This document discusses drugs affecting the renin-angiotensin system and cardiac electrophysiology. It begins by providing an overview of the renin-angiotensin system (RAS), including that renin cleaves angiotensinogen to form angiotensin I which is converted to angiotensin II by ACE. Angiotensin II causes vasoconstriction, sodium retention, and increased blood pressure. The document then focuses on ACE inhibitors, describing their mechanism of blocking angiotensin II formation, uses in hypertension and heart conditions, and examples such as captopril, enalapril, and lisinopril.

1. CARDIAC ELECTROPHYSIOLOGY AND
DRUGS AFFECTING RENIN-
ANGIOTENSIN SYSTEM
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Drugs of Cardiovascular System
• Drugs having major action on Heart and Blood vessels and
used in various important cardiac disease conditons.
• They act directly on heart structures or via Autonomic
Nervous system (ANS), Central Nervous System (CNS),
Kidney, Autacoids or Hormones:
1. Cardiac Glycosides
2. Sympathomimetics
3. Anticholinergic Drugs
4. Antiarrhythmics
5. Electrolytes
6. Thrombolytic
7. Anticoagulants
8. Antihypertensive
9. Analgesics

3. Recall Heart Anatomy !
1. Right Coronary
2. Left Anterior Descending
3. Left Circumflex
4. Superior Vena Cava
5. Inferior Vena Cava
6. Aorta
7. Pulmonary Artery
8. Pulmonary Vein
9. Right Atrium
10. Right Ventricle
11. Left Atrium
12. Left Ventricle
13. Papillary Muscles
14. Chordae Tendineae
15. Tricuspid Valve
16. Mitral Valve
17. Pulmonary Valve
18. Aortic Valve (Not pictured)

4. Recall Heart Physiology !
• SA node
• AV Junction
• Bundle of His
• His-Purkinje
• Myocardial cells
• Electrical potential
• Autonomic Nervous
system

5. Major Heart Receptors
- Autonomic

6. Major Ion Channels

7. Myocardial Cells
Action potential
 Depolarization
 Repolarization
 Critical electrolytes
 Sodium, potassium, calcium
 Excitability

8. Cardiac
Electrophysiology
• Recall: to function efficiently, heart needs to contract
sequentially (atria, then ventricles) and in synchronicity
• Relaxation must occur between contractions (not true for
other types of muscle [exhibit tetany  contract and hold
contraction for certain length of time]
• Coordination of heartbeat is a result of a complex,
coordinated sequence of changes in membrane potentials
and electrical discharges in various heart tissues

9. Myocardial Cells
• 2 types – Pacemaker and non
pacemaker
– Pacemaker and conducting cells –
SAN, AVN, Bundle of His and
Purkinje`s fibres
– Non pacemaker – Working
Myocardial Cell (WMC) or CMC
• Sinus rhythm means rhythm
originates in SAN
• Sinus tachycardia means tachycardia
but rhythm originates in SAN – fever,
exercise etc.
• Tachycardia = heart rate > 100 per
minute
• Sinus Bradycardia = heart rate < 60
per min.
• Escape rhythm: Rhythm which is not
generated by SAN, but other, e.g.
AVN or bundle of His etc.

10. Cardiac Action Potential -
Five phases (0,1,2,3,4)
• Phase 0 – opening of fast Na channels and rapid
depolarization
• Drives Na+ into cell (inward current), changing membrane
potential
• Transient outward current due to movement of Cl- and K+
• Phase 1 – initial rapid repolarization
• Closure of the fast Na+ channels
• Phase 0 and 1 together correspond to the R and S waves of the
ECG
• Phase 2 - plateau phase
• sustained by the balance between the inward movement of Ca+
and outward movement of K+
• Has a long duration compared to other nerve and muscle tissue
• Normally blocks any premature stimulator signals (other muscle
tissue can accept additional stimulation and increase contractility
in a summation effect)
• Corresponds to ST segment of the ECG.

