1. Diuretics are commonly used antihypertensive drugs that work by reducing blood volume and vascular resistance. Loop diuretics are most potent while thiazides and potassium-sparing diuretics are weaker. (2) Vasodilators relax arterioles to lower blood pressure but can cause reflex tachycardia and fluid retention. Hydralazine specifically dilates arterioles. (3) Both diuretics and vasodilators are often combined with other drugs to offset their side effects on fluid balance and heart rate.

1. 1
Cardiovascular and Renal
Pharmacology

2. 2
Diuretics
• Chemicals that increase the rate of urine formation and
Sodium excretion.
• Kidney: make 0.5% of total body Wt; consume 7% of total
body oxygen
• Nephron: basic urine forming unit
 Constitutes: glomerulus & long tubular portion
• RBF: 650ml/min, GFR = 125ml/min only 1ml/min of urine

3. 3

4. 4
• Proximal tubule
 65% of filtered Na+ reabsorbed
Transport mechanisms: Na+–H+-exchange, Na+-phosphate cotransport, Na+-
glucose, Na+-lactate, and Na+–amino acid cotransport
Na+–H+- exchange is the primary mechanism (40%)
 Highly permeable to water /isotonic re-absorption/
 Most of the K+filtered is reabsorbed by proximal tubules.
 Less diuretic potential
Several transport proteins mediate reabsorption
Compensatory reabsorption in the more distal portions reduces the impact
of diminished upstream Na+recovery.

5. 5
• Loop of Henle
 25% of filtered load of Na+ reabsorbed.
 DTL: permeable to water, permeability to NaCl & urea
is low
 ATL: permeable to NaCl & urea but is impermeable to
water

6. 6
 ATL: reabsorbs NaCl;
25% of the filtered sodium is reabsorbed
Transport is mediated by Na+-K+-2Cl-cotransport
Little net K+reabsorption occurs
Tubular fluid becomes dilute as it passes through the ATL
Impermeable to water & urea
• Distal convoluted tubule (DCT)
 5-8 % of filtered Na+ reabsorbed /actively/
 Reabsorption is mediated by Na+-Cl-cotransport
 Water permeability of the DCT is regulated by
antidiuretic hormone (ADH, or vasopressin).
 The main source of urinary K+is tubular secretion by
DCT and collecting ducts

7. 7
• Collecting duct
 5 to 7% of filtered Na+ reabsorbed.
 Electrolyte composition: modulated by aldosterone
 Water permeability: modulated by ADH. In the
absence of ADH, the collecting ducts are essentially
impermeable to water.

8. 8
Inhibitors of Carbonic anhydrase
• Acetazolamide, Dichlorphenamide,
methazolamide, dorzolamide
• Site of action: proximal tubule- primary
• Collecting duct - secondary
• Mechanism of action: Inhibition of Carbonic
Anhydrase activity.

9. 9
• Pharmacological effects
 Urinary excretion of HCO3
- (35% of filtered load)
 Increased urinary pH & metabolic acidosis
 Excretion of 5% filtered Na+ & 70% of filtered K+
 Increased phosphate excretion
 Reduce intraocular pressure
 Increase CO2 levels in peripheral tissue:- reduce CO2
levels in expired gas

10. 10

11. 11
• PharmacoKinetics
 All are orally effective
 Protein binding moderately high
 Distributed to site of action: glomerular filtration &
proximal tubular secretion
 Eliminated as unchanged or as metabolites in urine

12. 12
• Adverse effects
 Drowsiness, Skin toxicity, bone marrow toxicity
 Metabolic acidosis, urinary alkalinization.
• Therapeutic uses
 Rarely used as diuretics
 Glaucoma, epilepsy
 Altitude sickness, to correct metabolic alkalosis

13. 13
Osmotic Diuretics
• Properties and MOA
 Water soluble and are hence freely filtered
 Insoluble in lipids and hence are poorly reabsorbed
 Pharmacologically inert
 Hence increase the osmolarity of tubular fluid
• Drugs: Mannitol, Urea, Glycerin, Isosorbide
• Site of action -Nephron segments which are
freely permeable to water

14. 14
• Pharmacokinetics
 Glycerin & Isosorbide: orally effective
 Mannitol & urea: orally ineffective (hence IV.)
 Elimination:
 Renal: Isosorbide, urea, Mannitol
Metabolism: glycerin, Mannitol (- 10%)

15. 15
• Adverse effects
 Headache, nausea, vomiting
 Dehydration
 Pain (urea)
 Hyperglycemia (glycerin)
• Therapeutic uses
 Treatment & prevention:- acute glaucoma &
Cerebral edema (sed ICP)

16. 16
Inhibitors of Na+-K+-2Cl- symport
• AKA: loop Diuretics, high ceiling diuretics.
• Drugs: Furosemide, Torsemide, Ethacrynic acid
• Site of action: - thick ascending limb (ThAL)
• Mechanism of action: inhibit Na+-K+-2Cl-
symport in the ThAL

17. 17

18. 18
• Pharmacological effects.
 ed urinary excretion of Na+ & Cl-
 ed excretion of Ca++ and Mg++
 ed excretion of HCO3
- & Phosphate – Furosemide
Some carbonic anhydrase inhibition activity
 ed excretion of K+
• Pharmacokinetics
 All are orally effective (bioavailability 60-100%)
 Highly protein bound: eliminated in the urine by
both glomerular filtration and tubular secretion
 Elimination: metabolism and also renal as unchanged

19. 19
• Adverse effects
 Related to diuretic efficacy; otherwise are rare
 Hypokalemia & /or ECFV depletion
 Cardiac arrhythmias:- hypokalemia
 Hypomagnesemia, hypocalcemia
 Ototoxicity (inner ear electrolyte imbalance)
 Hyperuricemia (2o gout)
 Abnormalities in serum lipids: LDL & TGs; HDL

20. 20
• Therapeutic use
 Acute pulmonary edema
 Chronic CHF, HTN
 Edema of nephrotic syndrome, edema of CRF
 Facilitate excretion during poisoning

21. 21
Inhibitors of Na+-Cl- symport
• AKA: Thiazide & thiazide like diuretics,
benzothiazides.
• Drugs: Chlorothiazide, Hydrochlorothiazide,
Indapamide
• Site of action: distal convoluted tubule
• Mechanism of action: inhibit Na+-Cl- symporter

22. 22
• Pharmacological effects
  Na+ & Cl- excretion /only 5% filtered Na+ load/
 Also possess carbonic anhydrase inhibition
  HCO3
- & Phosphate excretion
  excretion of K+
 Reduce uric acid excretion

23. 23

24. 24
• PharmacoKinetics
 All are well absorbed from GIT except chlorothiazide
 Extensive plasma protein binding
 Elimination mainly Renal as intact drug.
 Reach their site of action: - secretion in the PT & by
glomerular filtration.

25. 25
• Adverse Reaction
 Vertigo, headache, NVD, blood dyscrasias
 Photosensitivity, skin rashes
 ECFV depletion, hyponatremia, hyperglycemia.
 hyperuricemia
 se plasma LDL, total cholesterol & total TGs
• Therapeutic uses:
 Edema associated with CHF, Hepatic cirrhosis,
Nephrotic syndrome, CRF, glomerulonephritis
 HTN
 Nephrogenic diabetes inspidus!

