Drugs for Hypertention

DRUGS FOR HYPERTENTION    What is the hypertension? WHO is increase of systolic pressure over 140mmHg and diastolic pressure over 80mmHg. What is the systolic pressure? is the pressure in aortic artery and it is controlled by heart contraction, heart rate, vasoconstriction in aorta and cardiac output. What is the diastolic pressure? is the pressure the blood exerts within the arteries in between heartbeats, that is, when the heart is not actively ejecting blood into the arteries.  Mechanisms For Controlling Blood Pressure 1. Baroreceptors and the sympathetic nervous system  Baroreceptors are found on carotid sinus and aortic arch, detect any changes in blood pressure.  When blood flow is decreased the aortic arch reflex is decreased and parasympathetic is inhibited (decreased) while the sympathetic is stimulated. Blood Pressure = (CO) X (PVR) 2. Renin-angiotensin-aldosterone system  Reduction in renal pressure - intrarenal redistribution of pressure and increased absorption of salt and water.  Decreased pressure in renal arterioles and sympathetic activity – renin production – converts angiotensinogen to angiotensin I ---- angiotensinconverting enzyme (ACE)--- to angiotensin II  Angiotensin II:  Causes direct constriction of renal arterioles.  Stimulation of aldosterone synthesis – sodium absorption and increase in blood volume.  Pharmacological strategies  The Golden equation: BP= (CO * PVR) CO=HR x Stroke volume o To decrease the cardiac output: 1. Reduce the heart rate 2. Reduce the contractility 3. Reduce the conduction velocity (HR)  For these three we use Ca channel blocker and Beta blocker. 4. decrease blood volume  by Diuretics o To decrease the peripheral vascular resistance: 1. Use vasodilators: A) Calcium channel blockers: - Which inhibit smooth muscle contraction in blood vessels B) Alpha blocker: - Reduce the sympathetic tone (It is regulated majorly by alpha 1 receptor) C) Direct vasodilators 2. Decrease vasoconstrictors: - RAAS Inhibitors  Because RAAS is the major control of vasoconstriction.  Antihypertensive Drugs  Diuretics: 1. Thiazides: Chlorothiazide, Hydrochlorothiazide, chlorthalidone 2. Loop diuretics: Furosemide, Bumetanide 3. K+ sparing: Spironolactone, Triamterene and Amiloride MOA: Acts on Kidneys to increase excretion of Na and H2O – decrease in blood volume – decreased BP  Angiotensin-converting Enzyme (ACE) inhibitors:  Captopril, lisinopril., enalapril, ramipril and fosinopril (Prodrugs) MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral resistance and blood volume  Angiotensin-II receptor blockers:  Losartan, candesartan, Irbesartan, valsartan MOA: Blocks binding of Angiotensin II to its receptors  Centrally acting:  Clonidine, α- methyldopa MOA: Act on central α2A receptors to decrease sympathetic outflow – fall in BP  ß-adrenergic blockers:    Nonselective: Propranolol (others: nadolol, pindolol) Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol) MOA: Bind to beta adrenergic receptors and blocks the activity ß and α – adrenergic blockers:  Labetalol and carvedilol  α – adrenergic blockers:  Prazosin, terazosin, doxazosin, MOA: Blocking of alphaadrenergic receptors in smooth muscles - vasodilatation  Calcium Channel Blockers (CCB):   Nondihydropyridines: Verapamil, diltiazem, Dihydropyridines: nifedipine, Isradipine, amlodipine MOA: Blocks influx of Ca++ in smooth muscle cells – relaxation of SMCs – decrease BP  K+ Channel activators:  Diazoxide, minoxidil MOA: Leaking of K+ due to opening – hyper-polarization of SMCs – relaxation of SMCs  Vasodilators:  Arteriolar – Hydralazine (also CCBs and K+ channel activators)  Arterio-venular: Sodium Nitroprusside (malignant hypertension/hypertensive crises).  