11. Cardiac Action Potential
– contd.
• Phase 3 – repolarization
– K+ channels remain open,
– Allows K+ to build up outside the cell, causing the cell
to repolarize
– K + channels finally close when membrane potential
reaches certain level
– Corresponds to T wave on the ECG
• Phase 4 - resting phase (resting membrane
potential)
• At (-90mv) stable
• Phase cardiac cells remain in until stimulated
• Associated with diastole portion of heart cycle

12. Summary of ionic basis - WMCs

13. Cardiac Action Potential – Pacemaker
Cells – slow channels
• Present in SAN and AVN and His –Purkinje cells
• Most characteristic feature is in Phase-4, or slow diastolic depolarization
• After repolarization membrane potential decays spontaneously and
sudden automatic depolarization
• Therefore capable of generating own impulses
• Normally SAN has steepest phase-4
• Characteristics:
• Initiation at higher threshold (less negative (-75mv)
• Slow depolarization
• Low overshoot (+10mv), low amplitude
• Very slow a propagation
• Phase-1 and 3 are not clearly demarcated
• Can occur in fibres depolarized too much to support fast channels

14. Drugs Affecting Renin - Angiotensin System
What is Renin – Angiotensin System?
(Physiological Background)

15. RAS - Introduction
• Renin is a proteolytic enzyme and also called
angiotensinogenase (plasma ɑ2 globulin)
• It is produced by juxtaglomerular cells of kidney
• Renin acts on a plasma protein – Angiotensinogen (a
glycoprotein synthesized and secreted into the bloodstream
by the liver) and cleaves to produce a decapeptide
Angiotensin-I
• Angiotensin-I is rapidly converted to Angiotensin-II
(octapeptide) by Angiotensin Converting Enzyme (ACE –
dipeptidyl carboxypeptidase) (present in luminal surface of
vascular endothelium)
• Furthermore, degradation of Angiotensin-II by peptidases
produce Angiotensin-III

16. Types – Circulating RAS and Tissue RAS
• Circulating: Renin is the rate limiting factor of AT-II release
– AT-I is less potent (1/100th) than of AT – II
– Plasma t1/2 of Renin is 15 minutes
– AT-I is rapidly converted to AT-II by ACE (AT-II half life 1 mim)
– Degradation product is AT-III
– Both AT-II and AT-III stimulates Aldosterone secretion from Adrenal
Cortex (equipotent)
• Tissue RAS:
– Extrinsic local RAS: Blood vessels capture Renin and Angiotensinogen
to produce local AT-II
– Intrinsic local RAS: Many tissues Heart, brain, blood vessels, kidneys,
adrenals have all components of RAS in their cells – produce locally
– Important factor in these organs

17. RAS – Physiologcal Regulation
Vasoconstriction
Na+ & water
retention
(Adrenal cortex)
Kidney
Increased
Blood Vol.
Rise in BP
It is secreted in
response to:
• Decrease in arterial
blood pressure – also fall
in BP and blood volume
• Decrease Na+ in macula
densa
• Increased sympathetic
nervous activity
(-)
(-)

18. Actions of Angiotensin-II - CVS
Powerful vasoconstrictor particularly arteriolar and venular
 direct action
 by release of Adr/NA release (adrenal and adrenergic nerve endings)
 increased Central sympathetic outflow
• Promotes movement of fluid from vascular to extravascular
• More potent vasopressor agent than NA –promotes Na+ and
water reabsorption and no tachyphylaxis
• Overall Effect – Pressor effect (Rise in Blood pressure)
Cardiac action:
• Increases myocardial force of contraction (Ca++ influx promotion)
• Increases heart rate by sympathetic activity, but reflex bradycardia
occurs
• Cardiac output is reduced
• Cardiac work increased (increased Peripheral resistance)
• No arrhythmia - in contrast to NA

19. Chronic effects of Angiotensin-II
• Ill effects on chronic basis of exposure (Mitogenic effect!)
– Directly: Induces hypertrophy, hyperplesia and increased cellular
matrix of myocardium and vascular smooth muscles – by direct
cellular effects involving proto-oncogens and transcription of growth
factors
– Indirectly: Volume overload and increased t.p.r in heart and blood
vessels
• Hypertrophy and Remodeling (abnormal redistribution of muscle mass)
– Long standing hypertension – increases vessel wall thickness and
Ventricular hypertrophy
– Myocardial infarction – fibrosis and dilatation in infarcted area and
hypertrophy of non-infarcted area of ventricles
– CHF – progressive fibrotic changes and myocyte death
– Risk of increased CVS related morbidity and mortality
• ACE inhibitors reverse cardiac and vascular hypertrophy and remodeling