26. 26
Inhibitors of Renal epithelial Na+ channels (ENaC)
• Also called: K+ sparing diuretics
• Drugs: - Triameterene
• Site of action: collecting duct system
• Mechanism of action: inhibition of renal epithelial Na+
channels.

27. 27
• Pharmacological effect:
 Mild  in Na+ & Cl- excretion (2% of filtered Na+ )
 ed excretion of H+ & K+
• PharmacoKinetics
 Orally effective with bioavailability of 10-60%
 Moderately protein bound: enter the lumen via
filtration & secretion in the PT.
 Elimination metabolism: bile & urine (intact &
metabolite)

28. 28
• Adverse effects
 Nausea, Vomiting, headache, photosensitivity,
cramps, hyperkalemia, hyperglycemia.
• Therapeutic use
 Combination with other diuretics
 Decrease the Kaluretic effect of other diuretics.

29. 29
Antagonists of mineralocorticoid
receptors
• AKA: aldosterone antagonists, K+ sparing diuretics
• Drugs: Spironolactone
• Site of action: collecting duct system
• Mechanism of action: inhibit binding of
aldosterone to Mineralocorticoid Receptors.

30. 30
• Pharmacological effects
 Similar to ENaC inhibitors
• Pharmacokinetics: -
 Partially absorbed from GIT
 Extensive hepatic 1st pass: short half life

31. 31
• Adverse effects
 Hyperkalemia, metabolic acidosis: in Patients
with liver disease
 Drowsiness, lethargy, headache
 Gynecomastia, impotence
 Diarrhea, gastritis (PUD)

32. 32
• Therapeutic uses:-
 Combined with other diuretics (to decrease K+
excretion)*
 Primary hyper-aldosteronism (adrenal adenoma,
hyperplasia)
 Secondary hyper-aldosteronism (2o to CHF, CRF)
* Effect of two or more diuretics from different classes is additive or
synergistic if there sites or mechanisms of action are different

33. 33
Drugs for Hypertension
(HTN)

34. 34
Definition
• A sustained increase in blood pressure (140/90
mm Hg) [on repeated BP measurement]
• Criteria for HTN in Adults
Classification Blood Pressure (mm
Hg)
Systolic Diastolic
Normal < 120 < 80
Pre-hypertension 120 – 139 80 – 89
Hypertension, Stage 1 140 – 159 90 – 99
Hypertension, Stage 2  160  100

35. 35
• Is the most common cardiovascular disease in the
west (up to 27% of US adult population)
 Varies with age, race, environment etc
• Is one of the most important risk factors for both
coronary artery disease and cerebrovascular
accidents
• Effective treatment of HTN reduces morbidity and
mortality
Cont’d

36. 36
Regulation of normal BP
• Arterial BP = CO x TPR
• There are four anatomical regulating sites
1. Arterioles
2. Post-capillary Venules
3. The heart
4. The kidneys

37. 37
Main sites and mechanisms of BP control
1. Baroreceptor reflex:
 Mediated by autonomic nerves
2. Humoral mechanism:
 The Renin-Angiotensin-Aldosterone system (RAAS)

38. 38

39. 39
Baroreceptor reflex
• For rapid adjustment of BP
 Sensory input: receptors on carotid sinus and aortic arc
 Stimulus: stretch
• If BP is increased
 Carotid receptors are stimulated by stretch of blood vessels
 Results in the inhibition of sympathetic discharge
• If BP is decreased
 Stretch of blood vessels is reduced  ed baroreceptor activity
  disinhibition of sympathetic discharge

40. 40
Humoral Control
• For long term control of BP
• If mean arterial BP is reduced ,
 Renal perfusion pressure is reduced
 Increased reabsorption of salt & water
 Increased secretion of renin and the resulting increase in
Angiotensin II, which in turn causes
• Direct arteriolar vasoconstriction
• Increased secretion of aldosterone

41. 41
Classification of HTN
• Based on etiology
 Primary (essential) HTN
85-90% of all cases
No cause is identified
 Secondary HTN
10-15% of cases
Identifiable cause present

42. 42
Classification of
Antihypertensive agents
1.Diuretics
 Loop diuretics eg. Furosemide
 Thiazide diuretics eg. Chlorthiazide
 K+ sparing diuretics eg. Triamterene
 Mechanism: reducing blood volume

43. 43
Classification (cont’d)
2. Antiadrenergic agents
I. Centrally acting α2 agonists
II. Ganglionic Nicotinic receptor blocking agents
III. Adrenergic neuron blocking agents
IV. Adrenergic receptor blocking agents
 α-AR blockers
 β-AR blockers
 mixed α-, β-AR blockers

44. 44
Classification (cont’d)
3. Vasodilators
 Arteriolar dilators
 Mixed artery & venous dilators
4. Blockers of production or action of Angi II
 Angiotensin converting enzyme inhibitors
 Angiotensin II receptor blockers

45. 45
DIURETICS
 Antihypertensives alone, and enhance the efficacy of
other antihypertensive drugs
 Exact mechanism for reduction of arterial BP is not
certain
Initial  in extracellular volume  fall in CO
Maintained hypotensive effect during long-term therapy is
due to  in vascular resistance; CO returns to pretreatment
values and extracellular volume returns almost to normal

46. 46
• Loop diuretics
 Are most potent diuretic
 Block Na+/K+/2Cl- transport in thick ascending loop of
henle
 Include such drugs as furosemide, bumetanide,
ethacrynic acid, torsemide
 Used in severe HTN
When multiple drugs with Na+ retaining properties are used
In case of renal insufficiency
In case of CHF or cirrhosis

47. 47
• Thiazide diuretics
 Less potent diuretics
 Block Na+/Cl- cotransport in the distal convoluted
tubule
 Include: chlorothiazide, indapamide, hydrochlorothiazide,
chlorthalidone,
 Used in mild to moderate HTN
Along with other antihypertensive agents
In patients with normal renal & cardiac function

48. 48
• K+ sparing diuretics
 Weakest in diuretic potency
 Act distally in the collecting duct to either inhibit binding of
aldosterone to mineral corticoid receptors or inhibit epithelial
Na+ channel (ENaC).
 Avoid excessive K+ depletion
 Drugs include spironolactone, triamterene and
amiloride.

