Adrenoceptor blockers

Adrenoceptor blockers

 

α-Adrenergic blockers:

 

  • alpha 1 selective agent (eg, prazosin, doxazosin, terazosin) are moderately effective antihypertensive drugs.
  • They reduce vascular resistance and venous return.
  • The nonselective α blockers (phentolamine, phenoxybenzamine) are of no value in chronic hypertension because of excessive tachycardia.
  • They do, however, cause orthostatic hypotension, especially with the first few doses.
  • On the other hand, they relax smooth muscle in the prostate, which is useful in benign prostatic hyperplasia.

 

Prazosin: 

 

  • This prototype selective α1 antagonist dilates both resistance and capacitance vessels; effect on the former predominating.
  • Little reflex cardiac stimulation and renin release during long term therapy.
  • Autoregulation of NA release by α2 (presynaptic) receptors remains intact as they are not blocked.
  • Orthostatic hypotension, especially with the first few doses called ‘first dose effect’, and with dose increments. This disappears with continued therapy, but may persist in the elderly.
  • For this reason, prazosin is always started at low dose (0.5mg) given at bed time and gradually increased with twice daily administration till an adequate response is produced (max. dose 10 mg BD).
  • An oral dose produce peak fall in BP after 4-5 hours and the effect last for nearly 12 hours, though plasma t1/2 is only 3 hours. This may due to generation of active metabolites.
  • Prazosin causes bradycardia when used in treatment of hypertension. (1)
  • Prazosin causes substantial reduction in systemic arterial, pulmonary arterial and pulmonary venous pressures in both standing and sitting posture and also during walking. (2)
  • The reduced venous return to the heart, due to significant suppression of sympathetically mediated venoconstriction by small initial oral dosage of prazosin, contributes to the pathophysiology of the orthostatic hypotension and faintness, described as first dose phenomenon. (3)
  • High dose prazosin is safe, tolerable and effective for post traumatic stress disorder (PTSD) in adults. (4)
  • Patients have different response to different doses of prazosin. This efefct is due to different drug-receptor interaction. The BP response and dose could be predicted from the response of the first dose of prazosin. (5)
  • Prazosin is effective in treating chronic left ventricular failure. (6)
  • Prazosin is an effective antihypertensive drug in patients with chronic renal failure and it may be used with variety of other drugs. It should be used cautiously since patients with chronic renal failure may respond to smaller doses and significant postural falls in blood pressure may result. (7)
  • Prazosin is effective in the treatment of nightmares of post traumatic stress disorder patients. (8)
  • Prazosin decrease alcohol drinking during prolonged treatment and is useful in treating alcoholism and alcohol use disorders. It may also be useful for deterring the initiation of drinking in individuals with family history of alcoholism. (9)
  • Prazosin is effective in palliating symptoms of women with voiding dysfunction and improving their urodynamic parameters. (10)
  • Prazosin is not effective in treating Raynaud's phenomenon. (11)
  • Prazosin is effective in relieving symptoms in patients with benign prostatic hypertrophy (BPH), but transurethral resection of prostate (TURP) is better. (12)
  • Other advantages are:-
  1. Does not impair carbohydrate metabolism so suitable for diabetics, but not if neuropathy is present, because postural hypotension is accentuated.
  2. Has a small but favourable effect on lipid profile: lowers LDL cholesterol, and triglycerides, increases HDL.
  3. Affords symptomatic improvement in coexisting benign prostatic hypertrophy.

 

  • Adverse effects: generally well tolerated at low doses. Orthostatic hypotension, headache, drowsiness, dry mouth, weakness, palpitation, nasal blockade, blurred vision and rash. Ejaculation may be impaired in males: especially with higher doses. Fluid retention may precipitate CHF.

 

  • Use:
  • Moderately potent antihypertensive drug.
  • Not used as first line drug because fluid retention and tolerance gradually develops with monotherapy-necessitating dose increase-more side effects and risk of CHF.
  • It may be added to a diuretic + β blocker in those not achieving target BP.

 

  • Doxazosin, Terazosin: these are long acting congeners of prazosin with similar properties but suitable for once daily dosing.

 



 

 

β-Adrenergic blockers: (Propranolol, Atenolol, Metoprolol)

 

  • They are mild hypertensives; do not significantly lower BP in normotensives.
  • Additional BP lowering may be obtained when combined with other drugs.
  • The hypotensive response to them develops over 1-3 weeks and is then well sustained.
  • Mechanism:-(propanolol as prototype drug)
  • Initially t.p.r. is increased due to blockade of β mediated vasodilation and c.o. is reduced so there is little change in BP.
  • With continued treatment resistance vessels gradually adapt to chronically reduced c.o. and t.p.r. decreases-both systolic and diastolic BP fall.
  • Other mechanisms that may contribute are:
  1. reduced NA release from sympathetic terminals due to blockade of β receptor mediated facilitation of the release process.
  2. Decreased renin release from kidney (β1 mediated) and have better effects in hypertensives having high or normal plasma renin levels compared to those with low plasma renin.
  3. Central action reducing sympathetic outflow.

