2. Objectives
• Discuss properties of commonly used diuretics and their indications.
• Discuss the different treatment approaches of Hypertension
• Describe etiology & Causes of Heart Failure
• Discuss the Basic Pharmacology Of Drugs Used In Heart Failure
• Discuss about the pathophysiology of angina
• Describe the determinants of myocardial oxygen demand
• Discuss about the managements of angina
4. Renal Pharmacology
The main function of the kidney is:
The excretion of waste products such as urea, uric
acid and creatinine .
Regulate ABP by controlling blood volume and RAAS
Regulate RBC formation by producing erythropoeitin
The regulation of the salt, electrolyte and the volume
of the extracellular fluid.
Play a part in acid – base balance.
5. Renal Pharmacology
The functional units of the kidney is the nephron: The
nephron consist of:
• Glomerulus.
• Proximal convoluted tubule
• Loop of Henle; Play an important part in regulating
osmolarity of the urine and osmolarity of the body.
• Distal tubule
• Collecting duct
6. Renal Pharmacology
Diuretics:
• Increase output of urine
• Primary indications are hypertension and mobilization of
edematous fluid
Basic mechanism:
• Block reabsorption of sodium and chloride => water will
also stay in the nephron
• Diuretics that work on the earlier nephron have greatest
effect, since they are able to block more sodium and
chloride reabsorption
7. Renal Pharmacology
Diuretics:
Carbonic anhydrase inhibitors:
• Acetazolamide
carbonic anhydrase catalyzes formation of HCO3
-
and H+ from H2O and CO2
– Increased HCO3
- excretion causes metabolic
acidosis(Not in use as diuretic anymore)
– inhibition of carbonic anhydrase decreases [H+]
in tubule lumen
– less H+ for Na+/H+ exchange
– Increased lumen Na+, increased H2O retention
– Primary indications is glaucoma
– Aqueous humor has high [HCO3
-]
• Dorzolamide
CA-inhibitors => cross-allergenic with antibiotics
(sulfonamides) etc.
8. Renal Pharmacology
Diuretics:
• Loop diuretics (= high ceiling diuretics):
– inhibits reabsorption of ~25% of glomerular
filtrate
– Used for moderate to severe fluid retention
and hypertension
– Most potent diuretics available
– Act by inhibiting the Na+/K+/2Cl- symporter
in the ascending limb in the loop of Henle
Drug interaction: hypokalemia potentiates
digitalis toxicity
Major side effects: loss of K+(and Ca++ andMg++)
,dehydration leading to hypotension and dose-
related hearing loss (ototoxicity).
• Furosemide
• Bumetanide
9. Renal Pharmacology
Thiazide diuretics:
– Used for mild to moderate
hypertension, mild heart failure
– Medium potency diuretics
– Act by inhibiting the Na+/Cl symporter
in the distal convoluted tube
• – Major side effects: Hyponatremia,
hypokalemia and dehydration leading
to hypotension
– Drug interaction: hypokalemia
potentiates digitalis
toxicitynteractionsInteract
• Hydrochlorothiazide, Benzthiazide
Cyclothiazide
10. Renal Pharmacology
Diuretics:
Potassium-sparing diuretics:
• Prevent K + secretion by antagonizing
the effects of aldosterone in collecting
tubules.
– Aldosterone promotes reabsorption of
Na+ in exchange for K+
(transcriptionally upregulates the
Na+/K+ pump and sodium channels)
Drug interaction: ACE inhibitors(potentiate
hyperkalemia)
Spironolactone
– Aldosterone receptor antagonist
– Onset of action requires several days
• Amiloride; Trimterene
– Block sodium channels
– Quick onset
11. Renal Pharmacology
Diuretics:
Osmotic diuretics:
– Small, non-reabsorbable molecules that inhibit passive
reabsorption of water
– Predominantly increase water excretion without
significantly increasing Na+ excretion => limited use
– increases osmotic pressure specifically in the proximal
tubule and loop of Henle
• Mannitol(Prototype)
• Urea
• Glycerol
• Isosorbide
– Only given IV
13. Introduction
• Hypertension is a persistently elevated arterial blood pressure (BP).
• Arterial BP is the pressure in the arterial wall measured in
millimeters of mercury (mm Hg).
• The two typical arterial BP values are systolic BP (SBP) and
diastolic BP (DBP).
• SBP is achieved during cardiac contraction and represents the peak
value.
• DBP is achieved after contraction when the cardiac chambers are
filling, and represents the nadir value.
14. Etiology
• In most patients, hypertension results from an unknown
pathophysiologic etiology (essential or primary hypertension).
• More than 90% of individuals with hypertension have essential
hypertension.
• This form of HTN cannot be cured, but it can be controlled.
• Hypertension is a heterogeneous disorder that may result either
from a specific cause (secondary hypertension)
15. Etiology
• Secondary hypertension accounts for fewer than
10% of cases, and most of these are caused by
chronic kidney disease or renovascular disease.