49. 49
• Vasodilators
1. Oral vasodilators
 Hydralazine, Minoxidil
 Used for long term treatment of HTN
2. Parenteral vasodilators
 Nitroprusside, Diazoxide
 For treatment of hypertensive emergencies
3. Ca++ channel blockers
 Verapamil, Diltiazem
 For long term treatment of HTN & treatment of
hypertensive emergencies

50. 50
• Mechanism (vasodilators)
 All reduce TPR by relaxing arteriolar smooth muscle
Elicit baroreceptor & renal reflexes
 Cause tachycardia and salt & water retention
 Vasodilators should be combined with other
antihypertensive agents
 To counteract the reflex adverse effects

51. 51
Hydralazine
• Causes direct relaxation of arteriolar smooth
muscle, but does not relax veins
• The vasodilatation induces powerful stimulation of
sympathetic system (ed HR and contractility, ed
plasma rennin activity, and fluid retention)
• Postural hypotension is not common
• Well absorbed after oral administration

52. 52
• Adverse effects
 Tachycardia, aggravation of angina, fluid retention,
headache, sweating, flushing, nausea, anorexia
• Uses:
– Severe HTN & hypertensive emergencies in pregnant
women

53. 53
Minoxidil
• Metabolized by hepatic sulfotransferase to the active
molecule, minoxidil N-O sulfate
• Activates ATP-modulated K+ channel and results in
hyperpolarization & relaxation of smooth muscle (ed
TPR)
• ed CO (activation of sympathetic system)
• Potent stimulator of rennin release
• Has no effect on capacitance vessels
• Well absorbed orally

54. 54
• Adverse effects
 Retention of salt and water
 CVS effects:  in HR, myocardial contractility, and
myocardial O2 consumption
 Hypertrichosis (due to K+ channel activation). *Topical
minoxidil is marketed for the treatment of baldness.
• Therapeutic use
 Severe HTN that does not respond to other agents

55. 55
Sodium nitroprusside
• Potent , parentally administered vasodilator
• Activates guanylyl cyclase via release of NO
• Dilates both arteriolar & venular vessels
• Has rapid onset (30 s) & brief duration of effect (3 min)
• Causes only a modest in HR and an overall reduction in
myocardial demand for oxygen
• Metabolically degraded by the liver to thiocyanate, which are
excreted by the kidney (patients with impaired renal function
likely to develop toxicities)
•  Plasma rennin activity

56. 56
• Adverse effects are secondary to
 Excessive lowering of BP; and
 Accumulation of CN-
Metabolic acidosis, arrhythmias etc
Hypothyroidism (thiocyanate inhibits uptake of iodine)
• Therapeutic use
 Treatment of hypertensive emergencies (continuous
IV infusion)

57. 57
Ca2+ channel blockers (CCB)
• Inhibit Ca++ influx in to arteriolar smooth muscle
 Cause arteriolar dilatation; hence reduce TPR
• Specific drug classes
 Dihydropyridines: Nifedipine, Nicardipine
Potent arteriolar vasodilators
Less effect on heart rate & contractility
Adverse effects Tachycardia, headache, flushing, peripheral edema
 Phenylalkylamine: Verapamil
Decrease heart rate & contractility
Adverse effects: headache, dizziness, edema, bradycardia
 Benzothiazepines: Diltiazem
Intermediate effect on heart rate and blood vessels

58. 58
• Therapeutic uses
 Maintenance (long term) treatment of HTN
 hypertensive emergencies
 HTN coexisting with
Ischemic heart disease, Chronic pulmonary disease, DM,
and Variant angina

59. 59
Drugs that alter sympathetic nervous
system function
• Primary mechanism of action
 sympathetic activity to heart &/or blood vessels →
decease CO and/or TPR
• All the drugs elicit compensatory renal effects
 Sodium & water retention  expand blood volume
 Effective if used concomitantly with diuretics

60. 60
Centrally acting 2 agonists
• Include such drugs as clonidine, guanfacine,
guanabenz, -methyldopa
• Reduce sympathetic outflow from vasomotor
center of brain stem
• Methyldopa is preferred drug for treatment of
hypertension during pregnancy

61. 61
Ganglionic nicotinic receptor blockers
• Eg. Trimethaphan
• Are of historical value
• Currently no longer in use due to intolerable
adverse effects
• Adverse effects
Sympathetic: orthostatic hypotension, sexual
dysfunction ...
Parasympathetic: constipation, urinary retention, dry
mouth, blurring of vision..

62. 62
Adrenergic neuron blocking agents
• Reserpine
 An alkaloid from the root of Rauwolfia serpentina
 MOA
Inhibits the vesicular catecholamine transporter that
facilitates vesicular storage
Results in pharmacological sympathectomy
Depletes amines in CNS and peripheral adrenergic neuron

63. 63
 Pharmacological Effects
 in CO and TPR,  in HR, renin secretion
Salt and water retention
 Adverse effects
Sedation, impaired concentration, depression that can
lead to suicidal attempt
Contraindicated in patients with a history of depression.
Nasal stuffiness, exacerbation of peptic ulcer disease
 Therapeutic use: mild to moderate hypertension

64. 64
• Guanethidine
 MOA
Transported into neuronal terminals by uptake1
Concentrated in vesicles and deplete NE
 Adverse effects
Marked orthostatic hypotension, bradycardia
Doesn’t cross the BBB; hence no central adverse effects
 Therapeutic use:
Reserved for the treatment of severe HTN
– Due to severe adverse effects & its high efficacy.

65. 65
β-adrenoceptor blockers
• MOA
 β- adrenoceptor blockade
 myocardial contractility, HR & CO
 renin secretion (reduced levels of angiotensin II)
• Drugs differ in
 Lipid solubility
 Selectivity for the 1-AR subtype
 Presence/absence of intrinsic sympathomimetic activity
• All have similar antihypertensive efficacy

66. 66
• Drugs with out ISA
 Initially reduce CO, TPR; no change in BP.
 Latter TPR returns to pretreatment values while CO
remains reduced, hence BP is reduced
• Drugs with ISA: less effect on HR & CO (at rest)
 Reduce TPR reduced BP (β2- stimulation)
• Precautions
 Asthma , SA or AV nodal dysfunction
 CHF, DM
• NB: Sudden discontinuation causes rebound HTN

67. 67
1-AR blockers
• Prazocine,Doxazocine, Terazocine etc..
• Initially reduce arteriolar resistance and increase
venous capacitance  reduce BP
• Then sympathetically mediated reflex increase in
heart rate and plasma renin activity
• On long term use, vasodilatation persists; but the
CO, HR, and renin activity return to normal
  in BP

68. 68
• Adverse effects
 Increased risk of CHF
• Therapeutic use
 Not useful for monotherapy (should be combined with β
blockers, diuretics or other antihypertensive agents)
 For hypertensive patients with benign prostatic
hyperplasia

69. 69
• Renin
 Synthesized, stored, and released by the renal
juxtaglomerular cells.
• Angiotensinogen synthesized in the liver
• Renin cleaves angiotensinogen to angiotensin I (rate
limiting step in the process), which is then cleaved
by converting enzymes to angiotensin II
Drugs that alter the formation or
action of Angiotensin II

70. 70
• Angiotensin Converting enzyme (ACE/peptidyl
dipeptidase) converts AGN I to AGN II
• AGN II
 Metabolized by angiotensinases to inactive
metabolites

71. 71

72. 72

73. 73
Angiotensin converting enzyme inhibitors (ACE-I)
• Inhibit conversion of AG-I to AG-II
• Drugs include Captopril, Enalapril, Fosinopril…..
• Pharmacological effects
 Decrease PVR–due to reduced salt & water retention
 Prominent reduction in renal vascular resistance
 Inhibits inactivation of bradykinnin
 Reduced systemic BP – No change in HR & CO

74. 74

75. 75
• All ACEIs have similar
 Efficacy, therapeutic use
 Adverse effect profile, contraindications
• Pharmacokinetics-orally effective;
 Differ in absorption & hepatic first pass effect
 Elimination is in the urine;
• Therapeutic uses: HTN, Left ventricular
hypertrophy, Acute MI , CRF

76. 76
• Adverse effects: generally well tolerated
 Hypotension, dry Cough, Angioedema, hyperkalemia,
Acute renal failure, Fetal damage, Skin rashes,
proteinuria, glycosuria, etc

77. 77

78. 78
Angiotensin II receptor blockers
• Antagonize the effects of angiotensin II
 Block preferentially AT1 receptors
 Vasodilation, Increase salt and water excretion
 Reduce plasma volume, and
 Decrease cellular hypertrophy.
 Do not affect inactivation of bradykinin (contrast to
ACE-I), hence do not cause dry cough & angioedema
• AT2 may elicit antiproliferative and antigrowth responses.

