Diuretics Diuretics class Major site of action Special side effect (s) 1- Carbonic anhydrase inhibitor PCT Acidosis 2- Thiazide & thiazide- like PCT Hyperuricemia Hypokalemia 3- Loop diuretics Loop of Henle Hypokalemia Ototoxicity 4- Potassium-sparing DCT Hyperkalemia 5- Osmotic diuretic Glomerulus Hypovolemia & hypotension N.B: Thiazides are more effective in black & elderly Adverse effects: - Hypokalemia → Muscle pain & fatigue - Hyperglycemia : Inhibition of insulin release due to K+ depletion (proinsulin to insulin) → precipitation of diabetes - Hyperuricemia : Inhibition of ura te excretion → gout - Sudden cardiac death – torsade de pointes (hypokalemia) N.B: All the above metabolic side effects occur with higher doses (50-100 mg per day). But minimal with low doses (12.5 to 25 mg) e.g. average fall in BP is mmHg - Ototoxicity : with loop diuretics - Gynecomastia : with spironolactone
B-blockers - They are more effective for treating HTN in young & white people - They are useful in treating the following conditions: 1- Supraventricular tachyarrhythmia 2- Previous myocardial infarction 3- Angina pectoris 4- Chronic heart failure 5- Migraine headache
RAAS Renin release is stimulated by: - Vasodilators as hydralazine - Beta-agonist as isoprenaline - Alpha antagonist - Phosphodiesterase inhibitors - Most diuretics & anesthetics RAAS is inhibited by: - Inhibition of renin secretion (clonidine,methyl dopa,B blockers) - Renin antagonist (Aliskiren) - ACEIs & ARBs
ACEI N.B: They are more effective for treating HTN in young & white people Pharmacokinetics : 1- Captopril: - Available only orally, 70%-75% is absorbed - Partly absorbed and partly excreted unchanged in urine - Food interferes with its absorption - Half-life: 2hrs, but action stays for 6-12hrs 2- Enalapril: - Prodrug, converted to enalaprilate - The only drug in this class available I.V - Advantages over captopril: • Longer half life • Less side effects • Absorption not affected by food • Rash & loss of appetite are less frequent 3- Fosinopril: - Only ACE inhibitor not eliminated primarily by the kidneys & doesn ’ t require dose adjustment in patients with renal impairment 4-Lisinopril: - Not a prodrug
- Slow oral absorption - Less chance of 1 st dose phenomenon - Absorption not affected by food - Not metabolized - Excreted unchanged in urine - Long duration of action - Single daily dose, start with low dose 1 st line drug. Why? - No postural hypotension - Safe in asthmatics & diabetics - Prevention of 2ry hyperaldosteronism & K+ loss - Renal perfusion well maintained - Reverse the ventricular hypertr ophy & ↑ in lumen size of vessels - No hyperuricemia or deleterious effect on plasma lipid profile - No rebound hypertension - Minimal worsening of quality of life – general wellbeing, sleep & work performance etc.
Vasodilators Hydralazine: - Used to treat moderately severe HTN - Almost always administered in combination with a beta-blocker as propranolol (to balance the reflex tachycardia) and a diuretic (to decrease sodium retention) - SE: Lupus-like syndrome can occur with high doses, but its reversible on discontinuation of the drug Minoxidil: - Prodrug and converted to an active metabolite (minoxidil sulphate) - Used in severe malignant HTN refractory to other drugs - Used in ttt of alopecia (promote hair growth through enhancing microcirculation around hair follicles & also by direct stimulation of follicles & alteration of androgen effect of hair follicles) Side effects: - Sodium & water retention → volume overload, edema & congestive HF - Hypertrichosis Fenoldopam: - Arteriolar dilator - Acts as a dopamine receptor (D1) agonist
- Administered by continuous I.V infusion - Half-life: 10 min SE : Reflex tachycardia, headache, flushing Contraindications : Glucoma (as it ↑ intraocular pressure) Sodium nitroprusside: - Metabolized in RBCs producing N.O which activates guanyle c yclase → ↑ cGMP leads to relaxation of vascular smooth muscles Side effects: - Accumulation of cyanide, converted to thiocyanate. - Accumulation of cyanide leads to metabolic acidosis, arrhythmias, hypotension &death. It can be treated by thipsulphate - Thiocyanate toxicity after prolonged administration: weakness, disorientation and convulsion Diazoxide: One of its side effects is hyperglycemia, so it ’ s used to manage increased insulin release hypoglycemia caused by pancreatic cancer, surgery or other conditions
Drug combinations Never combine: - Alpha or beta blocker AND clonidine (Antagonism) - Nifedipine AND diuretic (synergism) - Hydralazine AND DHP or prazosin (same type of action) - Diltizem or verapamil AND beta blocker (bradycardia) - Methyl dopa and clonidine HTN and pregnancy: - No drug is safe in pregnancy - Avoid : diuretics, propranolol, ACE inhibitors, Sodium nitroprusside - Safer drugs : Hydralazine,Methyldopa, cardioselective beta blockers and prazosin