 

  • Despite short and different plasma half life their response is maintained over 24 hr with a single daily dose.
  • All β blockers, irrespective of associated properties, exert similar antihypertensive effect.
  • Drugs with intrinsic symapathomimetic activity (ISA) cause less/no reduction of HR  and c.o. but lower vascular resistance by β2 agonism.
  • Propanolol is used in treatment of hyoertension, does not produce postural or exercise hypotension. It produces best control of the supine blood pressure. It reduces cardiac output and reduces the cardiac component of pressor stimuli. It is contraindicated in obstructive airway disease and in uncompensated heart failure. (13)
  • Propanolol is used in the treatment of infantile hemangioma (IH). There is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation and its use in PHACE syndrome. (14)
  • Propanolol lowers the portal pressure and inhibits renin secretion in patients with chronic liver disease. It is used in prevention of variceal bleeding i patients with cirrhosis and ascites. (15)
  • Hypoglycemia occurs in children who recieve propanolol for the treatment of infantile hemangioma. (16)
  • Propanolol reduces serum HDL cholstrol, reduces the ratio of HDL to LDL + VLDL cholestrol, increases total triglycerides and increases serum uric acid. (17)
  • A combination of propanolol and nifedipine has either synergistic or an additive ffect in controlling maximal electroshock-induced seizure in mice. (18)
  • Propanolol significantly lowers heart rate and abolishes implicit racial bias, without affecting the measure of explicit racial prejudice. it does not affect subjective mood. (19)
  • The efficacy of systemic administration of propanolol in disrupting the reconsolidation of fear memories is limited. (20)
  • Treatment of 1-2 mg/kg/day propanolol is effective and is likely to replace as the first line of treatment of hemangioma in infants. It is associated with minimal side effects. (21)
  • Propanolol is effective, cheap, simple and safe in the treatment of traumatic memories which are characteristic of post traumatic stress disorder. (22)
  • The development of sclerosing peritonitis with extensive colonic involvement and colonic hemorrhage is seen with the therapy of propanolol. (23)
  • Nebivolol reduces t.p.r. by generating NO.
  • The nonselective β blockers slightly reduce RBF and g.f.r., but this is minimal in the β1 selective blockers and in those with ISA.
  • Non selective β blockers have an unfavourable effect on lipid profile-raise triglyceride level and LDL/HDL ratio).
  • They also decrease quality of life by causing decreased work capacity, fatigue, loss of libido and subtle cognitive effects (forgetfulness, low drive), nightmares and increased incidence of antidepressant use.
  • Many of these drawbacks are minimized in the β1 selective blockers and in those which penetrate brain poorly.
  • Use: Because of absence of postural hypotension, bowel alteration, salt and water retention; a low incidence of side effect, and once a day regimen, they are among the first choice drug recommended by JNC 7 and WHO-ISH, especially for relatively young non-obese hypertensives, those prone to psychological stress or those with ischaemic heart disease.
  • Rebound hypertension has occurred on sudden discontinuation of β blockers.
  • Contraindiactions: It is contraindicated in cardiac, pulmonary and peripheral vascular disease.

 



 

 

α + β Adrenergic blockers

 

Labetalol:

  • reduces t.p.r. and acts faster than pure β blockers. It is used i.v. for rapid BP reduction in hyperadrenergic states, cheese reaction, clonidine withdrawal, eclampsia, etc.
  • Oral labetalol therapy is restricted to moderately severe hypertension not responding to pure β blockers, because side effects of both α and β blocker occur with it.
  • Labetalol is safe and effective drug in patients with hypertension and renal function impairment. (24)
  • Labetalol causes decrease in both supine and standing arterial pressure and heart rate with no change in cardiac output and few side effects. (25)
  • Ingtravenous labetalol regimen is effective in the management of severe hypertension in pregnancy, though oral nifedipine controls hypertension more rapidly. (26)
  • Labetalol is an safe and effective antihypertensive agent in patients with acute myocardial infarction provided cardiac output is within or near the normal range. It is not contraindicated in pulmonary edema. (27)
  • Labetalol is well tolerated in hypertensive patients with chronic obstructive pulmonary disease. (28)
  • Labetalol is safe and effective antihypertensive, no tolerance is seen. Postural induced decrease in blood pressure is common. There are three types of side effects: non specific, related to alpha-blockade, related to beta-blockade. (29)
  • Raynaud's phenomenon of the nipple was seen in patient on labetalol for pregnancy induced hypertension. (30)
  • Labetalol has several advantage over pure beta-blocking drugs and offers an alternative in managing hypertension that is difficult to control. (31)

Carvedilol:

  • it is β + weak selective α1 blocker produces vasodilation and has additional antioxidant/free radical scavenging properties.
  • It is used for treatment of CHF, and is approved as antihypertensive as well.
  • Side effects are similar to long term labetalol; liver enzymes may rise in some.
  • Carvedilol maintains cardiac output, has less extended effect on heart rate and reduces BP by decreasing vascular resistance. It has a beneficial or at least neutral effect on metabolic parameters like glycemic contrl, insulin sensitivity and lipid metabolism. It can be used in patients with metabolic syndrome or diabetes without negative consequences. (32,33)
  • Carvedilol improve exercise tolerance and has anti-ischemic properties. It has other beneficial effects: antioxidant effects, reduction in neutrophill infiltration, apoptosis inhibition, reduction of vascular smooth muscle migration and improvement of myocardial remodelling post acute myocardial infarction. (34)
  • Carvedilol treatment in patients with heart failure is associated with significant improvement in left ventricular ejection fraction and left ventricular stroke work. There is a modest rise in myocardial oxygen consumption per beat. (35)
  • Carvedilol, when added to standard therapy, including ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well compensated heart failure. (36)
  • Carvedilol reduces the risk of death and need for hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with diuretics, digoxin, and angiotensin-converting enzyme inhibitors. (37)
  • Carvedilol reduces the risk of atrial and ventricular arrhythmias in patients with left ventricular systolic dysfunction after MI receiving an ACE inhibitor. (38)
  • Carvedilol has a greater portal hypotensive effect than propanolol in patients with cirrhosis. Its clinical applicability is limited by its systemic hypotensive effects. (39)
  • Combined treatment with enalapril and carvedilol prevent left ventricular systolic dysfunction in patients with malignant hemopathies treated with intensive chemotherapy. (40)
  • Carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. (41)
  • Though carvedilol reduces thge portal pressure, it is not superior to endoscopic variceal ligation (EVL) in preventing variceal bleed in payients with viral cirrhosis. (42)
  • Carvedilol is effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This is due to its ability to inhibit store-overload-induced calcium release (SOICR) through RyR2 channel. (43)

 

 

 



 

 

Comparative properties of β blockers

 

 

β blockers

Potency (on β1)

Partial agonistic action

Membrane stabilizing action

Lipid solubility

Daily dose (mg)

Oral bioavailability

(%)

First pass metabolism

Major route of elimination

Plasma t1/2 (hours)

Nonselective:

  1. propranolol

 

 

1

 

 

-

 

 

++

 

 

+++

 

 

40-480

 

 

~30

 

 

Yes

 

 

Hep.

