The document discusses cardiovascular pharmacology, focusing on vasoactive peptides that regulate vascular tone and blood flow, including vasoconstrictors like angiotensin II and vasodilators such as natriuretic peptides. It explains mechanisms of action, clinical roles, and pharmacotherapeutic applications of various peptides and antihypertensive drugs used to manage blood pressure and treat hypertension. Additionally, it outlines the physiological implications of these agents on the cardiovascular system and the importance of lifestyle modifications in managing hypertension.

1. CARDIOVASCULAR
PHARMACOLOGY

2. VASOACTIVE PEPTIDES
• At least 16 naturally occurring peptides either
constrict or dilate blood vessels. Many of
these peptides are present in nerve cells and
nerve terminals supplying systemic and
pulmonary blood vessels and the heart.
• Such neuropeptides are released locally as
neurotransmitters, and can influence vascular
tone, local and regional blood flow, arterial
blood pressure, and cardiac function.

3. • Defn: peptides that alter the tone of the vascular
smooth muscle
• Physiological role:
– Neurotransmitters
– Local & systemic hormones
• 2 major categories:
– Vasoconstrictors
– Vasodilators

4. Classification
• 1) Vasoconstrictors
– Angiotensin II
– Vasopressin
– Endothelins
– Neuropeptide Y
– Urotensin

5. Classification
• 2) Vasodilators
– Kinins (esp. Bradykinin)
– Natriuretic peptides
– Vasoactive Intestinal peptide
– Substance P
– Calcitonin gene-related peptide
– Adrenomedullin

6. Angiotensin II
• It is an octapeptide produced from Ang I by
angiotensin-converting enzyme (ACE), [component
of the RAAS]
Renin
Angiotensinogen angiotensin I
ACE
Angiotensin III Angiotensin II

7. RAAS

8. Ang II
• Effects
– Potent arteriolar vasoconstrictor (pressor effect 40x >NE)
– Stimulates release of Aldosterone & catecholamines by adrenal gland
– Stimulates ADH secretion from pituitary
– ↑proximal tubular Na+ reabsorption
• Signal transduction
– Binds to AT1 receptor, activates PLC --→ IP3, DAG
• Clinical Role
– Pathophysiologic mediator in some cases of hypertension (high-renin HT)
& heart failure (HF)
– Antagonists; ACEIs and ARBs used in Rx of HT & HF

9. Vasopressin (ADH)
• Synthesized in the hypothalamus & released from the
posterior pituitary.
• Mechanism of action; activation of:
– V1 receptors (via PLC & ↑Ca2+) → vasoconstriction
– V2 receptors (cAMP mediated) →  synthesis & insertion of
H2O channels in renal collecting tubules →antidiuresis
• Clinical role
– Normalises BP during acute hypotension
– Desmopressin, a V2 agonist used in Rx of pituitary diabetes
insipidus

10. Endothelins (ET)
• Isoforms: ET-1, ET-2, ET-3
– Paracrine & autocrine hormones in the vasculature
• Signal transduction:
– bind to ET receptors →activate PLC -> ↑IP3 & Ca2+
• Effects:
– Highly potent vasoconstrictors (via ETA receptor) > NE
– ↑smooth m proliferation
– Positive inotropic effect
• Clinical Role:
– Bosentan, an ET antagonist used to Rx Pulmonary
Hypertension

11. Production & Effects of Endothelin

12. Kinins
• Prototype: Bradykinin
• Signal transduction:
– via B receptors -→ ↑IP3, DAG; ↑cAMP & nitric oxide; vasodilator PGs
(PGE2 & PGE1)
• Effects:
– dilates arterioles (10X >histamine)
– ↑capillary permeability
– stimulates sensory n. endings→ pain
– Pro-inflammatory—[“triple response”]
• Clinical Role
– Antihypertensive effect of ACEIs
– Icatibant, a B2 receptor antagonist--- used to evaluate role of kinins in pain,
inflammation, etc.

13. Kallikrein-Kinin system

14. Natriuretic Peptides (NP)
• Examples:
– Atrial NP (ANP) & Brain NP (BNP)
– Synthesized and stored in the cardiac atria of mammals
• Mechanism of action:
– ↑cGMP-→ vasodilation
– ↓ALDO secretion & effects
– ↑GFR
• Clinical role:
– Nesiritide, a BNP derivative, approved for Rx of Heart failure
– Potential role in Rx of Hypertension

15. Biological actions of ANP & BNP
• Natriuresis
• Arterial vasodilation
• Inhibition of the RAAS
• Inhibition of sympathetic nervous function
• Inhibition of endothelin
• Increase in capillary permeability
• Anti-mitogenesis
• Inhibition of cardiac fibroblasts

16. Substance P
• Belongs to the tachykinin (neurokinins) family of peptides
– neurotransmitter in primary afferent sensory fibers
• Effects: via NK receptors (G protein-coupled)
– Stimulates cutaneous pain receptors
– Dilates arterioles (via NO) ; contracts veins, intestinal & bronchial smooth
m
• Clinical Role
– Capsaicin, the “hot” component of chilli peppers, releases and depletes
substance P from its stores in n. endings
• Used topically in arthritis and post-herpetic neuralgia

