Pharmacology Of Renal System

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 Introduction of Renal System
• 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 formed
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The Three Basic Renal Processes

Three basic processes:

1. Filtration
2. Reabsorption
3. Active Secretion.

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 INTRODUCTION TO DIURETICS
 Common terms
1. Diuretic : is an agent that increases urine volume
2. Natriuretic: is increase in renal sodium excretion
3. Aquaretic is increases excretion of solute-free water.
 Because natriuretics almost always also increase water
excretion, they are usually called diuretics.
 Osmotic diuretics and antidiuretic hormone antagonists
are aquaretics and are not directly natriuretic

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 Figure: the main site of nephron that the diuretic drug6
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Carbonic Anhydrase Inhibitor

 Acetazolamide
 Dichlorphenamide
 Methazolamide,
 Dorzolamide
• ↓ H+ formation inside
PCT cell
• ↓ Na+/H+ antiport
• ↑ Na+ and HCO3 in
lumen
• ↑ diuresis
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 Therapeutic uses
 Rarely used as diuretics
 Glaucoma: since the anterior chamber of the eye secretes sodium
chloride into the aqueous humor that requires carbonic anhydrase
activity
 Oral acetazolamide topical Dorzolamide and brinzolamide
 high-altitude illness or Mountain Sickness
 in rapidly ascend above 3000 m
 Nausea, headache, dizziness, insomnia, pulmonary edema, and
confusion)
 Related with induction of a metabolic acidosis
 Correcting Metabolic Alkalosis:
 Epleptic

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 Adverse Effect

 Drowsiness,
 Skin toxicity
 bone marrow toxicity
 Metabolic acidosis
 urinary alkalinization (Bicarbonaturia).

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 Osmotic Diuretics
 Mannitol, Urea, Glycerin,
Isosorbide
 Are hydrophilic,
 pharmacologialy inert
 Freely filtered through the
glomerulus &no reabsorption by
the renal tubule
 Act in proximal tubule and the
descending limb of Henle’s loop.
 Increase the osmolarity of tubular
fluid.
 Inhibits the osmosis of water into
the interstitial space
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 Clinical Indications :By increasing the osmotic pressure of
plasma, osmotic diuretics extract water from the eye and brain
 Mannitol is the commonly used Osmotic diuretics for the
treatmen
 Reduction of Intracranial Pressure : draws edematous fluid
from the brain into the blood
 Reduction of Intraocular Pressure: lower IOP by rendering
the plasma hyperosmotic with respect to intraocular fluids
 Enhancement of urinary excretion of : salicylates,
barbiturates, bromides, and lithium following overd

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 Thiazide Diuretics
 Inhibits the Na+/Cl−pump in the distal
convoluted tubule
 increasing sodium and water excretion.
 initially thiazide decreases extracellular volume
 Decrease in extracellular volume, lead to a
decrease in cardiac output and renal blood flow.
 On long-term therapy, the hypotensive effect is
due to decreased vascular resistance, but not on
CO ↓ed.
 On long-term therapy, the cardiac output returns
to pretreatment values, and extracellular volume
returns to almost normal due to compensatory
responses such as activation of the RAS
 Chlorothiazide &hydrochlorothiazide =thiazide-
diuretics
 Chlorthalidone, indapamide, and metolazone =
thiazide-like
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 Therapeutic Uses:
 Hypertension:
 Heart failure:
 Hypercalciuria: inhibit urinary Ca2+ excretion
 Used for osteoporosis treatments
 Diabetes insipidus: a unique ability to produce a hyperosmolar urine.
 increase proximal tubular water reabsorption & block the ability of the
DCT to form dilute urine.
 Thiazides can be utilized as a treatment for nephrogenic diabetes
insipidus.
 Edema associated with diseases of the:
 heart (CHF)
 liver (hepatic cirrhosis),
 kidney (nephrotic syndrome, chronic renal failure, and acute
glomerulonephritis)
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 The action of thiazides is limited in renal insufficiency
(CrCl <30 mL/min) due to the reduced secretion into
their site of action.
 Metolazone is an exception , which retains its potent
action in patients with renal dysfunction.
• Have low ceiling effect i.e. Natriuretic effect does
not increase with increase in dose

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 Adverse Effects
 Cause a side effect of hypokalemia
 Potassium-rich foods (e.g., dried fruit, bananas, potatoes,
and avocados
 insulin resistance(hyperglycemia): due to hypokalemia
 increases in LDL-C and triglycerides
 Hyperuricemia
 sexual dysfunction.
 Hypercalcemia:
 Hypomagnesemia with Symptoms
 muscle weakness, muscle tremor or twitching, mental
status changes, and cardiac arrhythmias
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 All are dose -dependent
 Loop diuretics
 inhibit the cotransport of Na+/K+/2Cl− in the luminal membrane in
the ascending limb of the loop of Henle & inhibit NaCl reabsorption
in the thick ascending limb (TAL).
 have the greatest diuretic effect among all the diuretics
 the ascending limb accounts for reabsorption of 25% to 30% of
filtered NaCl, and downstream sites are unable to compensate for
the increased Na+ load.
 The loop diuretics enhancing prostaglandin synthesis by inducing the
expression of the cyclooxygenase COX-2.
 increase the renal blood flow that contributes to their natriuretic
effect.
 can reduce the diuretic action of loop diuretics.
 NSAIDs an reduce the diuretic action of loop diuretics.
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 Furosemide, Torsemide, Bumetanide, and
Etha­crynic Acid
 are appropriate for
– severe hypertension
– sodium-retaining properties
– In renal insufficiency (GFR < 30 or 40 ml/min)
– In cardiac failure or cirrhosis
– hypercalcemia, hyperkalemia
– Anion Overdose(bromide, fluoride, and iodide)
– efficacy is superior to that of thiazides, potassium-
sparing diuretics, and aldosterone antagonists.