79. 79
Angiotensin II receptor blockers
• Peptides: Salarsan
• Non-peptides: orally active & potent
 Losartan, Valsartan, Telmisartan, Irbesartan
• Similar to ACEIs with regard to
 Pharmacological effect, Therapeutic use
 Adverse effects; and contraindications

80. 80
Conditions warranting special emphasis
• Pregnancy: Drugs used to be taken prior to pregnancy can be continued
 Except ACEIs & AT1 receptor antagonists
 Methyldopa is commonly used; Avoid β blockers
• Elderly: use smaller doses, simpler regimens
 Monitor for adverse drug effects
• DM: use drugs with fewer adverse effect on carbohydrate metabolism
 ACEIs, AT1 receptor blockers, CCB, and α1-AR blockers
• Asthma: avoid β- blockers.

81. 81
Non-Pharmacological therapy of hypertension
1. Reduction of weight
2. Salt restriction - 5mg/d of salt
3. Alcohol restriction
4. Physical exercise
5. Relaxation & Biofeedback
6. K+ supplementation
7. Stop smoking

82. Drug therapy of
Myocardial ischemia
82

83. Myocardial ischemia can result from:
•Reduction of blood flow to the heart that can be caused by stenosis,
spasm, or acute occlusion (by an embolus) of the heart's arteries.
•Resistance of the blood vessels. This can be caused by narrowing of
the blood vessels; a decrease in radius.
•Reduced oxygen-carrying capacity of the blood, due to several factors
such as a decrease in oxygen tension and hemoglobin concentration.
83

84. •Atherosclerosis;
 Most common cause of stenosis (narrowing of blood vessels) of the
heart's arteries and, hence, angina pectoris.
Artery wall thickens as a result of accumulation of fatty materials such as
cholesterol.
•Important consequences of coronary atherosclerosis include:
 Angina (ischemic chest pain)
 Myocardial infarction.
84

85. Angina: principal symptom of myocardial Ischemia.
Angina: heavy, pressing sub-sternal discomfort (pain), often
radiating to the left shoulder, left arm, jaw, or epi-gastrium.
Cause: imbalance b/n myocardial oxygen demand &
oxygen supplied by coronary vessels.
 Increased myocardial oxygen demand
Determined by Ventricular wall tension, HR, contractility
 Decreased myocardial oxygen supply
Determined by coronary blood flow (CBF), oxygen-carrying
capacity of the blood. 85

86. Determinants of CBF
 CBF is directly related to
Perfusion pressure (aortic diastolic pressure)
Duration of diastole
 CBF is inversely proportional to
Coronary vascular bed resistance
Determinants of Vascular Tone
 Arterial BP determines systolic wall stress
 Venous tone determines amount of blood returned
to heart, hence the diastolic wall stress
86

87. Types of Angina
1. Stable /exertional, typical, classic.../ Angina
 Underlying Pathology:- atherosclerosis in large coronary arteries
to cause fixed narrowing.
 Episodes precipitated by exercise, cold, stress, emotion, eating.
 Treatment principles: Decrease cardiac load (pre-& after load),
increase myocardial blood flow
 organic nitrates, β-antagonists and/or calcium antagonists
 Together with Rx of atheroma, usually including a statin,
prophylaxis against thrombosis with aspirin
87

88. 2. Vasospastic/Variant, prinzmetals.../ Angina
 Less common
 Cause: transient Vasospasm of coronary Vessels
 Associated: underlying atheromas
 Pain can occur at rest
 Treatment principles: ed Vasospasm of coronary Vessels.
 Rx with coronary artery vasodilators (e.g. organic nitrates, Ca
antagonists).
88

89. 3. Unstable /pre-infarction, crescendo.../ Angina
 Cause: recurrent episodes of small platelet clots.
 Site: ruptured atherosclerotic plague
 Precipitated: local Vasospasm
 Association: change in character, frequency & duration
of Angina (Stable) and prolonged episodic angina
 Treatment principles: inhibit platelet aggregation &
thrombus formation, decrease cardiac load, Vasodilate
coronary arteries.
89

90. Classification of Antianginal Agents
1. Organic nitrates
 Reduce preloads & after load, dilate coronary arteries.
Inhibits platelet aggregation.
2. Ca++ channel blockers
 Vasodilate coronary arteries. Reduce after load,
inhibit platelet aggregation
 Some; decrease HR, decrease contractility.
3. ß-adrenergic antagonists
 Decrease HR, contractility and after-load
90

91. Organic Nitrates
91

92. Drugs include:
 Amylnitrate
 Glycerol trinitrate(Nitroglycerine)
 Isosoribide dinitrate
 Isosoribide mononitrate
Are nitrites or nitrate esters of poly-glycols
All lead to the formation of nitric oxide (NO).
92

93. Nitric oxide (NO)
 An autacoid
 Plays critical roles as chemical messenger in
Cardiovascular tone
Platelet regulation
Immune regulation
93

94.  Mechanism of action: interact with heme moiety
& activates intracellular guanylyl cyclase
Activation of cGMP dependent protein kinases (PKG)
Smooth muscle relaxation: due to
Increased Ca++ efflux
Decreased Ca++ influx
Hyper polarization of sarcolemal membrane
94

95. Mechanism of relaxation by NO
95

96. Pharmacological effects(organic nitrates)
 Peripheral vasodilatation (more on veins)
Large reduction in preload: less in after load.
 Myocardial work load se in O2 demand.
 Dilate large epicardial coronary arteries
 Improve perfusion of ischemic myocardium.
 Inhibition of platelet aggregation
 Almost all smooth muscles are relaxed.
96

97. PharmacoKinetics
 Oral bioavailability is very low
Extensive hepatic first pass metabolism.
 Ellimination: glutathione-Organic nitrate reductase
 Reduction in liver to denitrated organic compounds 
glucuronide conjugation and excretion in kidney
97

98. Development of Tolerance
 Magnitude depends on dosage and frequency of use.
 Cause: ed capacity to release NO or of the
activation of mechanisms
 Workers in Explosive factories
Headaches, dizziness, and postural weakness during the
first several days of employment
Development of tolerance
Monday disease (reappearance of symptoms)
Dependence (withdrawal syndrome); on chronic
exposure to nitrates
98

99. Adverse effects: - mainly due to excessive
vasodilatation
 Severe head ache, dizziness, flushing
 Orthostatic hypotension, tachycardia
 Syncope (fainting)
Drug interaction
 Sildenafil (exaggerated response to nitrates)
99

