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C.82 Cardiology and Cardiac Surgery Toronto Notes 2023

Goldbcr gee At.f teclrocardiography. In:Jameson Jl. Fauci AS. Kasper 01. Hauser SI. Lon go Dt.Loscalro J. editors. Harrison's Principles ol Internal Medicine. 20e.New York: McGraw-Hill Education: 2018.

Goldstone A6.Chiu P. Baiocdu M.cl al. Mechanical or Biologic Prostlreseslor Aortic Valve and Mitral-Valve Replacement. N Engl J Med. 2017:377(191:184/ & J.

Gowda R.Khan I.Sacchi1. et al. History of the evolution ol echocardiography. Int J Cardiol 2004;97:1-6.

Guidelines lot percutaneous transluminal coronary angioplasty: a report ol the American College ol Cardiology/Am Heart Association Task Force on Assessment ol Diagnostic and Therapeutic Cardiovascular

ProceduresSubcommittee on percutaneous transluminal coronary angioplasty.J Am Coll Cardiol 1988:12:529 545.

Gray SO. Falovich DM. McCoubrie OL, elal. Amphelamine-related presentationsto an inner city tertiary emergency department: A prospective evaluation. Med J Aust. 2007:18G(7):336 9. doi:10.5694 j.1326- 5377.2007.lb00932.x.

Grimard BH,larson JM. Aortic stenosis:diagnosisand treatment.Am Fam Physician 2008;78(6):717- 724.

Gutierrez C.Blanchard 06. Atrial fibrillation: diagnosis and treatment.Am Fam Phys 2011:83:61 68.

HaasJ.Frese KS. Peil B.et al. Atlas ol the clinical genetics ol human dilated cardiomyopathy. Eur Heart J. 2014:36[18):1123-35.

HallettJW Jr.Abdominal aortic aneurysm: natural history and treatment.Heart Dis Stroke 1992:1:303-308.

HallettJW Jr.Management ol abdominal aortic aneurysms. MayoClin Proc 2000:75:395-399.

Halsell J.Riddle JR.Atwood JE, etal. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.JAMA 2003:289(24):3283.

Hammon JW.Hines MH.Extracorporeal Circulation.In:Cohn LH.Adams OH. editors.Cardiac Surgery in theAdult. 5e.Hew York:McGraw-Hill Education;2017.

Hannan EL.Race MJ.Watford G, etal.Long-Term Outcomes of Coronary-Artery Bypass Grafting versusStent Implantation.N Engl J Med.2005:352(21):2174-83. doi:10.1056/ NEJMoa040316.PM1D:15917382.

Hansen JT.Lambert DR.Netter's Clinical Anatomy,1sted.s.1.Elsevier:2005.

Harlan BJ.Starr A,Harwin FM.Illustrated handbook of cardiacsurgery.Hew York:Springer-Verlag;1996.

Harrington RA.Becker RC.Ezekowitz M, et al.Antithrombotic therapy for coronary artery disease:the seventh ACCP conference on antithrombotic and thrombolytic therapy.

Hayes D.Furman S.Cardiac pacing:how itstarted,where we are.where we are going.J Cardiovasc Electrophysiology 2004;15:619-627.

Heallie G.Giles M.Echocardiography and the general physician. Postgrad Med J 2004:80:84-88.

Heidenreich P.Eisenberg M. Kee L, etal. Pericardial Effusion in AI0S.Circulation 1995;92(11):3229-3234.

Heaton J. KyriakopoulosC. Pulmonic Stenosis.|U pda ted 2020 Dec1).In:StatPearls[Internet!.Treasure Island (FL):Slat Pearls Publishing;2021Jan-.Available from: https://www.ncbi.nlm.nih.gov,

'books

'

N8K5607S0/.

HiralzkalF. BaknsGL.Beckman JA, elal. 2010 ACCF/AHA/AAIS/ACR/ASAiSCA/SCAI/SIR/STS/SVM guidelines lor the diagnosisand management ol patients with thoracic aortic disease.J Am Coll Cardiol

2010;55:c27- e129.

Hokkcn R8. Takkcnberg JJ. van Hcrwcrden LA. et al. Excessive pulmonary aulogialt dilatation causes important aortic regurgitation. Heart. 2003;89(8):933- 4.

Hussain SI. Maidalany OS. Dunn A el al. Early and mid -term results of aulogialt tescue by Ross reversal: Aonc- valve disease need not become a two valve disease.J IhoracCardiovasc Surg. 2018:155(21:562- 72

Ibanez B.JamesS. Agewall S. el al. 2017 ESC Guidelineslor the management ol acute myocardial infarction in patients presenting with SI segment elevation:The Task Force lor the management of acute

myocardial infarction in patients presenting with ST segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018Jan 7:39(21:119- 77.

Imazio M,Brucalo A.Cemrn R. el al.A Randomized Inal ol Colchicine lor Acute Pericarditis. NE JM 2013:369:1522-1528.

Imazio M.Ocmichclis B.Cecchi E. et al.Cardiac troponin i in acute peiicarditis.JACC 2003:42(121:2144 2148.

Ho SY.Anatomy ol the mitral valve. Heart 2002:88(Suppl IV):iv5-iv10.

Jahama MS.Gottlieb RA.Mentzer JRM. Myocardial Protection. In:Cohn LH, Adams OH. editors. Cardiac Surgery in the Adult.5e.New York:McGraw- Hill Education; 2017.

JonasSH.Kligerman SJ. Burke AP.et al. Pulmonary Valve Anatomy and Abnormalities A Pictorial Essay ol Radiography, Computed Tomography (Cl), and Magnetic Resonance Imaging (MRI).J Thotac Imaging

2016;31:W4 W12.

Julius BK. Spillmann M. Vassalli G, et al.Angina pectoris in patients with aortic stenosis and normal coronary arteries. Mechanismsand pathophysiological concepts.Circulation.1997;95|4):892-8.doi:10.1161/01.

cir.95.4.892.

Radish AH.Buiton AE.Kennedy HL.ACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiography:a report of the ACC/AHA/ACP-ASIM task force on clinical competence.

Circulation 2001:104:3169-3178.

Kazui I.IzumotoH,Yoshioka K,etal.Dynamic morphologic changesin the normal aortic annulus during systole and diastole.J Heart Vahe Dis.2006;15(5):617-21.

Keane D.New catheter ablation techniques for the treatment of cardiac arrhythmias.Card Electrophysiol Rev 2002;6:341-348.

Kern KB.Lotun K.Patel N. el al.Outcomes olComatose Cardiac ArrestSurvivors With and Without ST-Segment Elevation Myocardial Infarction:Importance of Coronary Angiography.JACC Cardiovasc Intern.

2015;8(8):1031-1040. doi:10.101G/j.jcin.2015.02.021.

Khandaket MH. Espinosa RE. Nistiimura RA. et al. Pericardial disease:diagnosisand management. InMayo Clinic Proceedings Elsevier 2010 Jun1(Vol.85. No.6. pp.572-593).

Kim WY.Danias PG.Stuber M. et al. Coronary magnetic resonance angiography for the detection of coronary stenoses. NEJM 2001;345:1863-1869.

Kuklin JK. Pa gam F0. Goldstein 0J et al. American association lor thoracic surgery/mtcinational society for heart and lung transplantation guidelines on selected topics in mechanical circulatory support.J Heart

lung Iranspl 2020:39(3):18? 219.

Knuub J. V/rjns W.Sarastc A. el al. 2019 ESC Guidelines lor the diagnosis and management ol chronic coronary syndromes: The Task Foice for the diagnosisand managemenl ol chronic coronary syndromes of the

European Society ol Cardiology ( ESC). Eur Heart J 2019:41(3).

Krahn A. Klein G. Skane A, cl al. Inseitable loop recorder use lor detection ol mtermiltcnl arrhythmias. Pacing and Clinical Electrophysiof 2004;27:657-564.

