Positive Inotropic Agents Flashcards
Digoxin MOA?
- Selectively and reversibly binds to alpha subunit of Na+/K+ ATPase
- ↓ in outward Na+ movement and ↑ in intracellular Na+
- This ↓ outward movement of Ca2+ via Na+/Ca2+ exchanger.
- ↑ in intracellular Ca2+ concentrations
- Net effect is ↑ force of contractions
3 examples of cardiac glycoside drugs
- Digoxin
- Digitoxin
- Quabain
Digoxin’s Cardiac effects
- Positive inotrope
- Negative chronotrope
- Negative dromotrope
Digoxin’s indirect effect on the PSNS
- Indirectly activates vagal nuclei and nodose ganglion which slows HR
Neurohormonal effects of Digoxin
- Sensitizes baroreceptors which ↓ SNS and RAAS
Cardiovascular effects of Digoxin
- ↑ SV and CO
- ↓ Heart size
- ↓ LV end diastolic pressure and ↓ wall pressure
- ↓ O2 consumption
- ↑ Renal function and diuresis
- ↓ PAP and PWP
- Ventricular function curve (Frank Starling curve) shifts left and up
Effect of positive Inotropes such as Digoxin and Dobutamine on the Frank Starling Curve
Shifts the curve up and to the left towards normal - meaning there is greater CO or SV for a given level of left ventricular filling
Digoxin EKG effects
- Prolonged PR interval bco delayed conduction through AV node
- ST segment depression
- Short QT intervals
- T wave diminished or inverted
When Digitalis is Dc’d, how long does it take for ECG changes to disappear?
Weeks - Long half life
Why is it important to assess PTs on Digitalis for AMI?
SGT and T wave changes are common in PTs on Digitalis but may also suggest myocardial ischemia.
Clinical uses for Digoxin
- Rate control for SVTs
- Mgmt of chronic CHF
Digoxin Pharmokinetics
- Absorption in small intestine
- Bioavailability 70 to 100% depending on oral dosage form
- Distributes more to heart and skeletal tissue
- Onset 1.5 to 6 hrs (PO) and 5 to 30 mins (IV)
- Does not distribute into adipose tissue or cross placenta
- Low protein binding (20 to 30%)
- Loading and maintenance doses based on LBW
Digoxin Metabolism
- Small % metabolized by liver (not dependent on CYP450)
- Primarily excreted by kidneys (2/3 of unchanged drug)
- t 1/2 = 36hrs +/= 8 hrs (↑ with renal failure)
Explain why Digoxin is not removed by exchange transfusions and dialysis?
Most of the drug is bound to tissue and does not circulate in plasma.
Which diseases increase and decrease levels of Digoxin?
- Reduced by CHF, hypothyroidism, renal dysfunction
- Increased by hyperthyrroidism (because of high CO)
Digoxin Therapeutic Ranges
- Adults (0.5 to 2ng/mL)
- Pediatric (2.5 to 3.5ng/mL)
- CHF (0.5 to 0.9ng/mL)
When should you obtain Digoxin levels once the PT starts to take it?
6 to 8 hrs after a dose due to the long distribution phase
Take precaution when giving Digoxin to which PTs?
- Hypokalemia, hypomagnesemia, and hypercalcemia
Digoxin contraindicated in which PTs?
- Acute ↓ LV contractility
- Cardioversion
- Wolfe-Parkinson White Syndrome (causes VFIB)
- Severe A-V block
- Constrictive pericarditis
- Idiopathic hypertrophic sub aortic stenosis
Which drugs ↑ serum levels of digoxin and which ones ↓ serum levels of digoxin?
- ↑ digoxin levels by ↓ clearance (diltiazem, verapamil, quinidine, amiodorone, dronedarone, erythromycin)
- ↓ digoxin levels by ↑ clearance (antacids, rifampin, phenobarbital, phenytoin, metoclopramide
Drug-drug interactions with Digoxin
- ↑ Pharmacodynamic effect (Beta-adrenergic agonists and IV calcium)
- ↓ Pharmacodynamic effect (Halothane)
- Beta blockers ↑ risk of bradycardia and AV block
- Thiazide and loop diuretics can cause hypokalemia and hypomagnesemia
Which drugs can protect against Digitalis-enhanced cardiac automaticity?
