Antihypertensive Drugs

BBMS 3014
Advanced Pharmacology Course

Susan Leung
Department of Pharmacology and Pharmacy
The University of Hong Kong
Learning Outcomes

• Identify the need for maintaining normal blood pressure

• Describe the four major types of antihypertensive drugs

• Explain how these drugs produce their therapeutic effects

• Recognize the adverse effects and the limitation of different

antihypertensive agents

• Indicate the rationale of the use of combination regime

Hypertension

• Most Common Cardiovascular Diseases

• Persistent  Blood Pressure

- associated with  resistance to blood flow, normally with
normal cardiac output
  risk of coronary thrombosis, strokes, and heart and renal
failure

• Asymptomatic
- symptoms only reported when there is end-organ damage
Risk of Cardiovascular Diseases and
Hypertension

Mancia G et al. 2007. Eur Heart J 28: 1462-1536

Causes of Hypertension
• Essential or Primary Hypertension
- unknown cause
- multifactorial:
genetic inheritance
psychological stress
dietary factors e.g.  intake of sodium and cholesterol
life styles e.g. smoking
existing conditions e.g. obesity, diabetes

• Secondary Hypertension
- specific cause
e.g. pheochromocytoma
Cushing’s disease
primary aldosteronism
renal artery constriction
Regulation of Blood Pressure

Source: Harvey RA, Champe PC (Eds). Pharmacology 4th Edition. p.217

• Heart
- cardiac output  blood pressure

• Arterioles → peripheral vascular resistance

(PVR)  blood pressure
• Capacitance vessels

• Kidneys
- regulate intravascular fluid (blood volume)
Role of Sympathetic Nervous System in the
Regulation of Blood Pressure
Anti-hypertensive Drugs
• Diuretics   blood volume

• Angiotensin Converting Enzyme Inhibitors /

Angiotensin Receptor Antagonists /
Renin Inhibitors
 inhibit synthesis or action of angiotensin II
  peripheral vascular resistance
  blood volume (slightly diuretic)

• Vasodilators   peripheral vascular resistance

• Sympathoplegic (Sympatholytic) Agents

 interfere sympathetic nervous system
  peripheral vascular resistance
  cardiac output
Diuretics
Diuretics With Anti-hypertensive Actions

• Loop Diuretics
e.g. furosemide,
ethacrynic acid

• Thiazide Diuretics
e.g. hydrochlorothiazide, Cortex

chlorthalidone Cortex
Medulla
Medulla

• Potassium-Sparing
Diuretics
e.g. amiloride, spironolactone
Rang, Dale, Ritter, Moore; Pharmacology, 5th Edition
(1) Na+/H+ exchange PCT- proximal convoluted
(2) Na+/K+/2Cl- co-transport tubule
(3) Na+/Cl- co-transport TAL- thick ascending loop
DT - distal tubule
(4) Na+ channel
CT - collecting tubule
Loop Diuretics
 Loop of Henle – Thick Ascending Limb
Lumen Thick Interstitium
(urine) Ascending (Blood)
Limb
Na+ Na+
K+ ATP
2Cl- K+

K+ K+
(+)
Cl-
Potential
(2) Na+/K+/2Cl- TAL- thick ascending loop Mg2+, Ca2+
co-transport DT - distal tubule
(3) Na+/Cl- CT - collecting tubule
co-transport
(4) Na+ channel

Re-absorption of sodium chloride in the thick ascending

limb of the loop of Henle
- generated by Na+/K+/2Cl- co-transporter
 dilution of tubular fluid
 contribute to the medullary hypertonicity
Loop Diuretics
Lumen Thick Interstitium
(urine) Ascending (Blood)
Limb
Na+ Na+
K+ ATP
Loop Diuretics
e.g. furosemide,
 2Cl- K+
ethacrynic acid K+
(+) K+
Cl-
Potential
Mg2+, Ca2+