Kuon E. Krepkn M. Weiss W. cl al. The challenge presented by right atrial myxoma. Hen 2004; 29:702

Khush KK.Chetikh WS.Chambers DC. et al.The International Thoracic Organ Transplant Registry ol the International Society lor Heart and lung Transplantation: Thirty-sixth adult heart transplantation report -

2019:locus theme: Donor and recipient sice inalch. J Heart Lung transplant. 2019 Ocl;38(10):1056-66,

Kumar SR.Bansal H.Wells WJ. et al.Outcomes ol Reintervention on the Autograft Alter Ross Procedure. Ann Ihorac Surg.2016.

lakdawala NK.Stevenson LW. Loscalro J.Cardiomyopathy and Myocarditis.In:Jameson JL. Fauci AS. Kasper DL. Hauser SL. Longo OL. Loscalro J , editors. Harrison'

s Principles of Internal Medicine. 20e. NewYork.

NY:McGraw- Hill Education; 2018.

lam KY. Dickens P.Chan AC.Tumors ol the heart:A 20-year experience with a reviewof 12.485 consecutive autopsies.Arch Pathol Lab Med 1993;117:1027.

Lazam S.Vanoverschelde JL,Tribouilloy C. et al. Twenty-year outcome alter mitral repair versus replacement lorsevere degenerative mitral regurgitation:analysis of a large, prospective,multicenter,

international registry.Circulation.2017 Jan 31;135(5):410-22.

Lee TH.Boucher CA.Nomnvasive testsin patients with stable coronary artery disease (review). NEJM 2000;344:1840-1845.

Leon M8.Smith CR.Mack MJ,et al.Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. NEJM 2016:374:1609-1620.

Lenoir M.Emmott A.Bouhout I.et al.Autograft remodeling after the Ross procedure by cardiovascular magnetic resonance imaging:Aortic stenosis versus insufficiency.J IhoracCardiovasc Surg.2020.

Leshnower BG.ChenEP.Deep Hypothermic Circulatory Arrest.In:Cohn LH.Adams DH,editors.Cardiac Surgery in the Adult,5e.New York.NY:McGraw-Hill Education; 2017.

Levine GN.Bates ER. B HI JA.et al. 2016 ACC/AHAGuideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease:A Report of the American College of Cardiology:

American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol [Internet],2016 Sep 6:68110):1082-115.

ti-Saw- Hee FL.LipGY.Digoxrn revisited. 0JM 1998; 91:259.

Lin C-Y.Chang S- L ,Chung F- P.et al. Long -Term Outcome of Non Sustained Ventricular Tachycardia in Structurally Normal Hearts. PL05ONE. 2016;11(8):e0160181.

Lindahl B.loss H.Siegbahn A. et al. Maikers ol myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. NEJM 2000:343:1139-1147.

LipGYH.Kieuwlaat R. PistersR. et al. Refining clinical risk stratification lor predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor- based approach:the Euro heartsurvey on atrial

fibrillation.Chest 2010;137:263- 272.

little W.Freeman G. Pericardial Disease.Circulation 2006:113[12):1622-1632.

lopes LR.Elliott PM Hypertrophic Cardiomyopathies. In: Fustcr V. Harrington RA. Naiula J. Eapen 2J, editors. Hurst's Ihe Heart,14c. New York, NY:McGraw-Hill Education; 2017.

lopes RD.Hcizcr 6.Aronson R. et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. NEJM 2019:380:1509-1524.

LoukasM. Groat C , Khangura R. etal. The normal and abnormal anatomyol live coronary arteries. Clinical Anatomy 2009:22:114 128

luciani 68. lucchcsc6.0c Rita F, et al. Reparative surgery ol the pulmonary autogxall: experience with Ross teoperalions.Ear J Cardiothorac Surg. 2012:41|6):1309 14; discussion 14-5.

luciani GB, Vrscardi F. Prlati M. et al.The Ross-Vacoub procedure for aneurysmal aulogialt roots:a strategy to preserve autologous pulmonary valves.J Ihorac Cardiovasc Surg. 2010:139(31:536- 42.

Mack MJ.Icon MB.lhouranl R.el al. Transcalhcter aortic-valve replacement with a balloon-expandable valve in low- risk patients. NEJM 2019:380:1695-1705.

Mancini D. lielz K. Selection ol cardiac transplantation candidates in 2010.Circulation 2010;122(2):173-183.

Mancmi GBJ.Gosselin G. Chow B. et al. Canadian cardiovascularsociety guidelines for the diagnosis and management ol stable ischemic heait disease.Can J Cardiol 2014:30:837-849.

Martin E. Mohammadi S. Jacques F, et al.Clinical Outcomesfollowing the Ross Procedure in Adults:A 25-Year Longitudinal Study.J Am Coll Cardiol.2017;70(15):1890 9.

Martinez RM, O'Leary PW.Anderson RH. Anatomy and echocardiography of the normaland abnormal tricuspid valve.Cardiol Young 2006:16(Suppl 3):4-11.

Martmez-Gonzalez B. Reyes-Hernandez CG.Ouiroga Garza A.etal.Conduits used in coronary artery bypass grafting: A review ol morphological studies[Internet]. Vol . 23.Annals of Thoracic and Cardiovascular

Surgery.Japanese Association for Coronary Artery Surgery:2017.p.55-65.

Mastrobuoni S.de Kerchove L.Solan S, et al.The Ross procedure in young adults:over 20 years of experience in our Institution.EurJ CardiothoracSurg.2016;49[2):S07-12; discussion 12-3.

May J,White GH.HarrisJP.The complications and downside of endovascular therapies.Adv Surg 2001:35153-35172.

MazineA.Ghoneim A. El-Hamamsy I.The Ross Procedure:How I Teach It.Ann Thorac Surg.2018;105(5):1294-8.

Marine A.El-Hamamsy I.Verma S, etal.Ross Procedure in Adults for Cardiologists and CardiacSurgeons:JACC State-of-lhe-Art Review.J Am Coll Cardiol.2018;72(22):27G1-77.

Marine A.David TE. Rao V.etal.Long -Term Outcomes of the Ross Procedure Versus Mechanical Aortic Valve Replacement:Propensity-Matched Cohort Study.Circulation.2016;134[8):576-85.

McCauley J, Kern DE. Kolodner K. etal.Ihe “battering syndrome"

:Prevalence and dinical characteristics of domestic violence in primary care internal medicine practices. Ann Intern Med[Internet],1995[crted

2021Apr11];123(10):737-46.

McDonald M.Virani S.Chan M, etal. CCS/CHFS Heart Failure Guidelines Update:Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction.Canadian Journalof Cardiology.

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C83 Cardiology and Cardiac Surgery Toronto Notes 2023

2021Apt1:37(4):$31-46.

McCillion M.Arthur HM,Cook A, elal.Management olpatients with refractory angina:Canadian cardiovascular society/Canadian painsociety joint guidelines.Can JCardiol 2012;28:S20 S41.

McMuriay JJV.Solomon SO.InrucchiSE et al.Dapagliflocin inpatients withheart lailure andreduced ejection fraction.NEJM 2019:381:1995-2008.

Meeibaum S.Introduction and general background.In:myocardial contrast two- dimensional echocardiography.Meerbaum S.Meltzer R (Eds).Kluvrer Academic Publishers.Boston:1989.p.2.

Mehra MR,Kobashigawa J, Staling R.el al. Listing criteria lor heart transplantation:international society lor heart and lung transplantation guidelines lor Ihe cate olcardtac transplant candidates 2006.JHeart

lungIranspl 2006;25(9):1024-1042

Mehta M,Canter C.Hannan M. elal.Ihe 2016InternationalSociety lor Heart lungIransplanlaliorr listing criterialor heart transplantation:A 10 ye.ii update.J Heart lung Iransplant. 2016:36(11:1 23.