17. • Vasoactive Intestinal Peptide (VIP)
– 28-amino acid peptide
– regulates coronary blood flow, cardiac contraction & heart rate
• potent vasodilator, with +ve inotropic & chronotropic effects
– Mechanism:
• binds to VPAC1 & VPAC2 receptors→ ↑cAMP
• Some effects mediated by NO
• Calcitonin gene-related peptide (CGRP)
– 37-amino acid peptide
– Most potent hypotensive agent discovered to date
– Effects mediated via CGRP1 & CGRP2 receptors
– ↓BP, Heart rate
• Future role in Rx of hypertension & migraine

18. NITRIC OXIDE (NO)
• Synonym: Endothelium derived relaxing factor (EDRF)
• Physiological role
– Paracrine vasodilator
– Role in apoptosis & neurotransmission
• Properties
– Gas at body temperature
– Not stored in cells
– Rapidly diffuses from site of synthesis to surrounding tissues
– Rapidly mopped up by RBCs, high affinity for Hb
– Very short t1/2 ~ 4 sec

19. Release & effect of NO

20. Sources of NO
• (A) Endogenous: Synthesized from arginine by the
enzyme NO synthase (NOS).
– L-arginine + O2 ----NOS------→ NO + L-citrulline + H+
• Isoforms of NOS
– NOS-1 (cNos or nNOS) –constitutive-- epithelial & neuronal
cells
– NOS-2 (iNOS or mNOS) –inducible-- macrophages & vascular
smooth m cells
– NOS-3 (eNOS) –constitutive-- endothelial cells

21. Sources of NO
• NOS can be stimulated by some drugs
including:
– Acetylcholine & other muscarinic agonists
– Histamine
• In-vivo administration --→ vasodilatation
• (B) Exogenous NO donors
– Nitroprusside, Nitrates, & Nitrites

22. Effects of NO
• (a) Smooth m tone
– potent vasodilator & smooth m relaxant
– Activates guanylyl cyclase --  cGMP -→ dephosphorylates
and inactivates myosin light chains → m relaxation
• (b) Cell adhesion
– ↓expression of adhesion molecules by endothelial cells
• (c) Inflammation
– Facilitates inflammation; directly & thru prostaglandin
synthesis by COX II

23. Clinical role of NO
• 1) Cardiovascular
– (NO donors e.g. nitroprusside, nitrates & nitrites – used in
hypertension, ischemic heart disease, angina)
• 2) Pulmonary Hypertension (Rx INOmax®)
• 3) Acute respiratory distress syndrome (Rx INOmax®)
• 4) Erectile dysfunction (Rx Sildenafil [Viagra®]
– a PDE5 inhibitor -→ prolongs NO-induced ↑cGMP.

24. Experimental Role
• Studies on endothelial dysfunction
• How can Endothelium-mediated
vasodilatation be inhibited?
– Remove endothelium
– Enhance binding of NO with Hb
– Inhibit NOS --- using analogs of L-arginine
– Knock-out mutation of the eNOS gene

25. HYPERTENSION
Peter Nuwagira, MPS

26. ANTIHYPERTENSIVE DRUGS
• WHAT YOU NEED TO KNOW
– What is Hypertension?
– Normal regulation of Blood Pressure
– Pathophysiology as a basis for pharmacotherapy
– Mechanism of action of the drugs/Classification
– Objective of therapy
• Control BP
• Prevent complications
– Non-pharmacological management

27. BP
Classification
SBP
(mm Hg)
DBP
(mm Hg)
Normal <120 and <80
Prehypertension 120– 139 or 80– 89
Stage 1 hypertension 140– 159 or 90–99
Stage 2 hypertension 160 or 100
Based on: Classification of Hypertension
Definition: Elevated Blood Pressure (BP).
(JNC7 2003)

28. Basis for Pharmacotherapy
• Understand normal regulation of BP
• Arterial BP = Cardiac Output (CO) X Peripheral
Vascular Resistance (PVR)
– CO ~ blood flow
– PVR ~ resistance to passage of blood in precapillary
arterioles
• CO = Stroke Volume (SV) X Heart Rate (HR)

29. Anatomic Sites of BP Control

30. Anatomic Sites of BP Control
• Arterioles (resistance vessels)
• Post-capillary Venules (capacitance vessels)
• Heart (pump)
• Kidney (intravascular fluid volume & osmolarity)
• CNS (central sympathetic discharge)

31. Regulation of BP
• BP is a well regulated parameter
• How is it regulated?
– Immediate → Baroreflexes
– Long-term → Humoral mechanisms

32. Baroreceptor Reflex Arc

33. Regulation of BP
• 1) Baroreflexes
– Mediated by autonomic nerves
– BP --> stimulates carotid baroreceptors (BR) → inhibition of central
sympathetic discharge → ↓BP
-↓BP → ↓stretch of BR →↓BR activity →↓inhibition of central sympathetic
discharge → BP
• Effects of  sympathetic discharge:
– constriction of arterioles ( → PVR)
– CO, by  contractility of the heart
–  constriction of venules → Venous return -→ CO
What are the receptor mechanisms involved??

