Hypertension Therapy and Market Report

The term Cardiovascular is derived from two word namely Cardio and Vascular and the drugs which suppress the BP are known as antihypertensive, Commonly  used classification by clinicians is Primary or essential hypertension and Secondary hypertension. The present work deals with a market survey of recent available drugs of a hypertensive class and a comparison among the drugs.

ANTIHYPERTENSION: MANAGEMENT AND DRUG THERAPY; A MARKET SURVEY

 

Vyas Mohit ^1*; Dwivedi Sumeet²; Pandey Deepak³; Dwivedi Abhishek⁴; Tomar S. Gajendra¹ and Gautam Surya Prakash¹       

1, Smriti College of Pharmaceutical Education, Indore, MP-India

2, Chordia Institute of Pharmaceutical Educatiuon, Indore, MP-India

3, Pentagon Labs, Dewas, MP-India

4, NRI Institute of Pharmaceutical Science, Bhopal, MP-India

 

ABSTRACT

The term Cardiovascular is derived from two word namely Cardio and Vascular and the drugs which suppress the BP are known as antihypertensive, Commonly  used classification by clinicians is Primary or essential hypertension and Secondary hypertension. The present work deals with a market survey of recent available drugs of a hypertensive class and a comparison among the drugs.

* Corresponding Author

E-Mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Mob. No. 9893478497 {mospagebreak}

INTRODUCTION

The term Cardiovascular is derived from two word namely Cardio and Vascular and the drugs which suppress the BP are known as antihypertensive, Commonly  used classification by clinicians is Primary or essential hypertension and Secondary hypertension.

 

PRIMARY HYPERTENSION

 

Primary hypertension means that the cause for hypertension is not known. However, the risk even for primary hypertension are

1. Excessive salt intake.
2. Stressful life style
3. Sedentary life style
4. Obesity
5. Excessive alcohol intake
6. Cigarette smoking/ Tobacco consumption
7. Genetic factors
8. Diabetes Mellitus
9. Dyslipidemias like hypercholesterolemia, hyperttriglyceridemia, etc.

 

SECONDARY  HYPERTENSION

 

Secondary  hypertension means that the cause is known. Hypertension is secondary to (or may be co-existing with) the following pathophysiological conditions :

1. Renal artery steonsis: (narrowing of the lumen of renal artery), or renal parenchymal disease, etc is one of the commonest cause of secondary hypertension.
2. Diseases of adrenal gland such as Cashing syndrome and primary hyper-aldosteronism may also lead to secondary hypertension , dishing syndrome is characterized by obesity and muscular weakness associated with excessive production of cortisol due to adrenal pituitary dysfunction. Primary hyper-aldosteronism is a condition characterized by excessive production of aldosterone and typically by loss of body potassium, weakness and elevated blood pressure.
3. Excessive functioning of thyroid gland known as hyperthyroidism will generally lead to systolic hypertension.
4. Coarctation of aorta will head to hypertension.

 

DRUG INDUCED HYPERTENSION

Usage of various drugs may also lead to hypertension. Oral contraceptives , liquorice, NSAIDs, glucocorticoids, cocaine, etc are among the commonly used drugs that may cause hypertension.

COMPLICATION OF UNTREATED HYPERTENSION

Uncontrolled chronic hypertension leads to damage of cardiovascular system, renal system, brain, and eyes.

1. Complications  of cardiovascular system

             *   Left ventricular hypertrophy

             *   Congestive Heart Failure

             *   Ischemic Heart Disease

2. Cerebral Stroke
3. Renal Disorders
4. Hypertensive retinopathy – Damage to eyes

HYPERTENSION AND CO-EXISTING DISORDERS

Treatment of hypertension with the following co-existing disorders deserve special attention of the physician.

·                     Diabetes Mellitus

·                     Renal Disorders

·                     Hypercholesterolemia

·                     Heart Failure

·                     Bronchial Asthma

·                     Cerebral Stroke

MANANGEMENT OF HYPERTENSION

There are two ways of treating hypertension that are complementary to each other:

Non – Pharmacological management, and

Pharmacological management.