Mehran R, Baber U.Sharma SK et al.licagrelor with or without aspirinin high risk patients alter PCI.NEJM 2019:381:2032-2042.

Mehta SR.Bainey KR.Cantor WJ. et al.2018 CCS

'

CAJC Focused Update of theGuidelines lor theUse of Antiplatelet Therapy.Can J Cardiol.2018 Mar:34(3):214-233.

Mehta SR.Wood BA.Storey RF.etal.Complete revascularization with muthressel PCI lor myocardial infarction.NFJI4 2019:381:1411-1421.

Mehta SR.Bainey KR.Cantor WJ,et al.2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update ol the Guidelines lor the Use of Antiplatelet Iherapy.Can JCardiol

[

Inlcrncll. 2018 Mar 1:34|3|:214-33.

Michaud GE. Stevenson WG. CommonAtrialFlutter,Macrorccntranl.andMullrlocal Atrial tachycardias.In: JamesonJl. Fauci AS.Kaspei 01.Hauser SI.longoDl, loscalroJ. editors. Harrison's Principles ol

Internal Medicine.20e.New York,NY:McGraw-Hill Education:2018.

Miller JM, Rochrtte CE.Dewey M,etal.Diagnostic performance of coronary angiography by 64-rowCT.NEJM 2008:359:2324-2336.

Moliterno DJ.Jacuzzi JL.Evaluation and Managementof Hon-St-Segment Elevation MyocardialInfarction.In:Fuster V.Harrington RA.Narula J,Fapen 2J.editors.Hurst’sIhe Heart.14e.Hew York, NY:McGrawHill Education:2012.

Mooijani H.Viola II.Ohn SK.Key questions in cardiac surgery.1st cd.Ilm Publishing Limited:2011.

Morrison U.Devlin SM.KonlosMC.el al.Ihe association olmaximum troponin values post out ol hospital cardiac arrest with electrocardiographic findings,cardiac repcrlusion procedures andsurvival to

discharge: A sub-study of ROC PRIMED.Resuscitation.2017:111:82-9.

Muchtar E,Blauwet LA.Gertz MA.Restrictive Cardiomyopathy.Circulation Research. 2017:121|7):819-37.

Mulla S.Asuka E.Siddiqui WJ.Tricuspid Regurgitation.(Updated 2020Jul 27).In:StatPearis (Internet).TreasureIsland|FL):StatPearls Publishing:2021Jan.

Ilarayan SM. Krummen DE.Approach To The Patient With Cardiac Arrhythmias.In:Fuster V.Harrington RA.Harula J.Eapen ZJ.editors.Hurst's The Heart.14e.New York.NY:McGraw-Hill Education: 2017.

Neumann FJ. Sousa Uva M. Alrlsson A.elal. 2018 ESOEACIS Guidelines on myocardial revascularization.Fur Heart J 2019:40:87165.

Occhslin E. Klaassen S.tell ventriculai nontoinpndion. J Am Coll Cardiol 20I9:?3(13):16121615.

0'Gara P,Kushner F.Ascheim D.et al.2013 ACCF,

'AHA guideline lor the management of Si-Elevation myocardial infarction:a report ol the American College ol Cardiology Foundation/AmericanHeart Association

Taskforce on practice guidelines.Circulation 2013:127(4).

O'Meara E. McDonald M.Chan M etal.CCS.'CHFS heart lailureguidelines:clinical trialupdate on functional mitralregurgitation.SGLT2inhibitors. ARNI inHFpEF, and tafamidis inamyloidosis.Can J Cardiol

2020;36(2|:159169.

Ommen SR, MilalS. Burke MA.et al. 2020 AHAfACC Guideline loi the Diagnosis and Treatment olPatients With Hypertrophic Cardiomyopathy. Circulation. 2020;142|25):o558 eG31.

O'Neil W.DixonS.(linesC.The year ininterventional cardiology. J Am CollCardiol 2005:45:1117-1134.

Otto CM.Hishimura RA. Bonow R0.etal.2020 ACC,

'

AHA Guideline for the Management ol Patients With Valvular HeailDisease:A Report ol the AmericanCollege olCardiology,

'American Heart Association Joint

Committee on ClinicalPractice Guidelines.Circulation.2021;143(5):e72-e227.

Packer D.Evolution of mapping and anatomic imaging of cardiac arrhythmias.JCardio Electrophysiol 2004:15:839-854.

Panchal AR.Bartos JA.Cabanas JG.el al. Part 3: Adult 8asic and Advanced lifeSupport: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Circulation 2020 October 20:142116 suppl 2|:S366 S468.

Patel MR,Mahaffcy KW. Garg J. etal.Rivaroxaban vs. warfarin innonvalvular atrial fibrillation. NEJM 2011:365:883-891.

Patel MR.Singh M.Getslr BJ. O'Neill W.ST-Segment Elevation Myocardial Infarction.In:Fuster V.Harrington RA.Narula J. Eapen ZJ,editors.Hurst's theHeait.14e.New York.NY:McGraw-Hill Education:2017.

Pelliccia A,Solberg E.Papadakis M.etal.Recommendations for participabon in competitive and leisure time sport inathletes with cardiomyopathies,myocarditis,andpericarditis:position statement of the Sport

CardiologySection of the European Association of Preventive Cardiology (EAPC).Eur Heart J 2018:40(1):19-33.

Picano E.Stress echocardiography: a historical perspective. AJM 2003:114:126-130.

Picard F, Sayah N.Spagnoll V.Adicdj J.Varenne 0. Vasospastic angina: A literature review of current evidence. Archives of Cardiovascular Diseases. 2019:112(1)44 55.doi:10.1016,j.acvd.2018.08.002

Pinto YM.Elliott PM.Arbustrni E.etal.Pioposal lor a revised definition oldilated cardiomyopathy,hypokinetic non dilated cardiomyopathy,and its implications lor clinical practice:a position statement ol IhcESC

working groupon myocardial and perxcaidial diseases.Eur Heart J.2016:37|23):1850- 8.

Pitt MPI.Bonser RS.The natural history olthoracic aortic aneurysm disease:an overview.JCardSurg1997;12(SuppI):270-278.

Pitt B.Remme W.ZannadF.et al.Eplerenone.a selective aldosterone blocker,in patients withleft ventricular dysfunction alter myocardial infarction.NEJM 2003:348:1309-1321.

Poh CL.Buratto E.larobina M. et al.Ihe Ross procedure in adults presenting with bicuspid aorbe valve and pure aortic regurgitation:85% freedom from reoperation at 20 years.Eur J Cardiothorac Surg.

2018:54(31:420 6

Pokhrel B,Levine S.PCSK9 Inhibitors.Itcasure Island:StatPearis Publishing;2019.

Poterucha TJ,Kochav,J,O'Connor DS.et al.Cardiac tumors:clinical presentation,diagnosis,and management Curt Treat Options Oncol 2019:20|8):66.

Pope JH.Rulhazer R.Beshansky JR.et al.Clinical features ol emergency department patients presenting with symptoms suggestive of acute cardiac ischemia:A multicenler study. J Thromb Thrombolysis

(Internet).1998 [died 2021Apr 11|;6|1):63-74.

Powell JT.Brown1C.The natural history of abdominal aortic aneurysmsand their risk of rupture.Adv Surg 2001:35:173-185.

Piabhakar Y. Goyal A. Khalid N,el al.Pericardial decompression syndrome:a comprehensive review. World J Cardiol 2009:11(12):282 291.

Practice Guidelines (Committee onExercise Testing).JACC 1997:30:260 315.

Prystowsky EN.Topol EJ, Calilf RM.et al. textbook of cardiovascular medicine.3rd ed.Philadelphia:Lippincott Williams £ Wilkins:2007.Chapter:Electrophysiology and pacing.

RabiD,ClementF.McAlister F.etal.Effect ol perioperativeglucose-insulin-potassiurn infusions onmortality andatrial fibrillation after coronary artery bypass grafting:a systematic review and meta-analysis.Can

J Cardiol 2010:26:178-184.

