Atenolol Explained

Watchedfields:changed
Verifiedrevid:458476745
Width:200px
Width2:200px
Chirality:Racemic mixture
Tradename:Tenormin, others
Dailymedid:Atenolol
Pregnancy Au:C
Legal Au:S4
Legal Status:Rx-only
Routes Of Administration:Oral, intravenous
Class:Selective β1 receptor antagonist
Bioavailability:40–50%
Protein Bound:6–16%[1]
Metabolism:Minimal
Onset:

<5 minutes
Oral: <1 hour

Elimination Half-Life:6–7 hours
Duration Of Action:>24 hours
Excretion:Urine (>85%, 50% oral)
Cas Number:29122-68-7
Atc Prefix:C07
Atc Suffix:AB03
Pubchem:2249
Iuphar Ligand:548
Drugbank:DB00335
Chemspiderid:2162
Unii:50VV3VW0TI
Kegg:D00235
Chebi:2904
Chembl:24
Iupac Name:(RS)-2-acetamide
C:14
H:22
N:2
O:3
Smiles:O=C(N)Cc1ccc(cc1)OCC(O)CNC(C)C
Stdinchi:1S/C14H22N2O3/c1-10(2)16-8-12(17)9-19-13-5-3-11(4-6-13)7-14(15)18/h3-6,10,12,16-17H,7-9H2,1-2H3,(H2,15,18)
Stdinchikey:METKIMKYRPQLGS-UHFFFAOYSA-N

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality in those with the condition.[2] [3] Other uses include the prevention of migraines and treatment of certain irregular heart beats.[4] It is taken orally (by mouth) or by intravenous injection (injection into a vein).[4] It can also be used with other blood pressure medications.[4]

Common side effects include feeling tired, heart failure, dizziness, depression, and shortness of breath. Other serious side effects include bronchial spasm. Use is not recommended during pregnancy and alternative drugs are preferred when breastfeeding.[5] It works by blocking β1-adrenergic receptors in the heart, thus decreasing the heart rate and workload.

Atenolol was patented in 1969 and approved for medical use in 1975.[6] It is on the World Health Organization's List of Essential Medicines.[7] It is available as a generic medication.[8] In 2021, it was the 47th most commonly prescribed medication in the United States, with more than 14million prescriptions.[9] [10]

Medical uses

Atenolol is used for a number of conditions including hyperthyroidism,[11] hypertension, angina, long QT syndrome, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and the symptoms of alcohol withdrawal.[12]

The role for β-blockers in general in hypertension was downgraded in June 2006 in the United Kingdom, and later in the United States, as they are less appropriate than other agents such as ACE inhibitors, calcium channel blockers, thiazide diuretics and angiotensin receptor blockers, particularly in the elderly.[13] [14] [15]

Available forms

Atenolol is available in the form of 25, 50, and 100mg oral tablets.[16] It is also available in the form of oral tablets containing a combination of 50 or 100mg atenolol and 50mg chlortalidone. Atenolol was previously available in a 0.5mg/mL solution for injection as well, but this formulation was discontinued.

Side effects

Hypertension treated with a β-blocker such as atenolol, alone or in conjunction with a thiazide diuretic, is associated with a higher incidence of new onset type 2 diabetes mellitus compared to those treated with an ACE inhibitor or angiotensin receptor blocker.[17] [18]

β-blockers, of which atenolol is mainly studied, provides weaker protection against stroke and mortality in patients over 60 years old compared to other antihypertensive medications.[19] [20] [21] Diuretics may be associated with better cardiovascular and cerebrovascular outcomes than β-blockers in the elderly.[22]

Overdose

Symptoms of overdose are due to excessive pharmacodynamic actions on β1 and also β2-receptors. These include bradycardia (slow heartbeat), severe hypotension with shock, acute heart failure, hypoglycemia and bronchospastic reactions. Treatment is largely symptomatic. Hospitalization and intensive monitoring is indicated. Activated charcoal is useful to absorb the drug. Atropine will counteract bradycardia, glucagon helps with hypoglycemia, dobutamine can be given against hypotension and the inhalation of a β2-mimetic such as hexoprenalin or salbutamol will terminate bronchospasms. Blood or plasma atenolol concentrations may be measured to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 3 mg/L during therapeutic administration, but can range from 3–30 mg/L in overdose victims.[23] [24]

Interactions

Interactions with atenolol include catecholamine-depleting drugs like reserpine, calcium channel blockers, disopyramide, amiodarone, clonidine, prostaglandin synthase inhibitors like indomethacin, and digitalis glycosides.[25] Most of these interactions involve either additive cardiovascular effects or reduction of atenolol's effects.