- inhibit Na+/K+/2Cl- co-transport in the thick ascending loop of

Henle
 inhibit Na+ and Cl- re-absorption
  renal excretion of water and Na+
  loss of K+ and H+ in collecting tubule
  re-absorption of Mg2+ and Ca2+
Adverse Effects of Loop Diuretics
• Hypokalemia
 exacerbate cardiac arrhythmias
- reversed by  Na+ intake or K+ replacement

• Metabolic Alkalosis
- due to  loss of H+ in collecting tubule
 further compromise cardiac function
- reversed by K+ replacement

• Hyponatremia
- due to depletion of Na+
 extracellular fluid depletion
(hypotension, reduced GFR, circulatory collapse, thromboembolic
episodes, hepatic encephalopathy)
Adverse Effects of Loop Diuretics
• Hypomagnesemia
- exacerbate cardiac arrhythmias

• Hyperuricemia
- due to hypovolemia causing  re-absorption of uric acid
 gout

• Hyperglycemia, Hyperlipidemia

• Ototoxicity (more likely with ethacrynic acid)

- due to inhibition of electrolyte transport
in the inner ear
- mostly reversible
- least likely with oral administration

• Sulfonamide-related Allergic Reactions

(not with ethacrynic acid, which is a phenoxyacetic acid derivative)
Causes for Resistance to Loop Diuretics
• Reduction in renal blood flow
[e.g. in renal failure or induced by drugs]
  delivery of diuretics to the kidneys
 accumulation of endogenous organic acids
  active transport of diuretics at the proximal tubule

• Drug interaction
-  expression of Na+/K+/2Cl- co-transporter e.g. NSAID
- compete for organic acid transport system in the proximal
tubule e.g. probenecid

• Increased proximal tubular Na+ reabsorption

[e.g. in hepatic cirrhosis, nephrotic syndrome or heart failure]
  delivery of Na+ to the loop of Henles
Thiazide Diuretics
 Distal Tubule
Lumen Distal Tubule Interstitium
(urine) (Blood)
Na+
ATP
Na+
K+
Cl- K+
Cl-
Na+
Ca2+ Ca2+
(2) Na+/K+/2Cl- TAL- thick ascending loop
co-transport DT - distal tubule
(3) Na+/Cl- CT - collecting tubule
co-transport
(4) Na+ channel

Re-absorption of sodium chloride in the distal

convoluted tubule
- generated by Na+/Cl- co-transporter
 dilution of tubular fluid
[Note: most Na has been reabsorbed at sites before reaching the distal tubule]
Thiazide Diuretics
Lumen Distal Tubule Interstitium
(urine) (Blood)
Na+
ATP
Na+
Thiazide Diuretics  Cl- K+
K+
e.g. hydrochlorothiazide,
chlorthalidone Cl-
Na+
Ca2+ Ca2+

- inhibit Na+/Cl- co-transport in the distal convoluted tubule

 inhibit Na+ and Cl- re-absorption
  re-absorption of Ca2+
Adverse Effects of Thiazide Diuretics

• Hypokalemia

• Metabolic Alkalosis
Similar to
• Hyponatremia, Hypomagnesemia Loop Diuretics

• Hyperuricemia
Adverse Effects of Thiazide Diuretics
• Hypercalcemia
- rare
- unmask hypercalcemia due to other causes
e.g. hyperparathyroidism

• Hyperglycaemia
 exacerbate diabetes
- may involve reduced insulin secretion and alterations in
glucose metabolism
- partially reversed with correction of hypokalemia

• Hyperlipidemia
- may return towards baseline after prolonged use

• Sulfonamide-related Allergic Reactions

Potassium-Sparing Diuretics
 Collecting Tubule
Lumen Collecting Interstitium
(urine) Tubule (Blood)

Na+

K+ Na+
ATP
H2O K+

(2) Na+/K+/2Cl- TAL- thick ascending loop Cl-

co-transport DT - distal tubule
(3) Na+/Cl- CT - collecting tubule HCO3-
co-transport ATP
(4) Na+ channel
H+ Cl-

