Antihypertensive Drugs

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Antihypertensive Drugs
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Hypertension The most common disease causing
various complications
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Antihypertensive Drugs

• Overview
• Classification of
• antihypertensive drugs
• Antihypertensive drugs
• Rational application of
• antihypertensive drugs

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A. Overview

• Hypertension
• essential hypertension 90
• secondary hypertension 10
• Criterion of hypertension
• diastolic blood pressure ? 90 mmHg
• systolic blood pressure ? 140 mmHg

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A. Overview

• Major factors influencing blood pressure

Arterial blood pressure
Cardiac output
Peripheral resistance
?
arteriolar tone
?
Blood volume
Contractility
Filling pressure
Heart rate
Venous tone
Baroreceptors and sympathetic nervous system
Renin-angiotention-aldosterol system (RAAS)
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Regulation of blood pressure (neural endocrine
pathways)
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Regulation of blood pressure Targets of
antihypertensive drugs
Sympathetic
Endocrine/body fluid
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Peripheral resistance and vascular tone and
elasticity
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Arterial wall hypertrophy and sclerosis
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B. Classification of Antihypertensive Drugs

• Diuretics
• Sympathetic nervous system inhibitors mainly,
  adrenoceptor antagonists
• Calcium channel blockers
• Regin-angiotensin system inhibitors
• Others
• Central antihypertensive drugs
• Vasodilators

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Noradrenergic nerve ending blockers
RAAS inhibitors 1. ACEIs 2. AT1 blockers
3. Renin inhibitors
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Commonly used antihypertensive drugs (1)
Diuretics Hydrochlorothiazide (2) Calcium
antagonists Nifedipine, amolodipine,
verapamil, etc. (3) Angiotensin?receptor
antagonists Lasartan, etc. (4)
Angiotensin-converting enzyme inhibitors
Captopril, enalapril, etc. (5) ?-Blockers
Propranolol, etc. (6) ?1-Blockers Prazosin,
doxazosin, etc. (7) Central sympatholytics
Clonidine, etc. (8) Potassium channel openers
Minoxidil, diazoxide, etc. (9) Vasodilators
Sodium nitroprusside, etc.
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C. Antihypertensive Drugs

• Diuretics
• 1. Pharmacological effects
• (1) Reducing plasma volume (cardiac output ?)
• (2) Reducing Na and Na-Ca2 exchange in
  vascular smooth muscle cells (Ca2i ?, peripheral
  resistance ? )

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Thiazides
K sparing diuretics
Loop diuretics
Main diuretics
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Na-Ca2 exchange ?, Ca2i ? in vascular smooth
muscle cells
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C. Antihypertensive Drugs

• 2. Clinical uses
• (1) Hypertension
• single or combined with other drugs
• mild to moderate hypertension
• particularly useful in the treatment of
  elderly patients, pure systolic hypertension,
  hypertension with heart failure
• (2) Other uses as diuretic agents, etc.

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C. Antihypertensive Drugs

• 3. Adverse effects
• plasma levels of renin ?
• hypokalemia
• hyperuricemia
• hyperglycemia
• hyperlipidemia

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• Calcium channel blockers
• 1. Pharmacological effects
• Relaxing vascular smooth muscles
• 2. Clinical uses
• Mild to severe hypertension (usually combined
  with ? receptor blockers )

Nifedipine ????
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C. Antihypertensive Drugs

• 3. Adverse effects
• Peripheral edema
• Reflex sympathetic activation
• Renin activity ?
• Other calcium channel blockers amlodipine, etc.

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• Renin-angiotensin system inhibitors
• ACEIs captopril ????, enalapril ????
• AT1 receptor antagonistslosartan ???
• Renin inhibitors enalkiren ????

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C. Antihypertensive Drugs
Renin inhibitors
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Angiotensinogen
Renin
Angiotensin I (decapeptide)
Angiotensin converting enzyme
Angiotensin II ( octapepetide)
Angiotensinase A
Angiotension III (heptapeptide)
Adrenal cortex
Aldosterone
Renin-Angiotensin-Aldosterone system (RAAS)
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C. Antihypertensive Drugs
Actions of angiotensin ?