 

 

3-5

Cardioselective:

  1. Metoprolol
  2. Atenolol

 

 

 

 

1

 

 

 

1

 

 

-

 

 

 

-

 

 

±

 

 

 

-

 

 

++

 

 

 

-

 

 

100-400

 

 

25-100

 

 

40-50

 

 

 

50-60

 

 

Yes

 

 

 

No

 

 

Hep.

 

 

 

Ren.

 

 

3-6

 

 

 

6-9

α + β blocker

  • Labetalol

 

 

1/3

 

 

+

 

 

+

 

 

±

 

 

300-600

 

 

~30

 

 

Yes

 

 

Hep.

 

 

4-6

 

        Hep.- Hepatic metabolism; Ren.- Renal excretion

 

 

 

 

 

 

 

 

 

 

 



 

 

Vasodilators: Oral

  • Drugs that dilate blood vessels by acting directly on smooth muscle cells through non autonomic mechanisms.
  • They act by four major mechanisms:
  • Release of NO (Nitroprusside, Hydralazine)
  • Opening of potassium channels which leads to hyperpolarization (Minoxidil, Diazoxide)
  • Blockade of calcium channels  (Verapamil, Diltiazem, Nifedipine)and
  • Activation of D1 dopamine receptors (Fenoldopam)

 

Calcium channel blockers

 

  • First line antihypertensive drugs because of their high efficacy and excellent tolerability.
  • All 3 subgroups of CCBs, viz. dihydropyridines (DHP, e.g. amlodipine), phenylalkylamine (verapamil) and benzothiazepine (diltiazem) are equally efficacious antihypertensives.
  • They lower BP by decreasing peripheral resistance without compromising c.o.
  • Despite vasodilatation, fluid retention is insignificant.
  • The onset of antihypertensive action is quick.
  • With the availability of long acting preparations, most agents can be administered once a day.
  • Their action is independent of patient’s renin status, and they may improve arterial compliance.
  • Do not compromise haemodynamics: no impairment of physical work capacity.
  • No sedation or other CNS effects: cerebral perfusion is maintained.
  • Not contraindicated in asthma, angina (especially variant) and PVD patients::may benefit these conditions.
  • Do not impair renal perfusion.
  • Do not affect male sexual function.
  • No deleterious effect on plasma lipid profile, uric acid level and electrolyte balance
  • Shown to have no/minimal effect on quality of life.
  • No adverse foetal effects: can be used during pregnancy (but can weaken uterine contractions during labour).
  • They are preferred in the elderly hypertensive.
  • The long acting DHPs are next to ACE inhibitors in reducing albuminuria and slowing disease progression in hypertensive/diabetic nephropathy.
  • They are most useful antihypertensives in cyclosporine induced hypertension in renal transplant recipients.
  • Use of rapid acting oral nifedipine for urgent BP lowering in hypertensive emergencies is out moded.
  • Others factors to concern in using CCBs as antihypertensives are:-
  • The negative inotropic/dromotropic action of verapamil/diltiazem may worsen CHF and cardiac conduction defects.
  • By their smooth muscle relaxant action they may worsen the gastroesophageal reflux.
  • CCBs (especially DHP) may accentuate bladder voiding difficulty in elderly males.
  • Ankle edema in some patients is due to increased hydrostatic pressure across capillaries of dependent parts as a result of reflex constriction of post capillary vessels in these vascular beds.

 

 

 

 

 



 

 

Hydralazine/Dihydralazine

 

  • It is directly acting arteriolar vasodilator with little action on venous capacitance vessels.
  • Reduces t.p.r. and causes greater decrease in diastolic than in systolic BP.
  • Reflex compensatory mechanisms are evoked which causes tachycardia increase in c.o. and renin release → increased aldosterone → Na+ and water retention.
  • Tachycardia is due to direct augmentation of NA release and myocardial contractility as well.
  • Hyperdynamic circulatory state is induced-angina may be precipitated due to increased cardiac work as well as steal phenomenon.
  • Tolerance to the hypotensive action develops unless diuretics or β blockers or both are given together to block the compensatory mechanisms.
  • Isosorbide dinitrate and hydralazine combination therapy is more beneficial than individual drug in patients with heart failure. (44)
  • The isosorbide dinitrate-hydralazine vasodilator tharpy enhances nitic oxide and reduces oxidative stress improves quality of life and survival in African American patients with heat failure. (45)
  • Hydralazine exerts beneficial effects on cardiac index, stroke volume index, left ventricular stroke work index and systemic vascular resistance both at rest and during exercise. It is associated with improvement in the radionuclide left ventricular ejection fraction both at rest and during exercise. (46)
  • Hydralazine should not be used as a first line drug in severe hypertension in pregnancy. (47)
  • Mechanism of vascular smooth muscle relaxant action is not clearly known-interference with Ca+ release, opening of K+ channels and/or NO generation may be involved.
  • Pharmacokinetics-well absorbed orally, undergo first pass metabolism in liver: chief metabolic pathway is acetylation. Bioavailability is higher in slowacetylators, but they are more prone to develop the lupus syndrome. The metabolites are excreted in urine, t1/2 is 1-2 hrs. However hypotensive effects lasts longer (12 hrs), probably because of its persistence in the vessel wall.
  • Dose: 25-50 mg  OD-TDS
  • Adverse effects are frequent and mainly due to vasodilatation.
  • Facial flushing, conjunctival injection, throbbing headache, dizziness, palpitation, nasal stuffiness, fluid retention, edema, CHF.
  • Parasthesias, tremor, muscle cramps, rarely peripheral neuritis.
  • Lupus erythematosus or rheumatoid arthritis like symptoms develop on prolonged use of doses above 100 mg/day. This is more common in women and in slow acetylators.
  • There is association between HLA-DR antigen and adverse reaction to hydralazine therapy. The distribution of DR antigens in the hydralazine-SLE patients is significantly different from that with idiopathic SLE. (48)
  • Use:-
  • It is used as a second line alternative only in combination with diuretic and/or β blocker for patients not achieving target BP with first line drugs.
  • It is one of the preferred antihypertensives during pregnancy, especially preeclampsia.
  • Parenterally, it is occasionally employed in hypertensive emergencies.
  • Also can be used in the management of CHF in combination with isosorbide dinitrate.