100. Therapeutic uses
 Treatment & prevention of all types of Angina
Variant angina
Stable angina
Unstable angina
100

101. 101

102. Ca2+ channel blockers
Role of Ca++ in cardiac & smooth muscles:
 Regulates contraction:- through changes in intracellular
concentration of Ca2+
 Cardiac: Ca2+ binds to Troponine
 Relieves inhibition of Actin-Myosine interaction
 Smooth: Ca++ binds to Calmoduline  Ca++-
Calmoduline complex
Triggers Actin - Myosine interaction
102

103.  Regulation of Cytoplasmic Ca++ Conc. plasma membrane
and ER
 At rest: Cytoplasmic (free) Ca++ Conc. is very low to extra
cellular Ca++ Conc.
 Stimulation  elevated cytoplasmic levels of Ca++
 Removal of stimulus  Conc. of Ca++ return to normal
 Ca++ Regulation influx through plasma membranes
 Plasma membrane Ca++ channels (3 types)
Voltage dependant
Receptor mediated
Receptor operated: open upon receptor occupancy
103

104. Voltage- gated: at least 3 types (L,T,N types)
 L- type: wide spread in the CVS, large sustained
conductance and inactivate slowly; slow in ward
current of A.P (heart)
Sensitive to Ca++ channel blockers.
 T-type: abundant in SA node
Less sensitive to Ca++ channel blockers; except mibefradil
 N- type: found only in neuronal cells.
Insensitive to Ca++ channel blockers.
104

105. Regulation of Ca++ efflux through plasmalemma.
 Ca++ pumps: against concentration gradient
 3Na+/ Ca++ exchanger: major mechanism in the
myocardium
Intracellular structures regulating cytoplasmic Ca++
conc
SR/ER: site for sequestration & rapid release of Ca++
• Release: Ca++ channels IP3-dependent, Ca++- dependent
• Re-sequestration: Ca++ pumps.
Mitochondria: slowly exchanging Ca++ reservoir.
• Ca++ uni-porters
• Electro-neutral Na+/Ca++ exchanger
105

106. Classification:- based on chemical structure.
 Benzothiazepines: Diltiazem
 Phenylalkylamines: Verapamil
 Dihydropyridines: Nifedipine, nicardipine,
Amlodipine, Nimodipine etc.
106

107. Site of action of Ca++-channel blockers.
 Bind to L-type Ca++-channels- prevent Ca++ influx.
different classes bind to different sites on the channel
different types of L-type channels exist.
 Bepridil; also blocks Na+ and K+ channels
 Mibefradil: also blocks T-type channels
107

108. Pharmacological Effects
Vascular smooth muscle
 Decreased intracellular ca++ in arterial S. muscle 
Relaxation
Decreased after load
 Little or No effect on venous beds
No effect on preload.
108

109. Effects on cardiac cells
 Negative Inotropy
Potent: Verapamil, diltiazem
Modest: Dihydropyridines
 Negative chronotropy/dromotropy
Verapamil; decrease rate of recovery of slow channel,
Diltiazem in AV conduction & SA node direct -Ve effect
Mibefradil: direct-Ve chronotropic & dromotropic
– Inactivation of T- channels (AV & SA. nodes)
Dihydropyridines: No direct effect on AV &SA nodes.
– Dihydropyridines -Ve ionotropy is overcome by strong arteriolar
dilation induced reflex sympathetic activation
109

110. Homodynamic effect
 Improve delivery of O2 to ischemic myocardium.
Coronary Vasodilation  increased CBF
Reduced HR increases time spent in diastole
 Reduced myocardial O2 consumption: Reduced HR &
contractility (exception: Dihydropyridines)
 Inhibit platelet aggregation
 Little or No effect on extra vascular smooth muscle
110

111. Adverse drug effects
 Due to excessive Vasodilatation: dizziness, headache,
hypotension, flushing, edema etc.
 Aggravation of myocardial ischemia: reflex
tachycardia
 Bradycardia, exacerbation of CHF
Contraindications (specially Verapamil & Diltiazem)
 Moderate to severe ventricular dysfunction
 SA or AV conduction disturbances
 Systolic BP less than 90mm Hg
111

112. Therapeutic Uses
 Angina; Variant, Exertional, and Unstable
 Are also employed in supraventricular arrhythmias
and Hypertension
112

113. -AR Blockers
 Most appear to be equally effective
 Commonly used drugs:
 Propranolol, Nadolol, Timolol, Atenolol, Metoprolol
 Mechanism: blocks ß- AR
 Have negative chronotropic & inotropic effect.
 Decrease myocardial oxygen consumption
 Improve myocardial perfusion: H.R.
 Decrease in total peripheral resistance
113

114. Arterial blood pressure (afterload) is reduced by
β-blockers. The mechanisms responsible for this
antihypertensive effect are not completely
understood, but are thought to involve
 a reduction in cardiac output
 a decrease in plasma renin activity
 an action in the central nervous system
 a resetting of the baroreceptors .
114

115. Adverse effect & C/Is
 Dangerously reduce myocardial performance
Contraindication: overt heart failure.
 Depress contractility & produce AV block.
 Contraindication:
 Asthma
 DM
115

116. Therapeutic Uses
 Exertional angina
 Unstable angina; reduce progression to MI.
 Myocardial infarction: improve mortality
 Combined with Nitrates &/or Ca++ channel blockers.
Not useful in Variant Angina
116

117. Summary Therapeutics of Angina
 General treatment objectives:
 Acute management: Nitrovasodilators.
 Chronic /maintenance/ management.
i. Non specific pharmacological risk factor modification
Hyperlipidemia (Lipid lowering agents), HTN (Antihypertensive),
DM (insulin, oral hypoglycemic agents), Obesity (Diet control),
Smoking (cessation…), Antiplatelet agents (Aspirin)
ii. Specific pharmacological treatments
Decrease oxygen demand
Increase oxygen supply
117

118. Stable Angina
 Maintenance treatment includes
Long acting Nitrates, CCB and ß-AR blockers.
Normotensive: Monotherapy with long acting Nitrates
Hypertensive: Monotherapy: CCBs or ß-AR blockers.
Persistent HTN, Sinus bradycardia, AV node dysfunction
• Long acting Dihydropyridines
 Combination therapy: if monotherapy is ineffective
• ß-blockers + long acting dihydropyridine CCB.
• Two CCBs with different selectivity, etc .
 Refractory: Surgical revascularization (Coronary by
pass, Angioplasty)
118

119. Vasospastic Angina
 Nitrates & CCBs are effective
 -blockers may worsen the angina
Unstable Angina
 Verapamil - effective
 Combination therapy
 Aspirin
 IV Heparin or thrombolytic Agents in some patients
119

120. Myocardial Infarction/MI/
 Occurs when a coronary artery has been blocked by thrombus.
 Fatal and common cause of death, usually as a result of mechanical
failure of the ventricle or from dysrhythmia.
 Cardiac myocytes rely on aerobic metabolism.
 If the supply of oxygen remains below a critical value, a sequence
of events leading to cell death (by necrosis or apoptosis) ensues.
120