Non-pharmacological Management:

Non-Pharmacological management is also essential controlling blood pressure. The various measures to be taken are as follows:-

1. Reduction in Body weight.
2. Cessation of smoking
3. Relaxation therapy
4. Dietary restrictions (low sodium, high calcium and potassium)
5. Moderation in intake of Alcohol
6. Moderate exercise – roughly 30 minutes per day.

Extra rest, prolonged vacations, moderate weight reduction, and dietary Na restriction are not as effective as antihperensive drug therapy. Patients with uncomplicated hypertension need not restrict their physical activities as long as their BP is controlled. Dietary restrictions can help control diabetes mellitus, obesity, and blood lipid abnormalities. In stage I hypertension, weight reduction to ideal levels, modest dietary Na restriction to <2  g / day, and alcohol consumption  to <1 oz/day may make drug therapy unnecessary. Prudent exercise should be encouraged. Smoking should be unambiguously discouraged.

Prehypertensive stage must be managed by nonpharmacological therapy. As stated above, mild hypertension can be managed by non-pharmacological therapy. It this does not succeed in 4 weeks or so, drug (pharmacological) treatment is required.

However, the drug therapy should be combined with non-drug therapy in order to get an effective control hypertension.

Pharmacological Management:

The various classes of drugs available are : ACE inhibitors, angiotension receptor blockers, beta blockers, and centrally acting drugs. Selection of the initial drug should be guided by age and race of the patient and by coexisting diseases or conditions  that may represent a contraindication for certain drugs (eg, asthma and P-blockers) or a special indication for certain drugs (e.g. angina pectoris and ^- blockers or Ca blockers).

If the initial drug is ineffective or causes intolerable adverse effects, another can be substituted (sequential monotherapy). Alternatively, if the original drug is only partially effective but well tolerated, the dose may be increased or a second drug can be added, which should be of a different class (stepped care).

{mospagebreak}DRUG THERAPY

DIURETICS

All  thiazide derivatives and their congeners are equally effective in equivalent doses. Metolalazone, indapamide, and the loop diuretics furosemide, bumetanide, ethacrynic  acid, and torsemide are no more effective than the thiazides but are preferred in patients with chronic renal failure.

The antihypertensive action of diuretics seems to be due to a modest reduction in plasma volume and a decrease in vascular reactivity, possibly mediated by shifts in Na from intracellular to extracellular loci.

 Picture: Diuretic Sites of Action (avalilabe only in pdf version in Downold )

A disadvantage of diuretics is sexual dysfunction , which occurs more commonly than with some of the other drugs proposed for initial therapy.

Metabolic adverse effects of diuretics (hypokalemia. Hypomagnesemia, hyperuicemia, hypercalcemia, hyperlipidemia) are dose related and if properly managed, do not usually prevent diuretic use. Spironolactone can cause breast tenderness, making amiloride or triamtercne preferable when a K-sparing drug is chosen for males. Diuretics uncommonly precipitate clinical type II diabetes or aggravate preexisting type II diabetes in susceptible patients. Most diabetes can tolerate a low-dose thiazide diuretic with little or no effect on the control of their diabetes, although  it may aggravate hyperinsulinemia. Exercise and weight loss will ameliorate but not eliminate these adverse effects.

 

Thiaide and related diuretics can increase cholesterol (mostly in the low-density Lipoprotein fraction) and triglyceride concentration, although long-term studies failed to show an adverse effect at > 1 yrs. Furthermore, increased concentration seems to occur only in susceptible patients, is apparent within 4 wk of treatment , and can be ameliorated by a low-fat diet,. Elevated concern ration of scrum cholesterol or triglycerides is not an a priori contraindication to the use of diuretics in the management of hypertension, because the lipidmic effect is more likely to occur in patients with normal concentrations than in patients with hyperlipidemia.

β-BLOCKERS

Beta-Blockers are competitive antagonists at beta – adrenergic receptor sites and are used in the management of cardiovascular disorders such as hypertension, angina pectoris, myocardial infraction, heart failure etc.

They are also administered to control symptoms of Sympathetic  overactivity in

1. Alcohol withdrawal,
2. Anxiety states,
3. Hyperthyroidism,
4. Themors and
5. Prophylaxis of migraine

Some beta-blockers are used as eye drops to reduce raised intra-ocular pressure in giaucoma.

