Antihypertensives

Anti hypertensive drugs
 
Most cases of hypertension are idiopathic, also called “primary’’ or “essential” hypertension. The strategies for treating it are based on the determinants of arterial pressure. These include reductions of blood volume, sympathetic effects, vascular smooth muscle tension and angiotensin effects. Unfortunately the baroreceptor reflex and the renin response in primary hypertension are reset to maintain the higher blood pressure. As a result, they respond to lower blood pressure with compensatory homeostatic responses, which may be significant. These compensatory responses can be counteracted with β blockers and diuretics or angiotensin antagonists.
 
 
Classification
 
1. Diuretics
 
  • Thiazides: Hydrochlorothiazide, chlorthalidone, Indapamide
  • High ceiling: Furosemide
  • K+ sparing: Spironolactone, Amiloride
 
2. Sympathoplegics
 
  • Centrally acting - clonidine, methyldopa
  • Ganglion blockers- hexamethonium, trimethaphan, mecamylamine
  • Postganglionic neuron blockers- Reserpine, Guanadrel
  • Alpha blockers-Prazosin, Doxazosin, Terazosin
  • Beta Blockers-Propranolol, Atenolol, Metoprolol‚Äč
  • Beta and alpha blockers-Labetalol, Carvedilol
 
3. Vasodilators, oral
 
  • Calcium channel blockers - verapamil, diltiazem, Nifidipine etc
  • Older Oral Vasodilators- Hydralazine, Minoxidil
 
4. Vasodilators, parenteral
  • Nitroprusside
  • Diazoxide
  • Fenoldopam
 
5. Renin antagonist
 
  • Aliskiren
 
6. Angiotensin antagonists
 
  • ACE inhibitors- Captopril, Benazepril, Enalapril, lisinopril
 
7. Angiotensin II receptor blockers (ARBs)
 
  • Losartan, Candesartan, irbesartan
 
Diuretics
 
These drugs lower blood pressure by reduction of blood volume and probably also by a indirect vascular effect. The diuretics most important for treating hypertension are the thiazides and the loop/high ceiling diuretics.
 
Thiazides (Hydrochlorothiazide, chlorthalidone, Indapamide)
 
The proposed mechanism of antihypertensive action is:
 
  1. Initially, the diuresis reduces plasma and e.c.f. volume by 5-15%, and this decreases c.o.
  2. Subsequently, compensatory mechanisms operate to almost regain Na+ balance and plasma volume; c.o. is restored, but the fall in BP is maintained by a slowly developing reduction in t.p.r.
  3. The reduction in t.p.r. is most probably an indirect consequence of a small (~5%) persisting Na+ and volume deficit. Decrease in intracellular Na+ concentration in the vascular smooth muscle may reduce stiffness of vessel wall, increase their compliance and dampen responsiveness to constrictor stimuli (NA, Ang II). Similar effects are produced by salt restriction; antihypertensive action of diuretics is lost when salt intake is high.
  4. Indapamide probably has additional vasodilator action exerted through alteration of ionic fluxes across vascular smooth muscle cell.
 