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 Situations in which, loop diuretics are preferable to
thiazides, including:
 malignant hypertension and volume-based hypertension
 chronic kidney disease (estimated GFR <30 ml / min
/1.73m2).
 left ventricular dysfunction
 severe edema
 Loop diuretics produce a more potent diuresis, but a
smaller decrease in PVR, and less vasodilation than
thiazide diuretics.
 thiazide is more effective at lowering BP than loop
diuretics in most patients.
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 Pharmacokinetics:
 Bound extensively to plasma proteins & filtration is limited
 Secreted efficiently by the organic acid transport system in the
proximal tubule
 Bumetanide and torsemide have significant hepatic metabolism
 65% of furosemide is excreted unchanged in urine & renal
disease prolong the t1/2.
 Bumetanide and torsemide have significant hepatic metabolism
 liver disease prolong the t1/2
 torsemide has a longer t 1/2 than other agents
 Oral bioavailability of furosemide varies (10%–100%).
 oral availabilities of bumetanide and torsemide are reliably
high.
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 Therapeutic Uses of Loop Diuretics

 Acute Pulmonary Edema

 Congestive Heart Failure
 Hypertension
 Hypercalcemia
 edema associated with chronic kidney disease

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 Adverse Effects
 Cause a side effect of hypokalemia
 Potassium-rich foods (e.g., dried fruit, bananas, potatoes,
and avocados
 insulin resistance(hyperglycemia)
 increases in LDL-C and triglycerides
 Hyperuricemia
 Hypomagnesemia with Symptoms
 muscle weakness, muscle tremor or twitching, mental
status changes, and cardiac arrhythmias
 Ototoxicity: Na+-K+-2Cl− symport inhibit in the inner ear
 All are dose -dependent
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 Potassium-sparing diuretics
 act in the late distal convoluted tubule & collecting
tubule
 Have two distinct mechanisms of action :
 epithelial sodium channel blockers
 aldosterone antagonists
 The late distal tubule and collecting duct have a limited
capacity to reabsorb solutes
 Na+ channel blockade in this part of the nephron, cause
small increases in NaCl excretion rates only mildly
(∼2% of filtered load).
 usually are employed for their antikaliuretic actions to
offset the effects of other diuretics that increase K+ 22
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 Epithelial Sodium Channel Blockers(ENaCs)

 Amiloride and triamterene:

 are inhibitors of epithelial sodium transport at the late distal
and collecting ducts.
 Na+ entry into the cell down the electrochemical gradient
created by the basolateral Na+ pump.
 higher permeability of the luminal membrane for Na+
depolarizes the luminal membrane
• This creating a lumen-negative trans-epithelial potential
difference
• Is an important driving force for the secretion of K+ into the
lumen via K+ channels in the luminal membrane & and H+
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 Blockade of Na+ channels hyperpolarizes the luminal
membrane, reducing the lumen-negative transepithelial
voltage.
 decreases K+, H+, Ca2+, and Mg2+ excretion rates.
 Amiloride and triamterene have little or no effect on renal
hemodynamics and do not alter TGF.
 Amiloride is eliminated predominantly by urinary excretion of
intact drug.
 Amiloride is more potent and longer acting than triamterene.
 Lithium is absorbed through epithelial Na+ channels in the CD
cells and cause diabetes insipidus.
 Amiloride is the drug of choice for this condition; it acts by
blocking the entry of lithium through these channels

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 Triamterene is metabolized in the liver to an active
metabolite & the metabolite is excreted in urine.
 hepatic disease and renal failure enhanced triamterene
toxicity .
• Triamterene has an incomplete absorption,
photosensitivity and impairment of glucose tolerance
& interstitial nephritis and renal stones.

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 Aldosterone Antagonists
 Spironolactone and eplerenone:
 do not require access to the tubular lumen to induce diuresis &
only diuretics that do not require access to the tubular lumen to
induce diuresis.
 synthetic steroids that antagonize aldosterone receptor
 Aldosterone is cause salt and water retention and increase K+
and H+ excretion by binding to specific receptor.
 Aldosterone regulates the expression of multiple gene products
called aldosterone-induced proteins
 These protein enhance trans-epithelial NaCl transport and
increased the lumen-negative transepithelial voltage
 increases the driving force for K+ and H+ secretion into the
tubular lumen.
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 spironolactone and eplerenone competitively inhibit
the binding of aldosterone to its receptor & block the
biological effects of aldosterone.
 referred to as aldosterone antagonists
 their clinical efficacy is a function of endogenous
aldosterone levels.
 The higher the endogenous aldosterone level, the
greater the effects on urinary excretion
 e.g. hepatic cirrhosis, CHF, nephrotic syndrome
enhance the efficacy & Addison’s disease null

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 Potassium-sparing Diuretics

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 PK
 Spironolactone is absorbed partially ( ∼65%),
 metabolized extensively in the liver in to active
metabolite with long t1/2 (1.6 vs 9 h).
 undergoes enterohepatic
 is highly protein bound
 Eplerenone has good oral availability
 is eliminated primarily by metabolism by CYP3A4
to inactive metabolites, with a t 1/2 of about 5 h.