Beta blockers can be characterized by their

Affinity for beta or beta ? receptor subtypes.

Intrinsic sympathornimetic activity,

Membrane – stabilizing activity,

Blockade of alpha adrenergic receptors , and

Pharmacokinetic properties including difference in lipid solubility.

{mospagebreak}CLASSIFICATION

Beta – blockers have different affinities for betai or beta  receptors. While, proparanolol has affinity for betai and beta 2 receptors, other drugs such as Bisoprolol, Atenolol and Metoprolol, have greater affinity for betai receptor only  and are decribd as Cardioselective. However selectivity is relative and as doses are increased , activity at beta 2 receptors becomes clinically important.

All  Blockers are  equivalent in terms of antihypertensive efficacy. If the patient also has diabetes mellilus chronic occlusive peripheral arterial disease or COPD it is preferable to use a cardioselective – blocker (acebutolol, atenolol, betaxolol, bisoprolol, tnetoprolol). However, Cardio selectivity is only relative and diminishes as the dose of the – blocker increases.

Table:1  Receptor specific action

Receptor	Site	Agonist/ Stimulation produces	Examples	Antagonist blockage produces	Examples
Beta 1	Heart	Increased heart force : positive inotropic effect increased Heart rate : Positive chronotropic effect	Adrenaline Isoprenaline Epinephrine Nor epinephrine Dobutamine Dopamine	Decreased heart force : negative inotropic effect Decreased Heart Rate : negative chronotropic effect	Atenolol Acebutolol Metoprolol
Beta 2	Bronchi Blood Vessels Uterus, G.U.T. Eye	Bronchodilatation	Adrenaline Salbutamol  Terbutaline Isoprenaline Bambuterol	Bronchocoristriction	Propranolol
Alpha 1	Blood Vessles	Vasoconstriction	Adrenaline Nor epinephrine Dopamine	Vasodilatation : Lowers blood pressure reduced work done by heart	Prazocin Carvedilol

 

Even cardio selective –blockers are contraindicaled in the presence of severe asthma or COPD with a prominent bronchospastic component. Use of a cardioselective p-blocker in the absence of one of these indications offers no advantage over nonselective – blockers.

- blockers  with intrinsic sympathomimetic activity (ISA – eg. Acebutolol, cartcolol. Penbutolol, pindolol) do not have an adverse effect on scrum lipids ; they are also less likely to produce severe bradycardia than are non-ISA –blockers. However, asymptomatic sinus bradycardia, even with rates in th 40s usually is not harmful. 

Disadvantages  of – blockers include a high incidence of CNS adverse effects (sleep disturbances, fatigue, lethargy) and contraindications (greater than firs-degree heart block, asthma, sick sinus syndrome, heart failure). Similar to diuretics can cause sexual dysfunction in men and metabolic adverse effects, including impaired glucose tolerance, depressed high density lipoprotein cholesterol, and increased serum total cholesterol and triglyceride concentrations.

Picture:  β – ADRENOCEPTOR BLOCKING DRUGS (avalilabe only in pdf version in the  Downold section)

{mospagebreak}Propanolol

Propanolol decreases heart rate, force of contraction (at relatively higher doses) and cardiac output (c.o.) It prolongs systole by retarding conduction so that synergy of contraction of ventricular fibres is disturbed. The effects on a normal subject are not appreciable, but become prominent under sympathetic over activity (exercise , emotion). Ventricular dimensions are decreased in normal subjects but dilatation can occur in those with reduced reserve – CHF may be precipitated or aggravated.

Metoprolol

It is the prototype of cardio selective (B1) blockers. Its potency to block cardiac stimulation is similar to proponolol but nearly 50 times higher dose is needed to block so induced vasodilatation, It is less likely to worsen asthma, but is not entirely safe. It may be preferred in diabetics receiving or oral hypoglycaemics. Patients who complain of cold hands and  feet while on Propanolol do better on methaprolol.

