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Renin
Renal Sympathetic Vascular
Angiotensin
Sodium Nervous Smooth
Aldosterone
Handling System Muscle
System
Vascular remodeling
Antihypertensive Agents
Sympatholytic Drugs
1. Diuretics
2. Calcium Channel Blockers 6.Alpha-1 Blockers
(CCB)
7.Beta Blockers (BB)
3. Angiotensin Converting
8.Alpha-2 Agonists
Enzyme Inhibitors (ACE-I)
9.Ganglionic Inhibitors
4. Angiotensin Receptor
Blockers (ARB) 10.Adrenergic Neural
5. Peripheral Vasodilators
Terminal Inhibitors
DIURETIC
Inhibition of
Sodium Reabsorption
++ Aldosterone antagonists
+ Loop diuretics
Diuretics: Thiazides
Potassium-Sparing Diuretics
Amiloride ; Triamterene
Second line anti-hypertensive drugs
Used in combination, or for correction of hypokalemia
Loop of Henle
Fuosemide [LASIX]; Bumetanide];
Ethacrynic Acid ; Torsemide
Second line anti-hypertensive drugs
Used in hypertensive patient with chronic renal
disease for volume/salt control
ACE Inhibitors
Antihypertensive Mechanisms
Inhibition of circulating RAS
Inhibition of tissue and vascular RAS
Modulation of sympathetic activity
Decreased formation of endothelin from endothelium
Increased formation of bradykinin and vasodilatory
prostaglandins
Decreased sodium retention (decreased aldosterone
secretion, and/or increased renal blood flow)
ACE Inhibitors ( … pril)
Captopril Moexipril
Enalapril Perindopril
Lisinopril Trandolapril
Benazepril
Fosinopril
Quinapril
Ramipril
Spirapril
ACE Inhibitors: ( … pril)
Side effects
Cough ( 10% of pts who receive this drugs)
Hypotension (first dose effect)
Hyperkalemia
Angioedema
Renal Insufficiency
Fetal injury (2nd & 3rd trimesters)
“High-dose Captopril” Adverse effects
( Neutropenia, Impaired taste, Proteinuria )
ACE Inhibitors ( … pril)
YES: (useful in) No: (avoid in)
Younger patients Renal artery stenosis
Post MI LV dysfunction Fluid-depleted patients
Patient with heart failure Pregnancy
Diabetic patients Premenopausal women
Non-diabetic nephropathy who may become
pregnant
Metabolic disorders
(hyperlipidemia, gout)
Ang II Receptor Blockers (...sartans)
Sartans are selective and competitive antagonists of angiotensin
II type 1 (AT1) receptors and do not inhibit AT2 receptors
Sympathetic
Nerve Endings Enhanced NE release Enhanced Vasoconstriction
Losartan
Valsartan
Irbesartan
Candesartan
Eprosartan
Tasosartan
Telmisartan
Ang II Receptor Blockers (...sartans)
Side effects
Dizziness
Angioedema has been reported rarely
Hyperkalemia, comparable with that seen in patients treated
with ACEIs
Risk of fetal injury and death; should not be use during the 2nd
and 3rd trimester of pregnancy
Risk of symptomatic hypotension in hypovolemic patients
Preload
Ang II
Aldosterone
BP= CO x TPVR
Ca++
Dihydropyridines * Phenylalkylamine
Amlodipine Verapamil
Felodipine
Isradipine Benzothiazepine
Nicardipine Diltiazem
Nimodipine
Nifedipine *
* long-acting or slow-release
formulations should be used
for high blood pressure
Calcium Channel Blockers
Peripheral ↑ ↑ ↑↑
Vasodilation
Heart Rate ↓↓ ↓ ↑
Cardiac ↓↓ ↓ 0/↓
Contractility
SA / AV Nodal ↓ ↓ 0
Conduction
Coronary Blood ↑ ↑ ↑↑
Flow
Calcium Channel Blockers
Side effects
Facial Flushing
Headaches
Non-pitting ankle edema
Constipation
Increased CHD mortality controversy:
1995 vs. 1997-2000 data (SYST-EUR
study)
Calcium Channel Blockers
Preload
Ang II
BP= CO x TPVR 2 1
Aldosterone
VSMCs
Resistance arterioles Capacitance venules
TPVR
- Blockers
Beta Blockers
Mechanisms and Sites of Action
Cardiovascular Disease
McMahon EG: Current Opinion Pharmacol, 1:190-196, 2001
Aldosterone Antagonists
Indication
Spironolactone [ALDACTON®]
- Hyperaldosteronism
- In severe heart failure (NYHA Class IV), improves
survival and reduces hospitalization (RALES Study)
Adverse effects : Hyperkalemia, Gynecomastia, menstrual irregular
Eplerenone
- Hypertension and post-MI heart failure (EPHESUS study)
- Anti-oxidant effects (?)
- Less adverse effects (gynecomastia)
- More expensive
Afterload
2 Vasomotor center
Volume
Kidneys Cardiac Output
1 Heart
Renin
Ang I 1
Preload
Ang II
BP= CO x TPVR 1 1
Aldosterone 1
1
Resistance arterioles Capacitance venules
TPVR 1 Receptors
Blockers
1- Receptor Blockers
Inhibition of Vasoconstriction
Induced by Endogenous
Catecholamines at
Arterioles and Veins
Prazosin
Terazosin
Doxazosin
Tamsulosin [for BPH]
Old drugs
Alpha-1 + Alpha 2 Blockers
Phenoxybenzamine
Phentolamine
1- Receptor Blockers
Side effects:
First dose hypotension
Dizziness, lethargy, fatigue
Palpitation, syncope
Peripheral edema
Incontinence
ALLHAT study results:
Not to be used as first-line agents
Afterload
2 Vasomotor center
Volume
Kidneys Cardiac Output
1 Heart
Renin
Ang I 1
Preload
Ang II
Aldosterone
BP= CO x TPVR
VSMC
Resistance arterioles Capacitance venules
TPVR Central
Agonists
Central 2–Agonists
Activation of Pre-synaptic
Diminished CNS
Alpha-2 Receptors Reduces
Sympathetic Outflow NE & EPI Release at Synapse
Alpha-2 Agonist
Post-synaptic
Rostral
Effector
Ventrolateral
Medulla
Pre-synaptic Neuron
Alpha-1 Receptor
Alpha-2 Receptor Beta Receptor
NE & EPI
Central 2–Agonists
Clonidine
Methyldopa (first choice for hypertension in pregnancy)
Old drugs:
[ Guanfacine]
[ Guanabenz ]
Combination Drugs in Hypertension
Beta-Blocker + Diuretic
Atenolol + Chlorthalidone ( Tenoretic ®)
Bisoprolol + HCTZ ( Ziac™ )
Metoprolol + HCTZ ( Lopressor ® HCT )
Propranolol + HCTZ ( Inderide ®, Inderide ® LA )
Timolol + HCTZ (Timolide ® )
Betaxolol + Chlorthalidone ( Kerledex ® )
Labetalol + HCTZ ( Normozide ®, Trandate ® HCT )
Combination Drugs in Hypertension