Adrenergic Receptors

Propranolol

Group xx

Adrenergic Receptors

ABSTRACT
Summarize your group’s Project. This is a summary of the Background, Results, Methods, and Discussion.

Our group chose Adrenergic receptors (ARs) as a target for this project by using a review strategy. ARs play a crucial role in controlling our physiological system. We were interested in researching heart attack as a condition in relation to ARs. Our group was able to find the structure of ARs. For pharmacological treatment, propranolol hydrochloride is a small molecule and it is one of the medications used for hypertension. Its structure, ligand binding mechanisms, and hydrogen bond interactions are included. In addition, Propranolol has a true binding pocket which is demonstrated. It is not only used for hypertension, but also for other indications related to the cardiovascular system. Its mechanism of action is thoroughly explained along with the prevention and treatment of hypertension. My group will review Propranolol (Innopran XL), a non-selective adrenergic receptor binder on the market.
BACKGROUND
(a) Different types of drug delivery methodologies can be utilized to maximize therapeutic efficacy and reduce adverse effects. Given the high cost of medication and potential adverse effects, modified drug delivery is the control of drug release to actualize patient compliance not achievable with conventional dosage forms, especially with drugs with short half-lives.1 Targeted drug delivery is the capacity of the drug to accumulate in the targeted organ selectively and quantitatively, free of the site, and methodology of administration.2 Targeted drug delivery is achieved when the local concentration of the drug at the disease site is higher, while the concentration in other non-target tissues is below to prevent negative side reactions.3 Hence, the objectives of modified and targeted drug delivery are to have drug quantity to achieve necessary/ great therapeutic effects, increase drug concentration on the site without negative impacts on non-target organs, increase efficacy, and lower treatment cost.1, 2

(b) One of the targets in targeted drug delivery systems is adrenergic receptors. Adrenergic receptors (ARs) are membrane G protein-coupled receptors mediating the activities of epinephrine and norepinephrine.3, 4 Epinephrine and norepinephrine, commonly described as (-)-adrenaline and (-)-noradrenalin, respectively, function as neurotransmitters of the sympathetic nervous system and central nervous system.3, 4 Nine members of ARs are distributed throughout the body and perform essential roles in physiological processes including response to stress, regulation of heartbeat rate and blood pressure, and control of metabolism.3, 4 ARs are also the target of diverse medications for various conditions, such as heart attack (thrombus in an artery leading to heart attack).4 Beta-adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension who have concomitant ischemic heart disease, heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-Blockers can be used in combination with other antihypertensive drugs to achieve maximal blood pressure control.5

Figure 1: The Structure of ARs3

(c) The nine members of ARs from the structure of the target starting with alpha (α) and beta (β) major types based on their pharmacological attributes (rank order potency of agonists).3 The β ARs are subdivided into beta-1, beta2, and beta-3. The α ARs are subdivided into alpha-1 (postsynaptic) and alpha-2 (presynaptic). The current structure of ARs is based on the classification scheme of alpha-1, alpha-2, and beta, which was further divided into subtypes such as alpha-1A, alpha-1B, aleph-1D, alpha-2A, alpha -2B,alpha-2C, beta-1, beta-2, and beta-3.3 Figure 1 is the schema of ARs structures and subtypes.

Figure 2. Propranolol (PDB ID:1DY4) Basic Chimer structure

Figure 3. Chimera Structure showing the Propranolol ligand binding interaction (Ligand ID: SNP)