• Constricting vessels, increase peripheral
  resistance and returned blood volume.
• Increasing sympathetic tension, promoting
  release of sympathetic transmitter.
• Stimulating release of aldosterone.
• Inducing expression of c-fos, c-myc, c-jun
  rapidly, and cardiovascular remodeling.

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C. Antihypertensive Drugs

• ACEIs
• 1. Pharmacological effects
• Inhibiting the production of Ang II
• Inhibiting the degradation of bradykinin
• Increasing ANP and scavenge free radicals

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ACEIs
ACEIs
AT1 blockers
Smooth muscle hypertrophy (vascular remodeling)
(-)
()
Implications of inhibition of RAAS
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C. Antihypertensive Drugs

• 2. Clinical uses
• Hypertension
• without reflex increase in the activity of
  sympathetic system
• effective in the management of patients
  with CHF, diabetes and ischemic heart disease.

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C. Antihypertensive Drugs

• 3. Adverse effects
• hypotension ( first dose phenomenon )
• renal injury
• dry cough
• hyperkalemia
• angioneuroedema
• rashes and altered tastes
• Contraindications renal artery stenosis,
  pregnant and lactational women

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C. Antihypertensive Drugs
AT1 receptor antagonists (angiotensin II
receptor antagonist)
Losartan ???
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C. Antihypertensive Drugs

• AT1 receptor antagonists
• Compared with ACEI
• Blocking actions of angiotensin II directly
• Not influencing bradykinin metabolism
• Protecting renal function
• Used for mild to moderate hypertension
• Less adverse effects

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C. Antihypertensive Drugs

• Renin inhibitors
• enalkiren ????
• Inhibiting whole RAAS
• Including renin antibody, peptide and nonpeptide
  renin inhibitors

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• Sympathetic system inhibitors
• Centrally acting adrenergic drugs
• Ganglion blockers
• Noradrenergic nerve ending blockers
• Adrenoreceptor blockers
• ? receptor blockers
• ? receptor blockers
• ? and ? receptor blockers

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Sympathetic system Targets of antihypertensive
drugs
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C. Antihypertensive Drugs

• Adrenoreceptor blockers
• ? Receptor blockers
• 1. Pharmacological effects
• (1) Decreasing cardiac output
• (2) Decreasing sympathetic outflow from CNS and
  releasing of noradrenalin from peripheral nerve
  endings
• (3) Inhibiting the release of renin from kidney
  (formation of angiotension and secretion of
  aldosterone)
• (4) Increasing production of PGI2
• (5) Increasing sensitivity of baroreceptor

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Main actions of ß receptor blockers on blood
pressure
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C. Antihypertensive Drugs

• 3. Clinical uses
• (1) Hypertension all kinds of hypertension
• more effective in young patients than
  elderly
• useful in treating coexisting conditions
  such as supraventricular tachycardia, previous
  myocardial infarction, angina pectoris, glaucoma
  and migraine headache
• (2) Other uses angina pectoris arrhythmias

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C. Antihypertensive Drugs

• 3. Adverse effects
• alterations in serum lipid patterns
• drug withdrawal reactions
• worsening asthma COPD
• cardiac depression

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• ?1 Receptor blockers

Prazosin ???
Terazosin ????
Doxazosin ????
Trimazosin ????
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C. Antihypertensive Drugs

• ?1 Receptor blockers
• 1. Pharmacological effects
• Relaxing arterial and venous smooth
  muscles
• Decreasing peripheral resistance
• 2. Clinical uses
• Hypertension mild to moderate (single) and
  severe hypertension (combined with diuretics and
  ? blockers)
• minimal changes in cardiac output, renal
  blood flow renin release and glomerular
  filtration regulation of blood lipid

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C. Antihypertensive Drugs

• 3. Adverse effects
• first dose phenomenon (postural
  hypotension)
• water and sodium retention

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• ? and ?1 Receptor blockers

Labetalol ????
Carvedilol ????
Amosulalol ????
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C. Antihypertensive Drugs

• ? and ?1 Receptor blockers
• Mild decrease of blood pressure
• Minimal changes in cardiac output and heart rate
• Used for all kinds of hypertension, including
  hypertensive emergency
• Less adverse effects