  • The fall in BP develops gradually over 2-4 weeks.
  • During long term treatment the heart rate and c.o. remain unaffected, while t.p.r. is reduced despite compensatory increase in plasma renin activity, which confirms persisting Na+ deficit.
  • They are mild antihypertensives, average fall in mean arterial pressure is ~10 mm Hg.
  • They potentiate all other antihypertensives (except DHPs) and prevent development of tolerance to these drugs by not allowing expansion of plasma volume.
  • They are more effective in the elderly and maximal antihypertensive efficacy is reached at 25mg/day dose, though higher doses produce greater diuresis. Their antihypertensive action is attenuated by NSAIDs.
  • Chlorthalidone is 1.5 to 2.0 times as potent as hydrochlorothiazide and has a much longer duration of action. (1)
  • The antihypertensive efficacy of hydrochlorothiazide in its daily dose of 12.5 to 25 mg is inferior to all other drug classes. It is an inappropriate first line drug for the treatment of hypertension. (2)
  • Telmisartan 40 mg with hydrochlorothiazide 12.5 mg provides clinically and statistically significant superior blood pressure reductions compared with losartan 50 mg with hydrochlorothiazide. Telmisartan 80 mg with hydrochlorothiazide 12.5 mg provide additional blood pressure reductions. (3)
  • Sodium restriction and hydrochlorothiazide combinatiuon therapy is very effective intervention to increase RAAS (renin angiotensin aldosterone system) blockade efficacy in type 2 diabetic nephropathy. (4)
  • A dosage of 200-300 mg hydrochlorothiazide daily is recommended for the treatment of severe heart failure. Thereafter, a dose of 25-100 mg per day will usually maintain the compensated state. (5)
  • Chlothalidone is the preferred diuretic than hydrochlorothiazide in hypertension treatment. It lowers the blood pressure, totala and low density lipoproteins cholestrol. It also lowers the potassium level whereas uric acid level is higher. (6)
  • Chlorthalidone is better diuertic in the treatment of hypertension than hydrochlorothiazide. (7)
  • Chlorthalidone reduces the risk of cardiovascular events (CVEs) by its ability to lower the blood pressure and pleiotropic effects like improvement in endothelial function, anti-platelet activity, oxidative status. It reduces the pulse wave velocity associated with endothelial dysfunction. It fosters hypokalemia, hyperglycemia, sympathetic discharge, and renin-angiotensin-aldosterone system. (8)
  • Once daily dosing with a combination of atenolol and chlorthalidone produces fall in supine blood pressure over a 24 h period but the efefct on exercise induced changes is not uniform. (9)
  • Azilsartan/ chlorthalidone can be considered as antihypertensive therapy option in patients for whom combination therapy is required (blood pressure .20 mmHg systolic or .10 mmHg diastolic above goal). (10)
  • In patients with hypertension already taking hydrochlorothiazide, switching to chlorthalidoen further reduce the systolic and diastlic blood pressures without clinically significant changes in renal function or electrolyte levels. (11)
  • In older patients with hypertension and 1 other coronary heart disease (CHD) risk factor, amlodipine or lisinopril is no better than chlorthalidone in lowering the risk of CHD or other cardiovascular disease (CVD) events. (12)
  • Indapamide treatment lowers the blood pressure and stimulates the renin angiotensin system. It causes hypokalemia, fractional excretion of potassium remain unchanged while renal calcium excretion is reduced. No effect on serum calcium is seen. (13)
  • Indapamide has a limited diuretic activity combined with antivasoconstrictive effects, resulting in decreased peripheral vascular resistance. THe blood pressure reducing effect is rapid in onset (within 1-2 weeks) and by 1 month reaches 65% of its maximum. The drug is well tolerated and side ffects are mild and rare, long term administration does not induce biochemical abnormalities. (14)
  • Indapamide is an effective antihypertesive drug and has no adverse effect on glucose tolerance in non-insulin-dependet diabetic patients. (15)
  • Indapamide SR is very effective in lowering systolic blood pressure- a major independent risk factor- notably in hyoertensive high risk patients with left ventricular hypertrophy, the elderly and diabetics. (16)
  • Routine administration of a fixed combination of perindopril and indapamide to patient with type 2 diabetes is well tolerated and reduces the risks of major vascular events, including death. (17)
  • The addition of low dose indapamide is useful strategy for the management of hypertension, as it reduces the blood pressure without marked side effects. (18)
  • Treatment with indapamide and perindopril is effective in fatal or non fatal stroke. (19)
  • Indapamide treatment in hypertensive patients can lead to hyponatremia and hypokalemia. (20)
Desirable properties of thiazides diuretics as antihypertensives are:
 
  1. Once a day dosing and flat dose-response curve permitting simple standardized regimens.
  2. No fluid retention, no tolerance.
  3. Low incidence of postural hypotension and relative freedom from side effects, especially CNS, compared to sympatholytics
  4. Effective in isolated systolic hypertension (ISH).
  5. Lessened risk of hip fracture in the elderly due to hypocalciuric action of thiazides.
  6. Low cost.
 
High ceiling diuretics:
 
