Pharmacology for the Adult-Gerontology Primary Care Nurse Practitioner
Mechanism of Action
Beta adrenergic blocking drugs (also known as beta blockers) work by blocking the action of catecholamines at their receptor sites (Porth & Matfin, 2009). Blockage of the beta receptors in the heart produces a decreased heart rate, decreased contractility and conductivity, which reduces the workload of the heart and decreases myocardial demand (Peterson & Roe, 2017). Blocking the action of beta 1 adrenergic receptors decreases sympathetic stimulation of the heart, resulting in negative chronotropic (decreased heart rate) and negative inotropic
(decreased contractility) effects both at rest and during activity (Cunningham, Brashers, & McCance, 2014; Peterson, Randle, & Randle, 2017). Blockage of the beta 1 receptors also decreases renin secretion from the juxtaglomerular cells, which can contribute to lowering blood pressure (Brenner & Stevens, 2013). The inhibition of beta 1 receptors translates into a decreased work demand on the heart with a reduced oxygen demand. It also allows more filling time between contractions for coronary artery filling, which provides for enhanced myocardial perfusion during diastole (Peterson & Roe, 2017). This beta blocking action results in lower blood pressure and suppresses ventricular arrhythmias which are the result of increased sympathetic stimulation and ischemia (Sanoski & Peterson, 2017).
Beta blocking drugs are divided into the categories of selective and non-selective medications. The first type of beta blocking drugs developed were the non-selective beta blocking drugs (Brenner & Stevens, 2013). These non-selective drugs block the beta 1 adrenergic receptors along with the beta 2 adrenergic receptors. Examples of non-selective beta blockers are nadalol, propranolol, pindolol, and timolol (Brenner & Stevens, 2013). The second category is known as the selective (cardio-selective) beta blocking drugs. These drugs block the beta 1 receptors which are located primarily in the cardiac tissue (Brenner & Stevens, 2013).
Atenolol, esmolol, and metoprolol are examples of cardio-selective beta blockers (Brenner & Stevens, 2013). It is important to note these drugs lose their cardio-selectivity when prescribed in high dose (Barranger & Hadley, 2017).
There is also a group of beta blockers known as the alpha and beta adrenoceptor antagonists. This group of drugs blocks the alpha and beta adrenergic receptors and includes the drug carvedilol (Brenner & Stevens, 2013). Carvedilol will be discussed in more depth later on in this paper.
Blocking the beta 2 adrenergic receptors in the bronchioles and smooth muscle of peripheral blood vessels in the skeletal muscle, and liver can result in adverse reactions (Brenner & Stevens, 2013). The first adverse reaction that may occur is bronchoconstriction, which can be dangerous for those with asthma or other obstructive lung diseases. Secondly, the beta 2 adrenergic blockers can mask the early signs of hypoglycemia in a patient with diabetes. Stimulation of glycogenolysis in the liver is inhibited, preventing release of glucose to alleviate hypoglycemia (Brenner & Stevens, 2013; Peterson et al., 2017). Usage of a selective beta blocker may be a better choice in these circumstances.
Carvedilol blocks the alpha 1, beta 1, and beta 2 receptors. Decreased heart rate and cardiac contractility result from the beta inhibition (Brenner & Stevens, 2013). Peripheral vascular resistance is decreased as a result of the blockage of alpha 1 receptors. This results in lowering blood pressure as well as reducing afterload which can be beneficial in conditions such as heart failure and hypertension (HTN) (Brenner & Stevens, 2013).
Therapeutic Effects: Indications and Therapeutic Use
The first indication of Beta adrenergic blockers is the treatment of hypertension. It is also indicated for the treatment of angina. Thirdly, Beta blockers are indicated for the treatment of arrhythmias, reducing recurrence of cardiac events in post-myocardial infarction patients and improving survival (Brenner & Stevens, 2013). These medications suppress ventricular and supraventricular arrhythmias by slowing down the ventricular heart rate (Sanoski & Peterson, 2017). Beta blockers lower blood pressure and decrease myocardial oxygen demands by decreasing workload of the heart (Sanoski & Peterson, 2017). Improving myocardial oxygenation can reduce the likelihood of arrhythmias, such as ventricular fibrillation (Sanoski & Peterson, 2017). Atenolol, esmolol, metoprolol, and propranolol are considered Class II antiarrhythmic drugs (Sanoski & Peterson, 2017).
