The document discusses cardiac electrophysiology and the renin-angiotensin system. It describes how cardiac myocytes in the sinoatrial and atrioventricular nodes can generate impulses, and how these impulses propagate through specialized conducting tissue. It also details the actions of angiotensin II, including its effects on vasoconstriction, sodium reabsorption, and aldosterone secretion. Common drugs for manipulating the renin-angiotensin system are also summarized, such as ACE inhibitors like lisinopril and angiotensin receptor blockers like losartan.

1. PREPARED BY-
MONIKA BHARDWAJ
Asst. Professor

2. INTERNAL ANATOMY OF HEART
2

3. CARDIAC ELECTROPHYSIOLOGY
1. Impulse Generation
Electrophysiologically, there are two types of
myocardial fibres.
(a) Nonautomatic fibres These are the ordinary
working myocardial fibres; cannot generate an
impulse of their own.
(b) Automatic fibres These are present in the
sinoatrial (SA) and atrioventricular (A-V) nodes,
and in the His-Purkinje system, i.e. Especialized
conducting tissue.

4. -100
-80
-60
-40
-20
0
20
Phase 0
Phase 1
Phase 2
Phase 3
Phase 4
Na+
ca++
ATPase
mv Cardiac Action
Potential
Resting
membrane
Potential
Na+
m
Na+
Na+
Na+Na+
Na+
h
K+
ca++
K+
K+K+
ca++ca++
(Plateau Phase)
K+K+K+ Na+
K+
Depolarization

5. -100
-80
-60
-40
-20
0
20
Phase 0
Phase 1
Phase 2
Phase 3
Phase 4
Na+
ca++
ATPase
mv Cardiac Action
Potential
R.M.P
Na+
m
Na+
Na+
Na+Na+
Na+
h
K+
ca++
K+
K+K+
ca++ca++
(Plateau Phase)
K+K+K+ Na+
K+
Depolarization
Phase 4
(only in
pacemaker cells

6. Pace maker action potential
(resting phase)

7. SAN
AVN
2.Impulse conduction
Impulses originate
regularly at a
frequency of 60-100
beat/ min

8. 8
HEART PHYSIOLOGY: CONDUCTING SYSTEM
Figure 18.14a

9. 9
ELECTROCARDIOGRAPHY

12. 3.

13. 4. REFRACTORY PERIOD
 Pharmacologically, the effective refractory period
(ERP) which is the minimum interval between two
propagating APs.
 i.e. Difference b/w two AP wave = ERP

14. AUTONOMIC INFLUENCE ON CARDIAC
ELECTROPHYSIOLOGY AND CONTRACTILITY
Sympathetic nervous system (SNS)- Adr
Causes-
Tachycardia (increase HR)
Shorten referactory period
Enhance coductivity and contractility
Parasympathetic nervous system (PNS)- Ach
Causes-
Bradycardia (increase HR)
Prolong referactory period
Decrease coductivity and contractility

16.  Preload – amount ventricles are stretched by
contained blood
 Contractility – cardiac cell contractile force
due to factors other than pressure applied by
EDV (end diastole volume)
 Afterload – back pressure exerted by blood in
the large arteries leaving the heart

18. RENIN ANGIOTENSIN SYSTEM
The angiotensin system participates
significantly in the pathophysiology of
hypertension, congestive heart failure,
myocardial infarction, and diabetic
nephropathy.

20.  Angiotensin – II is an octapeptide generated in plasma
from precursor plasma α2 globulin – involved in
electrolyte, blood volume and pressure homeostasis.
 Enzyme Renin generates inactive Angiotensin – I from
plasma protein).
 Angiotensin-I is rapidly converted to Angiotensin-II (A-II)
by Angiotensin Converting Enzyme (ACE) (present in
luminal surface of vascular endothelium).