Rahouma M. Arshia MJ.Elmously.A.etal.Cardiac tumors prevalence andmortality:A systematic review and meta- analysis.Int J Surg 2020:76:178 189.

Ramlavri B. Reardon MJ. Cardiac Neoplasms.In:Cohn LH.Adams DH. editors.Cardiac Surgery in the Adult. 5e.Hew York. NY: McGraw Hill Education:2017.

Rauch U.Oscndc Jl.Fuster V. et al.Thrombus formationon the atherosclerotic plaques:pathogcncsisand clinical consequences.Ann Intern Med 2001:134:224 238.

Reddy PS.Curtiss El.Urelsky BF.Spectrum olhemodynamic changes in cardiac tamponade.Am JCardiol (Internet],1990 Dec 15[cited 2021Apr H]:66(20):1487-91.

Rennard S, Decramer M,Calverley PMA.elal. Impact of C0PD in North America and Europe in 2000:Subjects' perspective of Confronbng C0PD International Survey.Eur Respir J (Internet].2002 Oct1(cited 2021

Apr 11);20(4):799-80S.

Risgaard 8. Winkcl BG. Jabbari R.et al.Buiden olSudden Cardiac Death inPersons Aged 1to 49 Years.Circulation:Arrhythmia andElectiophysiology. 2014:7|2):205 -11.

Romeo JIR.Popagcoigiou G.da Costa FED.et al.long term Clinical andEchocaidroqraphic Outcomes in Young and Middle aged AdultsUndergoing the Ross Procedure. JAMA Cardiol. 2021.

Rosen CL, Tracy JA.Ihe diagnosis ol lower extremity deep venous thrombosis.Em Med Clin N Am 2001:19:895 912.

Ross Dll. Replacement of aortic and mitral valveswitha pulmonary autografL lancet.1967:2(7523):956-8.

Rothman SA.Laughlin JC,Seltzer J.et al.Thediagnosis of cardiac arrhythmias:a prospective multi-center randomized study comparing mobile cardiac outpatient telemetry vs.standard loop event monitoring.J

Cardiovasc Electrophysiol 2007;18:241.

Runo JR.loyd JE.Primary pulmonary hypertension.In:lancet (Internet!.Elsevier B.V.; 2003 [cited 2021Apr 11).p.1533- 44.

Rutherford RB.Vascular surgery.4th cd.Toronto: WB Saunders: 1995. Chapter:Atherogenesis and Ihe medicalmanagement olatherosclerosis,p.222 234.

Ryan TJ.FaxonDP.Gunnar RM. et al.Guidelines lor percutaneous transluminal coronary angioplasty.Areport ol theAmerican College of Cardiology/American Heart Association Task Force on Assessment of

Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee onPercutaneous Transluminal Coronary Angioplasty).Circulation 1988;78(2)486-502.

Sabharwal H,LahiriA.Role of myocardial perfusion imaging for risk strabAcatron in suspected or known coronary artery disease.Heart 2003;89:1291-1297.

Salcedo EE.Cohen Gl. WhiteRO.et al.Cardiac tumors:diagnosisand management.Curr Probl Cardiol1992:17:73.

Saji AM.Sharma S.Pulmonary Requrgitation.[Updated 2020 Dec14|.In:StatPearis (Internet).TreasureIsland (Fl):StalPearls Publishing:2021 Jan.

Saikar M, Prabhu V. Basics ol cardiopulmonary bypass.Indian J Anncsth 2017:61(91:760 767.

Sapp JL, Wells GA.Parkasb R,et al.Ventriculai tachycardia ablationversus escalation olantiarahythmic drugs.HEJM 2016;375|2):111-21.

Schmieder FA,Comerota AJ.Intermittent claudication:magnitude ol the problem,patientevaluation.and therapeutic strategies.Am JCard 2001:87|Suppl):3D-13D.

Schoepf J,Becker C.Ohnesorge 8.etal.CT olcoronary artery disease.Radiology 2004;232:18-37.

Seidah NG.Awan Z.Chretien M.Mbikay M. PCSK9:a keymodulator of cardiovascular health.Circulation research.2014:114|6):1022-36

Seiruys PW, Morice MC.Kappclain AP,et al.Pcicutaneouscoioriaiy intervention vs.coronary-artery bypass grafting(or severe coronary arteiy disease.IIEJM 2009:360:961 972.

Seiruys PW,Unger F.Sousa JE.et al.Comparison ol coronary-artery bypass surgery and stenting lor Ihe treatment of multivessel disease. NEJM 200l;344(15):1117 1124

Shah SN.Gangwanr MK.OliveiII.Mitral Valve Prolapse.[Updated 2020 Nov 20).In:StatPearis (Internet). IreasureIsland (Ft): StatPearisPublishing:2021Jan .Available Horn:ncbi.nlm.nih.gov.

Shahian DM. O'BrienSM.ShengS.etal.Predictors ollongterm survival alter coronary arteiy bypass grading surgery:Results from thesociety of thoracic surgeons adult cardiac surgery database (Ihe ASCERI

Study).Circulation (Internet).2012Mar 27[cited 2021Apr 111;12S|12):1491-S00.

Shroyer At.Grover FI.Nattier B. etal.On- pump vs.off-pump coronary-artery bypass surgery.NEJM 2009:361:1827-1837.

Shroyet Al.Hattler B.Wagner TH.et al.Five year outcomes alter on-pumpand oil-pump coronary-artery bypass.HEJM 2017:377:623 632.

Srevers HH,Hummer W. Beyersdorf F.clal.The everyday used nomenclature olthe aortic root components:Ihe tower ol babel? Eur JCardiothorac Surg 2012:41:478 482.

Sievers HH,Stierle U.Petersen M.elal.Valve performanceclassification in 630 subcoronary Ross patients over 22 years. JTIroracCaidiovasc Surg. 2018:156(1):79-86.e2.

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C8I Cardiology and Cardiac Surgery Toronto Xotes 2023

Severs HH.Stierle U.Chantos EL et al.Amdbcentre evaluation ol the autograft procedure for young patentsundergoing aortic valve replacement:update on the German Ross Registry'

.Eur JCaidiothorac Surg.

2016:49(1):212-8.

Slvestri f.Bussam R.PavlehcN.etal.Metastases of the heart and pericardium.G Ital Cardiol1997;27:1252.

Simpson C.Dorian P.GuptaA.etal.CCSConsensus Conference 2003:Assessment of the cardiacpatientfor fitness to driveand fly:executive summary.Can J Cardiol 2004;20:1313-1323.

Skanes A,Klein G.KrahnA.et at.Cryoablation:potentials and pitfalls.J Cardiovasc Electrophysiol 2004:15:528-534.

Skillington PD.Mokh'

es HH.lakkenbergJJ.et al.IheRoss procedure using autologous support of thepulmonary autograft techniques and late results. J Thotac Cardiovasc Surg.2015:149(2Suppl)346-52-

Somberg J.Arrhythmia therapy.AmJ Therapeutics 2002:9:537-542.

Spertus JA.JonesPG.CoenU.et aL Iransmyocardial C02 laser revascularization improves symptoms,function,and quality of life:12-month results from a randomized controlled trial.Am JUed 2001:111(51:311

348.

Spinier S.BeesC.Review of prasugrel for the secondary prevention of atherothrombosis.J Hanag CarePharm 2009:15:383-395.

Stelzer P.Hepa J.Vargbese R.Operahverisksof the Ross procedure.J Thotac Cardiovasc Surg. 202l:161(3|:90S15.e3.

Stewart JA.Fraker 10 Jr.Slosky 0A.et al.Detection of persistent left superior vena cava by two-4mensional contrast echocardiography. J Clin Ultrasound1979:7:357.

StoneGW.KappeteinP.SabikJF.et at.Five-year outcomesafter PCIor CABGfot left main coronary disease.KEJH 2019:381:1820-1830.