Re-absorption of sodium chloride in the collecting tubule

- determine the final concentration of Na+ in the urine
- absorptive capacity depends on Na+ concentration in the lumen
 secretion of positive ions e.g. K+ and H+
Potassium-Sparing Diuretics
Lumen Collecting Interstitium
(urine) Tubule (Blood)

K+-Sparing Diuretics  Na+

e.g. amiloride,
spironolactone, eplerenone K+ Na+
ATP
H2O K+

Cl-
HCO3-
ATP
H+ Cl-

- inhibit Na+/K+ exchange in the collecting tubule

 inhibit re-absorption of Na+
  excretion of K+
Potassium-Sparing Diuretics
Lumen Collecting Interstitium
(urine) Tubule (Blood)

K+-Sparing Diuretics  Na+

e.g. amiloride,
spironolactone, eplerenone K+ Na+
ATP
H2O K+

Cl-
HCO3-
ATP
H+ Cl-

- Amiloride
- inhibits Na+ channel activity in the
collecting tubule
- Spironolactone, eplerenone
- antagonize aldosterone receptor
Actions of Aldosterone

1. activation of membrane-bound Na+

channels;
2. redistribution of Na+ channels from cytosol
to membrane;
3. de novo synthesis of Na+ channels;
4. activation of membrane-bound Na+/K+-
ATPase;
5. redistribution of Na+/K+-ATPase from
cytosol to membrane;
6 de novo synthesis of Na+/K+-ATPase;
7. changes in permeability of tight junctions;
8 increased mitochondrial production of ATP

AIP, aldosterone-induced proteins; ALDO, aldosterone; BM, basolateral membrane; LM, luminal
membrane; MR, mineralocorticoid receptor; CH, ion channel
Actions of Aldosterone

-  Na+ conductance in luminal

membrane
-  activity of Na+/K+-ATPase
in basolateral membrane
  reabsorption of sodium
chloride in collecting tubule

AIP, aldosterone-induced proteins; ALDO, aldosterone; BM, basolateral membrane; LM, luminal
membrane; MR, mineralocorticoid receptor; CH, ion channel
Aldosterone Antagonists e.g. spironolactone, eplerenone

- inhibit Na+ influx in the

collecting tubule
 inhibit Na+ re-absorption
  K+ excretion

AIP, aldosterone-induced proteins; ALDO, aldosterone; BM, basolateral membrane; LM, luminal
membrane; MR, mineralocorticoid receptor; CH, ion channel
Adverse Effects of K+-Sparing Diuretics
• Hyperkalemia
 exacerbate cardiac arrhythmias
- enhanced in renal diseases, or with intake of drugs like
ACE inhibitors / angiotensin receptor blockers
- reversed by thiazide diuretics

• Metabolic Acidosis
- due to inhibition of the excretion of H+
 further compromise cardiac function

• Gynecomastia, Impotence, Menstrual Irregularities

- selective to spironolactone
 spironolactone is also an antagonist for androgen and
progesterone receptors
(not with eplerenone – no effects on these receptors)
Characteristics of Diuretics
• Efficacy in reducing blood volume:
- loop diuretics > thiazide diuretics > K+-sparing diuretics

Cortex

Medulla

Rang, Dale, Ritter, Moore; Pharmacology, 5th Edition

Characteristics of Diuretics
• Efficacy in reducing blood volume:
- loop diuretics > thiazide diuretics > K+-sparing diuretics

• Thiazide Diuretics
- mild to moderate hypertension   10-15 mmHg
- longer acting with slightly safer profile
 for chronic use

• Loop Diuretics [limited antihypertensive usage]

- more acute and profound diuresis
 effective for more severe hypertension
 more adverse effects?
- short half-life  postdiuretic Na+ re-absorption

• K+-Sparing Diuretics [limited blood pressure lowering effect]

- combine with other antihypertensive drugs
 Inhibitors of
Renin-Angiotensin System
 Renin-Angiotensin System

Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction Fluid Retention Vasodilatation

- direct action on smooth muscle -  Na+ reabsorption in proximal tubule
-  sympathetic function -  release of aldosterone and vasopressin
 Inhibition of Renin-Angiotensin System

Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction Fluid Retention Vasodilatation

Angiotensin Converting Enzyme (ACE) Inhibitors
•  Formation of Angiotensin II
e.g. captopril, enalapril, lisinopril, quinapril

Angiotensin Receptor Blockers (ARB)

• Inhibit the Actions of Angiotensin II
e.g. losartan, valsartan

Renin Inhibitors
•  the Activity of Renin
e.g. aliskiren

  vasoconstriction   peripheral vascular resistance

  fluid retention   blood volume (slightly diuretic)
Adverse Effects of ACE Inhibitors / ARB /
Renin Inhibitors
• Severe Hypotension (e.g. in patients with fluid loss)

• Acute Renal Failure

• Hyperkalemia ( caution with K+-sparing diuretics)

• Risk of Fetal Hypotension, Renal Failure or

Malformation
( contraindicated during pregnancy)

• Dry Cough
more selective to ACE inhibitors
• Angioedema [due to  level of bradykinin]
Advantages of Angiotensin Receptor Blockers (I)
• More complete blockade of renin-angiotensin-
aldosterone system
(because angiotensin II can be formed through ACE-independent
pathways)
Angiotensinogen

Elastase Renin
Proteinase 3

Chymases Angiotensin I
Cathepsin G
Cathepsin G
Angiotensin
Elastase Converting Enzyme
Proteinase 3

Angiotensin II
Advantages of Angiotensin Receptor Blockers (II)
• Do not affect the functions of type II angiotensin
receptors
(AT2 receptors  vasodilatation  additional benefit?
 bradykinin release  angioedema?)
Insufficiency of ACE Inhibitors and ARB
• Interrupt the negative feedback action of angiotensin II
  renin release from the juxtaglomerular cells in the kidney
 limit the effectiveness of ACE inhibitors and ARB
 development of renin inhibitors
Angiotensinogen

Renin

Angiotensin I
Negative Feedback
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor
 Renin-Angiotensin System

Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction Fluid Retention Vasodilatation

- direct action on smooth muscle -  Na+ reabsorption in proximal tubule
-  sympathetic function -  release of aldosterone and vasopressin
 Renin-Angiotensin-Aldosterone System

Angiotensinogen
Renin Bradykinin
Angiotensin I
Angiotensin
Converting Enzyme
Angiotensin II
Angiotensin Receptor Inactive Metabolite

Vasoconstriction Fluid Retention Vasodilatation

- direct action on smooth muscle -  Na+ reabsorption in proximal tubule
-  sympathetic function -  release of aldosterone and vasopressin
Aldosterone “Escape”
• Alternative mechanisms for aldosterone production
 limit the effectiveness of angiotensin inhibitors (renin
inhibitors)
 ACE inhibitor resistance ?
 development of aldosterone antagonists
Angiotensin II

Angiotensin Receptor
Adrenocorticotrophic
Hormone (ACTH)
Positive Feedback
Aldosterone

 Potassium
Aldosterone Antagonists
e.g. spironolactone, eplerenone

• Compete with aldosterone for its receptors

• Considered as potassium sparing diuretics

[please refer to the notes in the previous slides]

 limited blood pressure lowering effect

Adverse Effects of Aldosterone Antagonists
[please refer to the notes in the previous slides]

• Hyperkalemia

• Metabolic Acidosis

• Gynecomastia, Impotence, Menstrual Irregularities

 spironolactone is also an antagonist for androgen and
progesterone receptors
(not with eplerenone – no effects on these receptors)

 Cautious with concomitant use with

ACE inhibitors/ARB (renin inhibitors)
Vasodilators
Vasodilators
• Calcium Channel Blockers
e.g. nifedipine and amlodipine (dihydropyridines), diltiazem, verapamil