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 Therapeutic Uses
 For the treatment of:
 Edema:
 Refractory edema due to secondary aldosteronism (cardiac
failure, hepatic cirrhosis, nephrotic syndrome, and severe
ascites).
 Spironolactone is the diuretic of choice in patients with hepatic
cirrhosis with fluid in the peritoneal cavity (ascites).
 Resistant hypertension : due to hyperaldosteronism (adrenal
adenomas or bilateral adrenal hyperplasia).
 Resistant hypertension is the use of three or more medications
without reaching the blood pressure goal & it is well responds
to aldosterone antagonists.
 The choice of diuretics in patients with hepatic cirrhosis.
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Hypokalemia:

• often given in conjunction with thiazide or loop diuretics to

prevent K+ excretion.
• Heart failure: employed at lower doses to prevent myocardial
remodeling mediated by aldosterone
• Adverse Effects:
 Hyperkalemia:
 Gynecomastia, impotence, decreased libido, and menstrual
irregularities: Spironolactone, but not eplerenone due to anti-
androgenic & anti-progesterone
 metabolic acidosis in cirrhotic patients.
 Spironolactone cause diarrhea, gastritis, gastric bleeding, and
peptic ulcer
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 Pharmacology of Cardiovascular System

 In this module:
 The learner will be able to
 Explain the pharmacology of
antihypertension drug
 Discussed the pharmacology of
heart failure

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 Pharmacology of Anti-hypertension Drugs

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 Objectives of the Session

 After the end of the lecture, you should be able to:

 Explain the pathophysiology mechanism of HTN
 List non pharmacology and pharmacology methods
of HTN treatment methods
 List different groups of antihypertensive drugs.
 Describe the PK and PD of each groups of anti-HTN
drugs.

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 Hypertension (HTN)
 is a state of elevated systemic blood pressure that
causes marked increment of cardiovascular risk.
 It is the most common cardiovascular disease.
 According to, 2017 guidelines from the American
College of Cardiology and American Heart
Association (ACC/AHA) HTN is defined as a
sustained rise of blood pressure of greater than
130/80 mm Hg .

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 Classification based on stages
 According to 2017 American College of Cardiology and
American Heart Association (ACC/AHA) guidelines.
Table: Blood Pressure Classification in Adults

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 Classification based on Etiology
1. Primary (essential) hypertension
 90-95% & the causative cannot be identified
 so-called because it was originally, albeit incorrectly,
thought that the raised blood pressure was ‘essential’ to
maintain adequate tissue perfusion
 Related with genetic and environmental factors
 Include:
 increased saturated fat, alcohol & salt intake
 obesity, physical inactivity, potassium and magnesium
depletion, Ca++, vitamin D deficiency, Cigarette
smoking and caffeine
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 2. Secondary Hypertension

 5-10% pts & cause can be identified

 Kidney diseases: Increased renin release due to
decreased perfusion
 Primary aldosteronism :Water and salt retention
 Cushing’s syndrome: 75–80%
 stimulation of mineralocorticoid receptors by cortisol
 Water and salt retention
 Pheochromocytoma
 Release of catecholamines from the tumors of the
adrenal chromaffin cells
 pregnancy, estrogen use, and medications
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 HYPERTENSIVE CRISES
 In which measured BP values are markedly elevated
 typically in the upper range of stage 2 hypertension.
 Classified as either:
 Hypertensive Emergency :BP > 180/120 mm Hg &
associated with organ damage
 Such as encephalopathy, myocardial infarction (MI),
unstable angina, pulmonary edema, eclampsia, stroke,
 Hypertensive Urgency: is manifested as a severe
elevation in BP 180/ 120 mm Hg without evidence of
acute or life threatening target organ damage.
 do not require immediate BP lowering
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 Pathophysiology of HTN
 To provide a framework for understanding the
pathogenesis and treatment options for hypertensive, it
is important to understanding of both normal and
elevated arterial pressure.
 Normal Regulation of Blood Pressure:
 Arterial pressure is determined by Cardiac output and
peripheral resistance

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02/12/2024 41
 Regulation of BP
Bp is regulated by short and long term
mechanisms
 Short term- sympathetic and parasympathetic
activation
 Long term- RAAS

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1. Baroreceptor reflex:
 Mediated by autonomic nerves
 Are responsible for a rapid, moment-to-moment adjustments in
blood pressure.
 A fall in blood pressure causes pressure-sensitive neurons
(baroreceptors in the aortic arch and carotid sinuses) to send
impulses to cardiovascular centers in the spinal cord.
increased sympathetic output to the heart and vasculature
decreased parasympathetic output to the heart and vasculature,

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2. Renin-Angiotensin-Aldosterone :

 The kidney provides long-term control of blood

pressure by altering the blood volume.
 A reduction of arterial pressure cause :
 The rise of sympathetic stimulation of β-1 receptor in
kidney to secret of enzyme renin.
 Low sodium intake and greater sodium loss also
increase renin release.
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Figure : Response of the autonomic nervous system and the renin–angiotensin–
aldosterone system to a decrease in blood pressure

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 Treatment of hypertension

 Hypertension is treated with

 Nonpharmacologic Therapy
 Pharmacologic Therapy

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 Nonpharmacologic Therapy
 Lifestyle modification may have an impact on morbidity and
mortality.
 Tablet : Lifestyle Modifications To Manage Hypertension

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 Pharmacological Therapy of Hypertension

Figure: Sites of action of the major classes of antihypertensive

drug
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 1. Diuretics
 Thiazides and related drug:
 Are inexpensive, and reduce clinical events.
 Initially term: Thiazides reduce blood pressure by reducing
circulating blood volume and cardiac out put through
increasing in urinary water and electrolyte particularly sodium
excretion.
 In the Longer-term: they reduce total peripheral resistance,
due to vasodilatory action.
 The cardiac out put and blood volume return gradually to
normal values.
 Thiazides are appropriate for mild or moderate hypertension
and normal renal and cardiac function

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 In severe hypertension combine with sympatholytic
agents or vasodilators
 The antihypertensive effectiveness is progressively
diminished when the glomerular filtration rate falls
below 30 mL/min.
 he antihypertensive action take 1 to 3 weeks to
produce a stable reduction in blood pressure
 chlorthalidone is 1.5 to 2 times more potent than
hydrochlorothiazide for BP reduction