• If the cause can be identified, hypertension in these
patients has the potential to be cured.
17. Renin-angiotensin-aldosteron system
• Important role in regulating blood volume, arterial pressure, and
cardiac and vascular function.
• Most important site for renin release is the kidney: sympathetic
stimulation (acting via β1-adrenoceptors), renal artery
hypotension (e.g.stenosis), and decreased sodium delivery to the
distal tubules stimulate the release of renin by the kidney.
• Renin acts upon a circulating substrate,angiotensinogen which
undergoes proteolytic cleavage to form the angiotensin I (AT I).
• Vascular endothelium, particularly in the lungs, contains
angiotensin converting enzyme (ACE),which cleaves off two
amino acids to form the angiotensin II (AT II).
18. Renin-angiotensin –aldosteron system
Angiotensin II
• Constricts vessels thereby increasing vascularresistance and arterial
pressure
• Stimulates the adrenal cortex to release aldosterone, which acts upon
the kidneys to increase sodium and fluid retention
• Stimulates the release of vasopressin (ADH) from the pituitary which
acts upon the kidneys to increase fluid retention
• Facilitates NE release and inhibits reuptake from nerve endings,
thereby enhancing sympathetic adrenergic function
• Stimulates cardiac and vascular hypertrophy
20. Risk factors
• Age (≥ 55 years for men and 65 years for women)
• Diabetes mellitus
• Dyslipidemia (elevated low-density lipoprotein-cholesterol,
total cholesterol, and/or triglycerides; low
highdensitylipoprotein-cholesterol)
• Family history of premature CV disease
• Obesity (body mass index ≥30 kg/m2)
• Physical inactivity
• Tobacco use
21. Management of HTN
• There are 2 treatment approaches:
1.Non pharmacological
2.Pharmacological
22. Life style modification
1) Weight reduction
.For every 10kg lost, SBP ↓ by 5-20mmHg
.Even small amount has impressive consequences
2) Exercise
.Even without weight loss ,it lowers incidence of HTN &
protects against CV disease
.30 min of aerobic activity >3 X /week
SBP ↓ by 4 – 9mmHg
23. Life style modification
3)Dietary changes
Sodium- No more than 100mmol/d
2.4g Na=6gm of NaCl
- ↓SBP by 2-8mmHg
- Diet rich in vegetables & fruits
.Low fat dairy product with less saturated & total fat
4) Moderation of alcohol
5) Avoidance of tobacco
.sympathetic outflow ↑es with each cigarette—arterial
stiffness
24. Classification of antihypertensive agents
• The categories include the following:
(1) Diuretics, which lower blood pressure by depleting the body
of sodium and reducing blood volume.
(2) Sympathoplegic agents, which lower blood pressure by
reducing peripheral vascular resistance, inhibiting cardiac
function
(3) Direct vasodilators, which reduce pressure by relaxing
vascular smooth muscle.
(4) Agents that block production or action of angiotensin and
thereby reduce peripheral vascular resistance and
(potentially) blood volume.
26. Diuretics
Thiazides:
• Chlorthalidone
• Hydrochlorothiazide
• Indapamide
• Dose in the morning to avoid nocturnal diuresis.
• hydrochlorothiazide and chlorthalidone are generally
preferred, with25 mg/day generally considered the
maximum effective dose
• chlorthalidone is nearly twice as potent as
hydrochlorothiazide; have additional benefits in
osteoporosis.
27. Mechanisms of Action Thiazides Diuretics
• Thiazides inhibit NaCl reabsorption from the luminal
side of epithelial cells in the DCT by blocking the
Na+/Cl– transporter (NCC).
• Thiazides actually enhance Ca2+ reabsorption.
Loop diuretics
• Bumetanide
• Furosemide
• Torsemide
• Dose in the morning and afternoon to avoid nocturnal
diuresis
28. Potassium sparing diuretics
Sodium channel blockers
• Amiloride
• Triamterene
• Dose in the morning or afternoon to avoid
nocturnaldiuresis
Aldosterone antagonists
• Eplerenone
• Spironolactone
• Spironolactone
• Dose in the morning or afternoon to avoid
nocturnaldiuresis.
29. ACE inhibitors
• The ACE inhibitors are one of the first choice drugs in all
grades of essential as well as renovascular hypertension
• Benazepril
• Captopril
• Enalapril
• Fosinopril
• Lisinopril
• Moexipril
• Perindopril
• Quinapril
• Ramipril
• Trandolapril
30. ACE inhibitors…
Mechanism of action
• ACE facilitates production of angiotensin II, which has a major
role in regulating arterial blood pressure.
• ACE principal location is in endothelial cells.
• ACE inhibitors block the conversion of angiotensin I to
angiotensin II, a potent vasoconstrictor and stimulator of
aldosterone secretion.
• ACE inhibitors also block the degradation of bradykinin and
stimulate the synthesis of other vasodilating substances
including prostaglandin E2 and prostacyclin.
• The common adverse effects are dry cough and angioedema.