34. Regulation of BP cont’d
• 2) Humoral Mechanisms
(a) Renin-Angiotensin-Aldosterone System (RAAS)
– ↓BP in renal arterioles → production of Renin →
Activation of the RAAS
(b) Local hormones (vasoactive substances): regulate
vascular resistance e.g.
- NO → vasodilation
- Endothelin → vasoconstriction

35. Effects of RAAS activation

36. Pathogenesis of Hypertension
• In Hypertension BP control is “dysregulated”
– BRs and renal blood-volume pressure control systems
appear to be “set” at a higher level of BP.
– Overactivation of the RAAS

37. Etiology of Hypertension
Primary - essential hypertension
➢no specific cause of hypertension can be found
About 85-90% of patients
Secondary - A specific cause of hypertension can be
established e.g.
➢Adrenal disorders (Cushing’s, pheochromocytoma)
➢Renal disease
➢Diabetes
Accounts for only 10-15% of HT patients

38. Essential Hypertension
The heritability of essential hypertension is
estimated to be about 30%.
Linked to mutations in several genes ;
➢e.g. variations of the angiotensinogen, ACE, or 2
adrenoceptor gene.

39. Etiology of Hypertension cont’d
Usually a combination of several abnormalities
(multifactorial).
Contributing factors
Genetic inheritance
Psychological stress
Environmental factors (e.g. smoking, physical inactivity)
Age (>55 in men, >65 in women)
Dietary factors
✓increased salt and decreased potassium or calcium intake
✓Obesity
✓Hyperlipidemia

40. Why is it very important to Treat or
control high BP?
• Avoid Complications: “End organ damage”
• Sustained Hypertension:
– 1) Damages blood vessels in the following organs:
eye, heart, vessels, brain & kidneys
– 2) Leads to an increased incidence of blindness,
coronary disease, cardiac failure arteriosclerosis,
renal failure,& stroke.

41. Complications

42. Complications cont,d

43. Antihypertensive agents
• Act at the anatomic sites involved in BP
control
• Interfere with normal mechanisms of BP
regulation
• Classification depends on:
– Principal regulatory site or
– Cellular mechanism of action

44. Drug Classification
• 1) Diuretics - ↓BP by depleting the body of sodium &
↓BV
• 2) Sympathoplegics - ↓BP by ↓PVR &CO
• 3) Direct Vasodilators – Relax vascular smooth m -→
vasodilatation -→ ↓PVR
• 4) RAAS antagonists - ↓Ang II or Aldo production or
block Ang II or Aldo receptors (-→ ↓PVR & CO)

46. Lifestyle Modifications to Manage HTN
Modification Recommendations Approximate Systolic
Blood Pressure
Reduction
Weight Reduction Maintain normal body weight (BMI
18.5-24.9)
5-20 mm Hg for each
10 kg weight loss
Adapt DASH eating plan Consume diets rich in fruits,
vegetables, low fat dairy and low
saturated fat
8-14 mm Hg
Dietary sodium reduction Reduce sodium to no more than
2.4 g/day sodium or
6 g/day NaCl
2-8 mm Hg
Increase physical activity Engage in regular aerobic activity
such as walking
(30 min/day on most days)
4-9 mm Hg
Moderate alcohol
consumption
Limit alcohol to no more than 2
drinks/d for men and 1 drinks/day
for women.
2-4 mm Hg
Source: The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure JNCVII. JAMA. 2003;289:2560-2572.

47. Diagnosis of HT
• Repeated, reproducible measurements of
elevated BP
– Use a sphygmomanometer
• Assess risk factors
• Assess presence of target organ damage
• Perform relevant laboratory and cardiac function
tests

48. Regulation of BP

49. Pathophysiology
• Arterial BP = CO X PVR
• CO = SV X HR
Any alterations in CO or PVR will affect BP

50. Basis of drug therapy
• SV-
• Diuretics
– CAI eg acetazolamide
– Thiazides eg hydrochlorthiazide
– Loops eg furosemide
– Osmotic eg mannitol
– Potasium sparing eg spironolactone
• drugs that alter RAS system
• ACEI eg captopril
• ARBs eg lorsatan
• Renin inhibitors eg alskeirin

51. • PVR- vasodilators
– Direct –oral & IV eg hydralazine
- IV eg nitroprusside
• CCB- ) Dihydropyridines
– 1st generation: Nifedipine
– 2nd “ : Amlodipine
• (II) Phenylalkylamines eg Verapamil
• (III) Benzothiazepines eg Diltiazem