21. TYPES – CIRCULATING RAS AND TISSUE RAS
 Circulating RAS: Renin is the rate limiting factor of
Ang-II release.
 Plasma t1/2 of Renin is 15 minutes
 Ang-I is less potent (1/100th) than of Ang-II
 Ang-I is rapidly converted to Ang-II by ACE (in vascular
endothelium- mainly lungs)
 Ang-II half life is 1 minute only
 Degradation product is Ang-III (heptapeptide) - 2-10 times less
potent than Ang-II
 Both Ang-II and Ang-III stimulates Aldosterone secretion from
Adrenal Cortex (equipotent)
 Ang-IV – different from all – mainly CNS action via AT4 receptor

22.  Tissue RAS:
 Blood vessels capture Renin and Angiotensinogen from circulation
– produce Ang-II (Extrinsic local RAS) – on cell surface – local
response
 Many tissues also - Heart, brain, kidneys, adrenal gland
synthesize all component of RAS and produce intracellularly Ang-
II (Intrinsic local RAS) - Important in these organs – regulates
organ function, cell growth/death

25. ACTIONS OF ANGIOTENSIN-II - CVS
Powerful vasoconstrictor particularly arteriolar and
venular
 direct action
 release of Adr/NA release (adrenal and adrenergic nerve
endings)
 increased Central sympathetic outflow
 Promotes movement of fluid from vascular to
extravascular
 Less prominent in cerebral, skeletal, pulmonary and
coronary
 Overall Effect – Pressor effect (Rise in Blood
pressure)
 More potent vasopressor agent than NA –promotes
Na+ and water reabsorption and no tachyphylaxis.
Cardiac action:
 Increases myocardial force of contraction (Ca++ influx promotion)
 Increases heart rate by sympathetic activity
 Cardiac output is reduced
 Cardiac work increased (increased Peripheral resistance)

26. ANG-II ON CHRONIC BASIS – ILL EFFECT
 Directly: Induces hypertrophy, hyperplasia and increased cellular matrix
of myocardium and vascular smooth muscles
 Indirectly: Volume overload and increased t.p.r in heart and blood
vessels
 Ventricular 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 myocardiac tissue death
 Risk of increased CVS related morbidity and mortality
 ACE inhibitors reverse cardiac and vascular hypertrophy
and remodeling

27. AT-II – PATHOPHYSIOLOGICAL ROLES
1. Mineralocorticoid secretion – Physiological
stimulus of Aldosterone secretion.
2. Electrolyte, blood volume and pressure
homeostasis: Renin is released when there is
change in blood volume or pressure or decreased
Na+ content:
I. Reduction in tension in afferent gromerulus - Intrarenal
Baroreceeptor Pathway (PG) activation – PG production -
Renin release
II. Low Na+ and Cl- conc. in tubular fluid– release of PGE2 and
PGI2 – more renin release (macula dense pathway)
III. Baroreceptor stimulation increases sympathetic impulse – via
β-1 pathway –cAMP trigger renin release

28.  Renin release – increased Ang-II production – acute
rise in BP direcytly acting by vasoconstriction and
indirectly, increased Na+ and water reabsorption.
 Long-loop negative feedback mechanism: Rise in
BP – decreased Renin release
 Short-loop -ve feedback mechanism: A-II also formed
locally in the Kidneys
 Activation of AT1 receptor in JG cells – inhibition of Renin
release
 Overall - Long term stabilization of BP – independent of salt
and water intake

30. ANGIOTENSIN RECEPTORS
 4(four) subtypes: AT1 and AT2 are main
receptors (opposite effects) – most of known
Physiologic effects are via AT1
 Both AT1 and AT2 are GPCR
 Utilizes various pathways for different tissues
 PLC-IP3/DAG: AT1 utilizes pathway for vascular
smooth muscles by MLCK
 Membrane Ca++ release: aldosterone synthesis,
cardiac inotropy, CA release - ganglia/adrenal medulla
action etc.
 Adenylyl cyclase: in liver and kidney (AT1)
 Intrarenal homeostatic action: Phospholipase A2

31. ACE INHIBITORS AND ARBS - DRUGS
 ACE Inhibitors:
Captopril, enalapril,
lisinopril, perindopril,
fosinopril, benazepril
ramipril and imidapril,
Benazepril quinapril,
trandolapril etc.
 ARBs: Losartan,
candesartan,
irbesartan, valsartan
and telmisartan

32. CAPTOPRIL …… TEPROTIDE
 It is a sulfhydryl containing dipeptide like proline which
abolishes the pressor action of A-I but not that of A-II by
inhibiting ACE: does not block A-II receptors.
 ACE – non-specific enzyme–and also splits off dipeptidyl
segment from bradykinin, substance P, natural stem cell
regulating peptide.
• Captopril increases plasma kinin levels – potentiate
hypotensive action of bradykinin - overall hypotensive effects
 But increased kinins – PG synthesis – cough and angioedema
 Rise in stem cell regulator peptide – cardioprotective
 But, BP lowering is not long term - depends on Na+
status and level of RAS.