Last, Beta blockers are indicated for treatment of heart failure. This is a more recent indication for use. For many years, it was felt beta blockers were contraindicated in heart failure (Brenner & Stevens, 2013). New recommendations suggest that beta blockers be used, in conjunction with diuretics and an ACE inhibitor, in heart failure patients with left ventricular dysfunction, as long as they are stable and meet the New York Heart Association (NYHA) criteria, class II to class IV (Peterson et al., 2017). Beta blockers should not be used in unstable heart failure patients, but can be started when condition is stable (Barranger & Hadley, 2017).
Carvedilol (coreg) is a non-selective, beta adrenergic blocking medication that also has alpha 1 adrenergic receptor inhibiting ability. Carvedilol has no intrinsic sympathomimetic activity (Brenner & Stevens, 2013). It comes in two formulations, immediate release and extended release. Carvedilol will be used as the prototype drug for beta blockers in this discussion of pharmacokinetics.
Absorption Carvedilol is rapidly absorbed following oral administration (GlaxoSmithKline,
2005). The drug undergoes first pass metabolism, with bio-availability of 30% (Brenner & Stevens, 2013; GlaxoSmithKline, 2005). The half-life of carvedilol is six to eight hours
(Brenner & Stevens, 2013). Absorption is slowed when the medication is taken with food. Although there is a delay in reaching peak plasma levels when the drug is taken with food, no significant difference in bioavailability has been found (GlaxoSmithKline, 2005). Plasma concentrations are in proportion to the dose administered (GlaxoSmithKline, 2005). Plasma levels of immediate release carvedilol average about 50% higher in the elderly compared to nongeriatric subjects (GlaxoSmithKline, 2008). Extended-release carvedilol capsules (Coreg CR) have approximately 85% of the bioavailability of immediate-release carvedilol tablets. Time of absorption is more prolonged with the extended release carvedilol, with peak concentrations five hours after administration (GlaxoSmithKline, 2008). The maximal concentration for extended release carvedilol was decreased when the medication was administered in a fasting state. The half-life of extended release carvedilol is not known (Wolters Kluwer, 2018). It is recommended that extended release carvedilol be given with food (GlaxoSmithKline, 2008).
Distribution Carvedilol is more than 98% bound to plasma proteins, primarily albumin. Steady state volume of distribution is 115 Liters, which means there is significant distribution into extravascular tissues. Plasma clearances range from 500 to 700 mL/min. Steady state dynamics of extended release carvedilol are similar to those observed in the immediate release formulations (GlaxoSmithKline, 2008).
Metabolism Carvedilolis a basic, lipophilic compound. It is metabolized by the liver (GlaxoSmithKline, 2008). In the liver, carvedilol undergoes first pass metabolism. The metabolism of carvedilol is influenced by the inhibition or induction of cytochrome P450 enzymes (GlaxoSmithKline, 2005). Examples of this influence can be illustrated with the drugs rifampin and cimetidine. Drug studies demonstrate that rifampin reduces the maximum concentration of carvedilol by about 70% (GlaxoSmithKline, 2005). In contrast, cimetidine increased the steady state of carvedilol by 30%, with no change in maximum concentration (GlaxoSmithKline, 2005). When tested, hydrochlorothiazide had no effect on the pharmacokinetics of cardvedilol (GlaxoSmithKline, 2005).
Excretion Carvedilol is excreted unchanged in the urine. Metabolites of carvedilol are excreted in the bile and feces (GlaxoSmithKline, 2005). Immediate release carvedilol levels have been reported to be increased in patients with renal impairment (GlaxoSmithKline, 2008) No studies have been performed with extended release carvedilol in patients with renal impairment. Onset and Duration of Action Carvedilol comes in two formulations, immediate and extended release. Oral administration of immediate release carvedilol has a rapid onset, with peak action of 1-2 hours, lasting for 7 to 10 hours (Wolters Kluwer, 2018). Extended release carvedilol has onset of 30 minutes, with a peak action of 5 hours and unknown duration (Wolters Kluwer,
Adult and Pediatric Dosages
Carvedilol has not been approved for administration to patients younger than 18 years old (GlaxoSmithKline, 2005). Carvedilol is available in immediate release tablets or extended release capsules. Tablet dosages are: 3.25 mg, 6.25 mg, 12.5 mg, and 25 mg. Capsules are manufactured in 10 mg, 20 mg, 40 mg, and 80 mg dosages. The extended release equivalents are: immediate release 3.25 mg bid of carvedilol is the equivalent of 10 mg extended release, immediate release 6.25 mg bid is the equivalent of 20 mg extended release, immediate release 12.5 mg bid is the equivalent of 40 mg extended release, and immediate release 25 mg bid is the equivalent to 80 mg extended release (Wolters Kluwer, 2018). Up to 50 mg of immediate release carvedilol may be given to patients > 85 kg (American College of Cardiology, 2012).