52. • HR- sympathoplegics
– Centrally-acting eg methyldopa
– ganglionic blockers eg trimethaphan
– adrenergic neuron blockers
• Non selective  blockers eg phentolamine
• 1 prazosin
• non selective beta blockers eg propranolon
• 1 Eg atenolol
• Mixed & blockers eg carvedilol

53. RAAS SYSTEM

54. RAAS system
• Angiotensinogen secreted from the liver is
converted to angiotensin 1 with the help of
renin
• Angiotensin 1 is converted to angiotensin 11
by ACE.
• Chymase enzymes can also produce
insignificant amounts of angiotensin 11

55. Actions of angiotensin 11:
➢CVS- vasoconstriction
-increased heart rate
➢ADRENAL- increase synthesis and secretion of
aldosterone
➢KIDNEY- increase sodium reabsorption in PCT
➢CNS- stimulate ADH release(drinking water)
➢Increase NA release from autonomic ganglia
Thus increase in BP

56. • Renin release mechanisms are embedded in a
feedback regulation:
• ↑ renin secretion- ↑ Ag 11- stimulate AT1
receptor at JG cell- ↓ renin release. This
termed short -loop negative feedback

57. • Ag 11- ↑ BP- ↓ renal sympathetic tone
• -↓ NaCl reabsorption
• -↑ pressure in pressure in
preglomerular vessels
• Causing inhibition of renin secretion
• This is termed the long- loop negative
feedback

58. Pharmacological agents influencing
renin release
• Loop diuretics- block NaCl reabsorption- ↓ BP
= ↑ renin release
• NSAIDs- ↓ PG synthesis= ↓ renin release
• ACE inhibitors, ARBs, renin inhibitors –
interrupt long and short-loop negative
feedback mechanisms and cause an increase
in renin release

59. ACE inhibitors
• Examples: captopril, enalapril, lisinopril,
ramipril, fosinopril
MOA – inhibition of angiotensin converting
enzyme, thus decreasing the activity of RAS
They decrease peripheral vascular resistance
without increasing CO, HR or contractility (safe
in ischemic heart disease)

60. PK
• Apart from captopril and lisinopril, the rest are
pro drugs
• captopril is less potent, has fast onset and
short duration of action and less absorption in
presence of food in GIT.
• Because of short and fast action, it can cause
postural hypotension which is not seen with
other ACEI.

61. •
captopril enalapril fosinopril ramipril
Chemical
nature
sulfhydryl carboxyl phosphinate carboxyl
Activity status Active Prodrug Prodrug Prodrug
Plasma t1/2 2 hrs 11 hrs 12hrs 4-48 hrs
Excretion Renal Renal Renal /hepatic Renal

62. Uses
Hypertension
CHF
Myocardial Infarction
Diabetic nephropathy

63. ADR
• Hypotension- in patients on diuretics or with CHF.
• Hyperkalemia- With usage of NSAIDs and β
blockers.
• Angioedema- Swelling of lips, mouth, nose,
larynx.
• Cough
• Foetopathic- Foetal growth retardation,
hypoplasia of organs
• Rashes, headache, proteinuria, acute renal
failure.

64. Angiotensin receptor blockers
• Examples: losartan, valsartan, telmisartan
candesartan, olmesartan
• MOA- they block angiotensin 11 type 1
receptor (AT1) receptor.
• They have the potential for more complete
inhibition of angiotensin actions compared to
ACEI
• Have no effect on bradykinin metabolism

65. PK
• Losartan – 1-2 hrs, active metabolite t1/2 3-4
hrs
-Bioavailability 36%
• Candesartan – highest affinity for AT1 receptor
• Olmesartan- Ester prodrug

66. Uses
• Hypertension- Produces same effect like ACE
inhibitors without the adverse effects.
• CHF
• MI

67. ADR
• Hypotension
• Hyperkalemia
• Headache, dizziness and weakness.

68. Combination of ACE inhibitors with
ARB
• To obtain more complete inhibition of the
RAS.
• To have a cardioprotective and
nephroprotective action.
• Vasodilation by:
– 1. Ang (1-7) production by ACE inhibitors
– 2. inactivation of AT2 receptors by ARBs.

69. Direct Renin Inhibitors
• Examples: Aliskiren, remikiren and enalkiren
• MOA- binds to the catalytic site of renin to
inhibit its action
• They decrease the activity of RAS and cause a
fall in BP
• They can be used for treatment of chronic
hypertension in patients who do not tolerate
1st line drugs

70. ADR
• Dyspepsia
• Abdominal pain
• Headache, dizziness

71. Malignant HT
- diastolic pressure > 130 mm Hg
- severe impact on cardiovascular system, kidneys and
central nervous system.
-May arise in previously normotensive individuals, but
more commonly as a complication of benign HT.
- Relatively uncommon (1-5% of hypertensive
patients).
- Aggressive treatment is required.

72. Complications of HT
• CVS complications
Heart- increased workload on left ventricle
 Left ventricular hypertrophy
→ left ventricular failure.
- Greater thickness of left ventricle
 decreased perfusion and ischaemia of
subendocardial region of myocardium.