  • Furosemide, the prototype of this class, is a strong diuretic, but the antihypertensive efficacy does not parallel diuretic potency.
  • It is a weaker antihypertensive than thiazides: fall in BP is entirely dependent on reduction in plasma volume and c.o. This is due to its brief duration of action.
  • The natriuretic action lasting only 4-6 hr after the conventional morning dose is followed by compensatory increase in proximal tubular reabsorption of Na+.
  • The Na+ deficient state in vascular smooth muscle may not be maintained round-the-clock.
  • The t.p.r. and vascular responsiveness are not reduced.
  • Moreover, they are more liable to cause fluid and electrolyte imbalance, weakness and other side effects.
  •  
  • The potential adverse effects of furosemide include RAAS (renin angiotensin aldosterone system) activation, urinary Mg2+ and Ca2+ excretion, reduction in intracellular cations, thiamine deficiency. (21)
  • High dose furosemide is logical and effective therapy for severe cardiac failure and relatively safe when administered cautiously. The maximum safe dose is probably no less than that used in renal failure. (22)
  • Though furosemide is used in the medical management of hypercalcemia, it is no longer recommended. (23)
  • Furosemide inhibits transport on the ascending limb of Henle's loop. It causes a fall in volume absorption along the early distal convolution in proportion to its baseline water permeability. It increases urine flow by abolishing the interstitial hypertonicity and consequently the osmotically driven solvent flow across the distal epithelium and collecting ducts. (24)
  • High dose isosorbide dinitrate given as repeated intraveous boluses after low dose furosemide is safe and more effective in controlling severe pulmonary edema than high dose furosemide with low dose isosorbide nitrate. (25)
  • Furosemide infusion therapy was associated with moderately negative cumulative fluid balance, electrolyte shifts and mild transient worsening of renal function. (26)
  • Furosemide stimulates prostaglandin E2 synthesis. The administration of furosemide to any pre term infants should be carefully weighed against the risk of precipitation of symptomatic patent ductus arteriosus. Infants with low birth weight treated with chronic furosemide are at risk for the development of intrarenal calcifications. (27)
  • Furosemide reduce the reabsorption of solute free water during hydropenia and inhibits the normal rise in free water excretion during sustained maximal water diuresis. It also reduce the permeability of collecting ducts to water. (28)
  • Continous infusion following a single loading dose is the preferred method for administration of furosemide than intermittent intravenous administration in patients with congestive heart failure. (29)
  • The kidneys are responsible for 85% of furosemide total clearance, either via excretion (43%) or biotransformation (42%) and probenecid inhibits both processes. (30)
  • Furosemide is used for prevention of exercise induced pulmonary hemeorrhage [EIPH]. (31)
  • Furosemide reversibly alter response magnituse reductions to tones and clicks of the chinchilla basilar membrane that are largest at low stimulus intensities and small or nonexistent at high intensities. Furosemide also inuce response phase lags that are largest at low stimulus intensities. (32)
  • They are indicated in hypertension only when it is complicated by:
a) Chronic renal failure: thiazides are ineffective, both as diuretic and as antihypertensive.
b) Coexisting refractory CHF.
c) Resistance to combination regimens containing a thiazide, or marked fluid retention due to use of potent vasodilators.
 
Drawbacks of diuretics
 
  1. Hypokalaemia-muscle pain, fatigue and loss of energy
  2. Erectile dysfunction in males.
  3. Carbohydrate intolerance: due to inhibition of insulin release (probably secondry to hypokalaemia which interferes with conversion of proinsulin to insulin), precipitation of diabetes.
  4. Dyslipidemia: rise in total and LDL cholesterol and triglycerides with lowering of HDL. This could increase atherogenic risk, but no direct evidence has been obtained.
  5. Hyperuricaemia: by inhibiting urate excretion- increased incidence of gout.
  6. Increased incidence of sudden cardiac death: attributed to episodes of torsades de pointes and ischaemic ventricular fibrillation precipitated by hypokalaemia.
 
Potassium sparing diuretics
 
  • Spironolactone, eplerenone and amiloride but not triamterene lower BP slightly.
  • They are used only in conjunction with a thiazide diuretic to prevent K+ loss and to augment the antihypertensive action.
  • Blockade of aldosterone receptors by spironolactone substantially reduces the risk of both morbidity and death among patients with sevre heart failure. (33)
  • The use of spironolactine reduces left ventricular mass and improves arterial stiffness in early stage chronic kidney disease. (34)
  • Spironolactone is not favoured because of its hormonal side effects. This problem has been offset in the newer aldosterone antagonist eplerenone, and it is increasingly used especially in refractory hypertension.
  • Hyperkalemia should be watched when K+ sparing diuretics are used with ACE inhibitors/ARBs.
  • The use of spironolactine is associated with high incidence of adverse effects (hyperkalemia and gynaecomastia). which may have an impact on the treatment compliance. (35)
  • Oral spironolactone can be used for treatment of acne vulgaris in post teenage female patients. (36)
  • Spironolactien is more effective than amiloride both as a diuretic and in conserving potassium in hypertensive patients with thiazide induced hypokalemia. (37)
  • Spironolactone has a specific antialdosterone effect that lowers the blood pressure especially in patients with aldosterone excess. (38)
  • African americans ehibits less hyperkalemia and more hypokalemia with spironolactone compared to non african americans. This shows that the safety and efficacy of mineralocorticoid receptor antagonists differ by race. (39)
  • Preoperative treatment with high dose, long term spironolactone therapy accurately predicts the response that might be expected after adrenal surgery. (40)
  • Spironolactone is an appropriate antihypertensive medication to add to the treatment of patients with resistant hypertension (3 antihypertensive medications at optimal doses). (41)
  • 50 milligrams of spironlactone thrice weekly significantly reduces the progression of Carotid intima-media thickness (CIMT) in hemodialysis patients. (42)
  • The risk of breat, uterus, ovary and cervix cancer is generally increased about 10-30% in spironolactone users. (43)
  • Spironolactone therapy is associated with agranulocytosis. Discontinuation of spironolactone results in normalization of the granulocyte count within 3 weeks. (44)
Current status of diuretics as antihypertensives
 
  • The JNC 7 recommends instituting low-dose (12.5-25 mg) thiazide therapy, preferably with added K+ sparing diuretic, as a first choice treatment of essential hypertension, especially in the elderly.
  • Higher doses are neither more effective nor safe.
  • If the low dose fails to reduce BP to desired level, another antihypertensive should be added, rather than increasing their dose.
  • However, in the treatment of severe hypertension when potent vasodilators/sympatholytics have induced fluid retention, higher dose of thiazides or a loop diuretic may be appropriate.
 