Figure 4. Propranolol true binding pocket within 5Ã…

Figure 5.
Shows the ligand SNP(1-(ISOPROPYLAMINO)-3-(1-NAPHTHYLOXY)-2-PROPANOL) in Green with several hydrogen bonds and interactions. SNP has hydrogen bonds with ASP214A distance of 2.672Ã…, HIS228A with a distance of 2.795Ã…, GLN175A with a distance of 2.762Ã…,
(d) Propranolol is used to treat hypertension (high blood pressure), irregular heart rhythms, pheochromocytoma (tumor on a small gland near the kidneys), certain types of tremor, and hypertrophic subaortic stenosis (a heart muscle disease).6 It is also used to prevent angina (chest pain), migraine headaches, and to improve survival after a heart attack.6 It works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure. 6 Hypertension is a common condition and when not treated, can cause damage to the brain, heart, blood vessels, kidneys, and other parts of the body.6 Damage to these organs may cause heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other problems.6 Hypertension is a complex polygenic disorder in which many genes or gene combinations influence blood pressure.7 Various environmental exposures, including components of diet such as excess intake of sodium and insufficient intake of potassium, calcium, magnesium; physical activity; and alcohol consumptions influence the blood pressure value.7 High blood pressure can be treatable and preventable through following healthy living habits such as eating a healthy diet, exercising and being active, not smoking, getting enough sleep, etc; and checking the blood pressure regularly.8

(e) Propranolol is a small molecule drug with the indication to treat hypertension and many other diseases that are related to the cardiovascular system. There are no new treatments that were developed for propranolol. At first propranolol was discovered mainly for the treatment of angina in the 1960s. Soon after that, propranolol was discovered that it also have therapeutic effects for other cardiovascular conditions such as hypertension, myocardial infarction, and arrhythmias. 9

Table 1. List of medications, both generic and brand for the hypertension disease. Chart
includes mechanisms of action, chemical structures, chemical properties and route of
administration and ADMET of each medication. Also included are the indications, doses,
contraindications, and clinically important interaction. 10, 11, 12

Name10, 11, 12 Propranolol Hydrochloride - Inderal® Carvedilol - Coreg®
Metoprolol Tartrate - Lopressor®

Mechanism of Action 10, 11, 12 A nonselective β-blocker by competing for available binding sites that stimulate the β-adrenergic receptors. A nonselective β-adrenergic blocking agent with α1-blocking activity A selective β1-adrenergic receptor blocker.
Chemical Structure 10, 11, 12
Structure of Propranolol Hydrochloride
Structure of Carvedilol
Structure of Metoprolol Tartrate
Physical/Chemical Properties 10, 11, 12 C16H21NO2•HCl
MW: 295.80 g/mol
LogP: 3.48
pKa: 9.42
Melting Point: 96°C C24H26N2O4
MW: 406.5 g/mol
LogP: 3.8
pKa:
Melting Point: 114.5°C C15H25NO3
MW: 684.82 g/mol
LogP: 2.15
pKa: 9.7
Melting Point: 120°C

ROA10, 11, 12 Oral
Intravenous Oral Oral
Intravenous
ADMET 10, 11, 12 A: Bioavailability 50%
D: Volume of distribution 4L/kg
M: metabolized primarily by most metabolites appearing in the urine
E: Elimination Half-life 8 hours
T: development of toxicity at 150 mg/kg/day A: Bioavailability 25% - 35%
D: volume of distribution of approximately 115 L
M: metabolized primarily in liver
E: Elimination Half-life 7-10 hours
T: development toxicity at 60 mg/kg/day A: Bioavailability 50%
D: volume of distribution of 3.2 to 5.6 L/kg
M: metabolized by CYP2D6
E: mean elimination half-life 3-4 hours. Elimination is mainly by biotransfor in the liver
T: High doses were associated with some maternal toxicity, and growth delay of
the offspring in utero, which was reflected in minimally lower weights at birth
Indication 10, 11, 12 Hypertension. Angina pectoris, chronic
Cardiac dysrhythmia
Essential tremor Congestion Heart Failure,
Hypertension Hypertension
Angina Pectoris
Myocardial Infarction
Common Adult Dose 10, 11, 12 40 mg twice daily 6.25 mg twice daily 100 mg daily in single dose or divided dose
Contraindication 10, 11, 12 Blood pressure less than 50/30 mmHg
Bronchial asthma or bronchospasm
Cardiogenic shock
Decompensated heart failure
Heart rate less than 80 beats/min Bronchial asthma, bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe
bradycardia Sinus bradycardia, heart block greater than first degree, cardiogenic shock, overt cardiac failure.
Sick-sinus syndrome
Severe peripheral arterial circulatory disorders