121. •Acute MI occurs when there is;
• an abrupt decrease in coronary blood flow following a
thrombotic occlusion of a coronary artery
•Previously narrowed by atherosclerosis.
•Pain is most frequent presenting complaint in patients with MI.
• Typically, the pain involves the central portion of the chest.
•Incidence is greater with multiple risk factors for Atherosclerosis
such HTN, DM, cigarette smoking, dyslipidemia ,obesity.
121

122. •Prevention of irreversible ischaemic damage following an episode
of coronary thrombosis is an important aim.
The main possibilities among existing therapeutic drugs;
 Thrombolytic and anti-platelet drugs (aspirin and clopidogrel) to open
blocked artery and prevent re-occlusion.
oxygen
Opioids to prevent pain and reduce excessive sympathetic activity
β-adrenoceptor antagonists
angiotensin-converting enzyme (ACE) inhibitors
122

123. Drug treatment of MI;
•Oxygen, 2-4 l/min, via facemask,
•Nitroglycerin, 0.5mg, sublingual, every 5 min up to 3 doses.
•Acetylsalicylic acid, 160-325 mg., chew and continue P.O. QD.
•Diazepam, 5mg P.O. 3-4 times daily.
•Morphine, (for control of pain), 2-4 mg IV. every 5 min.
•Heparin-for all patients with MI, 7500 units sc every 12 hr bid.
Followed by
•Warfarin, for at least 3 months-Tablet, 2mg, 5mg, 10mg
•Enalapril, 5 - 40 mg P.O. once or divided into two to three doses.
123

125. Congestive heart failure
 Definition: Inability of the heart to maintain a CO
which is adequate to meet the metabolic demands
of the body.
 Etiology - Almost all forms of cardiac diseases can
lead to heart failure.
 Classification
Right ventricular Vs Left ventricular failure
Acute Vs Chronic Heart failure
Diastolic Vs Systolic heart failure

126. •CHF is frequently, but not always, caused by a defect in myocardial
contraction.
•CHF may result from a primary abnormality in heart muscle, as occurs in
the cardiomyopathies, or in viral myocarditis .
•HF also results commonly from coronary atherosclerosis causing MI and
ischemia.
•HF may also occur in congenital, valvular, and hypertensive heart
disease in which the myocardium is damaged by the long-standing
hemodynamic overload.
126

127. Pathogenesis of CHF
 Lack or loss of contractile force  ed ventricular
function  reduced CO
 As a result, a variety of adaptive mechanisms are
activated
The compensatory mechanisms are either intrinsic or
extrinsic

128. 1. Neuro-humoral (extrinsic) compensatory
mechanisms
i. Sympathetic nervous system over activity
ed sympathetic and ed Parasympathetic outflow
Initial increase in HR, contractility, and vascular tone
– Increased preload, force, & HR; increases the CO
– Increased arterial tone increases the after load which leads to
decreased ejection fraction and hence, reduced CO
Increased RAAS
ii. Increased release of ADH
Increased water re-absorption

129. 2. Intrinsic (cardiac)compensatory mechanisms
 Myocardial hypertrophy
 ‘Remodeling’

130. Pathophysiology of cardiac performance
 Is a function of four primary variables
Increased preload
• Treatment: reducing preload (salt restriction, diuretic therapy
and venodilator drugs)
Increased Afterload
• Treatment: reducing arterial tone (arteriolar vasodilators)
Depressed intrinsic contractility of myocardium
• Treatment: increasing contractility using inotropic agents
Increased HR due to sympathetic over activity
• Treatment: reducing the HR (β blockers)

131. Chronic HF is typically managed by;
 non pharmacological approaches- a reduction in physical activity, low
dietary intake of sodium (<1500 mg/day).
treatment of comorbid conditions,
 And use of diuretics, inhibitors of RAAS & inotropic agents.
Drugs that exacerbate HF, such as NSAIDs , alcohol, calcium-channel
blockers, and some antiarrhythmic drugs, should be avoided if possible
131
5/11/2023

132. New York Heart Association Functional Classification
Functional
class
Description
I Patients with cardiac disease but without limitations of physical
activities. Ordinary physical activity does not cause undue
fatigue, dyspnea, or palpitation.
II Patients with cardiac disease that result in slight limitations of
physical activities. Ordinary physical activity results in fatigue,
palpitation, dyspnea or angina.
III Patients with cardiac disease that results in marked limitation of
physical activity. Although patients are comfortable at rest, less
than ordinary physical activity will lead to symptoms
IV Patients with cardiac disease that results in an inability to carry
on physical activity without discomfort. Symptoms of CHF are
present even at rest. With any physical activity, increased
discomfort is experienced.

133. Drugs used to treat heart failure:
Drugs with positive inotropic effect
Drugs without positive inotropic effect
1. Cardiac glycosides—Digoxin is frequently used drug.
2. Sympathomimetic drugs—Dopamine and dobutamine
a. Dopamine—Catecholamine, activates beta1 and dopamine
receptors and at very high doses alpha1 receptor
b. Dobutamine—Increases myocardial contractility; preferred
drug 133
5/11/2023

134. Drug groups commonly used in Heart Failure
 ACE inhibitors
 β blockers
 Angiotensin receptor blockers
 Diuretics
 Cardiac glycosides
 β agonists
 Vasodilators

135. Heart failure
Drugs with positive inotropic effect
1. Cardiac glycosides
– Includes digoxin and digitoxin
– Mechanism: The cardiac glycosides inhibit the Na+/K+-
ATPase pump, which causes an increase in intracellular Na+
=> slowing of the Na+/Ca++-exchanger => increase in
intracellular Ca++.
– slow the heart rate and increase the force of contraction
– Digitoxin: more lipid soluble and has long t1/2 than digoxin
– Therapeutic use of cardiac glycosides
• Congestive heart failure
• Atrial fibrillation & Atrial flutter
• Paroxysmal atrial tachycardia
135
5/11/2023

136. Mechanism of action
 Inhibition of cellular membrane Na+,K+-ATPase, the
cellular Na+ pump.
Potent, selective, and reversible
 Bind preferentially to the phosphorylated Na+, K+-
ATPase
Stabilizes the phosphorylated conformation
Extracellular K+ promotes DEPHOSPHORYLATION

137. Pharmacological Effects
Can be expressed as cardiac and extracardiac
Cardiac effects
 Positive inotropic effect
 Electrophysiological actions……

138. Actions:
Heart:
digitalis has direct on myocardium contractility and
electrophysiological property
In addition, it has vagommimetic action, reflexes
Due to alteration in haemodynamics and direct CNS
effect altering sympathetic activity
Digitalis causes a dose dependent increase in force of
contraction of the heart(posetive inotropic effect )

139. It decrease the heart rate
Improved circulation (due to positive inotropic action)
restores the diminished vagal tone and abolishes
sympathetic activity
In addition, digitalis slows heart by vagal and extravagal
actions
Kidney:
Diuresis is seen promptly in CHF patients, secondary to
improved circulation and renal perfusion
No diuresis occur in normal individuals or in patients
with edema by other causes
CNS:
digitalis has little effect on CNS
Higher doses cause CTZ activation-nausea and vomiting

140. Pharmacokinetics:
• All digitalis glycosides possess the same pharmacologic
actions, but they vary in potency and pharmacokinetics
• Digoxin is very potent, with a narrow margin of safety
and long half-life of around 36 hours.
• Digoxin is mainly eliminated intact by the kidney,
requiring dose adjustment based on creatinine
clearance.
• Digoxin has a large volume of distribution, because it
accumulates in muscle.
• A loading dose regimen is employed when acute
digitalization is needed.
• Digitoxin has a much longer half-life and is extensively
metabolized by the liver before excretion in the feces,
and patients with hepatic disease may require
decreased doses.