73. ➢Arteries
- Accelerated atherogenesis.
- Arterioles: Arteriolosclerosis
- Benign HT:
Deposition of eosinophilic (‘hyaline’)
material in vessel
walls due to influx of plasma proteins.

74. CNS
Rupture of micro-aneurisms of small penetrating
arteries  Intracerebral haemorrhage.
-  Risk of cerebral infarction due to atherosclerosis
of circle of Willis.
- Acute malignant HT: ‘Hypertensive encephalopathy’
due to cerebral oedema (headache, nausea and vomiting,
visual disturbances, seizures and disturbances of
consciousness).

75. Renal complications
 Ischaemic sclerosis of glomeruli and
tubular atrophy.
Proteinuria and microscopic haematuria,
especially in malignant HT .

76. VASCULITIS
Inflammation of blood vessel walls which may lead to
Thrombus formation in vessels with ischaemic effects.
-  Fragility of small vessels with petechial
haemorrages (skin and other organs).
- Weakening of vessel wall, with aneurism
formation.

77. Stepped care regimen
1. Lifestyle change- salt restriction, weight
reduction, stress reduction, exercise
2. Thiazide diuretic/ B-blocker/ ACEI
3. Step 2 in higher dose + additional drug
4. Use three or more drugs

78. DIURETICS

79. Introduction
Key terms:
• “Diuresis” – increase in urine volume
• “Natriuresis” – increase in renal Na+ excretion
• Nephron – the basic functional unit of the kidney
Learning Objectives
• Classify Diuretics
• Determine their mechanism/site action in relation to the nephron
• Learn the therapeutic uses
• Know the adverse effects
79

80. 80

81. Function of the Nephron
• Plasma entering the kidneys is filtered at the
glomerulus
• Components filtered include:
– Amino acids
– Glucose
– HCO3
-
– Electrolytes
• The kidney regulates ionic composition &
volume of urine by either reabsorption or
secretion of ions & H20.
81

82. Renal Tubule Transport
• PCT
– Isosmotic reabsorption of aa, glucose & numerous cations
– 60 – 70% Na+Cl- reabsorption
– major site for HCO3
- reabsorption [via carbonic anhydrase (CA)]
– *Target site for CA inhibitors
• TAL
– Pumps Na+,K+, 2Cl- out of lumen into the interstitium
– 20-30% of Na+ reabsorption [by the Na+/K+/ 2Cl- contransporter]
– Major site for Ca2+ & Mg2+ reabsrption
– Very low H2O permeability
– *Target site for loop diuretics
82

83. Renal Tubule Transport
• DCT
– Pumps Na+ & Cl- out of the lumen via a carrier
– 5-8% Na+ reabsorption
– Ca2+ reabsorption via PTH
– low H2O permeability
– *Target site for thiazide diuretics
• CCT (Collecting tubule/duct)
– Reabsorption of ions via channels
– 2-5% Na+ reabsorption with equivalent K+ or H+ ion loss
– Controlled by Aldosterone
– *target site for K+ sparing diuretics
– *target site for ADH that promotes H2O reabsorption
83

84. 84

85. 1. Carbonic anhydrase inhibitors
• Prototype: Acetazolamide
– Sulfonamide derivative
• Mechanism of action:
– Inhibits carbonic anhydrase in the PCT
• Pharmacological effects:
– Renal: HCO3
- diuresis
– Ocular: ↓ HCO3
- secretion into aqueous humor by the
ciliary epithelium-→ ↓IOP
– Brain: ↓ HCO3
- secretion into CSF by the choroid
plexus -→ acidosis of CSF → hyperventilation
85

86. 1. Carbonic anhydrase inhibitors
• Clinical Uses: generally a weak duiretic but used in:
– Glaucoma (IOP) ---- acetazolamide p.o; or dorzolamide
(topically)
– High altitude sickness
– Cerebral edema (e.g. in hydrocephalus, brain tumors)
• Adverse effects
– Hyperchloremic metabolic acidosis
– Cross-allergenicity with other sulfa drugs
– Renal stones
86

87. 2. Osmotic Diuretics
• Prototype: Mannitol
• Mechanism of action:
– Osmosis; it is freely filtered at the glomerulus
but poorly absorbed from the tubule, “holds
H2O in the lumen”
• Pharmacological effects:
– Renal: urine volume, Na+ excretion
– Brain: ↓ ICP
87

88. 2. Osmotic Diuretics
• Clinical Uses:
– Glaucoma
– Cerebral edema
– High solute overload ( as in severe hemolysis or
rhabdomyolysis)
• Adverse effects
– Headache, nausea & vomiting
– Hyponatremia (due to expansion of ECV)
– Relative hypernatremia if used extensively (due to severe
dehydration)
88