Atenolol is mainly eliminated renally without being metabolized by the liver or by cytochrome P450 enzymes.[26] [27] As a result, it has little or no potential for cytochrome P450-related drug interactions, for instance with inhibitors and inducers of these enzymes.

Beta blockers like atenolol can reduce or block the cardiovascular effects of sympathomimetics and amphetamines, such as hypertension and tachycardia.[28] [29] [30] [31] [32] [33] [34]

Atenolol has been found to be safe in combination with the non-selective monoamine oxidase inhibitor (MAOI) phenelzine and actually improved orthostatic hypotension and hypertensive reactions with phenelzine.[35] [36] [37] However, more research is still needed to assess whether addition of a beta blocker like atenolol to MAOI therapy is safe and effective for improving orthostatic hypotension with MAOIs.

Pharmacology

Pharmacodynamics

Atenolol is a beta blocker, that is, an antagonist of the β-adrenergic receptors. It is specifically a selective antagonist of the β1-adrenergic receptor with no intrinsic sympathomimetic activity (i.e., partial agonist activity) or membrane-stabilizing activity. However, the preferential action of atenolol is not absolute, and at high doses it can also block β2-adrenergic receptors.

Beta-blocking effects of atenolol include reduction in resting and exercise heart rate and cardiac output, reduction of systolic and diastolic blood pressure at rest and with exercise, inhibition tachycardia induced by isoproterenol (a non-selective β-adrenergic receptor agonist), and reduction of reflex orthostatic tachycardia. The beta-blocking effects of atenolol, as measured by reduction of exercise-related tachycardia, are apparent within 1hour and are maximal within 2 to 4hours following a single oral dose. The pharmacodynamic effects of atenolol, including beta-blocking and antihypertensive effects, last for at least 24hours following oral doses of 50 or 100mg. With intravenous administration, maximal reduction in exercise-related tachycardia occurs within 5minutes and following a single 10mg dose has dissipated within 12hours. The duration of action of atenolol is dose-related and is correlated with circulating levels of atenolol.

Pharmacokinetics

The absorption of atenolol with oral administration is rapid and consistent but is incomplete. About 50% of an oral dose of atenolol is absorbed from the intestines, with the rest excreted in feces. Maximal concentrations of atenolol occur 2 to 4hours following an oral dose, whereas peak concentrations occur within 5minutes with intravenous administration. The pharmacokinetic profile of atenolol results in it having relatively consistent plasma drug levels with about 4-fold variation between individuals.

The plasma protein binding of atenolol is 6 to 16%. Atenolol is classified as a beta blocker with low lipophilicity and hence lower potential for crossing the blood–brain barrier and entering the brain.[38] This in turn may result in fewer effects in the central nervous system as well as a lower risk of neuropsychiatric side effects.

Atenolol undergoes little to no metabolism by the liver. This is in contrast to other beta blockers like propranolol and metoprolol, but is similar to nadolol. Instead of hepatic metabolism, atenolol is eliminated mainly via renal excretion. Atenolol is excreted 50% in urine with oral administration and more than 85% in urine with intravenous administration.

The elimination half-life of atenolol is about 6 to 7hours. The half-life of atenolol does not change with continuous administration. With intravenous administration, atenolol levels rapidly decline (5- to 10-fold) during the first 7hours and thereafter decline at a rate similar to that with oral administration. The elimination of atenolol is slowed in renal impairment, with the elimination rate being closely related to the glomerular filtration rate and with significant accumulation occurring when the creatinine clearance rate is under 35mL/min/1.73m2.

Chemistry

The experimental log P of atenolol is 0.16 and its predicted log P ranges from −0.03 to 0.57.[39] [40] [41]

Society and culture

Changing medical practices

Atenolol has been given as an example of how slow healthcare providers are to change their prescribing practices in the face of medical evidence that indicates that a drug is not as effective as others in treating some conditions.[42] In 2012, 33.8 million prescriptions were written to American patients for this drug.[42] In 2014, it was in the top (most common) 1% of drugs prescribed to Medicare patients.[42] Although the number of prescriptions has been declining steadily since limited evidence articles contesting its efficacy was published, it has been estimated that it would take 20 years for doctors to stop prescribing it for hypertension.[42] Despite its diminished efficacy when compared to newer antihypertensive drugs, atenolol and other beta blockers are still a relevant clinical choice for treating some conditions, since beta blockers are a diverse group of medicines with different properties that still requires further research. As consequence, reasons for the popularity of beta blockers cannot be fully attributed to a slow healthcare system – patient compliance factor, such as treatment cost and duration, also affect adherence and popularity of therapy.[43]

