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Tuesday, March 05, 2019

Cardiovascular System (CVS) | Anti-hypertensive agents | Mechanism of action

Anti-hypertensive agents

Hypertension is defined as a sustained diastolic blood pressure greater than 90 mm Hg accompanied by an elevated systolic blood pressure (>140 mm)



Classification:

1.      ACE inhibitors
Captopril, Enalapril, Lisinopril, Perindropil, Ramipril
2.      Angiotensin (AT1) antagonist
Losartan, Candesartan, Irbasertan
3.      Calcium channel Blockers
Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine
4.      Diuretics
                               I.            Thiazides : Hydrochlorothiazides
                            II.            High ceiling : Furosemide
                         III.            K+ sparing : Spironolactone, Triamterene, Amiloride
5.      β-Adrenergic Blockers
Propranolol, Metoprolol, Atenolol.
6.      β + α Adrenergic Blockers
Labetalol, Carvediol
7.      α – Adrenergic Bockers
Prazocin, Tarazocin, Doxazocin, Phentolamine, phenoxybenzamine
8.      Central Sympatholytics
Clonidine, Methyldopa
9.      Vasodilators 
                               I.            Arteriolar : Hydralazine, Minoxidil, Diazoxide
                            II.            Arteriolar + Venous : Sodium nitroprusside

Non pharmacological Therapy:
      Weight reduction
      Increases exercise
      Salt Restriction
      Relaxation and stress management
      Supplement of K+1, Ca+2 And Mg+2
       Cessation of smoking and alcohol

ACE Inhibitors
The angiotensin-converting enzyme (ACE) inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexly increasing cardiac output, rate, or contractility. These drugs block the angiotensin converting enzyme that cleaves angiotensin I to form the potent vasoconstrictor, angiotensin II


Therapeutic uses:
            Most effective in hypertensive patients who are white. However, when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black hypertensive patients.   
Adverse effects
            Common side effects include dry cough, rashes, fever, altered taste,  hypotension (in hypovolemic states), and hyperkalemia.
            Reversible renal failure can occur in patients with severe renal artery stenosis.

Calcium Channel Blockers
Actions: Verapamil, diltiazem, nifdipine, and nicorandil decreases arterial pressure à decreases calcium influx into smooth muscle cells à decreases muscle tone and vascular resistance à vasodilators.
Therapeutic uses :
            Calcium channel blockers have an intrinsic natriuretic effect à  therefore, they do not usually require the addition of a diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.
Pharmacokinetic:
            short half-lives (tl/2 = 3 to 8 hours) following an oral dose à three times a day to maintain good control of hypertension. Verapmil and diltiazem available in sustained release preparations
Adverse effect :
            In 10% of patients, dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure. Verapamil should be avoided in treating patients with congestive heart failure due to its negative inotropic effects.


Diuretics
Thiazide diuretics
            Spironolactone à, a potassium-sparing diuretic, is often used with thiazides.
Therapeutic uses:
            Thiazide diuretics decrease blood in both the supine and standing positions; postural hypotension is rarely observed. Useful in the treatment of black or elderly patients, and in those with chronic renal disease.

Adverse effect:
             Thiazide diuretics induce hypokalemia and  hyperuricemia in 70% of patients, and hyperglycemia in 10% of  patients. Serum potassium levels should be monitored closely in patients who are predisposed to cardiac arrhythmias (particularly individuals with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia.

β-Adrenoceptor Blocking Agents
ü  The β-blockers are more effective for treating hypertension in white than in black patients, and in young patients compared to the elderly.
ü  Should not used in severe chronic obstructive lung disease, chronic congestive heart failure, severe symptomatic occlusive peripheral vascular disease and in diabetics.
ü  Should be avoided in treating patients with asthma, congestive heart failure, and peripheral vascular disease.
ü  CNS side effects such as fatigue, lethargy, insomnia, and hallucinations;
ü  The β-blockers may disturb lipid metabolism, decreasing high-density lipoproteins (HDL) and increasing plasma triacylglycerol.
                                                                                                                       



Centrally acting adrenergic drugs:
Clonidine :
à  This α2-agonist diminishes central adrenergic outflow. is used primarily for the treatment of mild to moderate hypertension that has not responded adequately to treatment with diuretics alone.
à  Useful in the treatment of hypertension complicated by renal disease à does not decrease renal blood flow or glomerular filtration .
à  Absorbed well after oral administration and is excreted by the kidney.
à  Because it causes sodium and water retention, clonidine is usually administered in combination with a diuretic.
à  It can produce sedation and drying of nasal mucosa.

α – Methyldopa:
            This α2-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS, è leading to reduced total peripheral resistance and a decreased blood pressure. Cardiac output is not decreased and blood flow to vital organs is not diminished à especially valuable in treating hypertensive patients with renal insufficiency.
            The most common side effects of α – Methyldopa are sedation and drowsiness.

Vasodilators 
ü  The direct-acting smooth muscle relaxants, such as hydralazine and  minoxidil à act by producing relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure.
ü  These agents produce reflex stimulation of the heart, resulting in the competing symptoms of increased myocardial contractility, heart rate, and oxygen consumption. These actions may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals.
           
ü  Vasodilators also increase plasma renin concentration, resulting in sodium and water retention. These undesirable side effects can be blocked by concomitant use of a diuretic and a β-blocker.
Hydralazine:
à causes direct vasodilation, acting primarily on arteries and arterioles à decreased peripheral resistance à reflex elevation in heart rate and cardiac output. Hydralazine à used to treat moderately severe hypertension.
Adverse effects of hydralazine à headache, nausea, sweating, arrhythmia, and precipitation of angina. A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug.
Minoxidil:
ü  It causes dilation of resistance vessels (arterioles) but not of venules. Administered orally for treatment of severe to malignant hypertension that is refractory to other drugs.
ü  Reflex tachycardia may be severe and may require the concomitant use of a diuretic and a β-blocker.
ü  Minoxidil causes serious sodium and water retentionà volume overload, edema, and congestive heart failure. This  drug is now used topically to treat male pattern baldness - alopecia
[Note: Minoxidil treatment also causes hypertrichosis (the growth of body hair).]
àAlways administered in combination with a β-blocker such as propranolol (to balance the reflex tachycardia) and a diuretic (to decrease sodium retention). Together, the three drugs decrease cardiac output, plasma volume, and peripheral vascular resistance.
             
Sodium nitroprusside :
 Ã¼  Nitroprusside I.V. à causes prompt vasodilation, with reflex tachycardia. Capable of reducing BP in all patients, regardless of the cause of hypertension.
ü  Nitroprusside is metabolized rapidly (tl/2 of minutes) and requires continuous infusion to maintain its hypotensive action. Sodium nitroprusside exerts few
ü  Adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production, although cyanide toxicity is rare à can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys.
ü  Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.




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