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 Loop diuretics
 The antihypertensive effect is mainly due to reduction of
blood volume.
 Situations in which, loop diuretics are preferable to
thiazides, including:
 malignant hypertension and volume-based hypertension
 chronic kidney disease (estimated GFR <30 ml / min
/1.73m2).
 left ventricular dysfunction
 Severe edema
 heart failure or liver cirrhosis
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 Potassium-sparing diuretics
 Amiloride and triamterene:
 are very weak antihypertensive agents in alone.
 often prescribed with potassium-wasting diuretics to
mitigate potassium losses.
 Spironolactone and eplerenone
 For the treatment of:
 Edema and hypertension with thiazide or loop diuretic.
 Resistant hypertension due to primary
hyperaldosteronism (adrenal adenomas or bilateral
adrenal hyperplasia).
 Refractory edema due to secondary aldosteronism
(cardiac failure, hepatic cirrhosis, nephrotic syndrome,
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 2. Vasodilators
 Drugs cause vasodilation:
 by opening potassium channels
 by releasing nitric oxide,
 by blocking calcium channels or
 by acting as agonists of dopamine receptors.
I. Arteriolar dilators: Hydralazine, Minoxidil, Calcium
Channel Blockers, Diazoxide, Fenoldopam
II. Vasodilators : Nitrates
III. Both Arterioles and Venules : sodium nitroprusside, ACE
inhibitors, ARBs, α-blockers.

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 Hydralazine
 Causes direct relaxation of arteriolar smooth muscle,
but does not relax veins
 The vasodilation induces powerful stimulation of
sympathetic system (ed HR and contractility, ed
plasma renin activity, and fluid retention)
 Well absorbed after oral administration
 first pass, so that bioavailability is low

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 A Potent vasodilators cause stimulates the sympathetic
nervous system.
 This vasodilation stimulates the sympathetic nervous system
and results in :
 A Reflex Tachycardia
 Increased PRA ↓ed hypotensive effect
 Fluid Retention: edema and weight gain
 So arterial vasodilators combined with agent that can
 Slow down heart rate e.g., β-blocker or CCB to
counteract reflex tachycardia,
 Diuretic (often a loop diuretic if used in severe CKD)
to minimize fluid retention.
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 PK
 Hydralazine is well absorbed
 Low bioavailability due to rapidly metabolized by
acetylation in the liver
 rapid acetylators have greater 1st –pass effect.

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 Adverse Effects

 Headache, nausea, anorexia, palpitations, sweating, and flushing.

 Reflex tachycardia and sympathetic stimulation may provoke angina

or ischemic arrhythmias.

 Lupus erythematosus

 Peripheral neuropathy (rare)

 Uses:
– Severe HTN & hypertensive emergencies in pregnant women

– 5-10mg intravenous every 20 minutes

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 Minoxidil
 Very efficacious orally active vasodilator.
 Opening of potassium channels in smooth muscle
 Due to greater potential antihypertensive effect
 Replaces the use of hydralazine.
 Associated with higher reflex sympathetic stimulation
 compensatory reflex tachycardia & precipitate angina.
 Sodium & Fluid retention: edema and weight gain
 combined with a β blocker, CCB and diuretic.

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 Hypertrichosis: eyebrows, on the cheeks, back of the
legs, arms, and scalp
 Stimulant to hypertrichosis (hair growth) for correction
of baldness.
 Topical minoxidil is an approved therapy for male
pattern baldness

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 Sodium Nitroprusside
• act by releasing NO from the endothelium
• Potent , parentally administered vasodilator
• Dilates both arteriolar & venular vessels
 reduced peripheral vascular resistance and venous return

• Has rapid onset (30 s) & brief duration of effect (3 min)

 a continuous infusion with careful monitoring to avoid

hypotension
 Used for the treatment of hypertensive emergencies (continuous IV
infusion) & severe heart failure.
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  Sodium nitroprusside in aqueous solution is sensitive to light and must

fresh before each administration and covered with opaque foil .

 When exposed to light, nitroprusside hydrolyses with formation

of cyanide
• Adverse effects are secondary to
 Excessive lowering of BP; and

 Accumulation of CN-
 Metabolic acidosis, arrhythmias etc
 Hypothyroidism (thiocyanate inhibits uptake of iodine)
 sodium thiosulfate facilitates metabolism of cyanide.
 Hydroxocobalamin form the nontoxic cyanocobalamin.
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 Diazoxide

 Dilates artery
 It is a potassium channel opener & causes hyperpolarization in
smooth muscle and pancreatic β cells.
 inhibits insulin release from the pancreas
 The blood pressure-lowering effect after a rapid injection is
established within 5 minutes and lasts for 4–12 hours.

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 Fenoldopam
 is a peripheral arteriolar dilator via dopamine D1
receptors agonist
 used for hypertensive emergencies and postoperative
hypertension .
 The major toxicities are reflex tachycardia, headache,
and flushing.
 Increases intraocular pressure and should be avoided
in glaucoma.

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 Calcium-Channel Blockers(CCB)

 Mediates by blocking the inward movement of calcium

by binding to L-type calcium channels in the heart and in
smooth muscle of the coronary and peripheral arteriolar
vasculature
 Generally, elderly and black patients have a greater BP
reduction with a CCB than with other agents (β-blockers,
ACEIs, and ARBs).
 CCBs do not alter serum lipids, glucose, uric acid, or
electrolytes
 all CCBs possess some coronary vasodilatin & used in
the management angina.
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 Three heterogeneous classes of Calcium Channel
Blockers:
1. Phenylalkylamines :verapamil
2. Benzothiazepines : diltiazem
3. Dihydropyrdine(nifedipine-like)
 verapamil and diltiazem are primarily on the heart,
 block the atrioventricular (AV) node, decrease heart
rate, and decrease cardiac contraction
 cardiac output yet still have vasodilatory effects
 They are used in the treatment of atrial fibrillation.
 avoided in patients with reduced ejection fraction