Stone GW.lerstenPS.Bubenste nB.etalA prospective,multicenter,randomized trialof percutaneous Iransmyocardial laser revascularization inpatients withnontecanalizable chrome total occlusions. J An

Coll Cardiol 20O2:39(tO):1S81 1587.

Stulak JH.Burkhart HH.Ssndt 3rd TH.etal.Spectrum and outcome of reoperations after the Ross procedure.Circulation.2010:122(121:1153-8.

TalancoGP.CrostaHLGennicoHB.etal.Cocaine and coronary artery diseases: A systematic renew of the literature[Internet],Vol.18.J Cardiovasc Med.Lippincott Williams and Wilkins:2017 cted 2021Apr 111.

p.291-4.

Tatdif JC.Kouz S.Waters DO.etal.Efficacy and safety of low-dose colchicine after myocardial infarcton.NJEM 2019:381:2497-505-

Thygesen K.Alpert J5.Jaffe AS.etal.Thirduniversal definition of myocardial infarchon.Eur Heart J 2012:33:2551-2567.

Thijssen J.Borieffs CJ.van Rees JB.etal.Driving restrictions afterimplantable cardioverter defibrillator implantation;an evidence-based approach.Eur Heart J 2011;32:2678-2687.

TowbinJ.forts A.Jefferies J.left ventricular non-compaction cardiomyopathy. Lancet 2015:386(9995)213 825.

lorii R.El-HamamsyI.Donya H.etal.Integrated morphologic and functional assessment of the aortic root iter different tissue valve root replacement procedures.J Thorac CardiovascSurg.2012343|6):H22-8.

TurpreAGG.Antman EH.Low-molecular-weight heparins in the treatment of acutecoronary syndromes.ArchIrfemHed 2001:161:1484-1490.

UnderwoodHJ.El Khoury G,Deronk D.et al.The aortic root:structure,function,andsurgicalreconstruction.Heart 2000:83:376-380.

Van DamUN.Fitzgerald EM.Pulsus Paradoxus.[Updated 2020 Nov19],In: StatPearls [Internet].Treasure Isfand(EL):StatPearlsPublishing:2021Jan-.Available from:https:/i

>wwwjrcbuibnjuh.gov >

books>

>

NBK482292.

Vander WallSJ.LopesBD.Asert>ergJ,etal.ldarucizumab for dabigatran reversal in the management of patients withgastrointestinal bleeding.Circulation 2019:139(61:748-756.

VanGeider 1C.GroerrvddHE.Cnjns HJ,et al.lenient vs.strict rate controlIn patients withatrial fibrillation.NEJH 362:1363-1373.

VermaS.SzmitkoPE.Weisef B0.et al.Clinician update:should radial arteries be usedroutinely for coronary arterybypassgrafting?Circulation 2004;1l0:e40-e46.

Viram S.DentS.Breeden-HasleyC.etal.Canadian cardiovascular society guidelinesfor evaluation and management of cardiovascular complications of cancer therapy.Can JCardiol 2016:32(7):831 841.

Way LW.Ooherty GH.Current surgical diagnosis and treatment.11th ed.Lange Medical BooksiHcGraw-HUi;2004.

Weilens J.Cartfac arrhythnvas:the guest for a cure.J Am Coll Cardiol 2004:44:1155-1163.

Welsh RC.Travers A.Huy-thI.etal.Canadian Cardiovascular Society WorkingGroup: providing a perspective on the 2007 focused update of the ACC/AHA 2004 guidelines for the management of ST elevation

myocardial infarction.Can JCardiol 2009:25:25-32.

Whellon PK.Carey RH.Aronow WS.etal.2017 ACC/AKA/AAPA/AIC/ACPM/AGS/APhA/ASH/ASPC/NHATCIUGuideline for the prevention,detection,evaluation,and management of high bloodpressure «iadults:

executive summary:areport of theAmerican college of cardiology/American heart association task force on clinical practice guidelines.Hypertension 2018;71(6):1269-324.

Wilson WM.Benson111.Ostevr HD.et al.Transcatheter Pulmonary Valve Replacement With theEdwards Sapren System:TheTorontoExperience.JACC Cardiovasc Inlerv.2015:8(14):1819-27.

Wong GC.Wefsford H.Ainsworth C.etal.2019 CanadianCardiovascular Society/Canadian Association of tntenenbonal Cardiology guidelines on the acutemanagement of ST-elevation myocardial infarchon:

focused update onregionalization andreperfusion.Canadian Journal of Cardiology.2019 Feb1:35(23:107-32.

Xanthopoulos A.Skoularigis J.Diagnosis of acute pericarditis.E J Cardiol Pract.2017:15.

VadavNIC SiddigueHS.Constrictive Pericarditis.[Updated 2021Feb17).ln:5tatPearls [Internetl- TreasureIsland (FL):StatPearls Publishing;2021Jan.

YangSC.CameronDE.Current therapy in thoracicand cardiovascular medicine.McGraw-Hill;2004.

Yeghiazarians Y.Sraunste nJB.Askari A.et al.Review article:unstable angina pectoris.NEJM 2000:342:101-114.

Timetbaum P.JosepftsonH.Theevolving role of ambulatory arrhythmia monitoring in general dinical practice.AnnIntern Med1999:130:848-856.

Zipes D.The year inelectrophysiology.JAm Coll Cardiol 2004;43:1306-1324.

Zipes DP.DiMarco JP.GJIetePC.etal.ACC AHA task force report guidelines (or clinical intracardiacelectropbysiological and catheter ablation procedures.JACC1995;26:555-573.

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Clinical Pharmacology

Max Solish, editor

Ming Li and Dorrin Zarrin Khat, associate editors

Vijithan Sugumar, EBM editor

Dr. David Juurlink and Dr.Cindy Woodland,staff editors

Acronyms

General Principles

Drug Nomenclature

Phases of Clinical Drug Testing

Drug Administration

Pharmacokinetics.

Absorption

Distribution

Elimination

Metabolism (Biotransformation)

Pharmacokinetic Considerations

Pharmacodynamics

Effects of Drugs on Receptors

Effectiveness and Safety

Therapeutic Indices

Therapeutic Drug Monitoring.

Adverse Drug Reactions

Approach to Suspected Adverse Drug Reactions

Variability in Drug Response

Drug Interactions

Autonomic Pharmacology

Parasympathetic Nervous System

Sympathetic Nervous System

Opioid Therapy and Chronic Non-Cancer Pain

Common Drug Endings

Landmark Pharmacology Trials

References

CP2

,CP2

CP3

CP7

CP10

CP10

CP12

CP13

CP14

CP14

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C.P2 Clinical Pharmacology Toronto Notes 2023

Acronyms

ACE angiotensin converting enzyme cGMP

ACh acetylcholine

ADE adverse drug event

ADR adverse drug reaction

ARB angiotensin receptor blocker

AUC area under the concentration- DIN

time curve

BBB blood-brain barrier

P-glycoproteln

pharmacokinetics

solute carrier

selective serotoninreuptake

inhibitor

total body water

therapeutic drug monitoring

therapeutic index

volume of distribution

cyclic guanosinc

monophosphate

clearance rate

COMT catechol-O-methyltransferase NE

CYP

INR international normalized ratio P-gp

milligram morphine equivalents PK

National Drug Code

norepinephrine (NPN)

nothing by mouth

nervous system

partition coefficient of a drug

pharmacodynamics

phosphodiesterase

MME

C NDC SLC

cytochrome P450 enzyme

drug identification number NS

Food and Drug Administration Po.v>

glomerular filtration rate

Henderson-Hasselbalch

NPO

TBW

FDA TDM

GFR PD Tl

( HH ’Dr Vd

General Principles

Drug Nomenclature

• DIN or NDC: Drug Identification Number assigned to each drug approved by Health Canada;