- Fentanyl
- Enflurane
- Isoflurane
Diagnosis of Digoxin Toxicity
- < 0.5ng/mL rules out toxicity
- 0.5 to 2ng/mL considered therapeutic but can be toxic in PTs with certain conditions or on certain meds
- > 3ng/mL is toxic
- Infants and children toxicity is above 3.5ng/mL
How can Anesthesia and Hypoxemia affect Digoxin toxicity?
- Hyperventilation during anesthesia can ↓ serum K+ causing hypokalemia
- Arterial Hypoxemia ↑ sympathetic activity which can ↑ digoxin toxicity
Why do the elderly have an ↑ risk of developing Digoxin toxicity?
- ↓ Renal function
- ↓ muscle mass
- Drug/drug interaction (they take more meds)
Digoxin effects on certain serum Electrolytes
- K+ : Digitalis competes for K+ binding sites at the Na+/K+, so hypokalemia ↑ digoxin effects while hyperkalemia ↓ digoxin effects
- Mg+ : Hypomagnesemia ↑ digoxin’s effect
- Ca2+ : Hypercalcemia ↑ digoxin’s effect
SxS of Digoxin toxicity
- N and V (most common)
- Visual disturbances
- CNS symptoms (confusion, drowsiness, fatigue, weakness, dizziness, headache, neuralgia)
Cardiovascular SxS of Digoxin Toxicity
- PAT with AV block (most common)
- Vtac, Vfib, (most likely to cause death)
- Sinus bradycardia
- PVCs
- AV block
Treatment of Digoxin Toxicity
- Digibind or Digifab
- Correct underlying issue (i.e. hypokalemia)
- Maintain serum K in normal levels (4 to 5.5mmol/L)
- Lidocaine IV or Phenytoin may be used for digoxin induced ventricular arrhythmias
- Activated charcoal for overdose
- Atropine or pacemaker for bradycardia
Which treatment options should be avoided for digoxin toxicity?
- Sympathomimetics - will wisen arryhthmias
- Quinidine and Amiodarone - will ↑ digoxin levels
- Cardioversion is CONTRAINDICATED
Digoxin Immune Fab (Digifab) MOA
- Digiband is an antigen binding agent from antibodies produced in sheep
- Fab molecule bind digoxin making them unavailable to bind recepters
- Digband/digoxin binded molecule is then excreted by kidneys
Selective Phosphodiesterase PDE Type III inhibitors MOA?
- Aka cAMP PDEIII inhibitors
- Non-catecholamine, nonglycosie compound that exert competitive inhibition of the isoenzyme PDEIII
- Inhibition of PDE III ↑ cAMP in in cardiac muscle
- ↑ cAMP ↑ Ca+ which ↑ inotropic effects
Why are PDE III Inhibitors referred to as Inodilators?
They have inotropic effects as well as decreasing preload and afterload at the same time.
Effect of using catecholamines with Selective PDE III Inhibitors
- Catecholamines also ↑ cAMP but via Beta receptors, so they can used together to get a synergistic effect without getting toxicity
Selective PDE III Inhibitors clinical uses
- Acute left ventricular dysfunction
Selective PDE III Inhibitors current products
- Milranone (primacor)
- Inamrinone (inacor) - replaced with milranone because of its tendency to cause thrombocytopenia
Milranone shouldn’t be used in which PTs?