When starting this medication, the lowest dose should be started, 3.25 mg bid. Dose should be increased over a period of two weeks, with the patient being closely monitored by the provider for dizziness (Peterson et al., 2017). This is primarily due to vasodilation caused by blocking the alpha 1 receptors (Peterson et al., 2017). This drug should not be given for clinically-evident hepatic impairment (American College of Cardiology, 2012). No dosage adjustments are needed for renal impairment (American College of Cardiology, 2012). When a geriatric patient is being switched from immediate release carvedilol to extended release carvedilol, it is recommended that a lower dosage be started, to minimize any dizziness or hypotension that might occur. As that dosage is tolerated, it may be titrated up to be equivalent to the immediate release dosage the patient had previously taken (GlaxoSmithKline, 2008).
Modes of Administration
Carvedilol is administered by oral route only. As mentioned, it is available in both immediate release and extended release formulations (Wolters Kluwer, 2018). The extended release formulation assists patients with compliance in the medication regime. Capsules should not be chewed or crushed or taken in divided doses (Wolters Kluwer, 2018). The contents of the capsule may be mixed into applesauce and consumed immediately, for those who have trouble swallowing capsules (Wolters Kluwer, 2018). It is recommended that both immediate and extended release carvedilol be taken with food (Wolters Kluwer, 2018).
The primary adverse effects of carvedilol are dizziness, hypotension, bradycardia, weight increase, and lack of energy. Adverse effects with carvedilol manifest themselves early in the treatment regime. Patients should be asked to report dizziness or orthostasis. Careful titration of dosages and monitoring of blood pressure, heart rate, and weight gain should be carried out by the provider to prevent harm to the patient (Peterson et al., 2017).
Contraindications and Precautions, Pregnancy Concerns
Patients with a history of asthma, AV block, bradycardia, decompensated heart failure, sick sinus syndrome without a pacemaker, and hepatic disease should not receive carvedilol (American College of Cardiology, 2012). Carvedilol is recommended for those with symptomatic heart failure, who are not experiencing hypotension, increased vascular congestion, or any significant AV conduction disorders (Brenner & Stevens, 2013).
Carvedilol should be used with caution in those with thyroid disease. There is a possibility of this drug masking the cardiac symptoms of hyperthyroidism (Wolters Kluwer, 2018). Patients should be counseled to report a heart rate of less than 55 beats per minute to their providers. Dosage of carvedilol will be reduced to avoid severe bradycardia (GlaxoSmithKline, 2005).
Carvedilol has produced teratogenic effects in rats and rabbits (GlaxoSmithKline, 2005).
No adequate studies have been done in pregnant women. Carvedilol is rated a Pregnancy Category C at this time (GlaxoSmithKline, 2005). It is recommended carvedilol be used in pregnancy only if the benefits outweigh the risks (GlaxoSmithKline, 2005). Studies in rats have demonstrated that carvedilol is excreted in breast milk. There is serious potential for adverse reactions to occur in nursing infants, such as bradycardia (GlaxoSmithKline, 2005).
Recommendation is that breast feeding be discontinued, if the drug is essential to the mother
(Wolters Kluwer, 2018). Safe pediatric use of carvedilol has not been established
Caution should be used when discontinuing this medication. Patients should be instructed to confer with the provider so that the medication can be tapered over a period of 14 days (Barranger & Hadley, 2017). Abrupt discontinuation of this drug can precipitate serious cardiac events in patients with coronary artery disease (Barranger & Hadley, 2017).