National DrugCode assigned by FDA ( US), equivalent to the DIN in Canada

• DIN -H M: identification number assigned to registered homeopathic products in Canada

• NPN:Natural Product Number; refers to natural health products (excluding homeopathic

medicines) regulated by the Natural and Non-Prescription Health Products Directorate within Health

Canada

• chemical name: describes chemical structure; consistent in all countries via International Union of

Pure and Applied Chemistry (e.g. N-(4-hydroxyphenyl)acetamide = acetaminophen)

• non-proprietary (generic) name:approved name (requires approval from nomenclature committee),

official name (listed in pharmacopeia), often referred to as the generic name; may contain an ending

similar to drugs in its class (e.g. atorvastatin, pravastatin,simvastatin)

• proprietary (trade) name: the brand name or registered trademark (e.g. Lipitor")

Phases of Clinical Drug Testing

• pre-clinical:assessments of the drug before it is given to humans(e.g.laboratory studiesin cells or

animals) to examine PK and PD properties and potential toxicities

• phase I:first administration to a small number of healthy volunteers, following preclinical studies; to

explore PK and safely

• phase il:first administration to patients,smallsample sizes; primarily to determine safety and

efficacy, dose range and PK

• phase 111: comparative studies(new drug vs. placebo orstandard of care) to establish safety and

efficacy in a larger group of patients; generally involves double-blinded KC Is

• phase IV:post-marketing surveillance, wider distribution; to determine effectiveness (in contrast to

efficacy), monitor long-term drug effects, and detect previously unappreciated ADRs

Set Lardmark Clinical Pharmacology Trialstable

for more information on resultsfrom the BNTk62b 2

t rial,one ol Ibe first otiose III global trials utilizing

BNI162b2 mRNA vaccine in presenting COVtD-19 in

persons1Syr and older.

Drug Administration

• choice of route of administration depends on available formulations, local and systemic effects,

desired time to onset and/or duration of action, adherence, and other patient characteristics

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Table1Routes of Drug Administration

Route Advantage Potential Disadvantages

Oral (P0) Convenient,easy to administer

Large surface area for absorption

Inexpensive relative lo parenteral administration Adverse Gl effects

Incomplete absorption

See Landmark Clinical Pharmacology Inals table

lor more Information on resultsfrom tl*

A1US

trial, which is the Ihsttiiai utihimg long-acting

cabolegravir and nlpivinne inlramuscular injections

for mainland nee of HIV-1suppression vs.standard

daily oral anbretroriral therapy. lire trial isexpected

to improve longterm HIV-1suppression medication

adherence.

Hepatic and intestinal first-pass effect

Higher likelihoodol drug drug,

'drug - food - interactions

May be allectcd by dietary lactors

Requires an intact Gl system

Affected by Gl motility

Buccal/Sublingual (SI) Rapid onset of action

No hepatic first- pass effect

Small hepatic first- pass effect

Use when NPO.vomiting,or unconscious

Must be lipid-soluble, non-irritating

Inconvenient, irritation at site of application

Erratic absorption

Appropriate for limited number of drugs

Little ability to undo inappropriate drug administration

Risk of infection, bleeding, vascular injury, and

extravasation

Mote expensive

Requiressterile conditions and trained professionals

Rectal (PR)

No hepatic first-pass effect

Provides rapid onset of action

Easy to titrate dose

Intravenous (IV)

Intramuscular (IM) Depotstorage if oil- based -slow release of drug Pain/hematoma at site of injection

Aqueoussolution -

rapid onset of action (e.g.

epinephrine for serious allergic reactions)

Subcutaneous (SC) Constant, even absorption

Alternative lo IV

Pain at site of injection

Smaller volumes than IM

Easier administration (can be self -administered) Possible tissue damage from multiple injections

Direct into CSF

Bypass BBB and blood-CSF barrier

Immediate action in lungs

Rapid delivery lo blood

No hepatic first- pass effect and generally less

presystemic clearance

Risk of infection and CSF leak

Invasive procedure

Musi be gas. vapour, or aerosol

Intrathecal

Inhalation

Topical (skin, mucous membranes. Easy to administer

eyes)

Transdcrmal

Effects are generally limited to siteof application

Localiied (limited systemic absorption)

Drug absorption through intad skin

No hepatic first- pass effect

Local effect

Irritation dtsite of application

Delayed onset of action

Others (Inlraperitoneal. Intra - Risk of infection and hemorrhage

articular)

Pharmacokinetics

• “what the body doesto the drug” -i.e. the fate of a drug in the body following administration

• definition: the time-course of drug absorption, distribution, metabolism, and elimination from the

body (ADME) following drug administration

Absorption

•definition: movement of the drug from the site of administration into bloodstream

Mechanisms of Drug Absorption

•most drug absorption involves passive diffusion

•other mechanisms include active transport, facilitated diffusion, and pinocytosis/phagocytosis

Factors Affecting the Rate and Extent of Drug Absorption

•lipophilicity (Pofw)

•local blood flow at the site of administration (e.g.sublingual vessels facilitate rapid absorption of

sublingually-administered medications)

•molecularsize (e.g. drugs with smaller molecular weights are absorbed faster; drugs with large

molecular weights (i.e. >1000 Da) are not as easily absorbed by passive diffusion)

• pH and drug ionization

drugs are usually weak acids (e.g. ASA) or weak bases (e.g. ketoconazole) and thus exist in ionized

and non-ionized forms in the body

non-ionized (uncharged) forms cross cell membranes more readily by passive diffusion than

ionized (charged) forms

the ratio of ionized to non-ionized forms is determined by body compartment pH and drug pKa

(as per the Henderson-Hasselbalch equation )

• totalsurface area for absorption (e.g.small intestinal villi are the primary site of absorption for

most orally-administered drugs)

•drug transporters

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Bioavailability (F)

• definition:proportion of dose that reachessystemic circulation in an unchanged state and is available

to access the site of action

• lower F usually reflects limited drug absorption orsignificant first

-pass effect

• IV dose has 100% bioavailability (I

;

= l)

First-Pass Effect

• definition:metabolism (i.e.biotransformation) of the drug prior to reaching systemic circulation,

resulting in reduced F

• can occur with PO administration of a drug: G1 tract (absorption with possible metabolism) -> portal

vein to liver (

possible first-pass metabolism) > systemic circulation

• with rectal administration, 50% of drug absorbed in the colon goes through the portal system

Drug Transporters

• there are many drug transporters that can affect the uptake or efflux of drugsfrom cells and

organelles, and affect drug absorption,distribution, and elimination

• P-glycoprotein (P-gp) is a transport protein of clinical relevance asit isfound in a wide variety of body

tissues (including the small intestinal epithelium, proximal tubule, bile canaliculi, and BBB) where

it acts as a multidrug efflux pump and provides a “natural defence mechanism"

against drugs and

xenobiotics

• P-gp limits the absorption and enhances the elimination of its many P-gp substrates (e.g. digoxin,

etoposide, paclitaxel, tacrolimus, cyclosporine, apixaban)

• some drugs (e.g.most macrolide antibiotics) inhibit P-gp,leading to increased serum concentrations

of P-gp substrate drugs; P-gp inducers (e.g. rifampin, St.John’

s wort) increase efflux activity leading to

decreased serum concentrations

• some tumours overexpress P-gp leading to multidrug resistance to chemotherapeutic agents

• other members of the ATP BindingCassette (ABC) superfamily and the Solute Carrier (SLC)

superfamily of drug transporters also affect drug absorption; members of the SLC superfamily

generally function as uptake drug transporters

Distribution

• definition: movement of drugs between different body compartments and to their sites of action

• major body fluid compartments include plasma, interstitial fluid, intracellular fluid, and transcellular

fluid (e.g.CSF,peritoneal, pleural)

• tissue compartmentsinclude fat, muscle, and brain

Factors Affecting the Rate and Extent of Drug Distribution

• physical and chemical properties of the drug (e.g. P»/w, pKa, and size)