31. Angiotensin II Receptor Blockers
• Candesartan
• Eprosartan
• Irbesartan
• Losartan
• Olmesartan
• Telmisartan
• Valsartan
• May cause hyperkalemia in patients with chronic kidney disease
or in those receiving potassium-sparing diuretics, aldosterone
antagonists, ACE inhibitors, or direct renin inhibitor
• Do not cause a dry cough and angioedema like ACE inhibitors ;
do not use in pregnancy
32. Angiotensin II Receptor Blockers…
Mechanism of action
• Angiotensin II is generated by the renin-angiotensin pathway
(which involves ACE) and an alternative pathway that uses
other enzymes such as chymases.
• ACE inhibitors block only the renin-angiotensin pathway,
whereas ARBs antagonize angiotensin II generated by either
pathway.
• The ARBs directly block the angiotensin type 1 (AT1) receptor
33. Angiotensin II Receptor Blockers…
• Unlike ACE inhibitors, ARBs do not block the breakdown of
bradykinin.
• While this accounts for the lack of cough as a side effect,
there may be negative consequences because some of the
antihypertensive effect of ACE inhibitors may be due to
increased levels of bradykinin.
34. Adverse effects
• Cough is very uncommon.
• Renal insufficiency,
• Hyperkalemia,
• Orthostatic hypotension.
• Angioedema is less likely to occur than with ACE inhibitors,
• ARBs should not be used in pregnancy.
35. Calcium channels blockers
• The dihydropyridines (DHPs) are the most potent Ca2* channel
blockers.
Mechanism of action of calcium channel blockers
• The common property of all CCBs is to inhibit Ca2* mediated
slow channel component of action potential (AP) in
smooth/cardiac muscle cell.
• The two most important actions of CCBs are:
– Smooth muscle (especially vascular) relaxation.
– Negative chronotropic, inotropic and dromotropic action on
heart.
36. Calcium channels blockers…
Dihydropyridines:
• Amlodipine
• Nicardipine SR
• Nifedipine long-acting
• Nisoldipine
Adverse effects
• More reflex sympathetic discharge (tachycardia),
dizziness, headache, flushing, and peripheral edema;
have additional benefits in Raynaud’s syndrome
37. Calcium channels blockers…
Non-dihydropyridines:
• Diltiazem
• Verapamil
Adverse effects
• Patients receiving β-blocking drugs are more sensitive to the
cardiodepressant effects of calcium channel blockers.
• dizziness, headache, flushing, and peripheral edema.
• Constipation is particularly common with verapamil
38. Clinical uses
• Hypertension
• Cardiac arrhythmias
• Hypertrophic cardiomyopathy
• Nifedipine is an altenative drug for premature labour
• Myocardial infarction
• Angina pectoris
40. Alpha1-adrenergic antagonists
Mechanism:
– Blocking alpha-1 receptors: doxazosin, prazosin, and terazosin
Therapeutic Uses of Alpha Adrenergic Receptor Blockers
1/Pheochromocytoma
• useful in the preoperative management of patients with
pheochromocytoma
2/Hypertension
3/ treatment of peripheral vasospastic disease ie Raynauds disease to
improve perfusion
4/ Treatment of local excess concentration of a vasoconstrictor in order
to prevent necrosis.
5/ Urinary Obstruction: BPH
• improving urine flow
• partial reversal of smooth muscle contraction in the enlarged
prostate and in the bladder base.
42. Centrally acting hypotensive drugs(a2 - selective agonists)
a2 - selective agonists
Activate presynaptic a2 receptors in the cardiovascular control
center in the CNS => reduced sympathetic nervous system
activity => blood pressure decrease
α2 stimulation leads to decrease Norepinephrine release In
adrenergic nerve terminals (presynaptic).
Clinical applications:
Hypertension
• Clonidine
• Guanfacine
• Methyldopa
43. Clonidine
• It is α2 – selective agonist
• However, this is sympatholytic agent,
used in treatment of hypertension
– It acts centrally at presynaptic α2-adrenoceptor.
This leads to decrease in NE release and to
decrease in PVR.
• Overdose stimulates peripheral postsynaptic α1
adrenoceptors & cause hypertension by
vasoconstriction
44. Clonidine
Adverse effects
• Sedation, depression
• Sexual dysfunction
• Bradycardia
• Withdrawal syndrome (rebound hypertension) follows abrupt
discontinuation of long-term therapy with clonidine in some
hypertensive patients.
Methyldopa
• Centrally acting antihypertensive agent.
• metabolized to α-methylnorepinephrine in the brain
– activate central α2 receptors and lower blood pressure in a
manner similar to that of clonidine.
• Safe and preferable anti-hypertensive agent during pregnancy
45. Clinical Uses
• The primary indication: mild and moderate hypertension
– that has not responded adequately to treatment with a
diuretic or a1-blockers.
• For severely hypertensive patients, clonidine has been used in
combination with a diuretic, a vasodilator, and alpha1-blocker.