Notes and References

  1. Web site: DailyMed - TENORMIN- atenolol tablet. DailyMed . 30 June 2021. 20 November 2023. https://web.archive.org/web/20220127140640/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=746db603-a6e1-4dc3-c2d8-92314419098c. 27 January 2022. live.
  2. Tomiyama H, Yamashina A . Beta-Blockers in the Management of Hypertension and/or Chronic Kidney Disease . International Journal of Hypertension . 2014 . 919256 . 2014 . 24672712 . 3941231 . 10.1155/2014/919256 . free .
  3. DiNicolantonio JJ, Fares H, Niazi AK, Chatterjee S, D'Ascenzo F, Cerrato E, Biondi-Zoccai G, Lavie CJ, Bell DS, O'Keefe JH . β-Blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature . Open Heart . 2 . 1 . e000230 . 2015 . 25821584 . 4371808 . 10.1136/openhrt-2014-000230 .
  4. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 9780857113382. 151–153. 76.
  5. Web site: Atenolol use while Breastfeeding . Drugs.com . 23 December 2018 . 23 December 2018 . https://web.archive.org/web/20181223121344/https://www.drugs.com/breastfeeding/atenolol.html . live .
  6. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery. 2006. John Wiley & Sons. 9783527607495. 461.
  7. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  8. Web site: Atenolol Monograph for Professionals . Drugs.com . AHFS . 23 December 2018 . 18 April 2019 . https://web.archive.org/web/20190418043029/https://www.drugs.com/monograph/atenolol.html . live .
  9. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  10. Web site: Atenolol – Drug Usage Statistics . ClinCalc . 14 January 2024 .
  11. Book: Rehman B, Sanchez DP, Shah S . Atenolol . StatPearls . StatPearls Publishing . Treasure Island (FL) . 2021 . 30969666 . http://www.ncbi.nlm.nih.gov/books/NBK539844/ . 5 September 2021 . 10 October 2022 . https://web.archive.org/web/20221010053047/https://www.ncbi.nlm.nih.gov/books/NBK539844/ . live .
  12. Web site: Atenolol. The American Society of Health-System Pharmacists. 8 May 2018. 18 April 2019. https://web.archive.org/web/20190418043029/https://www.drugs.com/monograph/atenolol.html. live.
  13. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH . Beta-blockers for hypertension . The Cochrane Database of Systematic Reviews . 1 . CD002003 . January 2017 . 1 . 28107561 . 5369873 . 10.1002/14651858.CD002003.pub5 . Further research should be of high quality and should explore whether there are differences between different subtypes of beta-blockers or whether beta-blockers have differential effects on younger and older people [...] Beta-blockers were not as good at preventing the number of deaths, strokes, and heart attacks as other classes of medicines such as diuretics, calcium-channel blockers, and renin-angiotensin system inhibitors. Most of these findings come from one type of beta-blocker called atenolol. However, beta-blockers are a diverse group of medicines with different properties, and we need more well-conducted research in this area." (p. 2-3) .
  14. Web site: Ladva S . 28 June 2006. NICE and BHS launch updated hypertension guideline. dead. https://archive.today/20080511034248/http://www.nelm.nhs.uk/Record%20Viewing/viewRecord.aspx?id=567178. 11 May 2008. 19 August 2012. National Institute for Health and Clinical Excellence.
  15. Cruickshank JM . Are we misunderstanding beta-blockers . International Journal of Cardiology . 120 . 1 . 10–27 . August 2007 . 17433471 . 10.1016/j.ijcard.2007.01.069 .
  16. Web site: Drugs@FDA: FDA-Approved Drugs . accessdata.fda.gov . 8 July 2024.
  17. Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlöf B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman JM, Snapinn S . Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study . Journal of Hypertension . 20 . 9 . 1879–86 . September 2002 . 12195132 . 10.1097/00004872-200209000-00035 . 23613019 .
  18. Elliott WJ, Meyer PM . Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis . Lancet . 369 . 9557 . 201–7 . January 2007 . 17240286 . 10.1016/s0140-6736(07)60108-1 . 37044384 .
  19. Lindholm LH, Carlberg B, Samuelsson O . October 2005. Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis . The Lancet. en. 366. 9496. 1545–1553. 10.1016/S0140-6736(05)67573-3. 16257341. 34364430.