 

  • It is contraindicated in older patients and in those with ischaemic heart disease.

 



 

 

Minoxidil

 

  • It is powerful vasodilator, the pattern of action resembling hydralazine.
  • It also elicits strong compensatory reflexes.
  • It is a prodrug-converted to an active metabolite by sulfate conjugation which is an opener of ATP operated K+ channels; acts by hyperpolarizing smooth muscle.
  • A single dose of minoxidil increases heart rate slightly, increase cardiac index, decrease mean arterial pressure and systemic vascular resistance in patients with chronic left ventricular failure caused by ischemic or primary cardiomyopathy. It does not affect right atrial, pulmonary arterial and pulmonary wedge pressures. (49)
  • Severely compromised renal function associated with malignant hypertension can be improved by controlling blood pressure with minoxidil. (50)
  • Use:
  • It is indicated only rarely in severe or life threatening hypertension. 
  • It is indicated in long term treatment of severe hypertension along with propanolol and furosemide. (51)
  • In alopecia-it increases growth of body hair; applied topically (2% twice daily) in male pattern baldness and alopecia areata.
  • 5% minoxidil foam used for alopecia areata can lead to generalized hypertrichosis. (52)

 

Vasodilators, parenteral

 

(Nitroprusside, Diazoxide, Fenoldopam)

 

Sodium Nitroprusside:

  • It is rapidly (within seconds) and consistently acting vasodilator; has brief duration of action (2-5 min) so that vascular tone can be titrated with the rate of i.v. infusion.
  • It relaxes both resistance and capacitance vessel: reduces t.p.r. and c.o. by decreasing venous return.
  • Myocardial work is reduced-ischaemia is not accentuated, as occurs with selective arteriolar dilators.
  • Little reflex tachycardia is produced in supine posture. Plasma renin is increased.
  • In patients with heart failure and ventricular dilation, it improves ventricular function and c.o. mainly by reducing aortic impedance (afterload) and also by lowering atrial filling pressure (preload).
  • Mechanism: Endothelial cells, RBCs (and may be other cells) split nitroprusside to generate NO which relaxes vascular smooth muscle. This occurs both enzymatically and nonenzymatically. The enzymes involved are different from those that produce NO from glyceryl trinitrate. Nonenzymatically it is converted to NO (and CN) by glutathione. This may be responsible for different pattern of action compared to nitrates and no nitrate like tolerance develops to nitroprusside action.
  • Sodium nitroprusside produces profund and controllable hypotension accompanied by an unchanged or augmented cardiac output. It is suitable for neurosurgical anesthesi. Contraindications are hypothyroidism and altered cobalamin metabolism. (53)
  • Sodium nitroprusside, when used for short term deliberate hypotension, does not cause an increased incidence of metabolic acidosis compared with the use of anesthetic agents alone. (54)
  • There is a substantial downward displacement of the diastolic pressure- volume curve during introprusside infusion, with left ventricular pressure being lower for any given volume of nitroprusside. This might be due to direct relaxant effect of nitroprusside on the ventricular muscek, similar to relaxant effect on vascular smooth muscle. (55)
  • Sodium nitroprusside is effective in improving cerebral blood flow and oxygenation in otherwise refractory cerebral vasospasm in humans. (56)
  • The relaxation and Ca2+ decrease induced by sodium nitroprusside in vascular smooth muscle cells is potentiated by endothelial production of NO by cNOS-activation. (57)
  • Intracoronary sodium nitroprusside is used as a hyperemic agent in fractional flow reserve measurements. It is preferred to intracoronary adenosine as a routine clinical stimulus and has an additional advantage of showing a longer plateau phase. (58)
  • In the cyanide/thiocyanate cycle, only cyanide is directly responsible for any acute toxicity attributed to sodium nitroprusside. (59)
  • Sodium nitroprusside is still a reasonable agent to use in the management of patients with hypertension and can be safely used beyond doses of 2 µg/kg/min. In lieu of cyanide levels, monitoring of lactic acid levels is a reasonable measure to ensure safety. (60) 
  • NecroX-5 suppresses sodium nitroprusside (SNP) induced cell death through inhibition of JNK activation and suppression of both downregulation of Bcl-2 protein expression and caspasse-3 cleavage. This may facilitate the development of antidote to SNP toxicity in cardiac cells. (61)
  • Rebound hypertension after cessation of sodium nitroprusside is associated with elevation of plasma renin activity. This rebound hypertension may be attributed to the unoposed effects of renin angiotensin system after rapid plasma disappearance of SNP. (62) 
  • Use-
  • It is a popular drug to manage hypertensive emergencies; 50 mg is added to a 500 ml bottle of saline/glucose solution. The infusion is started at 0.02 mg/min and titrated upward with the response: 0.1-0.3 mg/min is often needed. It decomposes at alkaline pH and on exposure to light: the infusion bottle should be covered with black paper.
  • To produce controlled hypotension, in refractory CHF, pump failure accompanying MI and in acute mitral regurgitation.
  • Nitroprusside is split to release cyanide. The latter is converted in liver to thiocyanate which is excreted slowly. If larger doses are infused for more than 1-2 days, excess thiocyanate may accumulate and produce toxicity, including psychosis.
  • Side effects: palpitation, nervousness, vomiting, perspiration, pain in abdomen, weakness, disorientation and lactic acidosis (caused by the released cyanide).