33. CAPTOPRIL – CONTD.
 In normotensives:
 With normal Na+ level – fall in BP is minimal
 But restriction in salt or diuretics - more fall in BP
 In CHF (increased renin) – marked fall in BP
 Most effective greater fall in BP: therfore use in
Renovascular and malignant hypertension.
 Essential hypertension: 20% hyperactive RAS and
60% normal in RAS
 Contributes to 80% of maintainence of tone – lowers BP

34. CAPTOPRIL – CONTD.
 Actions:
 Decrease in peripheral Resistance
 Arteriolar dilatation and compliance of larger arteries increased
 Fall in Systolic and Diastolic BP - No effect on Cardiac output
 No reflex sympathetic stimulation – Can be used safely in IHD
patients
 Little dilatation of capacitance vessels
 Minimal Postural hypotension
 Renal blood flow is maintained – Ang-II constricts them
 Cerebral and coronary blood flow – not affected
 Pharmacokinetics:
• 70% absorbed, partly metabolized and partly excreted
unchanged in urine
• Food interferes absorption
• T1/2 = 2 Hrs (duration of action 6-12 Hrs)

35. CAPTOPRIL – ADVERSE EFFECTS
1. Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substance P breakdown in lungs
2. Hypotension – initial sharp fall in BP –in patient of CHF treated
with diuretics. (1st dose phenomenon)
3. Hyperkalemia- in renal failure patients with K+ sparing diuretics,
NSAID and beta blockers (routine check of K+ level)
4. Acute renal failure: in patients of CHF and bilateral renal artery
stenosis (narrowing of renal arteries).
5. Angioedema: swelling of lips, mouth, nose etc. – 0.5%
6. Rashes, urticaria(skin rashes, itchy bumps) etc. – 1 – 4%
7. Dysgeusia: loss or alteration of taste
8. Foetopathic: hypoplasia of organs, growth retardation etc.
9. Neutripenia(low conc. of neutrophils) and proteinuria(excess
protein in urine).
 Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia

36. ACE INHIBITORS - ENALAPRIL
 It’s a prodrug – converted to enalaprilate
 Enalaprilate directly Not used orally – poor
absorption- prodrug used.
 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

37. ACE INHIBITORS – LISINOPRIL
 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 and 20 mg tab –
start with low dose

38. ACE INHIBITORS – RAMIPRIL
 It’s a popular ACEI now - long acting and extensive
tissue distribution.
 It is also a prodrug with long half life (8-18 hr.)
 Tissue specific – Protective of heart and kidney.
 Uses: Diabetes with hypertension, CHF, AMI and cardio
protective in angina pectoris.
 Dose: Start with low dose; 2.5 to 10 mg daily.
 Advantages:
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).

39. USES - ACEI AND HYPERTENSION
 1st line of Drug: advantages renovascular and resistant
cases of hypertension .
 No postural hypotension or electrolyte imbalance (no fatigue
or weakness)
 Safe in asthmatics and diabetics
 Prevention of secondary hyperaldosteronism and K+ loss
(diuretics)
 Renal perfusion well maintained
 Reverse the ventricular hypertrophy and increase in lumen size
of vessel
 No hyperuraecemia (increase uric acid conc. in blood) or
deleterious effect on plasma lipid profile
 No rebound hypertension
 Minimal worsening of quality of life – general wellbeing, sleep
and work performance etc.
 1st choice of drug for diabetic hypertensive patients.

40. ACE INHIBITORS – USES
 Congestive Heart Failure:
 Reduction in preload and afterload.
 Some benefits - Reduction in pulmonary artery pressure, right atrial
pressure, systemic vascular resistance.
 Improved Renal perfusion (Na+ and water excretion).
 CO and stroke volume increases – with reduced heart rate (less
cardiac work).
 1st line of drug with beta-blocker and diuretics in all cases.
 Myocardial Infarction: 0 – 6 weeks
 Reduces mortality
 Also reduces recurrent MI
 Extension of therapy – in CHF patients.
 Prophylaxis of high CVS risk subjects: Ramipril – post MI,
diabetes etc.
 Diabetic Nephropathy and non-diabetic nephropathy – reduce
albuminuria (both type 1 and 2) – higher creatinine clearance.
 Schleroderma crisis: Rise in BP and deteriorating renal
function (Ang –II).

