetics
- T1/2: 13-19 hrs (,uch shorter than amiodarone)
- hepatic metabolism by CYP3A4
  - inhibits CYP2D6, CYP3A4, and P-glycoprotein
Adverse effects: No iodine = no thyroid problems
- hepatic toxicity - avoid in patients with liver disease
- contraindicated in patients with (increased mortality)
  - permanant atrial fibrillation
  - severe heart failure
  - conduction problems

What type of drug is Dofetilide?

Uses?

Phamacokinetics?

Adverse effects?

Drug-drug interactions?

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Dofetilide

pure I_Kr-channel blocker (oral)

Uses
- maintain sinus rhythm
  - atrial flutter/fibrillation (rhythm control)
  - ventricular tachyarrhythmia
pharmacokinetics
- 20% of drug metabolized by CYP3A4
- 80% renal excretion unchanged
Adverse effects: Narrow therapeutic index
- Torsades de Pointes - problem at treatment start
- Required: treatment must be initiation in-hospital to monitory for Torsades de Pointes over a 3-day period
Drug-drug interactions: drugs to avoid
- plasma levels increased by verapamil, ketoconazole, trimethoprims/sulfamethoxazole, hydrochlorothiazide, and cimetidine (OTC)

What type of drug is Ibutilide?

Phamacokinetics?

Adverse effects?

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Ibutilide (IV only) - potassium channel blocker

also increase slow inward Na⁺ current

Uses
- pharmacologically conert atrial flutter or fibrillation into sinus rhythm
Pharmacokinetics
- rapid hepatic metabolism with T1/2 2-6 hours
Adverse effects: Torsades de Pointes
- patients must be monitored for several hours following termination of ibutilide treatment to monitor for Torsades de Pointes

What type of drug is Sotalol?

Uses?

Phamacokinetics?

Adverse effects?

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Sotalol - Potassium channel blocker

also a nonselective B-blocker (Class II)

Uses
- maintain sinus rhythm
  - atrial flutter/fibrillation (Rhythm control)
  - ventricular arrhythmias
Pharmacokinetics
- renal excretion: unchanged (fewer drug-drug interaction problems)
Adverse effects
- torsades de pointes
- recommended to initiate treatment in-hospital setting, but many cardilogists do not follow this recommendation
- bronchospasm - due to B₂-receptor block

What are the 2 classes of calcium channel blockers?

What do they do?

Uses?

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Dihydropyridine
- selectively inhibits smooth muscle I_Ca-L current
  - smooth muscle relaxation
    - antihypertensive drugs
    - antianginal drugs
Non-dihydropyridine (Class IV antiarrhythmic drugs)
- more selectively inhibits cardiac muscle I_Ca-L current
  - slows heart rate (SA & AV nodes) and decreases cardiac contraction strength (ventricular myocytes)
    - antiarrhythmic drugs
    - antianginal drugs

How do Class IV drugs work?

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SA node: decrease AP rate (HR)
AV node: slow conduction velocity
myocytes: decrease EADs & DADs

Describe the mechanism of action for the calcium channel blockers

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Block cardiac I_Ca-L indirectly reduce NCX activity
- increases AP threhold in SA & AV nodes
  - reduced heart rate - SA node
  - Reduced maximum AV node rate
  - slowed conduction through AV node - rate control
- reduce plateau depolarization of AP (phase 2, I_Ca-L )
- Suppress ectopic excitability
  - suppress EADs - block I_Ca-L
  - Suppress DADs – suppress NCX action by I_Ca-L block

What are th Antiarrhythmic Class IV drugs?

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Diltiazen
Verapamil

Clinical uses of Class IV drugs? Common adverse effects?

* Clinical uses * supraventricular and ventricular tachycardias * atrial flutter/fibrillation: **rate control** * other uses: angina, occasionally hypertension * Common adverse effects * GI: constipation * CV: heart block, heart failure, hypotension, bradycardia, and asystole (esp. rapid IV) * _Contraindicated_: heart failure with low ejection fraction, slow heart rate, low blood pressure * _contraindicated_: Wolff-Parkinson-White syndrome

Pharmacokinetics of Verapamil & Diltiazem? Drug-drug interactions?

* Pharmacokinetics * both metabolized by CYP3A4 * both also moderate blockers of CYP3A4 * both inhibit P-glycoprotein * potential drug-drug interactions * e.g. statins (CYP3A4) * e.g. dofetilide (p-glycoprotein & CYP3A4) -- **AVOID**

What is the mechanism of action of **adenosine**? Use? Pharmacokinetics? Adverse Effects?

* MOA: activation of adenosin receptors * adenosine receptors - GPCR: activates G_i * reduces intracellular cAMP * slows heart rate * reduced I_Ca-L - decreased cAMP to decreased PKA * reduced I_f - decreased cAMP to decreased PKA * activates G-protein-activated inward rectifier K⁺ (GIRK) channels * slows conduction velocity * inhibits I_Ca-L - decrease cAMP to decrease PKA * increases ERP in AV node * Dialates coronary and peripheral vessels * inhibits I_Ca-L - decrease cAMP to decrease to PKA activity * Use * _acute_ termination of paroxysmal supraventricular tachycardia (PSVT) * Pharmacokinetics (IV only) * rapid onset, short duration of action - T1/2 - _10_ * Adverse effects * flushing, dyspnea * cheest pain, transient heart block, bronchoconstriction

What is the mechanism of action of **Cardiac glycoside**? Use? Pharmacokinetics? Adverse Effects?

* MOA * enhanced vagal tone: increased muscarinic receptor activation of GIRK * slows HR (SA node) * Afib * slows conduction through AV node - **Rate control** * Inhibits Na+/K+ ATPase (pump) * positive inotropic agent **(HF)** * indirect inhibition of NCX to increase intracellular Ca²⁺ * Uses * **Atrial flutter/fibrillation ONLY: Rate control** * heart failure: inotropic agent * Pharmacokinetics * P-glycoprotein transport * Hepatic metabolism * Rena excretion: 50-70% unchanged * Adverse effects * Arrhythmias * Bradycardia - vagomimetic effect * ventricular tachycardia * excessive [Ca²⁺]_I runs NCX backwards * high NCX activity generates DADs * DADs can produce ectopic activity * Drug-drug interactions * P-glycoprotein inhibitors * Amiodarone, dronedarone, diltiazem, verapamil, propranolol * Can increase plasma digoxin levels ot increase toxicity

Uses for **Magnesium sulfate**?

* Corrects hypomagnesemia * may suppress EADs * uses: * refractory ventricular arrhythmias, and drug-induced torsades de pointes arrhythmias

use for potassium chloride?

* corrects hypokalemia, which may suppress ectopic pacemakers and prevent or terminate some arrhythmias

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Antiarrhythmic Agents II Flashcards

(33 cards)