Anti Hypertensive drugs

Hypertension: Definition
• Higher resting BP than ‘normal’
(systolic >140mmHg; diastolic >90mmHg)
• Incidence = 10 - 20%
• Results in target organ damage (blood vessels & heart)

• Decreasing BP prevents vessel damage & reduces morbidity

and mortality rates

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 Hypertension: Classification
Based on the 8th report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood (JNC 8).
 Regulation of BP

Arterial blood pressure is directly proportional to

• Cardiac output (CO) &
• Peripheral vascular resistance (PVR)

CO & PVR are controlled by 3 mechanisms:

• Baroreflexes, mediated by autonomic nervous system
• Renin – Angiotensin - Aldosterone system
• Local release of hormones from vascular endothelium
Nitric oxide=Vasodilation & Endothelin -1=Vasoconstriction

Most antihypertensive drugs ↓BP either by ↓CO or by ↓PVR or both

 Hypertension: Causes
Primary (Essential) Hypertension: About 90%-95%.
Aetiology not known
• Genetic factors and environmental factors
Secondary Hypertension: About 5%-10%.
• Renal and Renal vascular disease
• Endocrine
• Cushing’s syndrome
• Conn’s syndrome
• Hypothyroidism/Hyperthyroidism
• Primary hyperparathyroidism
• Pheochromocytoma
• Congenital adrenal hyperplasia
• Acromegaly
• Stress-induced
• Drug induced:
• Corticosteroids, oral contraceptive pills, nasal decongestants, alcohol
Treatment of Hypertension
•Lifestyle modification

•Antihypertensive agents
Antihypertensive drugs : Sites of action
MOA of ACEI’s & ARB’s
 ACE inhibitors
Captopril
Enalapril
Lisinopril
Perindopril
MOA:
• Prevent angiotensin II formation and inhibit bradykinin breakdown ( Ang II, 
bradykinin )
• Decreased peripheral resistance (vasodilator)
• Increased sodium & water excretion
Decrease preload and afterload
Pharmacokinetics

• All are prodrugs  except Captopril and Lisinopril and are converted to the active
agents by hydrolysis, primarily in the liver.
• All of the ACE inhibitors except Fosinopril and Moexipril are eliminated primarily by
the kidneys; doses of these drugs should be reduced in patients with renal
insufficiency.
 ACE inhibitors: adverse effects
• Dry cough ( bradykinin )
• Hypotension (start with low dose)
• Hyperkalemia
• Teratogenicity (Fetal hypotension, anuria & renal failure)
• Precipitate renal failure in patients with bilateral renal artery stenosis
or stenosis of the renal artery of a solitary kidney
• Angioedema
• swelling of lips, mouth, nose, larynx may develop. (can be life threatening
swelling of airways- this is at least twice more common in black pts > white)
• Altered taste sensation
Drug interactions:
• K+ supplements or K+-sparing diuretics can result in hyperkalemia
• NSAIDs may impair the hypotensive effects of ACE inhibitors by blocking
bradykinin mediated vasodilation.
 ACE inhibitors
Indications:
Hypertension
Heart failure
Preserve renal function in diabetes (diabetic nephropathy)

Contraindications:
Pregnancy
Renal artery stenosis
Less effective in patients of African origin (low renin)

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 Angiotensin receptor blockers (ARBs)
Losartan
Valsartan
Irbesartan
Candesartan
AT1 receptor antagonists: inhibit angiotensin-induced vasoconstriction and aldosterone
output
(actually Ang II, unchanged bradykinin- c.f. ACE inhibitors)
  total peripheral resistance (vasodilator)
  sodium & water excretion
Indications:
Hypertension, heart failure, diabetic nephropathy
For patients intolerant to ACE inhibitors (e.g. Dry cough)
Adverse effects:
see ACE inhibitors, e.g. hypotension (less), hyperkalemia
Cough and angioedema can occur but are uncommon.
Avoid in pregnancy, beware renal artery stenosis
 Renin inhibitors
Aliskiren
 Direct inhibition of enzyme renin on its substrate angiotensinogen
 ↓ Ang I and in consequence Ang II
   total peripheral resistance (vasodilator)
  sodium & water excretion
Indications:
Hypertension, renoprotective-diabetic nephropathy
Adverse effects:
hypotension, hyperkalemia, headache, diarrhea
Contraindicated in pregnancy

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 Endothelin receptor antagonists
Vasodilators

Endothelin-1:
-stimulates ETA and ETB receptors
-ETA receptor mediates vasoconstriction
-ETB receptor mediates vasodilatation (NO; PGI2)
-overriding effect is vasoconstriction/ BP

Bosentan - nonselective (ETA and ETB receptor) antagonist

Ambrisentan: Selective ETA receptor antagonist

Used in pulmonary hypertension

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 Diuretics
Thiazides: Most commonly used diuretics as antihypertensives
• Inhibit NaCl reabsorption by blocking Na+/Cl- cotransporter in
distal convulated tubules => Natriuresis
• Initially: ↓ Blood volume & CO ===↓ BP
• After 6–8 weeks, CO returns toward normal while ↓ PVR
=> ↓ BP

Loop diuretics: Most efficacious agents with rapid onset of action

• Inhibit Na/K/2 Cl cotransporter in the thick limb of ascending
loop of Henle. => Natriuresis => ↓ Blood volume & ↓ BP

Potassium-sparing diuretics
• Aldosterone receptor antagonist: Spironolactone
• Sodium channel blockers: Amiloride
 Diuretics
Uses:
• Mild to moderate hypertension (Thiazides)
• Severe hypertension (Furosemide)
• Potassium-sparing diuretics are useful with Loops/ Thiazides to prevent
hypokalemia and to enhance their natriuretic effects.
• Congestive heart failure (Spironolactone)
Adv effects (Thiazides)
• Hypokalemia
• Hyperuricemia
• Hyperglycemia
• Hyperlipidemia
• Erectile dysfunction