20. Remodeling

21. Actions of Angiotensin-II
• Adrenal cortex: Enhances the synthesis and release of
Aldosterone
– In distal tubule Na+ reabsorption and K+ excretion
• Kidney: Enhancement of Na+/H+ exchange in proximal tubule
– increased Na+, Cl- and HCO3 reabsorption
– Also reduces renal blood flow and promotes Na+ and water retention
• CNS: Drinking behaviour and ADH release
• Peripheral sympathetic action: Stimulates adrenal medulla to
secrete Adr and also releases NA from autononic ganglia

22. Angiotensin Receptors
• 2 (two) subtypes: AT1 and AT2 – most of known Physiologic
effects are via AT1
– Both are GPCR – A1 is important
• Utilizes various pathways for different tissues
– PLC-IP3/DAG – Ca++: AT1 utilizes pathway for vascular smooth muscles
by MLCK
– Membrane Ca++ channels: Ca release - aldosterone synthesis, cardiac
inotropy, CA release - ganglia/adrenal medulla action etc.
– DAG: PKc – promotion of cell growth
– Adenylyl cyclase: in liver and kidney (AT1)
– Intrarenal homeostatic action: Phospholipase A2, LT and PG
production
– Long term effects on smooth muscles and myocardium – MAP kinase,
TAK2 tyrosine protein kinase and PKc

23. Angiotensin-II – Pathophysiological Roles
1. Mineraocorticoid secretion
2. Electrolyte, blood volume and pressure homeostasis: Renin is released
when there is change in blood volume or pressure or decreased Na+
content
– Reduction in tension in afferent gromerulus - Intrarenal
Baroreceptor Pathway activation – PG production - Renin release
– Low Na+ conc. in tubular fluid – macula densa pathway – COX-2
and nNOS are induced – release of PGE2 and PGI2 – more renin
release
– Baroreceptor stimulation increases sympathetic impulse – via
beta-1 pathway – renin release
• Renin release – increased Angiotensin II production – vasoconstriction
and increased Na+ and water reabsorption
• Rise in BP – decreased Renin release - Long term stabilization of BP is
achieved – long-loop negative feedback mechanism

24. Role of Angiotensin-II – contd.
• Short-loop negative feedback mechanism:
– activation of AT1 receptor in JG cells – inhibition of Renin
release
– Long term stabilization of salt and water intake
• Pharmacological importance:
– Drugs Increasing Renin release:
• ACE inhibitors and AT1 antagonists enhance Renin release
• Vasodilators and diuretics stimulate Renin release
• Loop diuretics increase renin release
– Decrease in Renin release:
• Beta blockers and central sympatholytics
• NSAIDs and selective COX-2 inhibitors decrease Renin release

25. Role of Angiotensin-II – contd.
3. Hypertension
4. Secondary hyperaldosteronism
Inhibitors of RAS:
• Sympathetic blockade
• ACE inhibitors
• AT1 receptor antagonists
• Aldosterone antagonists
• Renin inhibitory peptides and Renin specific antibodies

26. ACE inhibitors
• Captopril, lisinopril, enalapril, ramipril and
fosinopril etc.

27. Captopril
• MOA:
– ACEIs block action of ACE – so no AT-II
– Also increases plasma kinin level (temporary)
• Depends on Na+ status and level of RAS
• In normotensives:
– With normal Na+ level – fall in BP is minimal
– But restriction in salt or diuretics - more fall in BP
• Renovascular and malignant hypertension – greater fall in BP
• Essential hypertension: 20% hyperactive RAS and 60%
hypoactive in RAS
– Contributes to 80% of maintainence of tone – lowers BP
– But no long term relation of fall in BP by captopril and PRA activity

28. Captopril – contd.
• Actions:
– Decrease in peripheral Resistance
– Arteriolar dilatation and increased compliance of larger arteries
– Fall in Systolic and Diastolic BP
 No effect on Cardiac output
 No interference with capacitance vessels - No Postural hypotension
 No reflex sympathetic stimulation
 Can be used safely in IHD patients
 Renal blood flow is maintained – greater dilatation of vessels
 Basal level of aldosterone decreased
• Pharmacokinetics:
• 70% absorbed, partly metabolized and partly excreted unchanged in urine
• Food interferes absorption
• T1/2 = 2 Hrs (6-12 Hrs)