Atenolol

A  relatively selective B1 blocker having low lipid solubility. It is incompletely absorbed orally, but first pass metabolism is not significant. Because of longer duration of action, once daily dose is often sufficient. Side effects related to CNS action are less likely. No deleterious effects on lipid have been noted . Effective dose for most individuals falls in a narrow range. It is one the most commonly used B blockers for hypertension and angina. 

  Ca⁺⁺ – CHANNEL  BLOCKERS

Calcium Channel blockers are also known as Calcium antagonists, Calcium entry Blockers , slow Calcium channel blockers.  These  Agents  inhibits  the  cellular influx  of  calcium,  which  is  responsible  for  contraction  of smooth muscle.  The  Calcium  channel  blockers  primarily  affect  tissues  in  which depolarization  dependent  upon  calcium  rather  than sodium  influx,  these includes  vascular  smooth  muscle,  myocardial  cells  and  cells  within  the Sino-atrial  (SA) and  atriventricular  (AV)  nodes.  The  main  action  of  calcium  channel  blockers  includes  dilation  of  coronary  and  peripheral  arteries  and  arterioles  with little  or  no effect  on  venous  tone,  a  negative  inotropic  action,  reduction  of heart  rate and  slowing  AV  conduction.

The  classification  of  calcium channel  blockers  is  based  on  their  chemical  structure.

Dihydropyridine : Nifedipine,  Amlodipine

Benzothiazepin : Diltiazem

Phenylalkylamine : Verapamil

Dihydropyridine  have  greater  selectivity  for vascular  smooth  muscle  then  myocardium  and  therefore  their main  effect  is  vasodilatation.  They  have  little  or  no action  at  the  SA  and AV  nodes and  negative  inotropic  activity  seen  at  therapeutic  doses.

Picture: Calcium channel  (avalilabe only in pdf version in the  Downold )

They  are  mainly  used  in  treatment  of  hypertension  and  angina.

Regulation  of  intracellular  calcium  concentration

There  are  a variety  of  ion  pumps,  channels  and  exchangers  that  are  directly  involved  in controlling  intracellular Calcium,  Thus,  there  are many  possible  sites  for  therapeutic  agents  act :

They  are widespread  in the  cardiovascular  system  and  are  responsible  for  the  plateau  phase  (slow inward current) of the  action  potential. L-channels are  sensitive  to  Calcium channel blockers  and  may  triggers release  of internal  calcium.  Cardiac  L-channels  are  regulated  by  camp-dependent  protein  kinase  (phosphorylation  enhances  the  probability  of  the  channel opening at a given  membrane  potential).

Activated  at  more  negative  potentials  that  L-channels and  inactivating  rapidly,  these may  be  involved  in  rhythmic/pacemaker  activities  and  triggers  for  other  ionic  events. They  are  not  sensitive  to  Calcium  channel  blockers.

These  appear  to  be  found  only  in neuronal   tissues  and  are   not  apparently  sensitive  to  Calcium  channel  blockers.

Ca  blockers  are  potent peripheral vasodilators and reduce BP by decreasing TPR. The diphenylalkylamine derivative verapamil and the benzothiazepine derivative diltiazem slow the heart rate, decrease atrioventricular conduction, and have a negative inotropic effect on myocardial contractility , similar to p-blockers. Consequently, they should not be prescribed for patients with greater than first-degree heart block or left ventricular failure. In general, P-blockers and verapamil or diltiazem  should not be prescribed in the same regimen for patients with left ventricular dysfunction.

The dihydropyridine derivatives (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisodipine) have a lesser negative inotropic effect than the nondihydropyridines but can sometimes cause reflexive tachycardia. These drugs are more potent vasodilators than are the nondihydropyridines and shoud therefore be more effective. However, in longterm antihypertensive  therapy, they do not seem to be more potent than ondihydroridine Ca blockers.

Short-acting nifedipine has been associated nonrandomized case-control and cohort studies with increased rates of MI compared with other classes of drugs and therefore should not be used to treat hypertension (for which it is not indicated) . Short-acting diltiazem  also is not indicated for treating hypertension. Long-acting Ca blockers are preferred. Ca blockers do not have metabolic adverse effects.

A Ca blocker is preferred to – blockers a for hypertensive patients with angina pectoris who also have bronchospastic disease or Raynauld’s disease.