46. β- blockers
• Selective beta 1 blockers decrease cardiac output through
negative chronotropic and inotropic effects on the heart and
inhibition of renin release from the kidney.
Cardioselective beta blockers
• Atenolol
• Betaxolol
• Bisoprolol
• Metoprolol tartrate
• Metoprolol succinate
• They are less likely to provoke bronchospasm and
vasoconstriction and may be safer than nonselective β blockers in
patients with asthma, chronic obstructive pulmonary disease
(COPD),diabetes, and peripheral arterial disease.
• Abrupt discontinuation may cause re-bound hypertension
47. β-Blockers
Nonselective:
• Nadolol
• Propranolol
• Timolol (Blocadren)
• Abrupt discontinuation may cause rebound
hypertension;
• Inhibit β1- and β2-receptors at all doses(can
exacerbate asthma…)
• Have additional benefits in patients with tremor,
migraine headache, thyrotoxicosis
48. Β and α-Blockers
Mixed α- and β-blockers:
• Carvedilol
• Carvedilol phosphate
• Labetalol
• Abrupt discontinuation may cause rebound hypertension
• Additional α-blockade produces more orthostatic hypotension
50. Adverse effects of beta blockers
• Bradycardia
• Atrioventricular (AV) conduction abnormalities
• Acute heart failure.
• Acute exacerbations of bronchospasm in patients with asthma
or COPD.
• Cold extremities
• Raynaud's phenomenon because of decreased peripheral
blood flow.
51. Vasodilators
• Vasodilators produce a direct relaxation of vascular smooth
muscle and thereby result in vasodilation.
• The vasodilators decrease total peripheral resistance and thus
correct the hemodynamic abnormality that is responsible for
the elevated blood pressure in primary hypertension.
• In addition, because they act directly on vascular smooth
muscle, the vasodilators are effective in lowering blood
pressure, regardless of the etiology of the hypertension
52. Vasodilators: Classes
• Arterial vasodilators
– Minoxidil, Diazoxide: Potassium Channel Openers
– Hydralazine
Hydralazine
• The vasodilation depends in part on the presence of an intact
blood vessel endothelium.
– This implies that hydralazine causes the release of nitric oxide, which
acts on the vascular smooth muscle to cause relaxation.
• Arterial and venous dilators:
– Sodium nitroprusside: Releases NO
53. Clinical Uses
• Hydralazine is generally reserved for moderately hypertensive
ambulatory patients
– whose blood pressure is not well controlled either by diuretics or
– by drugs that interfere with the sympathetic nervous system.
• It is almost always administered in combination with
– a diuretic and beta-blocker
Adverse Effects
headache, flushing, nasal congestion and tachycardia.
54. Minoxidil
• Minoxidil (Loniten) is an orally effective vasodilator.
• It is more potent and longer acting than hydralazine
• It depends on in vivo metabolism by hepatic enzymes to
produce an active metabolite, minoxidil sulfate.
• Minoxidil sulfate activates potassium channels,
– resulting in hyperpolarization of vascular smooth muscle and
relaxation of the blood vessel.
55. Clinical Uses
• Severe hypertension that may be life threatening and
• hypertension that is resistant to milder forms of therapy.
Adverse Effects
• include headache, nasal congestion and tachycardia.
56. Diazoxide
• Diazoxide is chemically similar to the thiazide diuretics.
– But devoid of diuretic activity.
• Diazoxide is a very potent vasodilator and is available only for
intravenous use in the treatment of hypertensive
emergencies.
• The mechanism by which diazoxide relaxes vascular smooth
muscle is related to its ability to
– activate potassium channels and produce a hyperpolarization of the
cell membrane
57. Clinical Uses
• Diazoxide is administered intravenously for the treatment of
hypertensive emergencies
• particularly
– malignant hypertension,
– hypertensive encephalopathy, and
– eclampsia.
• It is effective in 75 to 85% of the patients to whom it is
administered and rarely reduces blood pressure below the
normotensive range.
58. Adverse Effects
• The chief concern is the side effects associated with the
increased workload on the heart,
– which may precipitate myocardial ischemia
• may stop labor, because it relaxes uterine smooth muscle.
59. Arterial and venous vasodilators: Sodium
Nitroprusside
• Sodium nitroprusside is a potent directly acting vasodilator
– capable of reducing blood pressure in all patients, regardless of the cause
of hypertension.
• It is used only by the intravenous route
– for the treatment of hypertensive emergencies.
• The actions of the drug are similar to those of the nitrites and
nitrates that are used as antianginal agents.
– depends on the intracellular production of cGMP.
60. Clinical Uses
• Sodium nitroprusside is used in the management of
hypertensive crisis.
• Because the drug reduces preload and afterload,
– it improves ventricular performance and in fact is
sometimes used in patients with refractory heart
failure, even in the absence of hypertension.
61. Ganglionic blocking agents
• The basis for these agents lies in their ability to block
transmission through autonomic ganglia.