• Potassium Channel Openers

e.g. minoxidil

• Nitrovasodilators
e.g. nitroprusside, nitroglycerides

• Hydralazine

• Diazoxide

• Fenoldopam
Calcium Channel Blockers
e.g. nifedipine and amlodipine (dihydropyridines), diltiazem, verapamil

• Inhibit voltage-operated calcium channels (L-type)

- in the blood vessels
  vasoconstriction
  peripheral vascular resistance
- in the heart
  rate and force of contraction
  cardiac output

• Adverse Effects
- depends on selectivity on cardiac or vascular smooth muscle
- drugs with vascular selectivity e.g. nifedipine (dihydropyridines)
 reflex tachycardia
- drugs with cardiac selectivity e.g. verapamil
 heart failure [exaggerated by b-adrenoceptor blockers]
Characteristics of Calcium Channel Blockers
• Short half-life e.g. nifedipine
 oscillation in blood pressure
 surges in sympathetic reflex activity within each
dosage interval [limited clinical usage]

• Sustained-release formulations/Long half-life

relative constant plasma concentration
  adverse effects e.g. flushing, dizziness, peripheral oedema

• Actions in nonvascular smooth muscle

- inhibit contraction of lower oesophageal sphincter
 gastroesophageal reflux

• Variations in antihypertensive effectiveness

- effective for isolated systolic hypertension
- effective in patients with low renin status
e.g. elderly and African-Americans
Potassium Channel Openers e.g. minoxidil

• Dilators of Arterioles
  peripheral vascular resistance

• Adverse Effects
- reflex tachycardia
- reflex retention of Na+ and water

• Used as last resort to treat severe hypertension [in

combination with other antihypertensive drugs]
Nitrovasodilators e.g. nitroprusside, nitroglyceride
• Vasodilators of Arteries and Veins
  peripheral vascular resistance
  amount of blood returning to the heart

• Nitroprusside
- intravenous infusion  limited clinical use
- rapidly  blood pressure and short-acting
 for hypertensive crisis e.g. during surgery
- break down to thiocyanate
 thiocynate toxicity [e.g. disorientation, convulsions]
especially in patients with renal insufficiency
 only short term treatment [risk  if infused for > 24-48 hours]

• Organic Nitrates e.g. nitroglycerin

- tolerance
 not useful for long-term therapy
Mechanism of Action of Nitrovasodilators
(e.g. nitroglycerin, isosorbide dinitrate)

Nitrovasodilator
 nitric oxide (NO)

Production of cyclic
guanosine
monophosphate
(cGMP)

dephosphorylation of
myosin light chain

relaxation
Unwanted Effects of Nitrovasodilators
(e.g. nitroglycerin, isosorbide dinitrate)

• Tolerance (Tachyphylaxis)
-  response to nitrates
- due to frequently repeated or continuous exposure to
nitrates
with long acting nitrates (isosorbide dinitrate)
or prolonged infusion or slow-release forms of short-acting nitrates
(nitroglycerin)
 administered with a “nitrate-free” period
(8 to 12 hours each day;
usually at night with low physical activity
= low demand for O2)
Unwanted Effects of Nitrovasodilators
(e.g. nitroglycerin, isosorbide dinitrate)

• Dependence
- Withdrawal Symptoms
  risk of coronary and digital arteriospasm
 Not to withdraw nitrovasodilators abruptly from a
patient after chronic therapy

• Adverse Effects
- headache
- postural hypotension
(transient episodes of dizziness and weakness)
- tachycardia
Precautions with the Use of Nitrovasodilators
(e.g. nitroglycerin, isosorbide dinitrate)

Effect of Nitrovasodilator
- enhanced by
phosphodiesterase (PDE)
inhibitor, e.g. sildenafil
 reflex tachycardia
Compensatory Responses to Vasodilators