41. DRUG INTERACTIONS
1. Synergistic effect with diuretics in hypotenive
patients by depleting sodium concentration and raising
renin level.
2. Indomethacin (NSAIDs) decrease salt water retension-
opposite action than ACE inhibitors- in elderly
patients receiving combination therapy of ACEi
+diuretics, NSAIDs ppt renal faliure.
3. Severe hyperkalamia with K-supplement/K-sparing
diuretics.
4. Antacid reduce bioavailability.
5. ACEi reduce lithium clearance.

42. AT1 RECEPTOR

44. ANGIOTENSIN RECEPTOR BLOCKERS (ARBS)
Losartan
Candesartan
Valsartan
Irbesartan
Eprosartan
Telmisartan

45. LOSARTAN
 Competitive antagonist of AT1 receptor – 10,000 times
binding affinity for AT1 receptor.
 Does not interfere with other receptors except TXA2 –
platelet antiaggregatory
 Blocks all the actions of Ang-II - - - vasoconstriction,
sympathetic stimulation, aldosterone release and renal
actions of salt and water reabsorption, growth promoting
effects in heart and blood vessels and central action (thurst)
etc.
 No inhibition of ACE

46. LOSARTAN
 Theoretical superiority over ACEIs:
 Cough is rare – no interference with bradykinin,
Substance P and other ACE substrates
 Complete inhibition of AT1 – alternative pathway
remains for ACEIs
 Result in indirect activation of AT2 – vasodilatation
 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 (increase uric acid in urine)

47. LOSARTAN
 Pharmacokinetic:
 Absorption not affected by food but unlike ACEIs its
bioavailability is low (30 – 40%)
 High first pass metabolism (losartan t1/2- 3-4 hr.)
 Carboxylated to active metabolite E3174 ( t1/2- 6-9 hr.)
 Highly bound to plasma protein
 Do not enter brain
 No dose adjustment in renal insufficiency
 Adverse effects:
 Foetopathic like ACEIs – not to be administered in
pregnancy
 Rare 1st dose effect hypotension & cough
 Low dysgeusia(loss of teste sensation) and dry cough
 Lower incidence of angioedema
 Available as 25 and 50 mg tablets

48. LOSARTAN/ARBS - USES
Same range of clinical utility with ACE inhibitors
1. Hypertension: Commonly prescribed now than ACEIs –
better than beta-blockers
2. CHF: Superiority over ACEIs uncertain
3. Myocardial Infarction – ACEIs preferred
4. Diabetic Nephropathy
5. Combination with ACEIs – theoretical
• ARBs: Ang II generated in local tissues by non-ACE mechanism
with ACEIs - ARBs block
• ACEIs: vasodilatation due to bradykinin & Ang (1-7) – not
produced by ARBs
• Increase in Ang II by ARBs – blocked by ACEIs
• Increase in AT2 action with ARBs can be prevented by ACEIs

49. DIRECT RENIN INHIBITOR - ALISKIREN
 Nonpeptide – competitive blocker of catalytic site of Renin – Ang-
I not produced from Angiotensinogen
 Pharmacological actions:
 Causes fall in BP – Na+ depleted states more
 Plasma aldosterone level decreased – K+ retention occurs
 Equivalent to ACEIs and ARBs in reducing BP – combination of all 3 -
greater fall in BP
 Renoprotective – hypertension and DM – being evaluated
 Used as alternative – do not respond/tolerate 1st line
 Kinetics: Orally effective – low bioavailability (p-glycoprotein) –
half life = > 24 hours
 ADRs: Dyspepsia, loose motions, headache, dizziness – rash,
hypotension, hyperkalaemia, cough, angioedema etc.
 Contraindication - Pregnancy

50. MUST KNOW
 Drugs - ACEIs and ARBs
 ACEIs – Pharmacological actions and the common
ADRs
 Therapeutic uses of ACEIs
 Captopril, Ramipril, Losartan
 Role of ACEIs/ARBs in the management of
Hypertension, CHF and MI