 

Diazoxide

 

  • It is a thiazide derivative but lacks diuretic properties.
  • It is given as i.v. boluses or as an infusion and has duration of action of several hours.
  • This K+ channel opener arteriolar dilator was used in the past for rapid reduction of BP in hypertensive emergencies. Administered by rapid i.v. injection in place of nitroprusside, when regulated i.v. infusion or close monitoring is not possible.
  • This drug also reduces insulin release and can be used to treat hypoglycemia caused by insulin- producing tumors.
  • Diazoxide is used in the treatment of primary pulmonary hypertension and thromboembolic pulmonary hypertension. (63)
  • Diazoxide used in the treatment of pulmonary hypertension causes cardiac arrest (asystole), abdominal pain, distension. (64)
  • With diazoxide, hyperglycemia is not solely due to decreased insulin secretion or increased epinephrine secretion. It increase glucose production and inhibit glucose uptake. Somatostatin is capable of blocking the effect of diazoxide on glucose production. (65)
  • Some of the direct effects of diazoxide on the pancreas are mediated through alpha and beta-adrenergic receptor mechanisms. (66)
  • Many hypertensive children respond significanty to doses of diazoxide smaller than usually recommended 5 mg/kg. It has a significant dose response relation in hypertensive pediatric patients. (67)
  • Diazoxide is effective in the management of insulinoma and should be considered for all patients not cured by surgery or unsuitable for surgery. (68)
  • Diazoxide regulates key insulin-sensitive enzymes involved in regulation of adipose tissue metabolism. The modification of insulin-sensitive pathways can be therapeutically beneficial in the obesity management. (69)
  • Diazoxide can be used in the management of severe hypertension after electroconvulsive therapy. (70)
  • There is a mitoprotective effect of diazoxide for pancreas preservation and islet isolation. (71)

 

Fenoldopam

 

  • Dopamine D1 receptor activation causes prompt, marked arteriolar vasodilation.
  • Given by i.v. infusion.
  • It has short duration of action (10 min)
  • It is used for hypertensive emergencies.
  • Fenoldopam is a rapid acting, effective agent for intravenous control of blood pressure in children, The effective dose range is significantly higher in children undergoing anesthesia and surgery than adults. (72)
  • Fenoldopam produces a significant fall in systolic and diastolic blood pressure and renal vascular resistance. Urine flow rate, sodium excretion plasma renin activity and plasma aldosterone is increased. (73)
  • Fenoldopam decreases regional vascular resistance in the renal, mesenteric and hindquarters vascular beds of the conscious spontaneously hypertensive rat with mesenteric vascular bed demonstrating greatest activity. The vasodilation is due to stimulation of vascular dopamine-1 receptors. (74)
  • Intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion. (75)

 

Renin antagonist

 

  Aliskiren

 

  • It is the only available member of the latest class of RAS inhibitors which act by blocking catalytic activity of renin and inhibiting production of Ang I and Ang II.
  • It is an equally effective antihypertensive as ACE inhibitors and ARBs but experience is limited.
  • Presently it is a second line antihypertensive which may be employed when ACE inhibitors or ARBs cannot be used, or to supplement them.
  • There is no reduction in cardiovascular death or heart failure rehospitalization with the addition of aliskiren to standard therapy in patients who are hospitalized for heart failure and with reduced left ventricular ejection fraction. (76)
  • Addition of aliskiren to an ACE inhibitor and beta blocker has favorable neurohumoral effects in heart failure and is well tolerated. (77)
  • Combining aliskiren and ramipril provides a greater reduction in mean sitting diastolic blood pressure than either drug alone in patients with diabetes and hypertension. (78)
  • The combination of aliskiren and valsartan at the maximum recomended doses provides significantly greater reduction in blood pressure than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that with aliskiren and valsartan alone. (79)
  • Aliskiren has renoprotective effect that is independent of its blood pressure lowering effect in patients with hypertension, type 2 diabetes and nephropathy who are receiving the recommended rnoprotective treatment. (80)
  • Aliskiren, a direct renin inhibitor is an antihypertensive drug with potent antiproteinuric effect. When used alone or in combination, it can contribute to delay in progression of kidney disease. (81)
  • Aliskiren added to losartan provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function is better preserved with aliskiren in patients with insufficient BP control. (82)
  • In 2007, aliskiren was approved for the treatment of hypertension by US Food and drug administration and the European Medicines Agency. (83)

Pharmacokinetics-it is administered orally, but bioavailability is very low due to active extrusion of absorbed drug by P-glycoprotein. The drug is mainly eliminated in faeces; small amount in urine. The plasma t1/2 is >24 hrs, and its BP lowering effects persist for days after regular intake.

  • Adverse effects: mild –dyspepsia, abdominal pain, loose motions, headache and dizziness.
  • It is contraindicated during pregnancy.
  • Dose: 150-300 mg OD

 

References:

  1. Isaac Kobrin, Jochanan Stessman, Yoram Yagil, Drori Ben-Ishay. Prazosin induced bradycardia in acute treatment of hypertension. Arch Intern Med. 1983;143(10):2019-2023. 
  2. B Silke, WG Hendry, SH Taylor. Immediate and sustained haemodynamic effects of prazosin during upright exercise in man. Br Heart J. Dec 1981;46(6):663-670.
  3. GJ Schapel, WH Betts. The effect of a single dose of prazosin on venous reflex response, blood pressure and pulse rate in normal volunteers. Br J Clin Pharmacol. Dec 1981;12(6):873-881. 
  4. Maju Mathew Koola. High dose prazosin for the treatment of post traumatic stress disorder. Therapeutic advances in psychopharmacology. Aug 16,2013. 
  5. P Larochelle, P du Souich, P Larocque, J Armstrong. Prazosin plasma concentration and blood pressure reduction. Hypertension 1982;4:93-101. 
  6. WS Aronow, M Lurie, M Turbow, K Whittaker, S Van Camp, D Hughes. Effect of prazosin vs placebo on chronic left ventricular heart failure. Circulation. 1979;59:344-350. 
  7. JR Curtis, FJ Bateman. Use of prazosin in management of hypertension in patients with chronic renal failure and in renal transplant recipients. Br Med J 1975;4:432. 
  8. Seyed Mousavi, Majid Barati, Hamid Afshar, Nasrollah Bashardoust. The comparison between prazosin versus clonidine effects on combat related PTSD nightmares. Annals of general psychiatry 2006;5(Suppl 1):S190. 
  9. Janice C Froehlich, Brett J Hausauer, David L Federoff, Stephen M Fischer, Dennis D Rasmussen. Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake. Alcoholism: Clinical and experimental research. Sept 2013;37(9):1552-1560
  10. Sakineh Hajebrahimi, Yadollah Ahmadi Asbadr, Arash Azaripour, et al. Effect of tamsulosin versus prazosin on clinical and urodynamic parameters in women with voiding difficulty: a randomized clinical trial. International Journal of General Medicine. Jan 2011;4:35-39. 
  11. SL Nielsen, K Vitting, K Rasmussen. Prazosin treatment of primary Raynaud's phenomenon. European Journal of clinical pharmacology. 1983;24(3):421-423. 
  12. Sv Punekar, AR Kelkar, PM Gavande, NR Rao, JA Date, AR Prem. Alpha blocker prazosin for the treatment of benign prostatic hypertrophy (BPH). J Postgrad Med. 1995;41:99-101. 
  13. BNC Prichard, PMS Gillam. Treatment of hypertension with propanolol. Br Med J. Jan 1969;1(5635):7-16. 
  14. Beth A Drolet, Peter C Frommelt, Sarah L Chamlin, Anita Haggstrom et al. Initiation and use of propanolol for infantile hemangioma: report of a consensus conference. Pediatrics Jan 2013;131(1):128-140. 
  15. William G Rector Jr, Telfer B Reynolds. Propanolol in the treatment of cirrhotic ascites. Arch Intern Med. 1984;144(9):1761-1763. 
  16. Kristen E Holland, IIona J Frieden, Peter C Frommelt, Anthony J Mancini, David wyatt, Beth A Drolet. Hypoglycemia in children taking propanolol for the treatment of infantile hemangioma. Arch Dermatol. 2010;146(7):775-778. 
  17. P Leren, A Helgeland, I Holme, PO Foss, I Hjermann, PG Lund Larsen. Effect of propanolol and prazosin on blood lipids. The Lancet July 1980;316(8184):4-6. 
  18. SS Raju, HN Gopalakrishna, N Venkatadri. Efect of propanolol and nifedipine on maximal electroshock-induced seizures in mice: individually and in combination. Pharmacological Research. Dec 1998;38(6):449-452. 
  19. Sylvia Terbeck, Guy Kahane, Sarah McTavish, Julian Savulescu, Phillip J Cowen, Miles Hewstne. Propanolol reduces implicit negative racial bias. Psychopharmacology. Aug 2012;222(3):419-424. 
  20. Elizaveta V Muravieva, Cristina M Alberini. Limited efficacy of propanolol on the reconsolidation of fear memories.  Learn. Mem. 2010;17:306-313. 
  21. El Essawy R, Galal R, Abdelbaki S. Nonselective beta-blocker propanolol for orbital and periorbital hemangioma in infants: a new first line of treatment? Clinical Ophthalmology. Nov 2011;5:1639-1644.
  22. Robin PD Menzies. Propanolol treatment of traumatic memories. Advances in psychiatric treatment. 2009;15:159-160. 
  23. S Ahmad. Sclerosing peritonitis and propanolol. Chest 1981;79(3):361-362.  
  24. Ross R Bailey. Labetalol in the treatment of patients with hypertension and renal function impairment. Br J Clin Pharmacol. 1979;8(Suppl 2):135S-140S. 
  25. J Mehta, JN Cohn. Hemodynamic effects of labetalol, an alpha and beta adrenergic blocking agent, in hypertensive subjects. Circulation. 1977;55:370-375. 
  26. Badal Dhali, Shritanu Bhattacharya, Rajendra Prasad Ganguly, Shrirupa Bandyopadhyay, Mousumi Mondal, Mousomi Dutta. A randomized trial of intravenous labetalol & oral nifedipine in severe pregnancy induced hypertension. Int J Reprod Contracept Obstet Gynecol. 2012;1(1):42-46. 
  27. AD Timmis, MB Fowler, NSV Jaggarao, DA Chamberlain. Labetalol infusion for the treatment of hypertension in acute myocardial infarction. Eur Heart J. 1980;1(6):413-416. 
  28. RB George, K Manocha, JG Burford, SA Conrad, GT Kinasewitz. Effects of labetalol in hypertensive patients with chronic obstructive pulmonary disease. Chest 1983;83(3):457-460. 
  29. HJ Waal-Manning, FO Simpson. Review of long term treatment with labetalol. British Journal of Clinical Pharmacology. Feb 1982;13(S1):65S-73S. 