89. 3. Loop diuretics
• Prototype: Furosemide (Lasix®) – sulfonamide derivative
• Others:
– Bumetanide & Torsemide – ”
– Ethacrynic acid - phenoxyacetic derivative
• Mechanism of action:
– Inhibit cotransport of Na+, K+ & Cl- in the TAL of the loop of Henle
• Pharmacological effects:
– Renal:
• rapid/massive Na+ Cl- diuresis
• potassium wasting (due to excessive Na+ delivered in CT)
• loss of lumen positive potential( impaired absorption of other divalent
cations, Ca2+, Mg2+)
– Pulmonary: vasodilatory effect
89

90. 3. Loop Diuretics
Clinical Uses:
Hyperaldosteronism (mineralocorticoid excess)- [ e.g. liver
cirrhosis, chronic Heart failure)
Correct K+ wasting
Adverse effects
Hyperkalemia/hyperkalemic metabolic acidosis (because of
reduced K+ & H+ excretion)
Endocrine abnormalities (esp. Spironolactone – causes non-
selective MR receptor blockade) →
Gynecomastia (due to anti-androgenic effect)
Mentrual irregularities
90

91. 4. Thiazide diuretics
• Prototype: Hydrochlorothiazide – sulfonamide derivative
• Others:
– Chlorthalidone
– Bendroflumethiazide (Aprinox®)
– Metolazone
• Mechanism of action:
– Inhibit cotransport of Na+, Cl- in the early segment of the DCT
• Pharmacological effects:
– Renal:
• sustained/moderate Na+ Cl- diuresis
– Vascular: ↓peripheral vascular resistance
91

92. 4. Thiazide diuretics
• Clinical Uses:
– Edematous states - – chronic therapy
– Hypertension (most commonly used class in long term
therapy)
– Hypercalcemia
• Adverse effects
– Hypokalemic metabolic alkalosis
– Hypovolemia
– Ototoxicity
– Sulfonamide allergy
– Hyperuricemia (precipitation of gout, competes with uric
acid for renal secretion)
92

93. 5. Potassium-sparing diuretics
• 2 groups:
1) Aldosterone receptor antagonists (Spironolactone,
Eplerenone)
– Mechanism: Block intracellular ALDO receptors -→
↓expression of genes that control synthesis of epithelial
Na+ channels & Na+/K+ ATPase.
2) Na+ channel blockers (Amiloride, Triamterene)
• Pharmacological effects:
– Renal:
 Na+ clearence
• ↓K+ & H+ ion excretion (hence K+ sparing)
93

94. 5. Potassium-sparing diuretics
• Clinical Uses:
– Hyperaldosteronism (mineralocorticoid excess)- [ e.g.
liver cirrhosis, chronic Heart failure)
– Correct K+ wasting
• Adverse effects
– Hyperkalemia/hyperkalemic metabolic acidosis (because
of reduced K+ & H+ excretion)
– Endocrine abnormalities (esp. Spironolactone – causes
non-selective MR receptor blockade) →
• Gynecomastia (due to anti-androgenic effect)
• Mentrual irregularities
94

95. 95

96. Electrolyte changes produced by diuretic
drugs
96

97. Study questions: Ref Katzung
To further understand the Clinical Pharmacology of Diuretics,
discuss the basis for their use in management of the
following conditions:
1. Edematous states
– Heart failure
– Kidney disease
– Hepatic cirrhosis
– Idiopathic edema
2. Non-edematous states
– Hypertension
– Nephrolithiasis
– Hypercalcemia
– Diabetes insipidus 97

98. Study Questions cont’d
• How does the action of a diuretic that acts on cells in the
ascending limb of the loop of Henle cause an increase in
the urinary excretion of Mg2+ and Ca2+?
• How do indomethacin and probenecid affect the diuretic
action of frusemide?
• What is the precaution concerning the use of frusemide
in patients receiving aminoglycoside antibiotics?
• Patients who are allergic to ---------------should not take
frusemide, bumetanide, torsemide, acetazolamide or
thiazides.
98

99. Study questions cont’d
• For the items below (a-j) select the option that is
most closely associated with it (1-8) [in next 2 slides]
(a) Acetazolamide
(b) Amiloride
(c) Demecyclocycline
(d) Desmopressin
(e) Ethacrynic acid
(f) Frusemide
(g) Metozalone
(h) Mannitol
(i) Spironolactone
(j) Triamterene 99

100. Study questions Cont’d
• 1.Causes a self-limiting diuresis and a
hyperchloremic metabolic acidosis
• 2.Is not a thiazide but has its major effect in the
distal convoluted tubule
• 3.Increaseas the formation of dilute urine in
water-loaded subjects; used to treat SIADH
• 4.Useful in glaucoma and high-altitude sickness
100

101. Study questions Cont’d
• 5.Acts in the thick ascending limb of the loop of
Henle; no cross allergenicity with thiazides
• 6.Can reduce binding of aldosterone to its
receptor
• 7.Very useful in the treatment of acute
pulmonary edema
• 8. Most useful in a patient with brain edema
101

102. Sympathoplegics

103. Sites of Action

104. Classification
• Blockers of:
– Central sympathetic outflow
– Sympathetic ganglia
– Sympathetic nerve terminals
– - or -adrenoceptors