  20. Khan N, McAlister FA . Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis . CMAJ . 174 . 12 . 1737–42 . June 2006 . 16754904 . 1471831 . 10.1503/cmaj.060110 .
  21. Kuyper LM, Khan NA . Atenolol vs nonatenolol β-blockers for the treatment of hypertension: a meta-analysis . English . The Canadian Journal of Cardiology . 30 . 5 Suppl . S47-53 . May 2014 . 24750981 . 10.1016/j.cjca.2014.01.006 . free .
  22. Messerli FH, Grossman E, Goldbourt U . Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review . JAMA . 279 . 23 . 1903–7 . June 1998 . 9634263 . 10.1001/jama.279.23.1903 .
  23. DeLima LG, Kharasch ED, Butler S . Successful pharmacologic treatment of massive atenolol overdose: sequential hemodynamics and plasma atenolol concentrations . Anesthesiology . 83 . 1 . 204–7 . July 1995 . 7605000 . 10.1097/00000542-199507000-00025 .
  24. Book: Baselt R . Disposition of Toxic Drugs and Chemicals in Man. 8th. Biomedical Publications. Foster City, Calif.. 2008. 116–117.
  25. Web site: TENORMIN® (atenolol) Tablets Drug Label . December 2023 . Food and Drug Administration . 8 July 2024.
  26. Brodde OE, Kroemer HK . Drug-drug interactions of beta-adrenoceptor blockers . Arzneimittelforschung . 53 . 12 . 814–822 . 2003 . 14732961 . 10.1055/s-0031-1299835 . Atenolol is only minimally, if at all, metabolized and renally excreted in mostly unchanged form; thus an interaction with drugs that interfere with the hepatic metabolism is not to be expected. It is also very unlikely that the genetic polymorphisms of the CYP-family might affect the pharmacokinetics of atenolol. In fact it has been shown that plasma concentrations of nonmetabolized atenolol was not significantly different between “extensive” and “poor debrisoquine metabolizers” – in contrast to the plasma concentrations of metoprolol that were significantly increased in “poor metabolizers” (Dayer et al. 1985, Lewis et al. 1985). Furthermore, in healthy volunteers cimetidine (CAS 70059- 30-2) did not affect plasma concentrations of atenolol but significantly increased plasma concentrations of metoprolol or propranolol (Kirch et al. 1981)..
  27. Scheen AJ . Cytochrome P450-mediated cardiovascular drug interactions . Expert Opin Drug Metab Toxicol . 7 . 9 . 1065–1082 . September 2011 . 21810031 . 10.1517/17425255.2011.586337 . β-Blockers still represent widely prescribed drugs as they cover a wide spectrum of CV indications. Obviously, it is not trivial which β-blocker to choose as they differ both with regard to their PD and PK profiles [82]. It is well known when comparing the characteristics of atenolol, bisoprolol, metoprolol (each β-1 selective) and carvedilol (β-1 and β-2 nonselective). Among these β-blockers, atenolol is mainly eliminated by renal excretion; bisoprolol is in part excreted as parent compound via the renal route (50%); the other 50% are hepatically metabolized; whereas metoprolol and carvedilol are metabolized by CYP2D6. DDIs are mainly observed with those β-blockers that are metabolized via CYP enzymes. However, it should be emphasized that, in general, β-blockers are well-tolerated safe drugs with a large therapeutic index [83]..
  28. Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ . Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review . Drug Alcohol Depend . 150 . 1–13 . May 2015 . 25724076 . 10.1016/j.drugalcdep.2015.01.040 .
  29. Vetter VL, Elia J, Erickson C, Berger S, Blum N, Uzark K, Webb CL . Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing . Circulation . 117 . 18 . 2407–2423 . May 2008 . 18427125 . 10.1161/CIRCULATIONAHA.107.189473 . Amphetamines (Adderall, Dexedrine): Electrophysiological Effects of Amphetamines: Amphetamines have been associated with tachyarrhythmias and sudden death.113–115 Many of the electrophysiological effects of amphetamines may be initiated by the release of norepinephrine stores from presynaptic vesicles and blocking of norepinephrine reuptake.116,117 In addition, amphetamines are potent blockers of dopamine uptake and strong central nervous system stimulants. Dopaminergic Effects of Amphetamines: In addition to the β-agonist effects of amphetamines, the dopamine receptors D1 and D2 contribute to the cardiovascular effects of methamphetamine by producing a pressor response accounting for the increase in blood pressure. The D1 receptor also is involved in mediating the positive tachycardic effects of methamphetamine.117.