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 Dihydropyridines:
 Nifedipine, amlodipine, felodipine, isradipine, nicardipine,
Nimodipine, and nisoldipine.
 Clevidipine is a newer member & is formulated for intravenous use
only for severe hypertension.
 Due to rapid inactivation by plasma esterases & has 1 min t1/2.
 Amlodipine(5 mg qd), felodipine(5 to 10 mg) are long acting po &
are effective with once-a-day dosing.
 are potent arterial/arteriolar dilator, but do not much affect the veins
 They cause coronary vasodilatation and are used in patients with
coronary artery spasm (variant angina).
 Less effect on heart rate & contractility
 do not block AV nodal conduction and do not treat arrhythmias
 Sustained-release calcium blockers or long acting CCB provide
smoother blood pressure control and are more appropriate for
treatment of chronic hypertension
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 Other types of smooth muscle (e.g. biliary tract, urinary
tract and uterus) are also relaxed by calcium antagonists,
but these effects are less important therapeutically than
their actions on vascular smooth muscle.
 Nimodipine: produces selective blockade of calcium
channels in cerebral blood vessels.
 only approved application is prophylaxis of neurologic
injury following rupture of an intracranial aneurysm.
Benefits derive from preventing cerebral arterial spasm
that follows subarachnoid hemorrhage (SAH) and can
result in ischemic neurologic injury.
 Nimodipine must never be given intravenously, owing to a
risk of potentially fatal cardiovascular event
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 Adverse Effect of CCB

 Headache, Flushing, reflex tachycardia, and Peripheral

Edema due to their vasodilator action
 Headache, Flushing, Palpitations are due to arteriolar
dilators.
• Edema is due to an increase is due to arteriolar dilatation
and increased permeability of postcapillary venules, not
to net salt and water retention
 Gingival hyperplasia (overgrowth of gum tissue)
 Verapamil cause constipation : from blockade of calcium
channels in smooth muscle of the intestine.
 heart block :cause bradycardia
02/12/2024 71
 Centrally acting 2 agonists

 Include such drugs as clonidine, -methyldopa, Guanabenz

and guanfacine.
 α2-adrenoceptor agonists act at presynaptic autoreceptors in
the CNS to
 reduce sympathetic nervous out flow
 increase vagal out flow from the medulla . leading
 Decreases in heart rate & contractility
 reduces Vasomotor tone in peripheral arterial and venous
tone.
02/12/2024 72
 β-adrenoceptor blockers

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 Effects of β-Blockers

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 The negative chronotropic and inotropic effects such as
reductions account the initial antihypertensive effect.
 The longer term antihypertensive effect of β-antagonists is
due to decreasing the vasomotor tone that result decrease
in systemic vascular resistance on β1-adrenergic receptors
in the kidney
 Decreases the secretion of renin and thereby decreases
production of the potent vasoconstrictor, angiotensin II.
 All β-blockers are useful in mild to moderate HTN.
 Show a reduction in mortality after a myocardial
infarction and some also reduce mortality in patients with
heart failure
02/12/2024 75
 Cardio-selectivity to block β1 –receptors is desirable in
patient:
 asthma, chronic obstructive pulmonary disease
 peripheral vascular disease (intermittent claudication).
 reduction in the β2-mediated vascular blood flow or by
enhanced unopposed α1-agonist–mediated
vasoconstriction, nonselective β-blocker worsening the
symptom the patient experience with intermittent
claudication.

02/12/2024 76
 β-blocker with intrinsic sympathomimetic activity are
not recommended for hypertension or any other
cardiovascular disease
 because increase nighttime mean heart rate due to
their direct partial agonistic activity.
 In recent years, used less frequently in the initial
treatment of hypertension, due to not as efficacious as
diuretics or inhibitors of the RAS system.

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Commonly used β-Blockers in Hypertension treatment
 1-AR blockers
 Phenoxybenzamine, an irreversible α- blocker (α1 > α2)
• Prazocine, Doxazocine, Terazocine
• decreasing peripheral vascular resistance and increase venous capacitance 
reduce BP
• blood pressure is reduced more in the upright than in the supine position.
• Then sympathetically mediated reflex increase in heart rate and plasma renin
activity as result a β blocker and a diuretic are added
• In clinical trials of hypertensive patients, alpha blockade has not been shown to
reduce cardiovascular morbidity and mortality or to provide as much protection
against CHF as other classes of antihypertensive agents.
• primarily used in men with concurrent hypertension and benign prostatic
hyperplasia
02/12/2024 79
α-/β-Adrenoceptor–blocking Agents

 Labetalol and carvedilol block α1, β1, and β2

receptors.
 Carvedilol is mainly used in the treatment of heart
failure(left ventricular dysfunction).
 Labetalol is used in the management of gestational
hypertension and hypertensive emergencies.

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Renin- Angiotensin- Aldosterone Antagonists

 Renin, angiotensin, and aldosterone play important roles in essential

hypertension.
 Angiotensin II is formed angiotensin-converting enzyme
 It also formed by the enzymatic activity by proteases, e.g., tonin,
chymase, and cathepsins.
 High-renin patients may have a vasoconstrictor form of HTN
 Low-renin patients may have volume dependent HTN.
 HTN African Americans have low plasma renin and volume-
dependent hypertension.
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Figure : Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system.
ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers.
02/12/2024 82
 Angiotensin Converting Enzyme Inhibitors (ACE-I)

 Captopril, Enalapri, Benazepril, fosinopril, moexipril,

perindopril, quinapril, ramipril, and trandolapril.
 Actions of ACE-I including:-
 Reducing peripheral vascular resistance
 Vasodilation of both arterioles and veins 2nd to Ang-II.
 enhanced vasodilation from increased bradykinin level.
 decreased sodium and water retention 2nd to decrease the secretion
of aldosterone.
 reduce sympathetic nervous system activity
 Also reduce both cardiac preload and afterload, thereby decreasing
workload on the heart.
02/12/2024 83
02/12/2024 84
 more effective in plasma renin activity, younger white
patients & less effective in blacks and older persons.
 ACEI also are effective in low-to-normal plasma
renin activity may be due to potentiation of the
vasodilatory effects of bradykinin.
 the combination of an ACEI and a diuretic or calcium
channel blocker is potent.
 ACEI delay the progression of nondiabetic kidney
disease
 ACE inhibitors are preferred in the hypertensive
diabetic patient

02/12/2024 85
 PK
 Except Captopril and Lisinopril, all ACEIs are
prodrugs & require enzymatic conversion to their
respective active metabolites.