– results in a decrease in impulses passing down the
postganglionic sympathetic (and parasympathetic) nerves,
decreases vascular tone, cardiac output, and BP.
• The ganglionic blocking agents are extremely potent
antihypertensive agents and
• can reduce BP regardless of the extent of hypertension.
62. Ganglionic blocking agents…
Unfortunately,the ganglionic blocking agents are rarely
used.
• They produces numerous untoward severe responses,
– including marked postural hypotension, blurred vision, and
dryness of mouth, constipation, paralytic ileus, urinary
retention, and impotence.
• Certain intravenous preparations,
– such as the short-acting agent trimethaphan camsylate,
– are used occasionally for hypertensive emergencies and
– in surgical procedures in which hypotension is desirable to
reduce the possibility of hemorrhage.
64. Definition :HF
• Inability of the heart to pump an adequate amount of blood
to the body’s needs
• CONGESTIVE HEART FAILURE – refers to the state in which
abnormal circulatory congestion exists as result of heart
failure
9/2/2023 Pharmacology of heart failure by Fantu.K
65. Etiology of HF
• HF results from any disorder which prevents:
– The heart from contracting (Systolic Dysfunction)
and/or
– The ventricles from relaxing and filling with blood
(Diastolic Dysfunction)
• Systolic dysfunction is more prevalent
• Systolic and diastolic dysfunction may coexist
9/2/2023 Pharmacology of heart failure by Fantu.K
66. Causes of Heart Failure
• Systolic Dysfunction
– Reduction in muscle mass e.g. MI
• Leads to systolic contractile dysfunction
– Ventricular hypertrophy
• pressure overload
• volume overload
• Diastolic Dysfunction
– Myocardial infarction may slow ventricular
relaxation and increase ventricular stiffness
– Ventricular hypertrophy
9/2/2023 Pharmacology of heart failure by Fantu.K
67. Normal Heart Function
• What is Cardiac Output (CO)?
– Volume of blood ejected per unit time.
– CO = Heart Rate X Stroke Volume
• SV dependent upon:
– Preload: SV increase with ↑ in preload
– Afterload: SV decrease with ↑ in afterload
– Contractility
9/2/2023 Pharmacology of heart failure by Fantu.K
68. Pathophysiology: Compensatory Mechanisms
• Sympathetic Nervous System (SNS) Activation
– Tachycardia and increased contractility
• Increased preload by activating renin-
angiotensin-aldosterone system (RAAS)
– Na and water retention
• Vasoconstriction
– Helps shunt blood away from non-essential organs
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69. 9/2/2023 Pharmacology of heart failure by Fantu.K
Factors that precipitate HF
Factor Mechanism Therapeutic Strategy
1. Preload (work or stress
the heart faces at the end of
diastole)
increased blood volume and
increased venous tone---
>atrial filling pressure
-salt restriction
-diuretic therapy
-venodilator drugs
2. Afterload (resistance
against which the heart must
pump)
increased sympathetic
stimulation & activation of
renin-angiotensin system ---
> vascular resistance --->
increased BP
- arteriolar vasodilators
-decreased angiotensin II
(ACE inhibitors)
3. Contractility decreased myocardial
contractility ---> decreased
CO
-inotropic drugs (cardiac
glycosides)
71. Clinical Presentation of HF
• Left-sided failure
– Blood not effectively pumped from the left
ventricle to the peripheral circulation
• Right-sided failure
– Blood not effectively pumped from the right
ventricle into the lungs
9/2/2023 Pharmacology of heart failure by Fantu.K
72. Signs and Symptoms of HF
• Symptoms:
–Dyspnea
–Orthopnea
–Tachypnea
–Fatigue
–Cough
–Exercise intolerance
–Peripheral edema and ascites
• Signs:
•Pulmonary edema
•Cardiomegaly
9/2/2023 Pharmacology of heart failure by Fantu.K
73. Classifying and Categorizing the HF Patient
• 1. Functional Classification
New York Heart Association Functional Classification
• Class I No limitation of physical activity
• Class II Slight limitation of physical activity
• Class III Marked limitation of physical activity
• Class IV Unable to carry on any physical activity
w/o discomfort
9/2/2023 Pharmacology of heart failure by Fantu.K
74. basic pharmacology of drugs used in congestive heart
failure:
ACE inhibitors for HF
• Decrease the combined risk of death and hospitalizations
– Many trials have documented reductions in mortality of
25%
• Benefits are observed in mild, moderate or severe HF
• All patients with LV dysfunction should receive an ACE I (unless
intolerant)
– Symptomatic improvement may take several weeks.
– By reducing circulating angiotensin II levels, ACE inhibitors
also decrease the secretion of aldosterone, resulting in
decreased sodium and water retention
9/2/2023 Pharmacology of heart failure by Fantu.K
75. ACE inhibitors for HF
• ACE Inhibitors approved for the treatment of HF
• –captopril: Capoten®
• –enalapril: Vasotec ®
• –lisinopril: Zestril ®, Prinivil ®
• –quinapril: Accupril ®
• –fosinopril: Monopril ®
• –ramipril: Altace ®
• -- randolapril: Mavik ®
9/2/2023 Pharmacology of heart failure by Fantu.K
76. Beta Blockers for HF
• Best studied beta blockers in HF are carvedilol, metoprolol
extended/controlled release and bisoprolol:
• Benefits of beta-blockers in HF:
– Decrease combined risk of death or hospitalization
• Symptomatic improvement may occur after several months.