• pH of fluid

• binding to plasma proteins

• binding within compartments (i.e. depots)

• regional blood flow

• drug transporters

Plasma Protein Binding

• some drug molecules in the blood exist in an equilibrium of two forms:

1. bound to plasma protein: acidic drugs bind to albumin, basic drugs bind to al

-acid

glycoprotein

2. free (unbound):can leave the circulation to distribute into tissues and exert an effect,subject

to metabolism and elimination

• bound fraction is determined by drug concentration, binding affinity,and plasma protein

concentration (number of binding sites)

• reduced number of binding sites (e.g. hypoalbuminemia) or saturation of binding sites (e.g.

competition/displacement) may result in increased concentration of free drug, which is often cleared

with no harmful effects, although toxicity is possible

Volume of Distribution

• Vd:the apparent volume of fluid into which a drug distributes

• a calculated value (Vd) = amount of drug in body (i.e.dose administered) initial plasma drug

concentration

• a theoretical value that does not correspond to an actual physiologic volume; Vd can greatly exceed

TBW

• Total Body Water (TBW) represents the maximal anatomical fluid volume thought to be

accessible to a drug (~40 L for average adult)

• small Vd (<0.04 L/kg) generally correspondsto a drug that distributesin plasma and/or binds plasma

proteins to a high degree

• large Vd correspondsto a drug that distributes into tissues(fat, muscle, etc.);since most of the drug is

not located in blood,the measured drug concentration in blood islow; thus, when dividing the dose

by the blood/plasma drug concentration, it “appears" to distribute in a large volume

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• Vd of drugs that are highly bound to plasma proteins can be altered by liver and kidney disease due to

changes in plasma protein binding

• Vd of drugs changes with age

• Vd of drugs may change in the geriatric population based on the drug Po/w;in geriatric populations,

there is a reduction in total body water and total muscle mass, but an increase in total body fat

resulting in an increase in the V d of hydrophobic drugs

Depot

• a body compartment in which drug molecules tend to be stored and released slowly over a long period

of time

• fat is a depot for very lipid soluble drugs (e.g. diazepam,THC)

• some oil-based medications are injected 1M for slow release (e.g. depot medroxyprogesterone acetate

dosed q3mo; depot risperidone dosed q2 wk)

Barriers (Relative)

• anatomical body structures that limit or prevent diffusion of drug molecules,such as the placenta or

BBB (a barrier composed of tight junctions between capillary endothelial cells and astrocytes)

• physiological barrierssuch as drug transporters(e.g. P-gp), often serve as a natural defence

mechanism against drugs and xenobiotics

• need to consider dosing route and/or drug interactions for drug penetration across these barriers

• barriers are important in determining sites of action and side effect profiles of drugs (e.g. risk of C.NS

depression if drug crosses BBB, risk of harm to a fetus if drug crosses placenta)

Elimination

• definition:removal of a drug from the body

Routes of Drug Elimination

• kidney (main organ of elimination)

renal drug clearance = (glomerular filtration + tubularsecretion) -(tubular reabsorption)

renal function (assessed using serum creatinine) decreases with age (7.5 mL/min per decade) and

is affected by many disease states (e.g. diabetes)

processes affecting renal elimination:

1. glomerular filtration

- a passive process, thus only the free drug fraction can be eliminated

- drug filtration rate depends on GFR,degree of protein binding of drug, and size of drug

2. tubular secretion

- a saturable transport process allowing both protein-bound and free drug fractions to be

excreted

- distinct transport mechanismsfor weak acids (e.g. penicillin,salicylic acid, probenecid,

chlorothiazide) and weak bases(e.g.quinine, metformin, quaternary ammonium

compoundssuch as choline)

- drugs may block the secretion of other drugs if one or more share or inhibit the same

drug transporter (e.g. probenecid can inhibit the excretion of penicillin via organic anion

transporters)

3. tubular reabsorption:some drugs can be actively or passively reabsorbed back into the

systemic circulation, reducing their excretion

• stool:some drugs and metabolites are actively secreted into the bile or directly into the Cil tract

enterohepatic recirculation occurs when drugs are reabsorbed from the intestine and returned

to the liver to cycle between the intestine and liver, which can prolong the drug’s duration in the

body (e.g.some glucuronic acid conjugates that are excreted in bile may be hydrolyzed in the

intestines by bacteria back to their original form and can be systemically reabsorbed)

• lungs: elimination of anesthetic gases and vapours by exhalation

• other routes:sweat,saliva, and breast milk are generally lesssignificant routes, but saliva

concentrations of some drugs parallel their plasma concentrations (e.g.rifampin) and drug excretion

into breast milk is a concern for some drugs

Metabolism (Biotransformation)

• definition:chemical transformation of a drug in vivo

• sites of biotransformation include the liver (main), G1 tract,lung, plasma, kidney, and most other

tissues

• as a result of the process of biotransformation:

a prodrug (i.e.inactive drug) may be activated (e.g.tamoxifen to endoxifen; codeine to morphine)

a drug may be changed to another active metabolite (e.g.diazepam to oxazepam and others)

a drug may be changed to a toxic metabolite (e.g. acetaminophen to NAPQ1)

a drug may be inactivated, as with most drugs (e.g. acetaminophen to acetaminophen

glucuronide)

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Drug Metabolizing Pathways

• phase 1 reactions

oxidation, reduction, or hydrolysis reactions that introduce or unmask polar groups on a parent

compound to slightly increase watersolubility (e.g. hydroxylation, demethylation)

• the change in P«/« is typically minimal compared to phase II, and often phase I places a polar

“handle" on a hydrophobic drug to permit conjugation in phase II

• often mediated by cytochrome P450 (CYP) enzymes found in the endoplasmic reticulum

(primarily in hepatocytes, but in lots of other tissues)

• products of the reaction can be excreted or undergo further phase 11 reactions

• phase 11 (conjugation) reactions

conjugation with large endogenoussubstrates that are often polar (e.g.glucuronic acid,

glutathione,sulphate, acetyl groups, methyl groups,or amino acids)

• often substantially increases water solubility and renal elimination

• can result in biologically active metabolites (e.g. morphine glucuronide)

• can occur independently of phase I reactions (e.g. morphine to morphine glucuronides)

Examples of CYPSubstrates, Inhibitors,

and Inducers

drug-interactions.niedKtne.iu.edu/MainIa6le.aspx

Factors Affecting Drug Biotransformation

• genetic polymorphisms of metabolizing enzymes

• forsome enzymes,individual genotypes may alter the rate of drug metabolism (e.g. poor,

intermediate, extensive, or ultra-rapid metabolizers, with extensive being considered the

“normal"or average condition)

• may lead to toxicity (e.g. if poor metabolizer) or ineffectiveness (e.g. if ultra-rapid metabolizer) of

a drug at a normal dose

• tamoxifen, tramadol, and codeine are prodrugs activated by CYP2D6 (nonfunctional alleles

reduce effectiveness, whereas hypermorphic alleles impart “ultra-rapid metabolizer” phenotype)

• warfarin is metabolized by CYP2C9 (nonfunctional alleleslead to higher drug concentrations,

greater effect and lower dose requirements)

• enzyme inhibition may result from other chemical exposures including drugs and foods

• CYP inhibition leads to an increased concentration and bioavailability of the substrate drug (e.g.

erythromycin (CYP3A4 inhibitor) can predispose patients to simvastatin toxicity (metabolized by

CYP3A4))

• grapefruit juice is a potent inhibitor of intestinal CYP3A4,resulting in numerous drug

interactions(e.g.saquinavir AUC increased 3-fold,simvastatin AUC increased 17-fold)

• enzyme induction may be due to the same or other medications

for example,certain medications enhance gene transcription to increase the activity of

metabolizing enzymes

• a drug may induce its own metabolism (e.g. carbamazepine) or that of other drugs(e.g.

phenobarbital can induce the metabolism of oral contraceptive pills) by inducing the CYP system

