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Renin Angiotensin System<br>
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Modulation of Renin Release Renin
Released by the kidneys in response to low blood pressure/volume
Activates the renin-angiotensin system by cleaving angiotensinogen to angiotensin I
Angiotensin converting enzyme (ACE)
Cleaves angiotensin I to angiotensin II<br>
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The Renin-Angiotensin System Kininogen Bradykinin ACE Renin Aldosterone Inactive peptides Angiotensin I Angiotensin II Kallikrein Angiotensinogen<br>
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Angiotensin II Stimulates aldosterone secretion
Increases NaCl tubular reabsorption
Stimulates thirst and anti-diuretic hormones
Promotes arterial vasoconstriction<br>
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Strategies to Alter the Renin-Angiotensin System Inhibit angiotensin converting enzymes (ACE)
ACE inhibitors (ACEIs)
Antagonize the angiotensin II receptors
Angiotensin II receptor blockers (ARBs)
Inhibit aldosterone
Aldosterone antagonists<br>
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ACE Inhibitors (ACEIs) Kininogen Bradykinin ACE Renin Aldosterone Inactive peptides Angiotensin I Angiotensin II Kallikrein Angiotensinogen<br>
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ACE Inhibitors (ACEIs) Pharmacological Effect
Decreased angiotensin II concentrations
vasodilation
Increased bradykinin levels
vasodilation
Decreased aldosterone secretion
Na and H20 reabsorption
Ex: Lisinopril (Zestril®)<br>
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ACE Inhibitors (ACEIs) Captopril
Enalapril
Ramipril
Benazepril
Fosinopril<br>
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Adverse effects
Altered or reduced taste sensation (captopril only)
Hypotension
Hyperkalemia
Fatigue
Dry cough (~20%)
Due to bradykinin levels Angioedema
Swelling of the face and mouth (more common in AA patients; rare)
Due to bradykinin levels
Drug interactions
NSAIDs and ASA
Reduce the anti-hypertensive effect ACE Inhibitors (ACEIs)<br>
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Angiotensin II Receptor Blockers (ARBs) Pharmacological effects
Inhibit vasoconstriction
Inhibit aldosterone secretion
Inhibit sodium retention Comparison to ACEIs
Do not inhibit bradykinin inactivation
Fewer adverse rxns ( cough and angioedema)
Less effective vasodilation<br>
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Angiotensin II Receptor Blockers (ARBs) Side effects
GI upset
Hypotension
Fatigue
Hyperkalemia
Drug interactions
Fluconazole and ketoconazole anti-hypertensive effect
NSAIDs can renal toxicity<br>
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Angiotensin II Receptor Blockers (ARBs) Valsartan (Diovan)
Losartan (Cozaar)
Irbesartan (Avapro)
Olmesartan (Benicar)
Candesartan (Atacand)
Telmisartan (Micardis)<br>
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MOA
Inhibit NaCl reabsorption in the Loop of Henle by binding to the Cl- site of the cotransporter
Most potent diuretics
Ex: Furosemide (Lasix®) Loop Diuretics<br>
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Indications
Edema
CHF
Hepatic Cirrhosis
Renal dysfunction
HTN
Acute pulmonary edema
Hyperkalemia
Hypercalcemia Adverse effects
Hypokalemia
Hyponatremia
Weakness
Dry mouth
Lichenoid rxns
Orthostatic hypotension
Ototoxicity
Drug interactions
NSAIDs anti-hypertensive effect Loop Diuretics<br>
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MOA
Bind to the Na+Cl- cotransporter in the distal tubule and inhibit turnover
K+ is exchanged for Na+ K+ loss
Pharmacological effects
in NaCl reabsorption
Ca reabsorption
Ex) Hydrochlorothiazide (HCTZ) Thiazide Diuretics<br>
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Indications
HTN
Edema
CHF
Hepatic cirrhosis
Renal dysfunction
Corticosteroid therapy Adverse effects
Hypokalemia
Hyponatremia
Gout
Dry mouth, lichenoid rxns, orthostatic hypotension
Drug interactions
NSAIDs anti-hypertensive effects
Opiates orthostatic hypotension Thiazide Diuretics<br>
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MOA
Bind to and prevent nuclear translocation of the mineralocorticoid receptors
Pharmacologic effect
Na and H2O reabsorption
K retention
Ex: Spironolactone Aldosterone Antagonists<br>
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Adverse effects Indications Gynecomastia in men
Menstrual irregularities in women
Hyperkalemia Hypertension
Edematous states
Congestive heart failure (CHF)
Hepatic cirrhosis
Hypokalemia
Hyperaldosteronism Aldosterone Antagonists NSAIDs can
anti-HTN effect<br>
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Review: Volume Regulators Angiotensin-aldosterone system
Angiotensin converting enzyme inhibitors (ACEIs)
Lisinopril (Zestril®)
Angiotensin II receptor blockers (ARBs)
Valsartan (Diovan®)
Kidney
Thiazide diuretics
Hydrochlorothiazide
Loop diuretics
Furosemide
Aldosterone antagonists (K+ sparing diuretics)
Spironolactone<br>
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Calcium Channel Blockers<br>
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MOA
Block voltage-dependent L-type Ca2+ channels
Two main groups
Dihydropyridines (DHPs)
Primarily block channels in vascular smooth muscle
Arterial vasodilators
Non-dihydropyridines (Non-DHPs)
Primarily block channels in cardiac smooth muscle
Antiarrhythmics Calcium Channel Blockers (CCBs)<br>
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Dihydropyridines (DHPs) Non-dihydropyridines Indications
HTN
Angina
Can be used with -blockers
Example
Amlodipine (Norvasc®) Indications
Hypertension (HTN)
Atrial fibrillation (AF)
Supraventricular tachycardia (SVT)
-blocker co-administration is contraindicated
Examples
Diltiazem (Cardizem®)
Verapamil (Calan®) Calcium Channel Blockers (CCBs)<br>
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Sympathetic Nervous System Drugs<br>
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Sympathetic Nervous System (SNS)<br>
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MOA
1 receptor blockade
Smooth muscle relaxation
in TPR
Indications
Benign prostatic hypertrophy (BPH)
Hypertension (HTN)
Ex: Doxazosin (Cardura®) 1 Sympathetic Antagonists<br>
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MOA (inverse agonist)
Binds to 2 medullary receptors in the brain
Inhibits sympathetic outflow to the body
Inhibition of receptors in blood vessels
Indication
Hypertension (HTN)
Ex: Clonidine (Catapres®) 2 Sympathetic Agonists<br>
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blockers MOA
Competitive inhibitor of norepinephrine and epinephrine at receptors
Can be selective for 1 receptors in the heart or nonselective for both 1 and 2 receptors
Pharmacological effects
HR, PVR, plasma renin activity, in CNS sympathetic outflow, alteration in baroreceptor responsiveness
BP in hypertensive patients
Ex: Metoprolol (Toprol®)<br>
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Adverse Effects Indications Altered taste
Lichenoid reactions
Orthostatic hypotension
Dry mouth Hypertension
Ischemic heart disease
Heart failure blockers<br>
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/ Combination Products MOA
Antagonizes 1 and receptors
Pharmacological effects
HR and contractility
BP through blockade
Ex: Carvedilol (Coreg®)
Uses
Hypertension (HTN)<br>
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Conclusions Treatment for hypertension should be initiated when BP reaches 140/90 in patients over 60 and in patients with diabetes at any age.
The drug classes that treat hypertension include
Renin angiotensin system drugs
Diuretics
Calcium channel blockers
Sympathetic nervous system drugs<br>