Diuretics 1. Carbonic Anhydrase Inhibitors – Acetazolamide 2. Osmotic Diuretic – Glycerine, Mannitol, 3. Loop Diuretics – Bumetanide, Furosemide, Torasemide, Ethacrynic acid 4. Thiazide Diuretics – Clopamide, Chlorthalidone, Metolazone, Indapamide, Benzthiazide, Hydrochlorothiazide, 5. Potassium Sparing Diuretics  Aldosterone Antagonist  Spironolactone, Eplerone  Inhibition of renal epithelial Na+ channel  Triamterene, Amiloride (more potent)  A gentile man brings fruitsE and then cuts and mix them with big hands and starts eating them. 1. Carbonic Anhydrase Inhibitors  Acetazolamide  MOA: inhibit of Carbonic Anhydrase at PCT lead to secretion of HCO3- and water  Weak diuresis  Used for: a) Glaucoma (CA⬇️ Aqueous humor) b) Alkaline the urine (as antidot for acidic drugs) c) Acute mountain sickness also known as altitude sickness  Side effect: Metabolic acidosis 2. Osmotic Diuresis  Mannitol, Glycerine  MOA: cause osmotic retention of water, Increased hydrostatic pressure in glomerulus  I.V & oral (glycerine is given orally)  Potent  Used in Glaucoma, Poisoning 3. Loop diuretics  Frusemide/ Furosemide, Bumetanide, Torasemide, Ethacrynic acid  MOA: Act at Thick Ascending Limb of Henle (Na-K2-Cl inhibition)  The loop diuretics are the most efficacious diuretic drugs. Reduce reabsorption by 25%.  Bumetanide: *orally, by injection  Furosemide (Lasix): Orally or by injection Very common in ER (Lasix injection). Drug of choice in emergency cases  Rapid onset of action, consider in acute cases o Uses:  The drug of choice for acute pulmonary edema due to heart failure  Used only in complicated cases –Chronic Renal Failure, pulmonary edema in CHF cases  Used in Acute LVF, Pulmonary Edema  Nephrotic syndrome, ARF, Cerebral edema  Acute treatment of Hypertension  to reduce volume overload during transfusion o Side effects:  Ototoxicity: mostly Ethacrynic acid cause deafness  Hypocalcemia, Hyponatremia, Hypokalemia, Hypomagnesaemia  Hyperuricemia (competitive inhibitor)  Hyperglycemia (Inhibition of insulin release due to K+ depletion (proinsulin to insulin) – precipitation of diabetes)  Hyperlipidemia 4. Thiazides  Chlorothiazide: (CTZ) orally / Hydrochlorothiazide (HCTZ)  Chlorthalidone: It has a very long duration of action, once daily dose  Metolazone: potent  Indapamide: potent, low doses used  MOA: inhibit Na+ and Cl- reabsorption in DCT, causing net loss of Na+ and water in urine ■ Answer: Decrease in total peripheral resistance (TPR) due to deficit of little amount of Na+ and water (Na+ causes vascular stiffness) ■ Initially: diuresis – depletion of Na+ and body fluid volume – decrease in cardiac output ■ Used as first-line drug therapy for hypertension ■ long-term treatment: after 4 - 6 weeks, Na+ balance and CO is retained (plasma volume approaches a normal value), but BP remains low! Why? o Uses: HPT and CHF o Adverse Effects:  Hyponatremia  Hypokalemia – muscle pain and fatigue, cardiac arrythmia, CHF, IHD  Hypomagnesemia  hypercalcemia  Hyperglycemia: Inhibition of insulin release due to K+ depletion (proinsulin to insulin) – precipitation of diabetes  Hyperlipidemia: rise in total LDL level – risk of stroke  Hyperuricemia: inhibition of urate excretion- Acute gout attacks  All the above metabolic side effects – higher doses (50 – 100 mg per day)  But it’s observed that these adverse effects are minimal with low doses (12.5 to 25 mg) 5. Potassium-sparing diuretics  Weak diuresis  Spironolactone: MOA: Aldosterone antagonist, brand:     (Aldactone), act on collecting ducts, inhibit Na reabsorption and K+ secretion Triamterene and Amiloride: direct action on Na channel Main side effects:  hyperkalemia, especially in patients with chronic kidney disease or diabetes, and in patients receiving concurrent treatment with an ACE inhibitor, ARB, NSAID, or potassium supplement Spironolactone has antiandrogenic(Testosterone= androgen) effect may cause gynecomastia Triamterene may cause leg cramps and hyperuricemia. o Uses: a) Diuretic: Potassium-sparing diuretics are weak antihypertensives, it combined with thiazide or loop diuretics to counteract the potassium- and magnesium losing and perhaps glucose intolerance b) Hyperaldosteronism only spironolactone c) CHF  Thiazide and K sparing diuretics are combined therapeutically – DITIDE (triamterene + benzthiazide) is popular one