105. CNS sympathetic outflow blockers
• Site:
– Nucleus of tractus solitarius & Vasomotor center
• Examples: Clonidine, Methyldopa
• Mechanism of action:
– Clonidine is an 2-selective agonists – stimulate
presynaptic 2-receptors in the brain -→ ↓ central
adrenergic outflow

106. CNS sympathetic outflow blockers
• Methyldopa -Converted to alpha methyl
noradrenaline which acts on alpha-2
receptors in brain and causes inhibition of
adrenergic discharge in medulla –fall in
PVR and fall in BP
• Not used therapeutically now except in
Hypertension during pregnancy

107. CNS sympathetic outflow blockers
• Therapeutic uses:
– Hypertension (essential, PIH)
– Hypertensive emergencies → Clonidine
• Adverse effects:
– Salt retention
– Rebound HT-→ esp. Clonidine
– Sedation, drowsiness, somnolence
– Positive coombs test -→ methyldopa

108. Ganglion Blockers
• Examples: Hexamethonium, Trimethaphan
• MOA: block postganglionic sympathetic and
parasympathetic outflow
• Pharmacological Effects:
– Very potent BP lowering drugs
• Therapeutic uses:
– Considered obsolete because of toxicity

109. Ganglion Blockers
Adverse effects due to:
• 1)Parasympathetic blockade
– Blurred vision, constipation, urinary hesitancy,
impotence
• 2) Sympathetic blockade
– Retrograde ejaculation, orthostatic
hypotension

110. Sympathetic nerve terminal blockers
1) Reserpine & Guanethidine
• MOA - Binds tightly to storage vesicles at neuronal terminals and inhibit
concentration of catecholamines into vesicles. Catecholamines remain
in the cytoplasm-degraded. Reduce both cardiac contractility and
peripheral resistance
• Clinical use
– In combination with other antihypertensive especially thiazide diuretics are used in
management of HTN
• ADR
– C.N.S (sedation )
– Psychotic depression-may lead to suicide. Discontinue immediately signs if
depression start
– Nasal stuffiness

111. 4. Adrenoceptor Blockers
(i) -1 selective blockers: Doxazosin, Prazosin, Terazosin
• MOA: block post-synaptic vasoconstrictor effects of NE
• Pharmacological effects: relaxation of both arterial &
venous smooth muscle → ↓PVR
• Clinical Use:
– Hypertension
– Prostatism (BPH)
• Adverse effects:
– Dizziness
– Reflex tachycardia
– First-dose syncope [“first-dose phenomenon”]

112. 4. Adrenoceptor Blockers
(ii) Non-selective -blockers
– phentolamine (competitive inhibitor)
– Phenoxybenzamine (non-competitive inhibitor)
• Clinical use:
– secondary HT associated with excess catecholamine
release
– Pheochromocytoma (preoperatively , inoperable or
metastatic)
• Adverse effects:
– Excessive compensatory responses – reflex
tachycardia, Na+ & H2O retention

113. 4. Adrenoceptor Blockers
• (iii) -blockers
• Beta-1 receptors (heart)
• Beta-2 receptors (blood vessels, lungs)
Selective 1 Non selective
Atenolol Propanolol
Metoprolol Nadolol
Acetutolol Pindolol
Esmolol Timolol

114. Action of -adrenoceptor blocking drugs

115. -blockers
• Therapeutic uses
– Hypertension
– Supraventricular arrythmias
– Angina pectoris
– Myocardial infarction (prevent recurrence)
– Hypertrophic cardiomyopathy
– Migraine
– Somatic manifestations of anxiety (tremor, sweating,
tachycardia etc)
– Essential tremor
– Reflex tachycardia assoc. with use of other drugs

116. -blockers -adverse effects
Common:
• CVS: bradycardia, hypotension
• CNS: sleep disturbances – insomnia, nightmares,
hallucinations
• Sedation, fatigue
• Sexual dysfunction - ↓libido, impotence
Others:
• Altered serum lipid patterns – slight  plasma triglycerides,
↓HDL
• Drug withdrawal – rebound HT/ palpitations--→upregulation
of -receptors; therefore taper dose on withdrawal.

117. -blockers –Cautions/contraindications
• Chronic obstructive airways disease (COAD) ---
e.g. bronchial asthma
– Blockade of 2-mediated bronchodilation
– 1- blockers relatively safer
• Chronic CHF
• IDDM
– worsen glucose intolerance
– Mask symptoms of hypoglycemia -→ prolonged
hypoglycemia

118. 4. Adrenoceptor Blockers
(iv) Non-selective adrenoceptor blockers (1,
2, 1)
– Labetalol (1 = 2 = 1)
– Carvedilol (1 = 2 > 1)
• Pharmacological Effects:
– 1& 2 blockade -↓HR, ↓myocardial contractility,
↓myocardial O2 demand
– 1 blockade - ↓PVR
– antioxidant