- Pt’s with severe obstructive aortic or pulmonary valvular disease
- Severe CHF bco ↑ morbidity and mortality with chronic use
Milranone in PTs with Acidosis
Inotropic effects are ↓ bco ↓ cAMP formation in acidotic muscle
Milranone Characteristics
- Loading dose (50μg/kg/ IV over 10 mins, followed by CI of 0.375 to 0.75 μg/kg/min)
- Elimination t1/2 is 2.3 hrs
- Elimination is via kidneys (80% of drug excreted is unchanged)
Milranone Adverse Effects
- Hypotension
- Headache
- Thrombocytopenia
- Angina
- Ventricular arrhythmias
Theophyline
- Similar in structure to methylxanthine and caffeine
- Bronchodilator with anti-inflammatory, immunomodulatory, and stimulatory properties
- Available IV and PO
- ↑ contraction of diagram
- Is a CNS stimulant
- Stimulates release of endogenous catecholamines
Theophyline Clinical Uses
- Airflow obstruction associated with asthma and lung disease
- Bronchospasm due to asthma
- Primary apnea of prematurity
Theophyline MOA
Competitive antagonist of A1 and A2 adenosine receptors, resulting in bronchodilation
Theophyline Pharmokinetics
- Metabolized in liver by CYP450 system
- Active metabolites include caffeine
- 40% protein bound
- t1/2 is 8 hrs but 4 hrs in smokers
- Narrow therapeutic index
Aminophylline
- An ethylenediamine salt form of Theophyline
- 79% Theophyline
- Given IV
- Both theophylline and Aminophyline pass freely across placenta
Theophyline Therapeutic Range
5 to 15 mg/L
Clinical situations in which Theophyline clearance might be reduced?
- Elderly
- Cirrhosis
- CHF
- Fever
What would be the effect of reduced clearance of Theophyline?
Active metabolites such as caffeine would build up in body
Drugs that increase theophylline clearance
- Rifampin
- Phenytoin
- Phenobarbital
- Carbamazepine
- Cigarrette smoking (most significant)
Drugs that decrease Theophyline clearance
- Erythromycin and Clarythromycin
- Cimetidine and Cipro
- Diltiazem, amioderone, and propanolol
Theophyline Adverse effects
- Serum level of 15 to 25mg/L = headache, n and v (most common), tachycardia and palpitations
- Serum levels > 25mg/L = severe n and v, tachyarrhythmias, PVCs, Vtach, seizures, and death
- Theophyline relaxes the LES causing GERD and aspiration risks
Theophyline and Ketamine
Ketamine lowers Theophyline seizure threshold and increase risk for seizures in PTs
Theophyline and Benzos
Theophyline decreases the effectiveness of benzos
Theophyline and neuromuscular blocking agents
Theophyline decreases the effects of neuromuscular blocking agents
Pentoxifylline
- A methylxanthine derivative
- A hemrrheologic agent that ↑ flexibility erythrocytes and ↓ blood viscosity
- Improves blood flow to peripheral limbs
IV Calcium
- Used for positive inotropic effects –> ↑ SV
- Inotropic effects are enhanced in PTs with hypocalcemia and hyperkalemia
- Duration 10 to 20 mins
- Risk of arrhythmias if given to PTs taking digoxin especially if they have hypokalemia
IV Calcium dosing
- 5 to 10 mg/kg IV for Calcium Chloride
- Ca chloride or Ca gluconte IV can be given
- Ca Chloride contains 3x more Ca than Ca gluconate
IV Calcium Adverse Reactions
- Rapid injection cause hypotension, tingling, and oppression (sense of heat wave)
- Local burning sensation
- Irritating to veins
Glucagon
- Polypeptide hormone from Alpha cells in pancreas
- Produced by recombinant DNA technology
- Antihypoglycemic agent with positive inotropic and chronotropic effects
- May be given IM, IV, or SC
Glucagon MOA
- Binds to Glucagon receptors that are G-proteins coupled receptors and stimulates adenyl cyclase to ↑ cAMP
- ↑ cAMP promotes Ca influx
- Does NOT activate or bind to Beta adrenergic receptors
- Does not inhibit PDE
- Can evoke release of catecholamines
Glucagon clinical use
- Used to reverse beta blockers
- Reverse spasms in sphincter of oddi
- Tx of hyperglycemia
- Used to inhibit movement of GI tract during radiological procedures
Glucagon Side Effects
- N and V that is dose-dependent
- Tachycardia and HTN
- Hyperglycemia and Hypokalemia
Glucagon Effects in Pts with Afib
Abrupt increases in HR