Clinical Important Interaction s 10, 11, 12 May decrease effects of theophyllines or clonidine.
Barbiturates or rifampin may decrease effects.
Cimetidine may increase serum levels.
Hydralazine, propafenone, thioamines, or phenothazines may increase the effects. Risk of Anaphylactic reaction may be repeated with patients, who have had anaphylactic reaction before.
Pregnancy: Teratogenic Effects. Pregnancy Category C Risk of Anaphylactic reaction may be repeated with patients, who have had anaphylactic reaction before.
Pregnancy Category C

METHODS
The target of our group research are adrenergic receptors. Propranolol is a non-selective β-adrenergic receptor antagonist. The target name and structure was researched by Kaitlyn and the information was obtained from a variety of the articles “Drug-targeting methodologies with applications: A review” by Kleinstreuer C, Feng Y, Childress and “Drug targeting” by Torchilin. Kaitlyn and Seokjun were our chimera experts, who helped explain modifiable characteristics to better understand the concept of the research by also providing visual structures and interpreting the different parts of interactions of the drug molecules and providing figures to simplify the idea with the Chimera program. The disease information was researched by Tina and obtained from drug info from Medline Plus. Svetlana and Tina did the breakdown and the comparison of several drugs with similar indications based on multiple characteristics. The following drugs were indicated, Propranolol hydrochloride (Inderal), Carvedilol (Coreg) and Metoprolol Tartrate (lopressor) all from the links provided under the drugs name in the table. The information about its chemical structure, physical/ chemical properties, indication along with the dosing and common dosage forms, some clinically important interactions as well the contraindications of the drug were obtained from the Food Drug Administration about the medications. Last but not least, Abraham was the one interpreting the results and summarizing the ideas into useful data and conclusions to ease the understanding of the complex structures and information. Lastly, Varti wrote the abstract after everyone was done with his part to give the reader a general breakdown of the project. The project required research for different articles and each piece of information was found in different articles and each one the group members were able to link the sources, information and structure together to get to the full picture.

RESULTS
(a) A description (include schematics, diagrams and graphs) of your group’s modified and/or targeted drug delivery strategy. What is the mechanism of action? (Label and cite schematics, etc.)
(b) How much, how long and how often will the patient have to take your group’s modified and/or targeted, drug delivery system (dose)? Is it sustained, delayed, etc?
(c) Is it modified and/or targeted? Is it a biological, physical, or chemical targeting method, or a combination of these methods? Is it passive or active targeting? Will your group use liposomes, micro or nanoparticles, polymers, prodrugs, biologic, cells, gene therapy, nucleic acid therapy, or a combination of delivery systems, or a cocktail (combination of drugs), etc.?
(d) Dosage form: Is your drug delivery strategy oral? Transdermal? IV? Other?

Propranolol hydrochloride is an important medication for the treatment of hypertension. However, the traditional immediate-release tablet is dosed two to four times daily, which leaves greater opportunity for poor medication adherence. In addition, patients with hypertension may experience a rapid surge in blood pressure in the early morning. This period is known as the Morning Risk Zone since patients are at elevated risk of cardiovascular events.13 There is a need in the market for propranolol to be modified to an extended-release form to have peak effect during the morning to mitigate the morning risk zone.
Innopran XL contains propranolol hydrochloride and is an extended release capsule taken once by mouth daily at bedtime.14 In a clinical study conducted in 2005, Innopran XL showed 24-hour blood pressure control with peak plasma concentrations during the morning compared to traditional dosed propranolol.15 This drug exhibits modified-release since it alters the timing of the release of propranolol (Figure 6).

Figure 6. Plasma Concentration Versus Time Curve of InnoPran XL versus Traditionally Dosed Propranolol.15

The timed release property targets the Morning Risk Zone by the unique design of the drug release technology. Innopran XL is available as 80 mg or 120 mg capsules containing sustained-released beads.14 These beads carry the active pharmaceutical ingredient and are coated with dual membranes. The outer membrane is known as the delayed release membrane, and slows the release of propranolol hydrochloride after ingestion. The inner membrane is the controlled-release membrane and is responsible for the sustained release of propranolol.16 The composition of the bead membrane was unable to be found; however, a scheme of the bead has been published by the manufacturer (Figure 7).