Nifedipine :

            The  overriding action of  nifedipine is arteriolar dialatation > t.p.r. decreases, BP falls. The direct depressant effect on heart requires much higher dose, but a weak negative inotropic action can be unmasked after B blockers. It does not depress SA node or AV conduction. Reflex sympathetic stimulation of heart predominates  > tachycardia, increased contractility.

 

Amlodipine :

            Pharmacokinetically it is the most distinct DHP. It has complete but show oral absorption : peak after 6 to 9 hr – the early vasodilator side effects (palpitation, flushing, headache, postural dizziness) are largely avoided. Because of less extensive and less variable first pas metabolism, its oral bioavailability is higher and more consistent.

 

Diltiazem :

            It is a less potent vasodilator than nifedipine and verapamil, and has modest direct negative inotropic action, but direct depression of SA node and A-V conduction are equivalent to verapamil.

 

{mospagebreak}ACE  INHIBITORS

 

ACE  inhibitors  are  vasodilators that  reduce BP by interfering with the generation of agiotensm II from angiotensin I and by inhibiting the degradation of bradykinin, thereby decreasing peripheral vascular resistance without inciting reflex tachycardia. They reduce BP in many hypertensive patients, regardless of plasma rennin activity.

One of the advantages o ACE inhibitors in the management of hypertension is the low adverse effect profile. A dry irritating cough is the most frequent adverse effect. ACE inhibitors do not adversely affect serum lipids, plasma glucose, or uric acid. They tend to increase serum K, especially in patients with chronic renal failure or in patients taking K-sparing diuretics , K supplements, or NSAIDs. These drugs are least likely to cause sexual dysfunction in males. Angioedema is a rare adverse effect of ACE inhibitors and can be life-threatening if it  involves the larynx or the oropharyngeal area.

Picture: ACE Inhibtors  (avalilabe only in pdf version in the Downold )

ACE inhibitors reduce proteinnuria for patients with diabetic nephropathy and many retard glomerulosclerosis by selectively dilating the efferent (postglomerular) arteriole, thus reducing glomerular capillary pressure without compromising blood flow. They retard the loss of renal function in patients with nephropathy due to type I diabetes. If ACE inhibitors are prescribed for patient with chronic renal disease, especially when azotemia is present, serum crealinine and K levels should be monitored frequently. ACE inhibitors can cause acute renal failure in patients who have severe bilateral renal artery stenosis or severe stenosis in the artery to a solitary kidney, presumably because under these conditions GFR is maintained by angiotensin II-mediated constriction of the efferent arteriole, which is abolished by ACE inhibition. For the same reason , they can cause acute renal failure in hypovolemic patients and in patients with severe heart failure. Nevertheless, ACE inhibitors reduce mortality and re-hospitalization rates for patients with left ventricular dysfunction and ejection fractions < 40%.

Diuretics consistently enhance the antihypertensive activity or ACE inhibitors as much as , if not more than, they do for any other class of antihypertensive drugs

Angiotensin II receptor blockers block angiootensin II receptors and therefore interfere with the rennin-angiotensin system, perhaps more completely than do the ACE inhibitors . They do not block the degradation of bradykinin, which perhaps explains why they do not cause a dry irritating cough. To the extent that bradykinin may contribute to the hypotensive effect of ACE inhibitors , the angiotensin II receptor blockers may less effectively reduce B.P. However, the extent that tissue ACE is not blocked by ACE inhibitors, angiotensin II receptor blockers may more effectively reduce B.P. Studies have shown that they are equally effective as antihypertensive drugs. Angiotensin II receptor blockers seem to be remarkable free of adverse effect and have been implicated in fewer cases of angioedema than have the ACE inhibitors, but this adverse effect is very rare with either class or drugs. Presumably, angiotensin II receptor blockers have the same beneficial effects as ACE inhibitors in patients with left ventricular failure and in type I diabetics with nephropathy, but definitive controlled trials have not been reported. Precautions for the use of ACE inhibitors in patients with renovascular hypertension, hypovoluia, and severe heart failure also apply to the angiotensin II receptor blockers.