141. •The long half-life of digitalis compounds necessitates special considerations
when dosing.
•With a half-life of 40 hrs, digoxin would require several days of constant dosing
to reach steady-state, therapeutic plasma levels.
•Therefore, when initiating Rx, a special dosing regimen involving "loading
doses" is used to rapidly increase digoxin plasma levels.
•This process is termed "digitalization."
•For digoxin,therapeutic plasma concentration range is 0.5 - 1.5 ng/ml.
•It is very important that therapeutic plasma levels are not exceeded because
digitalis compounds have a relatively narrow TI.
• Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity, which is
manifested as arrhythmias, some of which may be life-threatening.
•If toxicity occurs with digoxin, it may take several days for the plasma
concentrations to fall to safe levels because of the long half-life.
141

142. Therapeutic uses:
Digoxin therapy is indicated in patients with severe left
ventricular systolic dysfunction after initiation of ACE
inhibitor and diuretic therapy.
Digoxin is not indicated in patients with diastolic or
right-sided HF.
Digoxin's major indication is HF with atrial fibrillation.
Dobutamine , another inotropic agent, can be given
intravenously in the hospital, but at present, no
effective oral inotropic agents exist other than digoxin.
Patients with mild to moderate HF will often respond to
treatment with ACE inhibitors and diuretics, and they
do not require digoxin.

143. Digitalization:
a. Slow digitalization:
In most mild cases, maintenance dose of
digoxin (average 0.25mg/day) is given from
the beginning
Full response takes 5-7 days to develop, but
the procedure much safer
b. Rapid oral digitalization:
Digioxin 0.5-1mg/day stat followed by 0.25
mg every 6hrs with carful monitoring and
watch for toxicity till response occurs
generally takes 6-24hrs

144.  Electrophysiological Actions (cont’d)
At therapeutic concentrations
• ed automaticity and ed resting membrane potential in
atrial and AV nodal tissues ( vagal tone &  sympathetic
activity)
• Prolongation of effective refractory period and ed
conduction velocity in AV nodal tissue
• Sinus bradycardia or arrest and/or prolongation of AV
conduction or higher-grade AV block
At higher concentrations
•  sympathetic nervous system activity & directly affect
automaticity  atrial and ventricular arrhythmias

145. Regulation of sympathetic activity
 CHF
ed sympathetic activity
Reduced tonic baroreflex suppression of CNS-mediated
sympathetic activity
 Cardiac glycosides
Increase baroreflex responsiveness to changes in carotid
sinus pressure

146. Extracardiac effects: on excitable tissues mainly
the GIT & CNS
 GIT – anorexia, nausea, vomiting, diarrhea
Direct irritant effect, stimulation of the CTZ in the CNS
 CNS – mainly vagal & CTZ stimulation
Disorientation, hallicunation, visual disturbances
restlessness etc
 Others
Gynecomastia (peripheral estrogenic effect)

147. Therapeutic uses
 Reserved for patients
With Atrial fibrillation
In sinus rhythm who remain symptomatic despite therapy
with adequate dosage of ACE-I and -AR antagonists

148. In general, cardiac Glycosides:
• Improve cardiac performance (=positive inotrope)
•Increases cardiac output
•Decreased sympathetic tone
•Increase urine output
•Decreased renin release
•Does not prolong life (only symptom relief)
•Digoxin levels must be closely monitored in the presence of renal insufficiency
•Quinidine, verapamil, and amiodarone, can cause digoxin intoxication, both by
displacing digoxin from tissue protein-binding sites and by competing with digoxin
for renal excretion
148
5/11/2023

149. Digitalis toxicity manifests as
 GI – nausea, vomiting, anorexia etc
 CNS – headache, hallucination, delirium, visual
disturbances etc
 Cardiac – bradycardia, heart block, arrhythmias

150. Digitalis toxicity is one of the most commonly encountered
adverse drug reactions.
Side effects often can be managed by discontinuing cardiac
glycoside therapy, determining serum potassium levels
(decreased K+ enhances potential for cardiotoxicity), and if
indicated, giving potassium supplements.
Digoxin levels must be closely monitored in the presence of renal
insufficiency, and dosage adjustment may be necessary.
Severe toxicity resulting in ventricular tachycardia may require
administration of antiarrhythmic drugs and the use of antibodies
to digoxin (digoxin immune Fab), which bind and inactivate the
drug.

151. Management of digitalis toxicity
 If mild GI or Visual disturbances - reduce the dose
 If cardiac arrhythmias occur check serum levels of
K+, Digoxin, Ca++ & Mg++
Correct electrolytes
Use anti arrhythmic agents like Lidocaine
Administer digitalis antibodies

152. Other agents used in
CHF

153. Phosphodiesterase inhibitors
Non selective PDEase inhibitors
 Methylxanthines e.g. Theophylline
 Has positive Inotropic effect, a bronchodilator and
increases renal blood flow
 Used for the treatment of acute left ventricular
heart failure and pulmonary edema; and also
bronchial asthma

154. Selective PDEase inhibitors (Bipyridines)
 Inamrinone, Milrinone
 Available for parenteral use only
 Selective inhibitors of type III PDEase enzyme in the
heart & smooth muscles
Increase the concentration of cAMP & cGMP
Increase Ca++ influx  increased cardiac contractility
Vasodilatation
 Used for the treatment of acute heart failure &
acute exacerbation of chronic heart failure

155. β-AR agonists
Dopamine, Dobutamine
 Used for short term use
 Dobutamine – a racemic mixture
At therapeutic doses it has positive Inotropic effect
Increases myocardial contractility (β1 effect)
Causes peripheral vasodilatation CO is increased; BP is
either increased, decreased or not changed
Adverse effects; excessive tachycardia or arrhythmias

156. Dopamine
 Action mediated through Dopamine receptors.
 Used for systolic HF along with shock e.g.
hemorrhage, dehydration
 Effect is dose related
≤ 2 μg/kg causes vasodilatation
2-5 μg/kg causes positive Inotropy
5-15 μg/kg causes vasoconstriction

157. β-AR blockers
Mechanism of action
 Resensitization of β-adrenergic pathway
 Anti-arrythmogenic effect
 Anti-remodelling effect
On initial use – decrease systolic function
On long term use (2-4 months) – improve
systolic function

158. Drugs - Not all β-blockers are effective in the
treatment of HF
 Carvedilol: non selective β blocker; α1 antagonist
 Bisoprolol, Metoprolol: selective β1 blocker
Use in CHF: improve symptoms, reduce
hospitalization and decrease mortality in class II
& class III patients

159. Diuretics
Used to relief symptoms of fluid retention
Do not decrease disease progression or mortality
Loop diuretics are the most effective
Thiazide diuretics less effective
Concurrent use of the two classes of diuretics
causes enhanced effect

160. Diuretics:
Diuretics relieve pulmonary congestion and peripheral edema.
These agents are also useful in reducing the symptoms of
volume overload, including orthopnea and paroxysmal
nocturnal dyspnea.
Diuretics decrease plasma volume and, subsequently, decrease
venous return to the heart (preload).
This decreases the cardiac workload and the oxygen demand.
Diuretics may also decrease afterload by reducing plasma
volume, thus decreasing blood pressure.
Thiazide diuretics are relatively mild diuretics and lose efficacy
if patient creatinine clearance is less than 50 mL/min.
Loop diuretics are used for patients who require extensive
diuresis and those with renal insufficiency.
Note: Overdoses of loop diuretics can lead to profound
hypovolemia.