  30. Naomi McGuinness, Vicky Cording. Raynaud's phenomenon of the nipple associated with labetalol use. J Hum Lact. Feb 2013;29(1):17-19. 
  31. Carolyn J Pearce, J David Wallin. Labetalol and other agents that block both alpha and beta adrenergic receptors. Cleveland Clinic Journal of Medicine. Jan 1994;61(1):59-69. 
  32. Panagiotis C Stafylas, Pantelis A sarafidis. Carvedilol in hypertension treatment. Vasc Health Risk Manag. Feb 2008;4(1):23-30. 
  33. Leonetti G, Egan CG. Use of carvedilol in hypertension: an update. Vascular health and risk management. May 2012;8:307-322. 
  34. Carol Chen Scarabelli, Louis Saravolatz II, Yahya Murad, Wen Shi Shieh, waqas Qureshi, Justin Di Rezze, Rodeo Abrencillo et al. A critical review of the use of carvedilol in ischemic heart disease. Am J Cardiovasc Drugs. 2012;12(6):391-401. 
  35. David M Kaye, Leonie Johnston, Gautam Vaddadi, Hanspeter Brunner-LaRocca, Garry L Jennings, Murray D Esler. Mechanism of carvedilol action in human congestive heart failure. Hypertension 2001;37:1216-1221. 
  36. Wilson S Colucci, Milton Packer, Michael R Bristow, E Michael Gilbert, Jay N Cohn et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation. 1996;94:2800-2806. 
  37. James T Willerson. Effect of carvedilol on mortality and morbidity in patients with chronic heart failure. Circulation. 1996;94:592. 
  38. Gerald V Naccarelli. Does carvedilol have antiarrhythmis properties? Nature Clinical Practice Cardiovascular Medicine. 2005;2:338-339. 
  39. Rafael Banares, Eduardo Moitinho, Ana Matilla, Juan Carlos Garcia-Pagan, Jose Luis Lampreave, Carlos Piera et al. Randomized comparison of long term carvedilol and propanolol administration in the treatment of portal hypertension in cirrhosis. Hepatology. Dec 2002;36(6):1367-1373. 
  40. Xavier Bosch, Montserrat Rovira, Marta Sitges, Adriana Domenech, Jose T Ortiz Perez, Teresa M de Caralt et al. Enalapril and carvedilol for preventing chemotharpy-induced left ventricular systolic dysfunction in patients with malignant hemopathies. J Am Coll Cardiol. 2013;61(23):2355-2362. 
  41. Robert E Shaddy, Mark M Boucek, Daphne T Hsu, Robert JBoucek, Charles E Canter, Lynn Mahony et al. Carvedilol for children and adolescents with heart failure. JAMA 2007;298(10):1171-1179. 
  42. Hasnain Ali Shah, Zahid Azam, Javeria Rauf, Shahad Abid Saeed Hamid Wasim Jafri et al. Carvedilol vs esophageal variceal band ligation in the primary prophylaxis of variceal hemorrhage: A multicentre randomized controlled trial. Journal of hepatology. April 2014;60(4):757-764. 
  43. Chris D Smith, Aixia Wang, Kannan Vembaiyan, Jingqun Zhang, Cuihong Xie, Qiang Zhou et al. Novel carvedilol analogue that suppress store-overload-induced Ca2+ release. J Med Chem. 2013;56(21):8626-8655. 
  44. BM Massie, B Kramer, E Shen, F Haughom. Vasodilator treatment with isosorbide dinitrate and hydralazine in chronic heart failure. Br Heart J. Apr 1981;45(4):376-384. 
  45. Melvin R Echols, Clyde W Yancy. Isosorbide dinitrate-hydralazine combination therapy in African Americans with heart failure. Vasc Health Risk Manag. Dec 2006;2(4):423-431. 
  46. Mark J Godberg, Barry A Franklin, Melvyn Rubenfire, Nicholas Z Kerin, Harold J Willens, Robert Ruskin, Mark Freidin, Gail Scheer. Hydralazine therapy in severe chronic heart failure: Inability of radionuclide left ventricular ejection fraction measurement to predict the hemodynamic response. J Am Coll Cardiol. 1983;2(5):887-893. 
  47. Laura A Magee, Chris Cham, Elizabeth J Waterman, Arne Ohlsson, Peter von Dadelszen. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003;327:955. 
  48. JR Batchelor, KI Welsh, R Mansilla Tinoco, CT Dollery, GRV Hughes, R Bernstein,P Ryan, PF Naish, GM Aber, RF Bing, GI Russell. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. The Lancet;315(8178):1107-1109. 
  49. JA Franciosa, JN Cohn. Effects of  minoxidil on hemodynamics in patients with congestive heart failure. Circulation 1981;63:652-657. 
  50. H Mitchell Perry Jr. Minoxidil and improvement of renal function in uremic malignant hypertension. Ann Intern Med. 1980;93(5):769-771. 
  51. L Wilburn, A Blaufuss, CM Bennet. Long term treatment of severe hypertension with minoxidil, propanolol and furosemide. Circulation. 1975;52:706-713. 
  52. Herskovitz I, Freedman J, Tosti A. Minoxidil induced hypertrichosis in a 2 year old child. F1000Research 2013;2:226. 
  53. Ian R Verner. Sodium nitroprusside: theory and practice. Postgrad Med J. Sept. 1974;50(587):576-581. 
  54. Gregory B Hammer, Sara G Connolly, Scott R Schulman, Andrew Lewandowski, Carol Cohane, Tammy L Reece, Ravinder Anand, Jeff Mitchell and David R Drover. Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children. BMC Anesthesiology 2013;13:9. 
  55. BR Brodie, W Grossman, T Mann, LP McLaurin. Effects of sodium nitroprusside on left ventricular diastolic pressure-volume relations. J CLin Invest. 1977;59(1):59-68. 
  56. Peter Vajkoczy, Ulrich Hubner, Peter Horn, Christian Bauhuf, Claudius Thome, Lothar Schilling, Peter Schmiedek. Intrathecal sodium nitroprusside improves cerebral blood flow and oxygenation in refractory cerebral vasospasm and ischemia in humans. Stroke. 2000;31:1194-1198. 