2
Effects blocked by diuretics
Effects blocked by b-adrenergic receptor  basis for combination therapy
blockers
Sympathoplegic / Sympatholytic
Agents
Sympathoplegic Agents
• Adrenergic Receptor Blockers
- inhibit b-adrenergic receptors in heart
e.g. propanolol, metoprolol, pindolol
- inhibit -adrenergic receptors in blood vessels
e.g. prazosin, doxazosin

• Adrenergic Neuron-Blocking Drugs

- inhibit release of neurotransmitters (noradrenaline) from
postganglionic sympathetic neurons
e.g. reserpine

• Centrally Acting
- affect sympathetic nervous system in the brain
e.g. methyldopa, clonidine
Sites of Action of Sympathoplegic Agents

Rang, Dale, Ritter, Moore; Pharmacology, 5th Edition

b-Adrenergic Receptor Blockers
e.g. propanolol, metoprolol, pindolol

• Inhibit b-adrenergic receptors in heart

  rate and force of contraction of heart
  cardiac output

• Inhibit b-adrenergic receptors in kidneys

  activation of renin production
  Na+ and water retention

• Inhibit peripheral presynaptic b-adrenergic receptors

  release of neurotransmitter (noradrenaline)
  sympathetic vasoconstrictor nerve activity
  peripheral vascular resistance
Adverse Effects of b-Adrenergic Receptor Blockers
e.g. propanolol, metoprolol, pindolol

• Inhibit b-adrenergic receptors in

respiratory tract Less with
 bronchospasm β1-selective
 contraindicated in patients with asthma or receptor
other forms of obstructive airways disease blockers
because of
• Inhibit b-adrenergic receptors in the liver their cardiac
selectivity
  risk of hypoglycemia
 contraindicated in patients with diabetes
Less with
• Inhibit b-adrenergic receptors in heart pindolol
  rate and force of contraction of heart because it has
small effect
  risk of arrhythmias and heart failure on heart
function
b-Adrenergic Receptor Blockers With
Vasodilating Effects
• Labetalol and Carvedilol
- inhibit β- and α-adrenergic receptors
• Nebivolol
- inhibits β1-adrenergic receptors
- stimulates release of nitric oxide from endothelial cells

Short-Acting b-Adrenergic Receptor Blockers

• Esmolol
- inhibits β1-adrenergic receptors
- short half-life (9-10 minutes)
 constant intravenous infusion
 for management of intraoperative and postoperative
hypertension, and for hypertensive emergencies
Precautions with b-Adrenergic Receptor Blockers
• Withdrawal syndrome
- due to upregulation/supersensitivity of b-adrenergic receptors
  sensitivity to sympathetic activation
 rebound hypertension, tachycardia, nervousness
 gradual dosage reduction

• Drug interaction
e.g. antihypertensive effects  by nonsteroidal anti-inflammatory drugs
risk of severe hypertension with adrenaline/cocaine administration

• Concurrent conditions
e.g. hypoglycemia
pheochromocytoma
clonidine withdrawal
 severe hypertension with
non-selective β-adrenergic
receptor blockers
1-Adrenergic Receptor Blockers
e.g. prazosin, doxazosin

• Inhibit 1-adrenergic receptors in arterioles and

venules
 dilate arterioles and veins
  peripheral vascular resistance

• Selectivity at 1-adrenergic receptors

 mild unwanted effects
e.g. dizziness, palpitations, headache

•  reflex retention of Na+ and water

 oppose antihypertensive action
 more effective when used in combination with diuretics or
b-adrenergic receptor blockers
Precaution with 1-Adrenergic Receptor Blockers
• “First-dose phenomenon”
- orthostatic hypotension with initial dose or after a dosage
increase
especially with concomitant administration of diuretic
Adrenergic Neuron-Blocking Agents
• Reserpine
- inhibit the uptake and storage of biogenic amines into
aminergic transmitter vesicles
 depletion of neurotransmitters (noradrenaline) in central
and peripheral neurons
  peripheral vascular resistance
  cardiac output
- relatively safe at low doses for mild and moderate
hypertension