9/2/2023 Pharmacology of heart failure by Fantu.K
77. Diuretics for HF
• Na & fluid restriction is important.
• Loops are strong diuretics even with decreased renal function.
– Available loop diuretics:
• 1. furosemide , 2. bumetanide , 3. torsemide , 4.
ethacrynic acid
• Initiation of diuretic therapy
– Initiate therapy with low doses of diuretic (i.e. lasix 20-40
mg/day) and increase dose until patient maintains stable
dry weight without dyspnea
9/2/2023 Pharmacology of heart failure by Fantu.K
78. 9/2/2023 Pharmacology of heart failure by Fantu.K
Clinical uses:
Treatment of edematous states (CHF & ascites)
Sometimes used in hypertension if response to
thiazide is inadequate but their short duration of
action is a disadvantage
Hyperkalemia
79. Vasodilators
• Initiating Dose Maximal Dose
• Nitroglycerin 20 g/min 40–400 g/min
• Nitroprusside 10 g/min. 30–350 g/min
• After diuretics, intravenous vasodilators are the most useful
medications for the management of acute HF.
Nitroglycerin & nitroprusside do have dilating effects on
arteries and veins.
results in a lowering of LV filling pressure, a reduction in mitral
regurgitation, and improved forward cardiac output, without
increasing heart rate or causing arrhythmias.
9/2/2023 Pharmacology of heart failure by Fantu.K
81. 9/2/2023 Pharmacology of heart failure by Fantu.K
DIGITALIS
PHARMACOKINETICS:
DIGOXIN DIGITOXIN
LIPID SOLUBILITY MEDIUM HIGH
ORAL BIOAVAILABILITY 75% >90%
HALF-LIFE 40 HRS 168 HRS
PLASMA PROTEIN BINDING 20-40 HRS >90 HRS
82. 9/2/2023 Pharmacology of heart failure by Fantu.K
PHARMACOKINETICS:
*digitalis must be present in the body in certain "saturating" amount
before any effect on congestive failure is noted .
This is achieved by giving a large initial dose in a process called
"digitalization“ -after intial dosages, digitalis is given in
"maintenance" amounts sufficient to replace that which is excreted
to avoid exceeding therapeutic range during digitalization:
- slow digitalization (over 1 week) is the safest technique
- plasma digoxin levels should be monitored
83. 9/2/2023 Pharmacology of heart failure by Fantu.K
MECHANISM OF ACTION
Inhibit Na+, K+ ATPase & increased intracellular Na+
content increases intracellular Ca2+ through a Na+ -
Ca2+ exchange carrier mechanism.
Increased myocardial uptake of Ca2+ augments Ca2+
release to the myofilaments during excitation invokes
a positive inotropic response
85. 9/2/2023 Pharmacology of heart failure by Fantu.K
EFFECTS IN HEART FAILURE
Stimulates myocardial contractility
Improves ventricular emptying
Increase cardiac output
86. 9/2/2023 Pharmacology of heart failure by Fantu.K
Positive inotropic drugs
-Adrenoceptor agonists
They are used intravenously in CHF emergencies
Example of -Adrenoceptor agonists :
Dobutamine
Exciting β1 Adrenoceptor → positive inotropic action →the
volume of output↑
Exciting β2 Adrenoceptor→dilate the vascular →
afterload↓
have benefits within short time
87. Aldosterone Antagonists for HF
Agents: spironolactone and eplerenone
Aldosterone is a neurohormone that plays a role in
sodium and water retention.
Dose; Spironolactone 12.5–25 mg qd 25–50 mg qd ;
Eplerenone 25 mg qd 50 mg qd;
ACEI or ARBS may not totally suppress aldosterone,
therefore aldosterone antagonist needed
9/2/2023 Pharmacology of heart failure by Fantu.K
88. • Monitoring parameters: Potassium within 1 week of
treatment.
• Gynecomastia (Not with eplerenone)
9/2/2023 Pharmacology of heart failure by Fantu.K
Aldosterone Antagonists…….
89. Angiotensin Receptor Blockers (ARBs)
for HF
• ARBs considered in patients intolerant to ACEIs
• Potential role of ARBs as adjunct therapy
9/2/2023 Pharmacology of heart failure by Fantu.K
91. Definition
Angina pectoris – is chest pain due to ischemia of the
heart muscle, generally due to obstruction or spasm of
the coronary arteries.
The main cause of Angina pectoris is Coronary Artery
Disease, due to atherosclerosis of the arteries feeding
the heart.
Ischemia may be defined as lack of oxygen and
decreased blood flow in the myocardium.