 
Sympathoplegics
 
  • Sympathoplegic drugs interfere with sympathetic (SANS) control of cardiovascular function.
  • The result is a reduction of one or more of the following:
o Venous tone
o Heart rate
o Contractile force of the heart
o Cardiac output
o Total peripheral resistance
 
Sympathoplegics are subdivided by anatomic site of action.
 
Centrally acting sympatholytics:
 
Alpha2- selective agonists (e.g,clonidine, methyldopa) cause a decrease in sympathetic outflow by activation of α2 receptors in the CNS. These drugs readily enter the CNS when given orally.
 
Clonidine
 
  • Clonidine is a imidazoline derivative having complex actions. It is a partial agonist with high affinity and high intrinsic activity at α2 receptors, especially α2A subtype in brainstem.
  • The major haemodynamic effects result from stimulation of α2A receptors present mainly postjunctionally in medulla (vasomotor centre). This decreases sympathetic outflow → fall in BP and bradycardia. Enhanced vagal tone contributes to bradycardia.
  • Though clonidine is capable of reducing NA release from peripheral adrenergic nerve endings (release inhibitory prejunctional α2 action), this is not manifest at clinically used doses.
  • It is moderately potent antihypertensive. It also activates imidazoline receptors present in the brain as well as periphery. Activation of medullary imidazoline receptors also causes decreased sympathetic outflow and fall in BP.
  • Clonidine exhibits the therapeutic window phenomenon: optimum lowering of BP occurs between blood levels of 0.2-2.0 ng/ml. At higher concentrations fall in BP is less marked due to activation of peripheral postsynaptic vasoconstrictor α2B receptors at the high concentrations so attained. This also explain transient increase in BP on rapid i.v. injection of clonidine.
  • On chronic administration of clonidine decrease in c.o. contributes more to the fall in BP than decrease in t.p.r. Cardiovascular reflexes are affected little. Decreased sympathetic flow to the kidney results in reduced renin release.
  • It is well absorbed orally; peak occurs in 2-4 hours; ½ to 2/3 of an oral dose is excreted unchanged in urine, the rest as metabolites. Plasma t1/2 is 8-12 hours. Effect of a single dose lasts for 6-24 hours.
  • The administration of low dose clonidine in patients undergoing noncardiac surgery increase the risk of clinically important hypotension and nonfatal cardiac arrest. (45)
  • In hyperadrenergic, hypertensive patients, the antihypertensive effect of clonodine involves a naloxone- reversible inhibition of central sympathetic outflow, probably mediated by the release of endogenous opioids. (46)
  • Clonidine decreases the sympathetic activity by a combination of central and peripheral effects, thus decreasing the blood pressure. (47)
  • Clonidine serves as an attractive option to treat neonatal abstinence syndrome because ithas a favorable adverse effect profile, is easy to administer and does not require a long tapering period. (48)
  • Clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Plasma catecholamine concentrations and vascular tone are markdly reduced by clonidine. (49)
  • Clonidine reduce surgical blood loss in lumbar spine posterior fusion surgery. It can be used in more complicated spine surgeries such as scoliosis and spinal deformity surgeries. (50)
  • Clonidine stimulates growth hormone release in pure autonomic failure (PAF) but not multiple system atrophy (MSA) and may serve as neuroendocrine marker in differentiating patients with MSA and a central autonomic defect from those with PFA witha peripheral defect. (51)
  • Small doses of clonidine, an alpha adrenergic agonist, improves the condition of children with Tourette's syndrome (TS) who are unresponsive to haloperidol. (52)
  • Clonidine disrupts performance in an attentional task requiring effortful processing, while leaving performance intact in tests requiring more autonomic processing. (53)
  • Clonidine can be used effectively with or withour diuretic in elderly hypertensive. (54)
  • The increase in anesthetic depth given by clonidine can be measured with bispectral EEG analysis and allows reduction of the propofol dose to achieve a specific dpth of anesthesia. (55)
  • Clonidine administered through epidural, intrathecal and local/topical route may be effective in chronic pain conditions where neuropathy is a predominant component. It is also effective where opioids are of limited use due to inadequate pain relief or adverse effects. (56)
  • Topical clonidine gel significantly reducesthe level of foot pain in painful diabetic neuropathy with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. (57)
  • Venlafaxine and clonidine are effective treatments in the management of hot flashes in patients with breast cancer. (58)
  • Addition of clonidine to bupivacaine prolongs the duration of post operative analgesia without any respiratory or hemodynamic side effects. (59)
  • Adverse effects include:
o Sedation
o Mental depression
o Disturbed sleep
o Dryness of mouth, nose and eyes
o Constipation
o Impotence
o Salt and water retention
o Bradycardia
o Postural hypotension
o On sudden withdrawal rebound hypertension can occur.
 