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C. Antihypertensive Drugs

• Centrally acting drugs

Clonidine ??? Methyldopa ????
Clonidine Methyldopa
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Action site of the centrally-acting drugs
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C. Antihypertensive Drugs

• 1. Pharmacological effects
• Diminishing central adrenergic outflow
• Activating ?2 and I1 receptor in medulla
• 2. Clinical uses
• Hypertension mild to moderate hypertension that
  has not responded adequately to treatment with
  diuretics alone.
• minimal changes in renal blood flow and
  glomerular filtration inhibit gastrointestinal
  secretion and mobility

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C. Antihypertensive Drugs

• 3. Adverse effects
• central and atropine-like side effects
• long-term uses
• water and sodium retention
• rebound phenomenon

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C. Antihypertensive Drugs

• I1 receptor agonists
• rilmenidine (????)
• moxonidine (????)

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• Ganglionic blockers
• Trimetaphan (???)
• Mecamylamine(????)
• Shor-acting
• Tolerance
• For controlling hypotension

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C. Antihypertensive Drugs
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C. Antihypertensive Drugs

• Noradrenergic nerve ending blockers
• Reserpine(???,???)
• Guanethidine (???)
• Decreasing NE storage in noradrenergic nerve
  endings
• Slow and lasting effects
• Central depression GI reactions digestive ulcer

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C. Antihypertensive Drugs

• Vasodilators

Hydralazine ???
Dihydralazine ????
Sodium Nitroprusside ???
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C. Antihypertensive Drugs

• Vasodilators
• Hydralazine(???)
• Dilating arteries and arterioles
• Decreasing peripheral resistance
• Reflexly elevating heart rate, cardiac output and
  renin release.
• Combined with ? blockers and diuretics.
• Adverse effects due to vasodilation and
  lupus-like syndrome can occur.

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C. Antihypertensive Drugs

• Nitroprusside sodium(???)
• Dilating small arteries and veins
• Used for treatment of emergency hypertension,
  hypertension with CHF, controlled hypotension and
  obstinate CHF
• Adverse effects due to hypotension in excess and
  sulfocyanate (????) poisoning.

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C. Antihypertensive Drugs

• Potassium channel openers
• Including minoxidil (????), nicorandil, diazoxide
  (???), etc.
• Dilating arteries (Ca2 influx ?)
• Reflexly elevating heart rate, cardiac output and
  renin release
• Used for treatment of obstinate and severe
  hypertension
• Adverse effects include sodium retention,
  palpitation, pilosis (??), etc.

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C. Antihypertensive Drugs
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D. Rational application of Antihypertensive Drugs

• Diuretics
• Calcium channel blockers
• Regin-angiotensin system inhibitors
• Sympathetic inhibitors
• Vasodilators

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D. Rational application of Antihypertensive Drugs

• 1. Prescribe according to the severity degree of
  hypertension
• (1) Mild diuretics, ? blockers, ACEI, calcium
  channel blockers (CCB), ?1 blockers, AT1
  blockers, single drug.
• (2) Moderate combined with two above drugs
• (3) Severe adding centrally acting drugs or
  vasodilators to the two combined drugs

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D. Rational application of Antihypertensive Drugs

• 2. Prescribe according to complications

indicated
contraindicated
CHF and/or COPD Diuretics, ACEI, CCB, prazosin ? Blockers
Renal failure ACEI, CCB methyldopa
Tachycardia ? Blockers
GI ulcer Clonidine Reserpine
Diabetes and gout ACEI, prazosin, CCB Thiazides
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D. Rational application of Antihypertensive Drugs

• hypertensive emergency vasodilators
  (nitroprusside sodium, diazoxide), loop diuretics
  (furosemide)
• elderly patients
• avoiding drugs that could induce postural
  hypotension (?1 blocker, larger dose of
  diuretics) and influence the cognizant ability
  (clonidine)
• Cardiac ischemia
• avoiding vasodilators

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D. Rational application of Antihypertensive Drugs

• 3. Combination of drugs
• 4. Avoid blood pressure to decrease too rapidly
  and excessively
• 5. Individual therapy