Antianginal drugs − are those that prevent or terminate
attacks of angina pectoris.
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93. Pathophysiology of ischemic heart disease
Angina pectoris is caused by transient episodes of
myocardial ischemia due to an imbalance in myocardial
oxygen supply and demand that may result from
− increase in myocardial oxygen
demand or,
− a decrease in myocardial oxygen supply, or
− sometimes from both.
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94. Pathophysiology of ischemic heart disease
All approved antianginal agents used in the
treatment of angina such as nitrovasodilators, beta
adrenergic receptor antagonists, Ca2+ channel
antagonists, and antiplatelet agents improve the
balance of myocardial oxygen supply and demand,
1. by dilating the coronary vasculature or
2. by reducing cardiac work
94
96. Grading of angina pectoris according to Canadian
cardiovascular society classification
Class I – Oridinary physical activity does not cause
angina. Angina occurs with rapid and
prolonged exertion at work or recreation
Class II – Slight limitation of ordinary activity. Angina
occurs on walking or climbing stair rapidly,
walking up hill or walking or climbing a stair
after meal
96
97. Grading of angina pectoris according to Canadian
cardiovascular society classification
Class III − Marked limitation of ordinary physical
activity. Angina occurs on walking one
to two blocks on level or climbing one
flight of stairs under normal
conditions and at a normal pace.
Class IV − Inability to carry on any physical
activity with out discomfort.
“ Angina symptoms may be present at
rest. ”
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99. Major risk factors
• Age (≥ 55 years for men, ≥ 65 for women)
• Cigarette smoking
• Diabetes mellitus (DM)
• Dyslipidemia
• Family history of premature cardiovascular disease
(men <55 years, female <65 years old)
• Hypertension (HTN)
• Kidney disease (microalbuminuria or GFR<60
mL/min)
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101. Types of Angina
• Angina occurs in three
overlapping patterns:
– Stable angina
– Unstable angina
– Prinzmetal (variant)
angina
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102. Stable Angina
Attacks are predictably
provoked by exercise,
emotion, eating or
coitus and subside when
the increased energy
demand is withdrawn.
The underlying
pathology is-severe
arteriosclerotic
affliction of larger
coronary arteries .
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103. Stable Angina
• Angina indicates that myocardial oxygen demand is
exceeding supply.
• “Stable” indicates the reproducible nature of the
angina; the same activity at the same intensity
faithfully produces symptoms.
• Typically this type of angina is relieved by rest or
acute use of nitroglycerin
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104. Unstable Angina
• Unstable angina occurs
when anginal symptoms
occur with less cardiac
demand.
• This is characterized by
Pain that occurs with
less excertion ,
cumulating pain at rest.
• Characterized by
worsening of a patient’s
anginal symptoms.
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105. Unstable Angina
• Unstable angina with rapid increase in duration and
severity of attacks is mostly due to rupture of an
atheromatous plaque
• Atheromatous plaque attract platelet deposition and
progressive occlusion of the coronary artery;
occasionally with associated coronary vasospasm.
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106. Prinzmetal (Variant) Angina
• It is induced by coronary artery vasospasm it
generally responds promptly to vasodilators.
• PVA has been associated with other vasospastic
disorders such as migraine headaches and Raynaud’s
phenomena.
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107. Prinzmetal (Variant) Angina
• Endothelial dysfunction has been considered as
primarily responsible for PVA.
• Attacks occur at rest or during sleep and are
unpredictable.
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109. Nitrates
Mechanism of Action
Nitrates decrease myocardial oxygen demand:
1. The primary effect is a reduction in venous tone which
results in venous pooling decreasing venous return
(decreased preload).
2. Arteriolar tone is less effectively reduced resulting in a
decrease in PVR (decreased afterload ) and decreased
blood pressure.
3. #s 1 & 2 decrease myocardial wall stress reducing O2
demand.
4. Dilation of coronary vessels or exerts a ~minor effect
on increasing O2 supply.
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110. Adverse effects
1. The most common side effect of nitrates is headache.
2. Postural hypotension & syncope particularly with
sublingual use.
3. Tachycardia induced by decreased PVR may itself
induce anginal symptoms especially with unstable
symptoms.
Tolerance
• Sustained treatment with nitroglycerin in vivo is
associated with reduced biotransformation of nitrate to
NO by endothelial mitochondrial enzyme aldehyde
dehydrogenase-2.
• Tolerance can be avoided by providing a “nitrate free”
interval daily;
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111. β-Blockers
• β-Blockers decrease O2 demands of the myocardium by
lowering the heart rate and contractility (decrease CO)
particularly the increased demand associated with exercise.
• They also reduce PVR by direct vasodilation of both
arterial & venous vessels reducing both pre- and after load.
These effects are caused by blocking β1 receptors.
111
112. β-Blockers
• Selective β1 antagonists (atenolol, metoprolol and
acebutolol) at higher dose cause bronchospasm.