02/12/2024 86
 Adverse Effects
 Dry cough: due to increased levels of bradykinin
 ACEI prevents the breakdown and inactivation of bradykinin,
 ARB or hydralazine–isosorbide are safe alternatives for cough
 Angioedema: a rare, but serious &requires discontinuation
of the drugs
 A painful swelling around the lips, eyes, throat, and other
body regions.
 may lead to airway closure, due to the intense swelling in the
neck. It due to bradykinin accumulation
 Are contraindicated for:-
 Pregnancy, bilateral renal artery stenosis, history of
angioedema
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 Hyperkalemia: 2nd to aldosterone blocking or due to
hypoaldosteronism.
 patients with CKD or volume depletion more
susceptible to hyperkalemia
 postural hypotension first few doses of the drug.
 a first-dose phenomenon
 Due to hypotension and reduced renal blood flow, ACEI
during the second and third trimesters of pregnancy
should not be used by pregnant women.
 Renal Insufficiency:
 predisposing conditions: dehydration, CHF, and NSAIFD

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 Angiotensin Receptor Blockers (ARBs)

 Losartan,valsartan Azilsartan, Candesartan, Eprosartan,

Irbesartan, Olmesartan, and Telmisartan
 Competitively antagonize the binding of angiotensin II
AGII receptors


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 Angiotensin II on AT1-R mediates :

 Vasoconstriction, salt and water retention

 Cardiovascular remodeling
 myocyte and smooth muscle hypertrophy,
 fibroblast hyperplasia
 cytotoxic effects in the myocardium
 possible increased concentrations of plasminogen activator
inhibitor
 inhibition of AT1 receptors directly prevents the pressor response
of Angiotensin II & results in upregulation of the RAAS.
 The Upregulation of the RAAS results in elevated levels of AgII
 Enhance the stimulation of AT2- receptors
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Angiotensin II on type 2 receptor (AT2R)
mediates :
 Vasodilation
 Sodium excretion
 Inhibition of cell growth and matrix formation
 improve vascular remodeling by stimulating smooth
muscle cell apoptosis.
 AT1R blockade induces an increase in AT2R activity
 The effect of angiotensin II on unblocked AT2Rs may
augment ARBs hypotensive effect.

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02/12/2024 92
 Renin Inhibitors

 Aliskiren is the first of a class of oral, nonpeptide

competitive inhibitors of the enzymatic activity of
renin.
 Blockade of the renin-angiotensin system is more
complete with renin inhibitors than with ACEIs or
ARBs.
 Monotherapy with aliskiren is as effective as an ACEI
or ARB for lowering blood pressure, but not more
effective.

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 Treatment of Hypertensive emergencies

 Occurs most often in African American men and in

individuals between the ages of 40 and 60.
 Two fundamental concepts in the management of
hypertensive emergencies.
1. immediate and intensive therapy:
 Clevidipine, esmolol, enalaprilat, fenoldopam, hydralazine,
labetalol, nicardipine, nitroglycerin, or nitroprusside
2. Slower BP reduction over the course of several hours or
days is acceptable.
 oral therapy using captopril, clonidine, labetalol, or
minoxidil
02/12/2024 94
 Quiz
1.A 68 man with a complain of hypertension and benign prostatic
hyperplasia best treated both case instantaneously A. β 2-
antagonist B.α1- blocker C. β 1- agonist D. CCB
2. Which drug is a contraindicated for pregnancy? A. Labetalol
B. ACE inhibitors C. Hydralazine D. Methyldopa
3. The drug of choice in pregnancy induced hypertension
treatment A. Enalapril B. Losartan C. Diuretic D. Methyldopa
4. Explain why beta blockers are contraindicated to treat
hypertension in asthmatic patient.
5. Explain how ACEI causes dry cough.

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 oral regimens using clonidine, captopril, labetalol, or
minoxidil are available
 lower BP acutely.
 These oral agents take several hours to adequately
lower pressure
 Are useful in treating hypertensive urgencies but not
emergencies.
 ACE inhibitors, other than captopril, are not useful for
acutely lowering BP because of a slower onset of
action.

02/12/2024 96
 Pharmacology of Heart Failure
• Objectives of lecture
• After the end of the lecture ,the learner should be able
to
 Explain heart failure
 List different categories of drugs for treatment of
heart failure
 explain the PD & PK of each pharmacological drugs
for heart failure treatment.

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 Pharmacology of Heart Failure
 Heart failure is the inability of the heart to provide
adequate blood flow (tissue perfusion) to meet the
body’s metabolic demands
 Results from any structural or functional cardiac
impairment of ventricle filling or ejection of blood.

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 Classification of Heart Failure

 Systolic Failure: Abnormal ventricular contraction

 a reduced mechanical pumping action (contractility)
and reduced ejection fraction (HFrEF).
 Diastolic Failure: Abnormal ventricular filling
 stiffening and loss of adequate relaxation
 in reducing filling and cardiac output
 Ejection fraction may be normal (preserved, HFpEF)

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 Low-output HF Vs High-output HF

 Low-output HF :
 is a diminished volume of blood being pumped by a
weakened heart in patients who have normal
metabolic needs.
 High-output Failure:
 Because of high metabolic demands, the heart unable
pump sufficient blood, even if the heart is healthy and
pumps a normal or even higher than normal volume
of blood

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 Determinants of Cardiac Workload

Cardiac performance is a function of four primary factors:

1. Preload: the volume of blood in the left ventricle (LV end-
diastolic volume).
2. Afterload: is the resistance to ventricular ejection
 Regulated by ejection impedance, wall tension, and regional
wall geometry
3. Contractility: is an intrinsic property of cardiac muscle
 Regulated by adrenergic nerve activity and circulating
catecholamines NE& EP
4. Heart Rate (HR): is controlled by the autonomic nervous
system
02/12/2024 101
 Regulation of cardiac output
 Stroke volume (SV) (the
volume of blood ejected with
each contraction
 Regulating by :
 preload, afterload, and contractility
 CO is the volume of blood
ejected per unit of time
(L/min) a
 CO = HR × SV

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 Pathophysiology of Heart Failure

 the syndrome of heart failure arises largely from

neurohumoral counter-regulation in response to low blood
pressure and reduced renal perfusion.
 When the heart fail to pump, the body activates several
complex compensatory mechanisms in an attempt to maintain
CO and oxygenation.
 Regulated by:
 Neurohumoral (extrinsic) compensation major mechanisms
 Sympathetic tone
 Activation of the renin–angiotensin–aldosterone system
(RAAS)
02/12/2024 103
 The baroreceptor reflex acts to be reset, with a lower
sensitivity to arterial pressure, in patients with heart
failure.
 As a result, baroreceptor sensory input to the
vasomotor center is reduced even at normal pressures
 sympathetic outflow is increased,
 parasympathetic outflow is decreased.
 causes tachycardia, increased cardiac contractility,
and increased vascular tone.

02/12/2024 104
 Vascular tone is further increased by angiotensin II
and endothelin,
 a potent vasoconstrictor released by vascular
endothelial cells.
 Vasoconstriction increases afterload
 further reduces ejection fraction and cardiac output.

02/12/2024 105
Heart Failure

Compensa
tory
responses

Some compensatory responses that occur during congestive heart failure. In addition to the
effects shown, sympathetic discharge facilitates renin release, and angiotensin II increases
02/12/2024 106
norepinephrine release by sympathetic nerve endings (dashed arrows).
02/12/2024 107
TABLE: New York Heart Association Functional
Classification

02/12/2024 108
American College of Cardiology/ American Heart
Association (ACC/AHA) Staging
Stages of Heart Failure
1. Stage A
At high risk for heart failure but without structural heart
disease or symptoms of HF
2. Stage B
• Structural heart disease but without signs or symptoms
of HF
3. Stage C
• Structural heart disease with prior or current symptoms
of HF
4. Stage D
02/12/2024 109
 Intervention of HF
Goals of treatment are :
 To alleviate symptoms
 To slow disease progression
 To improve survival

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 Non Pharmacological Treatment of HF

Chronic HF is typically managed by

 Fluid limitations (less than 1.5 to 2 L daily)
 Low dietary intake of sodium (less than 2000
mg/d)
 Treatment of comorbid conditions
 Careful use of diuretics
 Avoided drugs that cause HF
 nonsteroidal anti-inflammatory drugs (NSAIDs),
alcohol, nondihydropyridine calcium channel blocker
02/12/2024 111
 Pharmacologic Intervention in HF

 Drug provides the following benefits:

 reduced myocardial work load
 decreased extracellular fluid volume
 improved cardiac contractility
 reduced rate of cardiac remodeling.

02/12/2024 112
Classes of Drugs for Treatment of Heart Failure

1) angiotensin-converting enzyme (ACE) inhibitors

2) angiotensin receptor blockers
3) aldosterone antagonists
4) β-blockers
5) Diuretics
6) Direct vaso- and venodilators
7) Hyperpolarization-activated cyclic nucleotide-gated channel
blockers
8) Inotropic agents
9) the combination of a neprilysin inhibitor with an angiotensin
receptor blocker
10) Recombinant B-type natriuretic peptide
02/12/2024 113
 Angiotensin-converting enzyme inhibitors

Figure : Effects of ACE inhibitors

02/12/2024 114
 ACEIs
 Arterial dilation & decreasing systolic wall stress afterload.
 Venous dilation decreases LV congestion preload.
 Reduced volume
 modify cardiac remodeling independent of vasodilation
 promote salt excretion by enhancing renal blood flow(RBF) and
reducing the production of aldosterone diuretic response
 CO increases without an increase in HR
 ACEIs are the drugs of choice for initial therapy HF
 prescribed to all patients with HF caused by left ventricular systolic
dysfunction (LVSD) if no CI.
 Start with lowest dose to avoid bradycardia, hypotension, or renal
dysfunction
 Increase dose slowly at 2- to 4-week intervals to assess full effect and
tolerance.
02/12/2024 115
 Angiotensin II Receptor Blockers

 an alternative to ACE inhibitors in chronic heart

failure with reduced LVEF
 candesartan losartan, and valsartan have FDA
approved labeling for the treatment of H

02/12/2024 116
FDA approved & recommended ACEI & ARB for use in HF

02/12/2024 117
 Aldosterone Receptor Antagonists
Initial dose Maximum dose

 Aldosterone is a key pathological neurohormone &

exerts multiple detrimental effects in HF, are increased
in HF
 are antagonists of aldosterone one at the MAR,
 Prevents salt retention, myocardial hypertrophy
hypokalemia.
 Indicated in patients with symptomatic HFrEF or HFrEF
and recent myocardial infarction
 Potassium levels must be monitored closely
02/12/2024 118
 β-Blockers
 Decrease heart rate and inhibit release of renin.
 Prevent the deleterious effects of norepinephrine on the
cardiac muscle fibers
 decrease myocyte death from catecholamine induced
necrosis or apoptosis.
 Decreasing remodeling, Hypertrophy, improves
ventricular shape and cell death
 reduces ventricular mass,, and reduces LV end-systolic
and diastolic volumes
 reduce morbidity and mortality associated with HFrEF