The metabolism of carvedilol is affected by cytochrome P450 enzymes
(GlaxoSmithKline, 2005). The enzyme inhibitor, CYP P450 2D6, has been identified as one that increases carvedilol levels (GlaxoSmithKline, 2008). Rifampin has been shown to decrease the maximum concentration of carvedilol by 70% (GlaxoSmithKline, 2005). Cimetidine increases the bioavailability of carvedilol (Wolters Kluwer, 2018). Digoxin concentrations were demonstrated to increase by 15% in trials where digoxin and carvedilol were administered at the same time (GlaxoSmithKline, 2005). Both drugs slow the AV conduction system, so close monitoring of heart rate and digoxin level need to occur.
Carvedilol and other beta blockers should be given with caution in conjunction with medications that deplete catecholamines (monoamine oxidase inhibitors) (GlaxoSmithKline, 2005). Close monitoring of blood pressure and heart rate is needed. Potentiation of decreases in blood pressure and heart rate have been found to occur when carvedilol and clonidine are given together. Caution must be used. If one of these drugs is to be terminated, the beta blocker should be terminated first (GlaxoSmithKline, 2005).
Increased bradycardia, myocardial depression, and AV nodal conduction blockage has been noted when amiodarone and carvedilol are given concurrently (Wolters Kluwer, 2018). Close monitoring of heart rate and rhythm is necessary. Caution should be exercised if using these drugs together.
No significant drug/food interactions were noted with carvedilol.
Carvedilol is being explored in the area of gastroenterology. One study was conducted to explore the efficacy of carvedilol in reducing the progression of esophageal varices (and associated esophageal variceal bleeding) by decreasing the portal hypertension that is a characteristic of cirrhosis of the liver. Portal hypertension is viewed as the most important predictor of complications in cirrhosis of the liver (Bhardwaj et al., 2017). Portal hypertension can be assessed by measuring the hepatic venous pressure gradient (HVPG). Use of nonselective beta blockers is recommended therapy to reduce portal hypertension and to reduce variceal hemorrhage (Bhardwaj et al., 2017). It was hypothesized carvedilol might lead to a greater reduction in HVPG due to its alpha 1 adrenergic blocking effects (Bhardwaj et al., 2017). Carvedilol also has antioxidant properties and the ability to decrease smooth muscle cell proliferation (Bhardwaj et al., 2017). For these reasons, 140 patients with small esophageal varices were randomized to two groups of seventy. One group received carvedilol and an equal number received placebos in the second group. The study was conducted over the course of 24 months, with every patient completing minimally three endoscopic assessments. At the end of the study, it was found that fewer patients in the carvedilol group had progressed to large esophageal varices when compared to the placebo group. It was also concluded that carvedilol had slowed the time of progression from small to large varices compared to the placebo group. The time frame of progression to large varices increased from 18.7 months in the placebo group to 20.8 months in the carvedilol group. The study also concluded there was a reduction in HVPG of 8.64% in the carvedilol group at one year from the baseline assessment. This is compared to a 0.33% increase in HVPG in the placebo group (Bhardwaj et al., 2017). It was concluded carvedilol displayed efficacy in delaying the progression of varices in this sample of patients with cirrhotic liver disease but that further clinical studies should be conducted.
Patient Education Handout
American College of Cardiology. (2012). Carvedilol (Coreg) considerations for use. Retrieved
April 15, 2018, from acc.org: https://www.acc.org/~/media/Non-Clinical/Files-PDFsExcel-MS-Wordetc/Tools%20and%20Practice%20Support/Quality%20and%20Clinical%20Toolkits/AFi b%20Toolkit/Carvedilol.pdf?la=en
Barranger, K., & Hadley, D. E. (2017). Hypertension. In V. P. Arcangelo, A. M. Peterson, V. Wilbur, & J. A. Reinhold (Eds.), Pharmacotherapeutics for advanced practice (4th ed., pp. 257-273). Philadelphia: Lippincott Williams & Wilkins.
Bhardwaj, A., Kedarisetty, C. K., Vashishtha, C., Bhadoria, A. S., Jindal, A., Kumar, G., … Sarin, S. K. (2017). Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: A randomised placebo-controlled trial. Gut , 66 (10), 1838-1843.
Brenner, G. M., & Stevens, C. W. (2013). Pharmacology (4th ed.). Philadelphia: Elsevier.
Clayton, M. F., & McCance, K. L. (2014). Stress and Disease. In K. L. McCance, & S. E. Huether (Eds.), Pathophysiology the biologic basis for disease in adults and children (7th ed., pp. 338-362). St. Louis: Elsevier.