• β1 antagonists reduce the frequency and severity of
anginal episodes particularly when used in combination
with nitrates.
• β-Blockers in combination with nitrtates can be quite
effective.
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113. Ca+2 Channel Blockers
• Ca+2 channel blockers protect tissue by inhibiting the
entrance of Ca+2 into cardiac and smooth muscle cells
of the coronary and systemic arterial beds.
• All Ca+2 channel blockers produce some vasodilation
(↓ PVR) and (-) inotropes.
• May exacerbate CHF .
• They are useful in Prinzmetal angina in conjunction
with nitrates.
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114. Ca+2 Channel Blockers
Agents
1. Nifedipine: This Ca+2 channel blocker works mainly
on the arteriolar vasculature decreasing after load
• It has minimal effect on conduction or HR.
• It is metabolized in the liver and excreted in both the
urine & the feces.
• It causes flushing, headache, hypotension and
peripheral edema.
• Constipation.
• A reflex tachycardia associated with the vasodilation.
Dose: 10–20 mg TID PO; may increase to 120 mg/d.
114
115. Ca+2 Channel Blockers
2. Verapamil: The agents has its main effect on cardiac
conduction decreasing HR and thereby O2 demand.
• It also has much more (-) inotropic effect than other
Ca+2 channel blockers.
• It is a weak vasodilator.
• It is metabolized in the liver.
Dose: 40-760 mg TID oral, 5 mg by slow iv injection
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116. Partial fatty acid oxidation inhibitors
Ranolazine
• Is newer antianginal drug approved by US-FDA for
treatment of chronic angina pectoris in patients who
fail to respond to standard antranginal therapy.
• Acts by partially inhibiting fatty acid oxidation in
the myocardium, thus shifting metabolism to
glucose which requires less oxygen to metabolize
• FDA advisory committee recommended use only in
refractory cases of angina until safety concerns
have been addressed.
Dose:0.5-7.0 g BID
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117. Combination therapy
When monotherapy is unable to provide adequate relief in
tolerated doses, concurrent use of 2 or 3 drugs may be tried.
I. B blocker + long-acting nitrate combination is rational in
classical angina because:
(a) Tachycardia due to nitrate is blocked by B
blocker.
(b) The tendency of B blocker to reduce total
coronary flow is opposed by nitrate.
II. Nitrates with CCB
• Nitrates primarily decrease preload, while CCBs have a
greater effect on afterload. Their concurrent use may decrease
cardiac work to an extent not possible with either drug alone.
• This combination may be especially valuable in severe
vasospastic angina.
117
118. Combination therapy
III. B blocker + Nitrate + CCB
• Nitrates primarily decrease preload.
• CCBs mainly reduce afterload + increase coronary
flow.
• B blockers decrease cardiac work primarily by direct
action on heart.
118
119. Interventional Approaches
1. percutaneous coronary intervention
• Percutaneous coronary intervention is a non-surgical
method used to open narrowed arteries that supply
heart muscle with blood (coronary arteries).
• Percutaneous means "through unbroken skin.“
• Percutaneous coronary intervention is performed by
inserting a catheter through the skin in the groin or
arm into an artery.
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120. Non pharmacological treatment
• At the leading tip of this catheter, several different
devices such as a balloon ,cutting device
(artherectomy device) can be deployed.
• The catheter and its devices are threaded through the
inside of the artery back into an area of coronary
artery narrowing or blockage.
120
121. Non pharmacological treatment
• Percutaneous coronary intervention can be used to
relieve or reduce
‒ angina,
‒ alleviate congestive heart failure, and
‒ allows some patients to avoid surgical treatment
(coronary artery bypass graft or CABG) that involves
extensive surgery and often long rehabilitation time.
121
122. Non pharmacological treatment
2. Coronary Artery Bypass Graft surgery
• Coronary artery bypass grafting (CABG) is a type of
surgery that improves blood flow to the heart.
• Surgeons use CABG to treat people who have severe
coronary heart disease (CHD) mainly due to
atherosclerosis.
• In people with atherosclerosis, Over time, plaque can
harden or rupture (break open).
122
123. Non pharmacological treatment
• Hardened plaque narrows the coronary arteries and
reduces the flow of oxygen-rich blood to the heart.
• This can cause chest pain or discomfort called angina.
• If the plaque ruptures, a blood clot can form on its
surface.
• A large blood clot can mostly or completely block
blood flow through a coronary artery.
• This is the most common cause of a heart attack.
123
124. Non pharmacological treatment
• CABG is one treatment for CHD.
• During CABG, a healthy artery or vein from the body
is connected, or grafted, to the blocked coronary
artery.
• The grafted artery or vein bypasses (that is, goes
around) the blocked portion of the coronary artery.
This creates a new path for oxygen-rich blood to flow
to the heart muscle.
• Surgeons can bypass multiple coronary arteries
during one surgery.
124
125. Coronary Artery Bypass Grafting
Figure A shows the location of the heart. Figure B shows how vein and
artery bypass grafts are attached to the heart.
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