  57. Daniella Bonaventura, Claure N Lunardi, Gerson J Rodrigues, Mario A Neto, Lusiane M Bendhack. A novel mechanism of vascular relaxation induced by sodium nitroprusside in the isolated rat aorta. Nitric Oxide. June 2008;18(4):287-295. 
  58. Xiaozeng Wang, Shaosheng Li, Xin Zhao, Jie Deng, Yaling Han. Effects of intracoronary sodium nitroprusside compared with adenosine on fractional flow reserve measurement. The Journal of invasive cardiology. March 2014;3(26).  
  59. HE Spiegel, V Kucera. Some aspects of sodium nitroprusside reaction with human erythrocytes. Clinical Chemistry. DEc 1977;23(12):2329-2331. 
  60. Alissa Lockwood, John Patka, Marina Rabinovich et al. Sodium nitroprusside-associated cyanide toxicity in adult patients- fact or fiction? A critical review of the evidence and clinical relevance. Open access journal of clinical trials. Sept 2010;2:133-148. 
  61. Ha Kim, Seon Joong Lee, Soon Ha Kim, Kyung Soo Ko, Byoung Doo Rhee, Zhelong Xu, Nari Kim, Jin Han. NecroX-5 suppresses sodium nitroprusside- induced cardiac cell death through inhibition of JNK and caspase-3 activation. Cell Biology International. 5 Feb 2014. 
  62. James E Cottrell, Pavel Illner, Michael J Kittay, John M Steele Jr, Jerome Lowenstein, Herman Turndorf. Rebound hypertension after sodium nitroprusside-induced hypotension. Clinical Pharmacology and Therapeutics. 1980;27:32-36. 
  63. SW Wang, JE Pohl, DJ Rowlands, EG Wade. Diazoxide in the treatment of primary pulmonary hypertension. Br Heart J. May 1978;40(5):572-574. 
  64. J Buch, A Wennevold. Hazards of diazoxide in pulmonary hypertension. Br Heart J. Oct 1981;46(4):401-403. 
  65. Norman Altszuler, Jennifer Hampshire, Ety Moraru. On the mechanism of diazoxide induced hyperglycemia. Diabetes. Oct 1977;26(10):931-935. 
  66. Ian M Burr, Errol B Marliss, Werner Stauffacher, Albert E Renold. Diazoxide effect on biphasic insulin release: adrenergic suppression and enhancement of perifused rat pancreas. J Clin Invest. Jul 1971;50(7):1444-1450. 
  67. RC Boerth, WR Long. Dose-response relation of diazoxide in children with hypertension. Circulation. 1977;56:1062-1066. 
  68. GV Gill, O Rauf, IA MacFarlane. Diazoxide treatment for insulinoma: a national UK survey. Postgrad Med J. 1997;73:640-641. 
  69. Melissa Standridge, Ramin Alemzadeh, Michael Zemel, John Koontz, Naima Moustaid-Moussa. Diazoxide down regulated leptin and lipid metabolizing enzymes in adipose tissue of Zucker rats. The FASEB Journal. Mar 2000;14(3):455-460. 
  70. Robert P Kraus, Ronald A Remick. Diazoxide in the management of severe hypertension after electroconvulsive therapy. Am J Psychiatry. 1982;139:504-505. 
  71. Wang Yong, Wang Shusen, Harvat Tricia, Kinzer Katie, Zhang Lisa, Feng Feng et al. Diazoxide, a KATP channel opener, prevents ischemia-reperfusion injury in rodent pancreatic islets. CT-1035. Cell Transplantation. Epub;provisional acceptance 08/20/2013. 
  72. Gregory B Hammer, Susan T Verghese, David R Drover, Myron Yaster, Joseph R Tobin. Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients. BMC Anesthesiology 2008;8:6. 
  73. JN Harvey, DP Worth, J Brown and MR Lee. Studies with fenoldopam, a dopamine receptor DA1 agonist, in essential hypertension. Br J Clin Pharmacol. Jan 1986;21(1):53-61. 
  74. RW Lappe, JA Todt, RL Wendt. Effects of fenoldopam on regional vascular resistance in conscious spontaneously hypertensive rats. JPET Jan 1986;236(1):187-191. 
  75. Nancy L Allison, Jeffrey W Dubb, John A Ziemniak, Fred Alexander, Robert M Stote. The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics. Clinical Pharmacology and Therapeutics. 1987;41:282-288. 
  76. Selcuk Sen, Soner Sabirli, Tolga Ozyigit, Yagiz Uresin. Aliskiren: review of efficacy and safety data with focus on past and recent clinical trials. Ther Adv Chrnic Dis. Sept 2013;4(5):232-241. 
  77. John JV McMurray, Bertram Pitt, Roberto Latini, Aldo P Maggioni, Scott D Solomon, Deborah L Keefe, Jessica Ford, Anil Verma, Jim Lewsey. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circulation: Heart Failure. 2008;1:17-24. 
  78. Yagiz Uresin, Addison A taylor, Charles Kilo, Diethelm Tschope, Massimo Santonastaso, Ghionul Inbram, Hui Fang, Andrew Satlin. efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. Journal of Renin-Angiotensin-Aldosterone System. Dec 2007;8(4):190-200. 
  79. Suzanne Oparil, Steven A Yarows, Samir Patel, Hui Fang, Jack Zhang, Andrew Satlin. Efficacy and saftey of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double blind trial. The Lancet. July 2007;370(9583):221-229. 
  80. Hans-Henrik Parving, Frederik Persson, Julia B Lewis, Edmund J Lewis, Norman K Hollenberg. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433-2446. 
     
  81. Hernan Trimarchi. Role of aliskiren in blood pressure control and renoprotection. International journal of nephrology and renovascular disease. March 2011;4:41-48. 
  82. Frederik Persson, Julia B Lewis, Edmund J Lewis, Peter Rossing, Norman K Hollenberg, Hans-Henrik Parving. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. CJASN May 2011;6(5):1025-1031. 
  83. Chris Jensen, Peter Herold, Hans Rudolf Brunner. Aliskiren: the first renin inhibitor for clinical treatment. Nature reviews drug discovery. May 2008;7:399-410.