Figure 7. Timed-Release Design of Innopran XL beads.16

DISCUSSION
(a) Please indicate if your group’s strategy is a review of an existing product, review of a strategy being researched or in clinical trials, or a novel strategy.

(b ) Discuss the rationale of the drug delivery strategy. Explain part (b), (c) and (d) in the Results section above (why does the patient take it once a month, why is a particular targeting agent being used, why is it chemical targeting, or why are polymers or liposomes used, or why is your group using nanoparticle, biologic, small molecule, etc.).

(c ) A prediction of any problems that your group’s modified drug delivery strategy might encounter. This can include, but is not limited to: adverse effects, DDIs, DDIs with food, problems associated with the formulation, effective dose and/or how it will be administered (oral, IV, etc.), and how frequently it will need to be administered, ethical, economical, cost, etc.

REFERENCES

1. Kleinstreuer C, Feng Y, Childress E. Drug-targeting methodologies with applications: A review. World J Cli Cases. 2014; 2(12): 742-756. doi:10.12998/wjcc.v2.i12.742
2. Torchilin VP. Drug targeting. Eur J Pharm Sci. 2000; 11(2): S81-S91. doi:10.1016/s0928-0987(00)00166-4
3. Bylund D B. Adrenergic receptors. Ency Bio Chem. 2013; 57-60. doi.org/10.1016/B978-0-12-378630-2.00334-0
4. Wu Y, Zeng L, Zhao S. Ligands of adrenergic receptors: A structural point of view. Biomolecules. 2021; 11(7): 936. doi:10.3390/biom11070936
5. Frishman WH. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well. Prog Cardiovasc Dis. 2016;59(3):247-252. doi:10.1016/j.pcad.2016.10.005
6. Propranolol (Cardiovascular). Medline Plus. Updated August 15, 2017. Accessed April 2, 2022. https://medlineplus.gov/druginfo/meds/a682607.html
7. Whelton P, Carey R, Aronow W, ACC/AHA/AAPA/ABC/ACPM/ AGS/APhA/ASH/ASPC/ NMA/PCNA. Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Am Coll Cardiol. 2018; 71 (19): e127–e248. https://doi.org/10.1016/j.jacc.2017.11.006
8. Prevent high blood pressure. Centers for Disease Control and Prevention. https://www.cdc.gov/bloodpressure/prevent.htm. Published February 24, 2020. Accessed April 3, 2022.
9. Srinivasan AV. Propranolol: A 50-Year Historical Perspective. Ann Indian Acad Neurol. 2019;22(1):21-26. doi:10.4103/aian.AIAN_201_18
10. Wyeth Pharmaceuticals, Inc., Philadelphia. Product Information: Inderal LA(R), propranolol hydrochloride. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016418s080,016762s017,017683s008lbl.pdf. Accessed April 8, 2022.
11. GlaxoSmithKline Research Triangle Park, NC 27709. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020297s013lbl.pdf. Accessed April 8, 2022.
12. Novartis Pharmaceutical Corporation. Suffern, New York, 10901. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018704s025lbl.pdf. Accessed April 8, 2022.
13. Elliot W. Cyclic and circadian variations in cardiovascular events*1. American Journal of Hypertension. 2001;14(9). doi:10.1016/s0895-7061(01)02174-4
14. DailyMed - INNOPRAN XL- propranolol hydrochloride capsule, extended release. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd5601b3-4d87-4c3b-acac-b476e787609d. Accessed April 8, 2022.
15. Neutel JM, Rotenberg K. Comparison of a chronotherapeutically administered β blocker vs. a traditionally administered β blocker in patients with hypertension. The Journal of Clinical Hypertension. 2005;7(7):395-400. doi:10.1111/j.1524-6175.2005.04304.x
16. Healthcare Providers – innopran XL®. InnoPran XL® propranolol HCI 80mg 120mg extended release capsules. https://www.innopranxl.com/healthcare-providers/. Accessed April 8, 2022.