Cunningham, S. G., Brashers, V. L., & McCance, K. L. (2014). Structure and function of the cardiovascular and lymphatic systems. In K. L. McCance, & S. E. Huether (Eds.), Pathophysiology the biologic basis for disease in adults and children (7th ed., pp. 10831128). St. Louis: Elsevier.
Dargie, H. J., Colucci, W., Ford, I., Sendon, J. L., Remme, W., Sharpe, N. … Holcslaw, T. L.
(2001). Effect of carvedilol on outcome after myocardial infarction in patients with leftventricular dysfunction: The CAPRICORN randomised trial. The Lancet , 357 (May 5), 1385-1390.
Frishman, W. H. (2007). A historical perspective on the development of B-adrenergic blockers.
The Journal of Clinical Hypertension , 9 (4), 19-26.
Frishman, W. H. (2008). Fifty years of beta-blockers: A revolution in cv pharmacotherapy.
Retrieved April 15, 2018, from Cardiology Today: https://www.healio.com/cardiology/vascular-medicine/news/print/cardiologytoday/%7B58d8999e-a18c-4f8a-a747-38e2a1620e52%7D/fifty-years-of-beta-blockers-arevolution-in-cv-pharmacotherapy
GlaxoSmithKline. (2005, Feb). Coreg. Retrieved April 15, 2018, from accessdata.fda:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020297s013lbl.pdf GlaxoSmithKline. (2008, Dec). Highlights of prescribing information coreg cr. Retrieved April
15, 2018, from accessdata.fda:
Peterson, A. M., & Roe, C. C. (2017). Chronic stable angina. In V. P. Arcangelo, A. M. Peterson, V. Wilbur, & J. A. Reinhold (Eds.), Pharmacotherapeutics for advanced practice (4th ed., pp. 289-304). Philadelphia: Lippincott Williams & Wilkins.
Peterson, A. M., Randle, M. D., & Randle, T. L. (2017). Heart Failure. In V. P. Arcangelo, A. M. Peterson, V. Wilbur, & J. A. Reinhold (Eds.), Pharmacotherapeutics for advanced practice (4th ed., pp. 305-323). Philadelphia: Lippincott Williams & Wilkins.
Porth, C. M., & Matfin, G. (2009). Pathophysiology concepts of altered health states.
Philadelphia: Lippincott Williams & Wlikins.
Sanoski, C. A., & Peterson, A. M. (2017). Arrhythmias. In V. P. Arcangelo, A. M. Peterson, V. Wilbur, & J. A. Reinhold (Eds.), Pharmacotherapeutics for advanced Practice (4th ed., pp.325-355). Philadelphia: Lippincott Williams & Wilkins.
Schwarzer, R., Kivaranovic, D., Paternostro, R., Mandorfer, M., Reiberter, T., Trauner, M., … Ferlitsch, A. (2018). Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: A dose-response study. Alimentary Pharmacology & Therapeutics , 47, 1162-1169.
Spinler, S. A., & De Denus, S. (2008). Acute coronary syndromes. In J. T. Dipiro, R. L. Talbert, G. C. Yee, G. R. Matzke, B. G. Wells, & L. M. Posey (Eds.), Pharmacotherapy a pathophysiologic approach (7th ed., pp. 249-278). New York: McGraw Hill.
Sugerman, R. A. (2014). Structure and function of the neurologic system. In K. L. McCance, & S. E. Huether (Eds.), Pathophysiology the biologic basis for disease in adults and children (7th ed., pp. 447-483). St. Louis: Elsevier.
Sutters, M. (2012). Systemic hypertension. In S. J. McPhee, & M. A. Papadakis (Eds.), Current medical diagnosis & treatment (51st ed., pp. 420-449). New York: Lange.
Wolters Kluwer. (2018). Nursing 2018 drug handbook. Philadelphia: Wolters Kluwer.
All papers are written by ENL (US, UK, AUSTRALIA) writers with vast experience in the field. We perform a quality assessment on all orders before submitting them.
We provide plagiarism reports for all our custom written papers. All papers are written from scratch.
Contact us anytime, any day, via any means if you need any help. You can use the Live Chat, email, or our provided phone number anytime.
Get your money back if your paper is not delivered on time or if your instructions are not followed.