161. Spironolactone:
• Patients with advanced heart disease have elevated
levels of aldosterone due to angiotensin II stimulation
and reduced hepatic clearance of the hormone.
• Spironolactone is a direct antagonist of aldosterone,
thereby preventing salt retention, myocardial
hypertrophy, and hypokalemia.
• Spironolactone therapy should be reserved for the
most advanced cases of HF.
• Because spironolactone promotes potassium retention,
patients should not be taking potassium supplements.
• Adverse effects include gastric disturbances, such as
gastritis and peptic ulcer; central nervous system
effects, such as lethargy and confusion; and endocrine
abnormalities, such as gynecomastia, decreased libido,
and menstrual irregularities.

162. Inhibitors of the Renin-Angiotensin System:
• HF leads to activation of the renin-angiotensin
system via two mechanisms: 1) Increased
renin release by juxtaglomerular cells in renal
afferent arterioles occurs in response to the
diminished renal perfusion pressure produced
by the failing heart, and
2) renin release by the juxtaglomerular cells is
promoted by sympathetic stimulation.

163. • The production of angiotensin (a potent
vasoconstrictor ) and the subsequent
stimulation of aldosterone release that causes
salt and water retention lead to the increases
in both preload and afterload that are
characteristic of the failing heart.
• In addition, high levels of angiotensin II and of
aldosterone have direct detrimental effects on
the cardiac muscle, favoring remodeling,
fibrosis, and inflammatory changes.

165. Angiotensin-converting enzyme inhibitors:
• Vasodilation occurs as a result of the combined
effects of lower vasoconstriction caused by
diminished levels of angiotensin II and the potent
vasodilating effect of increased bradykinin.
• By reducing circulating angiotensin II levels, ACE
inhibitors also decrease the secretion of
aldosterone, resulting in decreased sodium and
water retention.

166. Actions on the heart:
ACE inhibitors decrease vascular resistance, venous
tone, and blood pressure, resulting in an increased
cardiac output
ACE inhibitors also blunt the usual angiotensin II
mediated increase in epinephrine and aldosterone
seen in HF.
ACE inhibitors improve clinical signs and symptoms
in patients also receiving thiazide or loop diuretics
and/or digoxin.
The use of ACE inhibitors in the treatment of CHF has
significantly decreased both morbidity and mortality.
Treatment with enalapril also reduces arrhythmic
death, myocardial infarction, and strokes.

167. ACE inhibitors
 First line drugs in the treatment of CHF
 Improve symptoms and slow progression of disease
  mortality and incidence of hospitalization
Angiotensin II receptor blockers
 As effective as ACE inhibitors

168. Indications:
ACE inhibitors may be considered for single-agent therapy
in patients who present with mild dyspnea on exertion
and do not show signs or symptoms of volume overload.
ACE inhibitors are useful in decreasing HF in asymptomatic
patients with an ejection fraction of less than 35 percent
(left ventricular dysfunction).
Patients who have had a recent myocardial infarction also
benefit from long-term ACE inhibitor therapy.
Early use of ACE inhibitors is indicated in patients with all
stages of left ventricular failure, with and without
symptoms, and therapy should be initiated immediately
after myocardial infarction.

169. Pharmacokinetics:
• All ACE inhibitors are adequately but incompletely absorbed
following oral administration.
• The presence of food may decrease absorption, so they
should be taken on an empty stomach.
• Except for captopril , ACE inhibitors are prodrugs that
require activation by hydrolysis via hepatic enzymes.
• Renal elimination of the active moiety is important for most
ACE inhibitors, an exception being fosinopril.
• Plasma half-lives of active compounds vary from 2 to 12
hours, although inhibition of ACE may be much longer.
• The newer compounds such as ramipril and fosinopril
require only once-a-day dosing.

170. Adverse effects:
These include postural hypotension, renal
insufficiency, hyperkalemia, angioedema, and
a persistent dry cough.
The potential for symptomatic hypotension
with ACE inhibitor therapy requires careful
monitoring.
ACE inhibitors should not be used in pregnant
women, because they are fetotoxic.

171. Angiotensin-receptor blockers:
Angiotensin-receptor blockers (ARBs) are nonpeptide, orally
active compounds that are extremely potent competitive
antagonists of the angiotensin type 1 receptor.
Losartan is the prototype drug.
ARBs have the advantage of more complete blockade of
angiotensin action, because ACE inhibitors inhibit only one
enzyme responsible for the production of angiotensin II.
Further, the ARBs do not affect bradykinin levels.
Although ARBs have actions similar to those of ACE inhibitors,
they are not therapeutically identical.
Even so, ARBs are a substitute for ACE inhibitors in those
patients who cannot tolerate the latter.

172. Actions on the cardiovascular system:
• All the ARBs are approved for treatment of
hypertension based on their clinical efficacy in
lowering blood pressure and reducing the
morbidity and mortality associated with
hypertension.
• As indicated above, their use in HF is as a
substitute for ACE inhibitors in those patients
with severe cough or angioedema

173. Pharmacokinetics:
All the drugs are orally active and require only once-a-day
dosing.
Losartan, the first approved member of the class, differs
from the others in that it undergoes extensive first-pass
hepatic metabolism, including conversion to its active
metabolite.
The other drugs have inactive metabolites.
Elimination of metabolites and parent compounds occurs in
the urine and feces; the proportion is dependent on the
individual drug.
All are highly plasma protein bound (greater than 90
percent) and, except for candesartan, have large volumes
of distribution.
Adverse effects: ARBs have an adverse effect profile similar to
that of ACE inhibitors.
However, ARBs do not produce cough.
ARBs are contraindicated in pregnancy.

174. Vasodilators
 Oral – Hydralazine, Isosorbide dinitrate
 Parenteral – Sodium nitroprusside, Nitroglycerine

175. Current recommendation for treatment of HF
1. Patients with evidence of fluid retention
Diuretics
Salt and fluid restriction
2. ACE inhibitors & β blockers
For initial & maintenance treatment
3. Digoxin to reduce symptoms & to slow ventricular
response to atrial fibrillation
 NB: in patients with severe HF – avoid β blockers
 Angiotensin II receptor blockers may be used in
patients intolerant to ACE inhibitors
 Spironolactone – decreases mortality in patients
with severe CHF.