• liver dysfunction (e.g. hepatitis, alcoholic liver, biliary cirrhosis, or hepatocellular carcinoma) may

decrease drug metabolism but it is not always clinically significant due to the liver'

s reserve capacity

• renal disease often results in decreased drug clearance

• extremes of age (neonates or elderly) have reduced biotransformation capacity, but toddlers often

have increased capacity'

, and dosesshould be adjusted accordingly

• nutrition may be involved, as insufficient protein and fatty acid intake decreases biotransformation,

and vitamin/mineral deficiencies may also impact metabolizing enzymes

• alcohol has varying effects; while acute alcohol ingestion inhibits CYP2E1, chronic consumption can

induce CYP2E1, increasing the risk of hepatocellular damage from acetaminophen by increasing the

production of the toxic metabolite (NAPQ1)

• smoking can induce CYP1A2, thus increasing the metabolism of some drugs (e.g. theophylline,

clozapine)

Pharmacokinetic Considerations

•definition: the term “pharmacokinetics" is used to describe given aspects of drug disposition (i.e. the

fate of drugs in the body) and encompasses absorption, distribution, metabolism, and elimination

(ADME)

•absorption, distribution,and elimination can be graphically represented (e.g. a graph of concentration

vs. time)

Time Course of Drug Action

•many kinetic parameters are measured after IV dosing because it avoids incomplete absorption, and

distribution for most drugs is rapid

•when drug doses or concentrations are plotted vs. time, the dose or concentration plotted on the

x-axis is often converted to a logarithmic scale (commonly loglO) to allow for easier mathematical

calculations

•the shape of the elimination phase of a concentration (or dose) or log-concentration (or log-dose)

vs. time curve indicates whether the drug undergoes a first-order rate of elimination (visualized as

a straight line on a log-dose orlog concentration vs. time curve) or a zero-order rate of elimination

(curvilinear on a log-dose or log-concentration vs. time curve)

•drugssuch as warfarin can exhibit hysteresis (for a single drug concentration, there may be two

different response levels)

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Half-Life

• definition:time taken for the serum drug concentration to decrease by 50%; usually refers to asthe

elimination half-life

• drugs with first-order kinetics (i.e. most drugs) require approximately four to five half-lives to reach

steady-state with repeated dosing, or for complete drug elimination once dosing isstopped

Steady-State Drug Concentration

• drug concentration remains constant when the amount of drug entering the system is equivalent to

the amount eliminated from the system

• determination of drug concentrationsin therapeutic drug monitoring is of greatest utility when

steady-state concentration has been reached

• special dosing situations

use a loading dose for drugs with a long half-life and/or when there is a clinical need to rapidly

achieve therapeutic levels (e.g. amiodarone, digoxin, phenytoin,some antibiotic settings)

use continuous infusion for drugs with a very short half-life and when there is a need for a longterm effect and multiple or frequently repeated doses are too inconvenient (e.g. nitroprusslde,

unfractionated heparin, naloxone)

Clearance Rate

• quantitative measurement of the volume of body fluid from which a substance is removed per unit

time

• Cl

= rate of elimination of drug > plasma drug concentration

• may be determined for a particular organ (e.g. liver or kidney), but if notspecified,represents the total

body clearance rate determined from the sum of individual clearance rates or by determining ke x Vd,

where ke is the elimination rate constant equal to In 2/half-life

Elimination Kinetics

• first-order kinetics(most common type)

• constant proportion of drug eliminated per unit time

» some drugs can follow first-order kinetics until elimination is saturated (usually at large doses) at

which point the Cl isless than would be predicted for a given concentration

shows linear relationship when plotted on a graph of concentration (log) vs.time (linear)

the concentration axis is converted to a log scale to allow for easier mathematical calculations

• non-linear or zero-order kinetics(less common, applies to a few drugs in the therapeutic range (e.g.

alcohol, phenytoin, Aspirin*) and is more commonly associated with overdose)

constant amount of drug eliminated per unit time, regardless of concentration;the concept of

half-life does not apply

saturation of various ADME processes creates non-linear kinetics, with first-order exhibited at

lower concentrations and zero-order exhibited at higher concentrations aftersaturation

the complexity of dosing drugs with non-linear kinetics has resulted in the creation of drugspecific nomograms to aid clinicians in dosing, with these drugs often being the target of TDM

(e.g. phenytoin, theophylline)

Loading and Maintenance Doses

• loading doses are used when an immediate effect is needed, with parenteral administration being the

most common way of giving a large dose to “fill up" the volume of distribution

• maintenance doses can be given after a loading dose, but are most commonly initiated without a

loading dose

steady-state levels are achieved after approximately five half-lives

can be given as either a continuous infusion (rare) or more commonly as intermittent oral doses

Pharmacodynamics

• study of “what the drug does to the body"

• definition:study of the effects of the drug on the body

Dose-Response Relationship

• graded dose-response relationship: relates dose to intensity of effect

Efficacy

• the maximum biological response produced by a drug

• measured by Emax (the maximal response that a drug can elicit or under optimal circumstances)

Potency

• measured by EC50 (the concentration of a drug needed to produce 50% of Emax);ED50 if dose is used

• a drug that reaches its EC50 at a lower dose is more potent (e.g.in l-

'

igure 1,drug A is more potent than

drug B) +

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CPS Clinical Pharmacology Toronto Notes 2023

E of A and C A C

too

Potency:

A>B>C

(both B and C

are less potent

than A)

Efficacy:

A'

C>B

E . .ofB 60

II

i

SO -

30

logldose)

ECaofA ECuofB

logldose)

EC sa Of C

A-»C increasing dose of reversible

competitive antagonist

At each dose of antagonist,increasing the

concentration of agonist can oveicome

the inhibition

©Jason Raina

Figure 1. Log(dose)-response curve illustrating efficacy and potency

Figure 2. The log(dose)-response

curve for reversible competitive

antagonism

Effects of Drugs on Receptors

Agonists

• drugs that mimic the effects of the endogenousligand and evoke a response when bound to the

receptor

affinity:the ability and strength of the agonist to bind to the receptor (e.g. the (32-agonist

salbutamol has greater affinity for {52-receptors than pi-receptors, thus it binds preferentially to

p2-receptors)

efficacy: the ability to replicate endogenous response via the receptor interaction (e.g. binding of

salbutamol to p2-receptors results in smooth muscle relaxation)

drug efficacy is often determined under ideal conditions whereas drug effectiveness is a better

measure of how the drug worksin real-world situations

• full agonists:can elicit a maximal effect at a receptor (e.g.methadone and morphine on the p opioid

receptorsystem)

• partial agonists: can only elicit a partial effect, irrespective of the concentration at the receptor; also

known as a ceiling effect (i.e. reduced efficacy compared to full agonists) (e.g. buprenorphine on the p

<2

logldose)

A -» D increasing dose of irreversible

antagonist

With co-administration of antagonist,

increasing dose of agonistdoes not completely

overcome antagonism,asseenin B

Eventually with high enough antagonism

concentrations, no amount of agonist can elicit

a response,asseen in 0

opioid receptor system)

Antagonists

• drugs that bind to receptors without activating them; they reduce the action of an agonist drug or of

an endogenous ligand

• chemical antagonism: direct chemical interaction between agonist and antagonist prevents agonistreceptor binding (e.g.chelating agentsfor the removal of heavy metals,such as charcoal)

• physiological/functional antagonism: drugs that produce opposite physiological effects (e.g. insulin

decreases blood glucose levels through its action at insulin receptors vs. glucagon raises blood glucose

levels through its action at glucagon receptors)

• pharmacological antagonism: antagonist binds to the same site as the agonist or an alternative

effector site and reduces the ability of the agonist to bind

• competitive antagonism: antagonist binds directly to the active site on a given receptor, without

activating it (i.e. zero efficacy) and blocks or displaces the agonist from the active site