  • Interactions: Tricyclic antidepressants and chlorpromazine abolish the antihypertensive action of clonidine, probably by blocking α receptors on which clonidine acts.
  • Use –Frequent side effects, risk of withdrawal hypertension and development of tolerance have relegated it to a 3rd or 4th choice drug. At present, it is occasionally used in combination with a diuretic.
 
Methyldopa:
 
  • This is α-methyl analogue of dopa, the precursor of dopamine (DA) and NA is one of the first rationally designed antihypertensives.
  • The α-methyl-NA (a selective α2 agonist) formed in the brain from methyldopa acts on central α2 receptors to decrease efferent sympathetic activity.
  • Because methyldopa decreases t.p.r. more than HR or c.o., it may be acting on a different population of neurons in the vasomotor centre than clonidine.
  • In large doses, methyldopa inhibits the enzyme dopa decarboxylase in brain and periphery → reduces NA synthesis and forms the false transmitter methyl-NA in periphery as well.
  • It is a moderate efficacy antihypertensive. Circulating levels of NA and renin tend to fall due to reduction in sympathetic tone. Inhibition of postural reflexes is mild.
  • Less than 1/3 of an oral dose is absorbed.
  • It is partly metabolized and partly excreted unchanged in urine. Antihypertensive effect develops over 4-6 hours and last for 12-24 hours.
  • Methyldopa penetrated into the brain, where it is converted into alpha-methylnorepinephrine. This amine stimulate the central alpha-adrenergic receptors and results in hypotensive effect. (60)
  • The patients on α-methyldopa may develop drug induced hepatitis, thus regular monitoring of liver function tests during treatment shoukd be implemented. (61)
  • The variation in sulfate availability may be one factor responsible for individual differences in the metabolism of clinically used doses of methyldopa. Platelet phenol sulfotransferase (PST) activity correlates with individual variations in the sulfate conjugation of methyldopa taken by mouth with sodium sulfate. (62)
  •  α-methyldopa is oxidised by cytochrome P-450-generated superoxide anion to a reactive semiquinone and/ or quinone. Thuis may play a role in hepatotoxicity. (63)
  • Methyldopa and (especially) labetalol are the antihypertensive drugs commonly used in pregnancy. (64)
  • Methyldopa decrease the plasma renin activity in Bartter's syndrome. (65)
  • Dose: 0.25-0.5 g BD-QID oral.
  • Adverse effects include:
o Sedation
o Lethargy and reduced mental capacity
o Cognitive impairment may develop
o Depression is associated with the use of alpha-methyldopa. (66)
o Dryness of mouth
o Nasal stuffiness
o Headache
o Fluid retention
o Weight gain
o Impotence
o Hematologic immunotoxicity
o Hemolytic anemia. (67)
o Mild postural hypotension and rebound hypertension on sudden withdrawal is mild and less common.
  • Interaction: Tricyclic antidepressants reverse its action by blocking its active transport into the adrenergic neurons
  • Use: infrequently used now, except to treat hypertension during pregnancy as it is safe for mother as well as foetus.
 
 
Ganglion-Blocking Drugs
  • Nicotine blockers that act in the ganglia are very efficacious, but because their adverse effects are severe, they are now considered obsolete.
  • Hexamethonium and trimethaphan are extremely powerful blood pressure lowering drugs.
 
Postganglionic sympathetic nerve terminal blockers
  • Drugs that deplete the adrenergic nerve terminal of its NA stores (eg, reserpine) or that deplete and block release of the stores (eg, guanethidine, guanadrel) can lower the BP.
  • The major compensatory response is salt and water retention.
  • In high dosages, these drugs are very efficacious but produce sever adverse effects and now considered obsolete.
 