29. Captopril – Adverse effects
• Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substanceP breakdown in lungs
• Hyperkalemia in renal failure patients with K+ sparing diuretics,
NSAID and beta blockers (routine check of K+ level)
• Hypertension: CHF and diuretic patients
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: CHF and bilateral renal artery stenosis
• Angioedema: swelling of lips, mouth, nose etc.
• Rashes, urticaria etc
• Dysgeusia: loss or alteration of taste
• Foetopathic: hypoplasia of organs, growth retardation etc
• Neutropenia
• Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia

30. ACE inhibitors - Enalapril
• It’s a prodrug – converted to enalaprilate
• Advantages over captopril:
– Longer half life – OD (5-20 mg OD)
– Absorption not affected by food
– Rash and loss of taste are less frequent
– Longer onset of action
– Less side effects

31. ACE inhibitors – Ramipril (Cardace)
• It’s a popular ACEI now
• It is also a prodrug with long half life
• Tissue specific – Protective of heart and kidney
• Uses: Diabetes with hypertension, CHF, AMI and cardio protective in
angina pectoris
• Blacks in USA are resistant to Ramipril – addition of diuretics help
• Dose: Start with low dose; 2.5 to 10 mg daily
• EBM Reports: 1) improves mortality rate in early AMI cases 2) reduces the
chance of development of AMI 3) reduces the chances of development of
nephropathy etc. (1.25, 2.55 … 10 mg caps)

32. ACE inhibitors – Lisinopril (Lipril/Listril)
• It’s a lysine derivative
• Not a prodrug
• Slow oral absorption – less chance of 1st dose
phenomenon
• Absorption not affected by food and not
metabolized – excrete unchanged in urine
• Long duration of action – single daily dose
• Doses: available as 1.25, 2.5, 5, 10 1nd 20 mg tab
– start with low dose

33. ACE inhibitors and hypertension
• 1st line of Drug:
– No postural hypotension or electrolyte imbalance (no fatigue or
weakness)
– Safe in asthmatics and diabetics
– Prevention of secondary hyperaldosteronism and K+ loss
– Renal perfusion well maintained
– Reverse the ventricular hypertrophy and increase in lumen size
of vessel
– No hyperuraecemia or deleterious effect on plasma lipid profile
– No rebound hypertension
– Minimal worsening of quality of life – general wellbeing, sleep
and work performance etc.

34. ACE inhibitors – uses
• Hypertension
• Congestive Heart Failure
• Myocardial Infarction
• Prophylaxis of high CVS risk subjects
• Diabetic Nephropathy
• Schleroderma crisis

35. Angiotensin Receptor Blockers (ARBs)
• Losartan
• Candesartan
• Valsartan
• Irbesartan
• Eprosartan

36. Losartan
• Competitive antagonist and inverse agonist of
AT1 receptor
• Does not interfere with other receptors except
TXA2
• Blocks all the actions of A-II - vasoconstriction,
sympathetic stimulation, aldosterone release
and renal actions of salt and water
reabsorption
• No inhibition of ACE

37. Losartan
• Theoretical superiority over ACEIs:
– Cough is rare – no interference with bradykinin and other ACE
substrates
– Complete inhibition of AT1 – alternative pathway remains for ACEIs
– Result in indirect activation of AT2 – vasodilatation (additional benefit)
– Clinical benefit of ARBs over ACEIs – not known
• However, losartan decreases BP in hypertensive which is for long period
(24 Hrs)
– heart rate remains unchanged and cvs reflxes are not interfered
– no significant effect in plasma lipid profile, insulin sensitivity and
carbohydrate tolerance etc
– Mild uricosuric effect

38. Losartan – contd.
• Pharmacokinetic:
– Absorption not affected by food but unlike ACEIs its bioavailability is
low
– High first pass metabolism
– Carboxylated to active metabolite E3174
– Highly bound to plasma protein
– Do not enter brain
• Adverse effects:
– Foetopathic like ACEIs – not to be
administered in pregnancy
– Rare 1st dose effect hypotension
– Low dysgeusia and dry cough
– Lower incidence of angioedema
• Available as 25 and 50 mg tablets

39. Losartan/ARBs - uses
• Hypertension
• CHF
• MI
• Diabetic Nephropathy
• Combination with ACEIs

40. Important
• ACEIs – Pharmacological actions and ADRs
• Therapeutic uses of ACEIs
• Role of ACEIs/ARBs in management of
Hypertension
• Losartan

41. Thank you
Next Class – Cardiac Glycosides