  Table: 2 Various effects of ACE inhibitor

Effects	Mechanism of action
1. Vasodilator	a)        Inhibition of Renin angiotensin System b)        Increased bradykinin c)        Decreased endothelin levels
2. Diuretic	Decreased Na+ retention due to decreased secretion of aldosterone
3. Regression of LVH	Inhibition of tissue Renin angiotensin system
4. Cardiac remodeling	Inhibition of tissue Renin angiotensin
5. Improvement in vascular remodeling	a)              Improvement in endothelial function b)             Inhibition of tissue Renin angiotensin
6. Increased arterial dispensability	Inhibition of tissue Renin angiotensin
7. Anti-atherosckerotic with decease in macrovascular disease	a)      Decreased cytosolic calcium b)      Decreased migration of smooth muscle cells c)      Improvement in endothelial function d)     Decrease production of prostaglandins PDGI
8. Antithrombotic	a)      Antiplatelet effect b)      Enhancement of endogenous fibrinolysis
9. Delayed onset of diabetes	Unknown

{mospagebreak}ACE  Inhibitors (Drugs)

 

Enalapril :-

 

 

 This is the second ACE inhibitor  to  be  introduced. It is a prodrug- converted in the body the enalaprilat (a tripeptide analogue) , which is not used as such orally because of poor absorption, but marketed as inject able preparation in some countries. Enalapril has the same pharmacological, therapeutic and adverse effect profile as captopril

Lisinopril :-

 It is the lysine derivative of enalprilate does not require hydrolysis to become active ACE inhibitor. Its oral absorption is slow (making first dose hypotension less likely). And incomplete, but unaffected by food. The duration of action is considerably longer, permitting single daily dose and ensuring uniform hypotensive action round the clock.

Perindopril :-

Another long acting ACE inhibitor with a slow onset of action : less chance of first administered periodopril is absorbed, only about 20% is converted to the active  metabolic perindoprilat.

 

Ramipril :-

The  distinctive feature of this long acting ACE inhibitor is its extensive tissue distribution. It may thus inhibit local rennin – angiotensin systems to a greater extent. Whether this confirms any therapeutic advantage is not known. The plasma t½ of its active metabolic ramiprilat is 9 – 18 hours.

 Table: 3 Comparative  features  of  ACE  inhibitors

Features	Enalapril	Lisinopril	Perindopril	Ramipril
1. Chemical nature	Carboxyl Group	Carboxyl Group	Carboxyl Group	Carboxyl Group
2. Activity status	Prodrug	Active	Prodrug	Prodrug
3. Bioavailability (as active form)	50%	25%	20%	60%
4. Time to peak action	4-6 hr	6-8 hr	6 hr	3-6 hr
5. Elimination t½	Renal	Renal	Renal	Renal
7. Duration of Action	24 hr	> 24 hr	> 24 hr	> 24 hr
8. Daily dose (mg)	2.5 – 40 mg	5-40 mg	2 – 8 mg	1.25 – 10 mg

 

DIRECT  VASODILATORS :

The  mechanism  of  direct  vasodilators (independent of the autonomic nervous system) is different from that of Ca Blockers and ACE inhibitors. Mnoxidil is more potent than hydralazine but is associated with more adverse effects, including Na and water retention and hirsutism, which are poorly tolerated by women ; it should be reserved for severe, resistant hypertension. Hydralazine has long been used as (and remains) a step-3 drug because its antihypertensive effect is additive to that of other vasodilating drugs. The lupus syndrome is rarely observed if the dosage is < 300 mg / day.

Prompt BP reduction with parenteral drugs is indicated for patients with hypertensive encephalopathy acute ventricular failure, or other true emergencies . IV diazoxide, sodium nitroprusside, enalaprilat, nitroglycerin, nicardipine, or labetalol is usually used for this purpose. Because diazoxide is a nondiuretic thiazide derivative that can cause fluid retention, furosemide 40 or 80 mg IV is usually given with it. Diazoxide is administered by rapid IV injections of 50 to 100 mg (1 to 1.5 mg/kg, <= 100 mg/dose) given 5 – 10 min until the BP reaches the optimal level. Adverse effects include nausea, vomiting, hyperglycemia, hyperuricemia, tachycardia, and , only occasionally, hypotension (generally without shock).