  30. Schindler CW, Zheng JW, Tella SR, Goldberg SR . Pharmacological mechanisms in the cardiovascular effects of methamphetamine in conscious squirrel monkeys . Pharmacol Biochem Behav . 42 . 4 . 791–796 . August 1992 . 1325059 . 10.1016/0091-3057(92)90031-a . free .
  31. Mores N, Campia U, Navarra P, Cardillo C, Preziosi P . No cardiovascular effects of single-dose pseudoephedrine in patients with essential hypertension treated with beta-blockers . Eur J Clin Pharmacol . 55 . 4 . 251–254 . June 1999 . 10424315 . 10.1007/s002280050624 .
  32. Hassan NA, Gunaid AA, El-Khally FM, Al-Noami MY, Murray-Lyon IM . Khat chewing and arterial blood pressure. A randomized controlled clinical trial of alpha-1 and selective beta-1 adrenoceptor blockade . Saudi Med J . 26 . 4 . 537–541 . April 2005 . 15900355 .
  33. O'Connell MB, Gross CR . The effect of single-dose phenylpropanolamine on blood pressure in patients with hypertension controlled by beta blockers . Pharmacotherapy . 10 . 2 . 85–91 . 1990 . 2349137 .
  34. O'Connell MB, Gross CR . The effect of multiple doses of phenylpropanolamine on the blood pressure of patients whose hypertension was controlled with beta blockers . Pharmacotherapy . 11 . 5 . 376–81 . 1991 . 1684039 .
  35. Book: Gadde KM, Krishnan KR . Management of Side Effects of Monoamine Oxidase Inhibitors . Balon R . Practical Management of the Side Effects of Psychotropic Drugs . CRC Press . Medical Psychiatry Series . 1998 . 978-0-8247-4630-8 . 8 July 2024 . 67–83 (71) . Interestingly, in one study, orthostatic hypotension was eliminated in a group of 61 patients treated for migraine headaches with phenelzine, when a beta-blocker, atenolol, was added (15). The authors have reported that hypertensive reactions were also less frequent when the two drugs were combined. We need further experience with this combination to determine whether addition of a beta-blocker is a safe and an effective strategy for alleviation of postural hypotension in depressed patients receiving an MAOI..
  36. O'Brien P, Oyebode F . Psychotropic medication and the heart . Advances in Psychiatric Treatment . 9 . 6 . 2003 . 1355-5146 . 10.1192/apt.9.6.414 . 414–423 . Postural hypotension is also a risk when antipsychotics are taken with β-blockers (probably because of pharmacokinetic interaction) or with diuretics (because of Na+ or volume depletion). The same hypotensive effects might be anticipated when tricyclic antidepressants or MAOIs are co-prescribed with peripheral antihypertensive agonists. One possible exception concerns phenelzine, whose hypotensive action was reversed on co-therapy with atenolol (Merikangas & Merikangas, 1995)..
  37. Merikangas KR, Merikangas JR . Combination monoamine oxidase inhibitor and beta-blocker treatment of migraine, with anxiety and depression . Biol Psychiatry . 38 . 9 . 603–610 . November 1995 . 8573662 . 10.1016/0006-3223(95)00077-1 . free .
  38. Cojocariu SA, Maștaleru A, Sascău RA, Stătescu C, Mitu F, Leon-Constantin MM . Neuropsychiatric Consequences of Lipophilic Beta-Blockers . Medicina (Kaunas) . 57 . 2 . February 2021 . 155 . 33572109 . 7914867 . 10.3390/medicina57020155 . free .
  39. Web site: Atenolol . PubChem . 1 August 2024.
  40. Web site: Atenolol: Uses, Interactions, Mechanism of Action . DrugBank Online . 13 August 2004 . 1 August 2024.
  41. Web site: DL-Atenolol . ChemSpider . 21 July 2022 . 1 August 2024.
  42. News: When Evidence Says No, But Doctors Say Yes. Epstein D. 22 July 2017. The Atlantic. 8 May 2018. 9 May 2018. https://web.archive.org/web/20180509150759/https://www.theatlantic.com/health/archive/2017/02/when-evidence-says-no-but-doctors-say-yes/517368/. live.
  43. Choi HY, Oh IJ, Lee JA, Lim J, Kim YS, Jeon TH, Cheong YS, Kim DH, Kim MC, Lee SY . Factors Affecting Adherence to Antihypertensive Medication . Korean Journal of Family Medicine . 39 . 6 . 325–332 . November 2018 . 30384549 . 6250947 . 10.4082/kjfm.17.0041 .

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