• Adverse Effects
- gastrointestinal disturbances
  gastric acid secretion ( avoided in patients with peptic ulcer)
- central nervous system disturbances
e.g. sedation, mental depression (not common with low therapeutic doses)
Centrally-Acting Sympathoplegic Agents
e.g. methyldopa, clonidine

• Central Nervous System

 stimulation of 2-adrenergic receptors in presynaptic
nerve endings
  adrenergic outflow

• Clonidine (less with methyldopa)

  heart rate
  cardiac output

• Adverse Effects
- central nervous system disturbances
e.g. sedation, mental depression
Mechanism of Action of Methyldopa
• Metabolism of methyldopa in adrenergic neurons
 Methylnoradrenaline
[methylnoradrenaline is not degraded in the brain by monoamine oxidase
 larger accumulation in vesicles than the noradrenaline that it displaces]
- displace noradrenaline in secretory vesicles
 methylnoradrenaline released instead of noradrenaline

Rang, Dale, Ritter, Moore; Pharmacology, 5th Edition

Methylnoradrenaline [metabolite of methyldopa]
• Cause vasoconstriction in the peripheral
- as potent as noradrenaline

• Inhibit adrenergic neuronal outflow

- by activating presynaptic 2-adrenergic receptors
 excessive inhibition of sympathetic output

Rang, Dale, Ritter, Moore; Pharmacology, 5th Edition

Adverse Effects of Methyldopa
• Central nervous system disturbance
- due to activation of 2-adrenergic receptors in the brain or
methyldopamine accumulation in dopaminergic neurons
 sedation, depression, mouth dryness, parkinsonian signs,
hyperprolactinemia

• Hepatotoxicity
- uncommon but potentially serious
- reversible with prompt discontinuation
 screening for hepatotoxicity after 3 weeks and 3 months
 avoided in patients with hepatic diseases

• Haemolytic anemia (rare)

- due to autoantibodies directed against erythrocytes
Limited Use
[primarily for hypertension during pregnancy]
Mechanism of Action of Clonidine
• 2-adrenergic receptor agonist
  adrenergic outflow
  rate and force of contraction of heart
  cardiac output
  risk of congestive heart failure in susceptible patients
  peripheral vascular resistance

Adverse Effects of Clonidine

• Central nervous system disturbances
• Withdrawal syndrome
  adrenergic discharge
 headache, sweating, tachycardia, hypertension
[avoid b-adrenergic receptor blocker]
Management of Hypertension
1. Non-pharmacological approaches
-  weight
-  sodium intake (to 2 g/day)
2. Pharmacological monotherapy:
- thiazide diuretics
- ACE inhibitors / ARB
- b-adrenergic receptor blockers
3. Alternative choices of monotherapy:
- calcium channel blockers
- sympathoplegic agents (not -adrenergic receptor blockers)
4. Combination Therapy
 effective blood pressure control while minimizing dose-
related adverse effects
- thiazide diuretics plus others
Prescription profiles of antihypertensive agents from 2001 to 2010 by
prescription episodes (N = 6,306,898).

Data Source: The Clinical Management System of the Hospital Authority of Hong Kong
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium
channel blocker.
Wong et al. 2013. Am J Hypertens 26: 931-938
Considerations of Anti-Hypertensive
Treatment
• Lifelong Treatment
 compliance of treatment
- oral preparation
- monotherapy versus multiple drugs
 monitor of unwanted/adverse effects

• Choices of Drugs
- level of blood pressure
- concomitant diseases
e.g. hypertension + angina:
- b-adrenergic receptor blockers /calcium channel blockers
hypertension + heart failure:
- diuretics / ACE inhibitors
hypertension + asthma:- avoid b-adrenergic receptor blockers
Conditions favouring the use of some antihypertensive drugs versus others

Mancia et al. 2007. Eur Heart J 28: 1462-1536

Compelling and possible contraindications to use of antihypertensive drugs

Mancia et al. 2007. Eur Heart J 28: 1462-1536

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