Sodium nitroprusside 0.25 to 10 ug/kg/min (for <= 10 min at the highest dosse to minimize the risk of cyanide toxicity) given by continuous IV infusion in 5% D/W can promptly reduce BP in a hypertensive crisis, but its evanescent effect and potency require almost continuous monitoring of BP in an ICU. Unlike diazoxide , it produces venodilation and arteriolar dilation and therefore reduces preload and afterload , making its especially useful for managing hypertensive patients with heart failure. Adverse effects include nausea, vomiting , agitation, muscular twitching, and cutis anserine (goose flesh if BP is reduced from prolonged therapy, especially in patients with renal failure. The drug should be discontinued if the serum thiocyanate concentration is > 12 mg/dI (206 pmol/dI).

Nitroglycerin, similar to sodium nitroprusside, relaxes the resistance vessels and the large capacitance veins. Compared with sodium nitroprusside, it has a greater effect on veins than on arterioles. IV infusions of nitroglycerin have been used to manage hypertension during and after coronary bypass, heart failure, acute MI, unstable angina pectoris, and acute pulmonary edema. Hemodynamic studies indicate that IV nitroglycerin is preferable to sodium nitroprusside in manging hypertension associated with severe coronary disease because it increases coronary flow, whereas sodium nitroprusside tends to decrease coronary flow to ischemic areas possibly because of a “steal” mechanism. The most frequent adverse reaction is headache, which occurs in about 2% of patients ; tachycardia , nausea, vomiting, apprehension, restlessness, muscular twitching, and palpitations have also been observed.

Enalaprilat is administered in a dose of 0.625 – 1.25 mg IV, can be repeated every 6 hours till desired response is achieved . Reduction in blood pressure usually occurs within 15 minutes, but the maximal hypotensive response after the first dose may not occur for up to 4 hours after administration. The maximum effects of the second and subsequent does may exceed those of the first dose. Although no regimen has been shown to be more effective than 1.25 mg every 6 hours, dosages as high as 5 mg every 6 hours were well tolerated for up to 36 hours in controlled clinical studies.

Labetalol 20 to 40 mg IV q 10 min or as an infusion is as effective as nitroprusside , diazoxide, or nitroglycerin in managing hypertensive crises. Serious hypotensive episodes have not been observed when labetalol is given by this method, and adverse effects have been minimal. Because of its P-blocking activity, labetalol should probably not be used for hypertensive emergencies in patients with acute left ventricular failure or in asthmatic patients.

Although short-acting nifedipine given orally usually reduces BP rapidly, it has been associated with acute cardiovascular and cerebrovascular events (sometimes fatal) and is not recommended for treating hypertensive emergencies or urgencies. It is not indicated for managing hypertension.

{mospagebreak}ANTIHYPERTENSIVES IN INDIA

  Table:4 The   commonly  used  antihypertensive  drugs

Class	Drug
Diuretics   Beta blocers   Alpha blockers   Calcium Channel Blockers   ACE inhibitors   Angiotensin II antagonists	Frusemide, Spiranolactone, Thiazide   Atenolol   Prazosin  hydrochloride   Nifedipine, Diltiazem, Amlodipine   Enalapril, Benazepril, Lisinopril, Ramipril   Fosinopril Losartan potassium

 

{mospagebreak}NEWER DRUG THERAPIES

Angiotensin II Receptor Antagonists

Angiotensin II (A II ) is produced in plasma by the sequential processing of circulating angiotensinogen by renin and Angiotensin I Converting Enzyme (ACE). Renin, produced by the kidney, is a major factor in regulating the production of A II in the circulation. Recently it has been recognized that local A II production also occurs in several tissues such as the brain, adrenal glands, the heart and blood vessels. In these tissues A II levels are regulated by uptake of A II from the circulation as well as by local formation and degradation of A II via a tissue renin angiotensin system (RAS). In the tissues Chymase and other enzymes convert angiotensin I (A I ) to A II in a process independent of blood ACE. In animal experiments ACE inhibition reduced basal A II formation by only 25%. A II receptor antagonists selectively compete with the binding of A II to its type I (AT₁ ) receptor. AT₁ receptor is present in all tissues and is responsible for most of the known actions of A II . The first four A II receptor antagonists are:

Losartan which produces a short surmountable AT₁ receptor blockade but its metabolite, EXP 3174, has a long duration of action and produces an insurmountableAT₁ blockade. It is 20 times more potent than the parent drug.