119. Non-selective adrenoceptor blockers cont’d
• Clinical Uses:
– HT
– Mild-moderate CHF
– Ischemic Heart disease
– Chronic stable angina
• Adverse effects:
– CVS: bradycardia, postural hypotension, syncope, AV
block
– GIT: A, N,V,D
– CNS: diziness, insomnia, somnolence

120. Vasodilators & CCBs

121. (A) DIRECT ACTING VASODILATORS
Classification:
• Orally & Parenterally active
– Hydrallazine
– Minoxidil
• Parenteral Only
– Nitroprusside
– Diazoxide

122. Hydralazine
• MOA:involves release of NO from vascular endothelial cells →
stimulation of guanylyl cyclase→ ↑cGMP in smooth m. cells
→ arteriolar dilation → ↓PVR
PK
• Hydralazine is well absorbed after oral administration.
• Under goes first pass effect of the liver following oral
absorption
• Its peak antihypertensive effect occurs in about 1 hour, and its
duration of action is about 6 hours.
• The drug is highly bound to plasma proteins and has a half life
of 1.5-3hours
• It’s metabolized in the liver and mainly excreted in urine.

123. • Clinical Use: mod-severe hypertension (in
combo with diuretic & β-blocker
• Side effects
• Hypotension
• Headache
• Tachycardia,
• Palpitations

124. Minoxidil
• Mechanism: opens K+ channels→ ↑IC K+ →
hyperpolarization of vascular smooth m. cells→
vasorelaxation
• Clinical Use:
– Severe – malignant HT (refractory to other drugs)
– Male pattern baldness (used topically- ↑
microcirculation around hair follicles
• Adverse effects:
– compensatory responses (reflex tachycardia, Na+ &
H20 retention)
– Volume overload, edema, CHF, Pericardial effusion

125. Sodium Nitroprusside
• Mechanism:
– stimulates release of NO in vascular smooth m. cells
– Vasodilator effect equal in both arterial & venous system
– Venodilation → ↓cardiac preload
• Clinical Use: Hypertensive emergencies
– adm. IV & requires continuous infusion coz of v.short t1/2.
• Adverse effects:
– Excessive hypotension
– Reflex tachycardia
– Cyanide toxicity
• Rx with sodium thiosulfate

126. Diazoxide
Mechanism: opens K+ channels→ ↑IC K+ → hyperpolarization of
vascular smooth m. cells→ vasorelaxation
• Effects: direct acting arteriolar dilator
Clinical use:
• Hypertensive emergencies
– Malignant HT
– Hypertensive encephalopathy
– Eclampsia
Adverse effects:
• Hypotension
• Hyperglycemia
• Na+ & H20 retention

127. (B) CALCIUM CHANNEL BLOCKERS
Classification: 3 Major classes
• (I) Dihydropyridines
– 1st generation: Nifedipine
– 2nd “ : Amlodipine, felodipine, Nisoldipine
• (II) Phenylalkylamines
– Verapamil
• (III) Benzothiazepines
– Diltiazem

128. CALCIUM CHANNEL BLOCKERS
Mechanism:
• Block voltage-dependent “L-type” calcium channels (important in
cardiac and smooth muscle of coronary & peripheral blood
vessels)
• ↓Ca2+ influx during action potentials → ↓IC Ca2+ → ↓smooth
muscle contractility (-ve inotropic effect)
Pharm effects:
• Vasorelaxation esp. Dihydropyridines
• ↓HR & Contractility (Diltiazem > Verapamil > Dihydropyridines)

129. Therapeutic Indications
• Hypertension (chronic therapy) – [esp. the dihydropyridines]
– Good oral bioavailabilty
– Fewer compensatory responses
– Relatively safer in patients with asthma, diabetes, angina & peripheral
vasc. Dx
– Effective in almost all forms of HT, in all races & at any age
– ↓incidence of stroke & improved cognition in the elderly
• Angina (prophylaxis & Rx) – [esp. Verapamil]
• Supraventricular tachyarrythmias [Verapamil]
• Other uses: Migraine, peripheral vasc. Dx, preterm labor

131. Adverse effects
• GIT disturbances - nausea, constipation [esp. Verapamil]
• Flushing, headache, dizziness, fatigue ---d/t arteriolar
dilation
• Peripheral edema – d/t arteriolar dilation >> venous
dilation →transcapillary pressure gradient {rather than
Na+ & H2O retention}
– Not common (coz of intrinsic natriuretic effect, esp. 2nd gen.
dihydropyridines)
• AV block, sinus node depression [esp. Verapamil] –d/t –
ve inotropic effect

132. Managing Special forms of HT
• DM- ACE, ARBs prevent nephropathy
• Renal disease- loops
• Pregnancy – methyldopa, nifedipine, labetalol
• Crisis/ urgency- (orals)- CCBs
• Emergency-(IV) sodium nitroprusside, glycerile
trinitrate, hydralazine
In @ case which drugs should be avoided and
why?

133. It has been a pleasure!
Thank you