References:
  1. Barry L Carter, Michael E Ernst, Jerome D Cohen. Hydrochlorothiazide versus chlorthalidone. Hypertension. 2004;43:4-9. 
  2. Franz H Messerli, Harikrishne Makani, Alexandre Benjo, Jorge Romero, Carlos Alviar, Sripal Bangalore. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring. J Am Coll Cardiol. 2011;57(5):590-600. 
  3. Joel M Neutel, Thomas W Littlejohn, Steven G Chrysant, Ashish Singh. Telmisartan/hydrochlorothiazide in comparison with losartan/ hydrochlorothiazide in managing patients with mild to moderate hypertension. Hypertension Research. 2005;28:555-563. 
  4. Arjan J Kwakernaak, Jan A Krikken, S Heleen Binnenmars, Folkert W Visser, Marc H Hemmelder, Arend Jan Woittiez, Henk Groen, Gozewijn D Laverman, Gerjan Navis. Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomized clinical trial. The Lancet Diabetes & Endocrinology, Early Online Publication, 5 March 2014. 
  5. Albert N Brest, WIlliam Likoff. Further observations on hydrochlorothiazide in the treatment of congestive heart failure. Chest 1960;38(2):167-169. 
  6. John M Flack, Domenic A Sica, Shawna Nesbitt. Chlorthalidone versus hydrochlorothiazide as the preferred diuretic? Is there a verdict yet? Hypertension 2011;57:665-666. 
  7. Norman M Kaplan. Chlorthalidone versus hydrochlorothiazide. A tale of tortoises and a hare. Hyopertension 2011;58:994-995. 
  8. George C Roush, Venkata Buddharaju, Michael E Ernst, Theodore R Holford. Chlorthalidone: mechanisms of action and effect on cardiovascular events. Current Hypertension Reports. Oct 2013;15(5):514-521.
  9. DN Bateman, CR Dean, JC Mucklow, CJ Bulpitt, CT Dollery. Atenolol and chlorthalidone in combination for hypertension. Br J Clin Pharmacol 1979;7(4):357-363. 
  10. Judy WM Cheng. Azilsartan/ chlorthalidone combination therapy. Integrated blood pressure control 2013;6:39-48. 
  11. Kathleen A Matthews, Michael J Brenner, Allison C Brenner. Evaluation of the efficacy and safety of a hydrochlorothiazide to chlorthalidone medication change in veterans with hypertension. Clinical therapeutics. Sept 2013;35(9):1423-1430. 
  12. JT Wright, BR Davis. Amlodipine or lisinopril was not better than chlorthalidone in lowwering CHD risk in hypertension. Evid Based Med 2003;8:105. 
  13. H Danielsen, EB Pedersen, ES Spencer. Effect of indapamide on the renin-aldosterone system and urinary excretion of poatssium and calcium in essential hypertension. Br J Clin Pharmacol. Aug 1984;18(2):229-231. 
  14. JR Thomas. A review of 10 years of experience with indapamide as an antihypertensibe agent. Hyoertension 1985;7:II152. 
  15. AD Harrower, G McFarlane, T Donnelly, CE Gray. Effect of indapamide on blood pressure and glucose tolerance in non-insulin-dependent diabetes. Hypertension. 1985;7:II161
  16. GM London. Efficacy of indapamide 1.5 mg, sustained release, in the lowering of systolic blood pressure. Journal of human hypertension. 2004;18:S9-S14.   
  17. Anushka Patel. Effects of a fixed combination of perindopril and indapapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet Sept 2007;370(9590):829-840. 
  18. Hirotsugu Yamada, Yuichiro Mishiro, Kenya Kusunose, Masataka Sata. Effects of additional administration of low dose indapamide on patients with hypertension treated with angiotensin II receptor blocker. J Cardiovasc Pharmacol Ther. Jun 2010;15(2):145-150. 
  19. David Tirschwell. Combined treatment with indapamide and perindopril but not perindopril alone reduced the risk for recurrent stroke. Evidence based medicine. April 2002;42(7). 
  20. Michael D Chapman, Ross Hanrahan, John McEwen, John E Marley. Hyponatermia and hypokalemia due to indapamide. Med J Aust. 2002;176(5):219-221. 
  21. Karl T Weber. Furosemide in the long term management of heart failure. J Am Coll Cardiol. 2004;44(6):1308-1310. 
  22. DL Kuchar, MF O'rouke. High dose furosemide in refractory cardiac failure. Eur Heart J. 1985;6(11):954-958. 
  23. Susan B LeGrand, DOna Leskuski, Ivan Zama. The narrative review: furosemide for hypercalcemia: An unproven yet common practice. Ann Intern Med. 2008;149:259-263.  
  24. Giulio Romano, Grazia Favret, Edda Federico, Ettore Bartoli. The site of action of furosemide. Pharmacological Research. May 1998;37(5):409-419. 