02/12/2024 119
 The ACC/AHA recommends that β-blockers be initiated in all
patients with NYHA FC I to IV or ACC/AHA stages B
through D HF if clinically stable.
 To date, three medications have strong evidence of reducing
mortality.
 Carvedilol, Bisoprolol, metoprolol succinate are FDA
approved for use in HF & shown a reduction in mortality
 metoprolol succinate and carvedilol are the most commonly
used Β-B in HF.
 β-blocker be initiated in clinically stable and euvolemic
 Should begin with the lowest possible dose &the dose may be
doubled every 2 to 4 weeks based on tolerance and vital signs

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 Diuretics
 Diuretics: produce rapid symptomatic improvement.
 Diuretics decrease plasma volume →decrease venous
return to the heart (preload) →cardiac workload and
oxygen demand.
1. Decrease preload and improve ventricular efficiency by
reducing circulating volume
2. Peripheral and pulmonary edema are relieve within
hours.
 Symptomatic improvement with ACEIs, β-Bs, and
digoxin take days to months to be fully realized
 Loop diuretics(furosemide, bumetanide, torsemide)
 are the most commonly used diuretics in HF.
02/12/2024 121
 used for patients who require extensive diuresis and those
 Angiotensin Receptor agonist–Neprilysin
Inhibitor
 Neprilysin is the enzyme responsible for breaking down
vasoactive peptides, such as
 angiotensin I and II, bradykinin, and natriuretic peptides.
 Inhibition of neprilysin augments the activity of the vasoactive
peptides.
 To maximize the effect of natriuretic peptides, stimulation of
the RAAS must be offset without further increase in
bradykinin.
 ARB, instead of an ACE inhibitor, is combined with a
neprilysin inhibitor to reduce the incidence of angioedema

02/12/2024 122
Effects of angiotensin receptor blocker–neprilysin inhibitors. ARB
= angiotensin receptor blocker; ARNI = angiotensin receptor
neprilysin inhibitor; AT1 = angiotensin type 1; NI, neprilysin
inhibitor; NP = natriuretic peptide; RAAS = renin– angiotensin–
aldosterone
02/12/2024 system; SNS = sympathetic nervous system. 123
 Sacubitril/Valsartan

• is a combines of an ARB with neprilysin inhibition.

leading to natriuresis, diuresis, vasodilation, and
inhibition of fibrosis.
• decreases afterload, preload, and myocardial fibrosis.
• An ARNI improves survival and clinical signs and
symptoms of HF, as compared to therapy with an
ACE inhibitor.
• orally active, administered with or without food
• quickly breaks down into the separate components.

02/12/2024 124
 Vaso- and Venodilators

 Dilation of venous blood vessels leads to a decrease in cardiac

preload by increasing venous capacitance.
 Nitrates are commonly used venous dilators to reduce preload
for patients with chronic HF.
 Arterial dilators, such as hydralazine, reduce systemic
arteriolar resistance and decrease afterload.
 in combination, these two agents have additive benefits in
alleviating the symptoms of HF and increasing exercise
tolerance.
 hydralazine– isosorbide dinitrate improved survival in severe
HF compared with placebo

02/12/2024 125
 Inotropic Drugs
 Positive inotropic agents enhance cardiac contractility
and, thus, increase cardiac output.
 The inotropic action is the result of an increased
cytoplasmic calcium concentration that enhances the
contractility of cardiac muscle.
 All positive inotropes in HFrEF that increase
intracellular calcium concentration have been
associated with reduced survival, especially in patients
with HFrEF.
 For this reason, these agents, with the exception of
digoxin, are only used for a short period mainly in the
inpatient setting.
02/12/2024 126
 Digitalis Glycosides
 The cardiac glycosides increase the contractility of
the heart muscle are used in treating HF.
 used as acute treatment of CHF as well as for
maintenance
 The digitalis glycosides have a low therapeutic index.

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 Mechanism of Action

Figure : Mechanism of action of digoxin. ATPase = adenosine triphosphatase

02/12/2024 128
 digoxin has beneficial neurohumoral and autonomic
effects
 caused by reducing sympathetic tone and stimulating
parasympathetic responses at serum concentrations
below those associated with positive inotropism
 Vagal tone is also enhanced, so both heart rate and
myocardial oxygen demand decrease.
 Digoxin slows conduction velocity through the AV
node, making it useful for atrial fibrillation.

02/12/2024 129
 PK
 Digoxin is available in oral and injectable
formulations
 has a large volume of distribution, due to accumulates
in muscle
 half-life of 30 to 40 hours
 is a substrate of P-gp, and inhibitors of P-gp, such as
clarithromycin, verapamil, and amiodarone
 eliminated intact by the kidney, requiring dose
adjustment in renal dysfunction.

02/12/2024 130
 Adverse Effects

 Has a very narrow therapeutic index.

 Anorexia, nausea, vomiting, blurred vision, or
yellowish vision of toxicity.
 increasing the risk of arrhythmias
 Hypokalemia lead to digoxin toxicity,
 because digoxin normally competes with potassium
for the same binding site on the Na + /K+ -ATPase
pump.
 Gynaecomastia: stimulate estrogen receptors in
breast tissue
02/12/2024 131
 β-Adrenergic Agonists
 β-Adrenergic agonists, such as:
 Dobutamine
 Dopamine
 improve cardiac performance by causing positive inotropic
effects and vasodilation.
 β-Adrenergic agonists ultimately lead to increased entry of
calcium ions into myocardial cells and enhanced contraction.
 Both drugs must be given by intravenous infusion and are
primarily used in the short-term treatment of acute HF in the
hospital setting.

02/12/2024 132
Figure : Sites of action by β-adrenergic agonists on heart muscle. AMP = adenosine
monophosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine
monophosphate; P = phosphate.
02/12/2024 133
 Phosphodiesterase Inhibitors

 Milrinone is a phosphodiesterase inhibitor that

increases the intracellular concentration of cAMP.
 increase of intracellular calcium and, therefore,
cardiac contractility and vasodilation.
 Milrinone is usually given by intravenous infusion for
short-term treatment of acute HF or severe
exacerbation of chronic heart failure..

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