  25. Gad Cotter, Einat Metzkor, Edo Kaluski, Zwi Faigenberg, Rami Miller, Avi Simovitz, Ori Shaham, Doron Marghitay, Maya Koren, Alex Blatt, Yaron Moshkovitz, Ronit Zaidenstein, Ahuva Golik. Randomised trial of high dose isosorbide dinitrate plus low dose furosemide versus high dose furosemide plus low dose isosorbide dinitrate in severe pulmonary edema. The Lancet. Feb 1998;351(9100):389-393. 
  26. George Thomsen, Louise Bezdjian, Larissa Rodriguez, Ramona O Hopkins. Clinical outcomes of a furosemide infusion protocol in edematous patients in the intensive care unit. Crit Care Nurse. December 2012;32(6):25-34. 
  27. Gian Maria Pacifici. CLinical pharmacology of furosemide in neonates: A review/ Pharmaceuticals 2013;6(9):1094-1129.  
  28. AG Fraser, JF Cowie, Anne T Lambie, JS Robson. The ffects of furosemide on the osmolality of the urine and the composition of renal tissue. JPET. Dec 1967;158(3):475-486. 
  29. M Lahav, A Regev, P Ra'anani, E Theodor. Intermittent administration of furosemide vs continuous infusion preceded by a loading dose for congestive heart failure. Chest 1992;102(3):725-731. 
  30. V Pichette, P du Souich. Role of kidneys in the metabolism of furosemide: its inhibition by probenecid. Journal of the American Society of Nephrology. JASN Feb 1996;7(2):345-349. 
  31. Thomas Tobin, Richard H Galley, Kimberly Brewer, Abelardo Morales Briceno, Diana Volloria Leon. Furosemide, the prevention of epistaxis and related considerations: A preliminary evaluation. Intern J Appl Res Vet Med. 2012;10(2). 
  32. MA Ruggero, NC Rich. Furosemide alters organ of corti mechanics: evidence for feedback of outer hair cells upon the basilar membrane. The Journal of Neuroscience. April 1991;11(4):1057-1067. 
  33. Bertram Pitt, Faiez Zannad, Willem J Remme, Robert Cody, Alain Castaigne, Alfonso Perez, Jolie Palensky, Janet Wittes. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717. 
  34. Nicola C Edwards, Richard P Steeds, Paul M Stewart, Charles J Ferro, Jonathan N Townend. Effect of spironolactone on left ventricular mass and aortic stiffness in early stage chronic kidney disease. J Am Coll Cardiol. 2009;54(6):505-512. 
  35. Jean Lachaine, Catherine Beauchemin, Elodie Ramos. Use, tolerability and compliance of spironolactone in the treatment of heart failure. BMC Clinical Pharmacology 2011;11:4. 
  36. Grace K Kim, James Q Del Rosso. Oral spironolactone in post-teenage female patients with acne vulgaris. J Clin Aesthet Dermatol. Mar 2012;5(3):37-50. 
  37. CF George, AM Breckenridge, CT Dollery. Comparison of the potassium retaining effects of amiloride and spironolactone in hypertensive patients with thiazide induced hypokalemia. The Lancet Dec 1973;302(7841):1288-1291.  
  38. Willibrord HL Hoefnagels, Jan IM Drayer, Anthony GH Smals, Peter WC Kloppenborg. Spironolactone and amiloride in hypertensive patients with and without aldosterone excess. Clinical Pharmacology and Therapeutics. 1980;27:317-323. 
  39. Orly Vardeny, Larisa H Cavallari, Brian Claggett, Akshay S Desai, Inder Anand, Patrick Rossignol, Faiez Zannad, Bertram Pitt, Scott D Solomon. Race influences the safety and efficacy of spironolactone in severe heart failure. Circulation: Heart Failure. 2013;6:970-976. 
  40. Richard F Spark, James C Melby. Aldosteronism in hypertension: The spironolactone response test. Ann Intern Med. 1968;69(4):685-691. 
  41. Joel C Marrs. Spironolactone management of resistant hypertension. Ann Pharmacother. Nov 2010;44(11):1762-1769. 
  42. Antonio Vukusich, Sonia Kunstmann, Cristian Varela, Daniela Gainza, Sebastian Bravo, Daniela Sepulveda, Gabriel Cavada, Luis Michea, Elisa T Marusic. A randomized, double blind, placebo-controlled trial of spironolactone on carotid intima-media thickness in nondiabetic hemodialysis patients. CJASN August 2010;5(8):1380-1387. 
  43. Robert J Boggar, Elisabeth W Andersen, Jan Wohlfarhrt, Mads Melbye. Spironolactone use and the risk of breast and gynecologic cancers. Cancer Epidemiology Dec 2013;37(6):870-875. 
  44. Adam A Fershkoa, Jennifer A Neelyc, Alejandro R Calvoa. Agranulocytosis associated with spironolactine therapy: A case report. World J Oncol. 2011;2(5):259-261. 
  45. PJ Devereaux, Daniel I Sessler, Andrea Kurz, Marko Mrkobrada et al. Clonidine in patients undergoing noncardiac surgery. N Engl J Med. 2014;379:1504-1513. 
  46. C Farsang, J Kapocsi, L Vajda, K Varga, Z Malisak, M Fekete, G Kunos. Reversal by naloxone of the antihypertensive action of clonidine: involvement of the sympathetic nervous system. Circulation. 1984;69:461-467. 
  47. BG Wallin, M Frisk Holmberg. The antihypertensive mechanism of clonidine in man. Evidence against a generalized reduction of sympathetic activity. Hypertension 1981;3:340-346. 
  48. Laura Broome, Tsz-Yin So. Neonatal abstinence syndrome: the use of clonidine as a treatment option. Neoreviews Oct. 2011;12(10):e575-e584. 
  49. Stewart A Metz, Jeffrey B Halter, R Paul Robertson. Induction of defective insulin secretion and impaired glucose tolerance by clonidine selective stimulation of metaboilic alpha-adrenergic pathways. DIabetes May 1978;27(5):554-562. 
  50. Zahra Taghipour Anvari, Nader Afshar-Fereydouniyan, Farnad Imani, Mojgan Sakhaei, Babak Alijani, Masood Mohseni. Effect of clonidine premedication on blood loss in spine surgery. Anesthesiology and Pain Medicine. 2012;1(4):252-256.
  51. TN Thomaides, KR Chaudhari, S Maule, L Watson, CJ Mathias, CD Marsden. Growth hormone response to clonidine in central and peripheral primary autonomic failure. The Lancet Aug 1992;340(8814):263-266. 
  52. DJ Cohen, JA Nathanson, JG Young, BA Shaywitz. Clonidine in Tourette's syndrome. The Lancet Sept 1979;314(8142):551-553. 
  53. P Jakala, M Riekkinen, J Sirvio, E Koivisto, P Riekkinen. Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers. Neuropsychopharmacology. 1999;21:495-502. 
  54. Chalemphol Thananopavarn, Michael S Golub, Mohinder P Sambhi. Clonidine in the elderly hypertensive: monotherapy and therapy with a diuretic. Chest 1983;83(2 Supplement):410-411. 
  55. SB Fehr, MP Zalunardo, B Seifert, KM Rentsch, RG Rohm=ling, T Pasch, DR Spahn. Clonidine decreases propofol requirments during anesthesia: effect on bispectral index. Br J Anaesth. 2001;86(5):627-632. 
  56. Anil Kumar, Souvik Maitra, Puneet Khanna, Dalim Kumar Baidya. Clonidine for management of chronic pain: A brief review of the current evidences. Saudi Journal of Anaesthesia. 2014;8(1):92-96
  57. Claudia M Campbell, Mark S Kipnes, Bruce C Stouch,Kerrie L Brady, Margaret Kelly, William K Schmidt, Karin L Petersen, Michael C Rowbotham, James N Campbell. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain. Sept 2012;153(9):1815-1823. 
  58. Annelies H Boekhout, Andrew D Vincent, Otilia B Dalesio, Joan van den Bosch, Joke H Foekema-Tons, Sandra Adriaansz, Sylvia Sprangers, Bastiaan Nuijen, Jos H Beijnen, Jan HM Schellens. Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: A randomized, double blinded, placebi controlled trial. Journal of clinical oncology. Sept. 2011. 
  59. Marzieh Lak, Hasan Araghizadeh, Shahnas Shayeghi, Behroz Khatibi. Addition of clonidine in caudal anethesia in children increases duration of post operative analgesia. Trauma Monthly. 2012 January;16(4):170-174. 
  60. PA van Zwieten, MJ Thoolen, PB Timmermans. The hypotensive activity and side effects of methyldopa, clonidien and guanfacine. Hypertension 1984;6:II28. 
  61. Soleiman Kashkooli, Brandon Baraty, Jamshid Kalantar. α-methyldopa-induced hepatitis during the postpartum period. BMJ case reports 2014. 
  62. Norman RC Campbell, Raja S Sundaram, Peter G Werness, Jon Van Loon, Richard M Weinshilboum. Sulfate and methyldopa metabolism: metabolite patterns and platelet phenol sulfotransferase activity. Clinical pharmacology and therapeutics. 1985;37:308-315. 
  63. E Dybing, SD Nelson, JR Mitchell, HA Sasame, JR Gillette. Oxidation of α-methyldopa and other catechols by cytochrome P-450-generated superoxide anion: possible mechanism of methyldopa hepatitis. Molecular Pharmacology. Nov 1976;12(6):911-920. 
  64. Ri-hua Xie, Yanfang Guo, Daniel Krewski, Donald Mattison, Kara Nerenberg, Mark C Walker, Shi Wu Wen. Trends in using beta blockers and methyldopa for hypertensive disorders during pregnancy in a canadian population. European Journal of Obstetrics & Gynaecology and reproductive biology. dec 2013;171(2):281-285. 
  65. Ronald G Strauss, Shakil Mohammed, Jennifer MH Loggie, William K Schubert, Alfred F Fasola, Thomas E Gaffney. The effect of methyldopa on plasma renin activity in a child with Bartter's syndrome. The Journal of Pediatric. Dec 1970;77(6):1071-1074. 
  66. William T McKinney, Francis J Kane. Depression with the use of alpha-methyldopa. Am J Psychiatry. 1967;124:80-81. 
  67. Charalampos Grigoriadis, Aliki Tympa, Angelos Liapis, Dimitrios Hassiakos, Panagiotis Bakas. Alpha-methyldopa-induced autoimmune hemolytic anemia in tnhe third trimester of pregnancy. Case reports in obstetrics and gynecology. Volume 2013 (2013).