Valsartan is also a potent AT₁ antagonist. The parent compound is the active drug. It has a half-life of 6-9 hours and is excreted in bile (70%) and by the kidneys (30%).

Irbesartan and Candesertan are long acting and produce insurmountable A II blockade. Irbesartan has a half-life of 11-15 hours, and is mainly cleared by the liver (78%) and by the kidneys (22%). Candesertan is a pro-drug and unlike other A II receptor antagonists, is cleared mainly by the kidneys (60%). Those latter two drugs differ from Losartan and Valsartan in that they have a clear dose-response relationship, which was not established with Losartan or Valsartan.

When A II receptor antagonists were compared with other hypotensive drugs, they were found to have an efficacy equivalent to that of ACE inhibitors, calcium antagonists and B-blockers^(,7,8,9,10). When the RAS is blocked, blood pressure becomes salt sensitive; thus diuretics enhance the BP lowering effect of A II antagonists. This has been demonstrated in several clinical studies. A II receptor antagonists as a class have excellent tolerability profile with an incidence of side effects similar to that of placebo. Unlike the ACE inhibitors, they do not induce cough. The only interclass difference is the ability of Losartan to increase urinary uric acid excretion and lower plasma uric acid.

Combining ACE inhibitors and A II receptor antagonists:

Long term use of ACE inhibitors produces marked elevation of A I in the circulation because its conversion to A II is blocked. This excessively available A I is taken by the tissue enzymes and is converted to A II locally giving A II actions which by-pass the circulation ACE block. Therefore the use of A II receptor antagonists to block the effect of this local A II on the AT₁ receptor can be complementary to the use of ACE inhibitors enhancing the hypotensive effect. In spite of this potential beneficial combination, the combined use of ACE inhibitors and A II receptor antagonists in the treatment of hypertension has not been thoroughly studied in well designed controlled trials. A preliminary study conducted on normotensive volunteers has suggested that combined administration of an ACE inhibitor and A II receptor antagonist induces an additional blood pressure reduction⁽¹¹⁾. On the other hand other therapeutic benefits of the combination of ACE inhibitors and A II receptor antagonists have been probed: in a pilot study on anterior myocardial infarction, the authors concluded that the addition of Losartan to Captopril improved the beneficial effects of ACE inhibition in patients with anterior myocardial infarction. The effect of the combination was also studied on proteinuria: the use of the combination produced more reduction in proteinuria than that which was effected by ACE inhibition or A II receptor antagonism alone. The main drawback of this study is the small number of patients.

(B)Endothelin antagonists.

The Endothelins encompass a family of three 21-amino acid isopeptides ET 1,2,3. The most important, Endothelin-1 (ET-1), is produced by endothelial, mesangial, glomerular epithelial and medullary collecting duct cells. The final step in the formation of ET-1 is the cleavage of Proendothelin (big ET) by an Endothelin-converting enzyme (ECE) (Fig1). ET-1 is the most potent endogenous vasoconstrictor yet identified: it is hundred times more potent than norepinephrine when compared on equimolar basis. It acts on two main receptors: ETa and ETb. Stimulation of the former receptor is responsible for the vasoconstrictive effect of ET-1, while ETb has a vasodilator effect conducted through stimulating the production of nitric oxide and prostaglandins. ET-1 is implicated in the pathogenesis of hypertension and its level was elevated in some of the studies on patients with essential hypertension. It was also found to contribute to increased vascular tone.

 Drugs against ET-1 have been developed with their actions mainly exerted at two sites: ET receptor and ECE.

(i) ET receptor antagonist: the first member of this class is Bosentan, an orally administered blocker of both ETa and ETb receptors. Initial trials have shown it to be effective in lowering blood pressure. In a dose of 100 to 500 mg per day it was found to produce a blood pressure lowering effect equivalent to Enalapril 20mg per day. Doses of up to 2000 mg were well tolerated but contributed no additional therapeutic benefit. An additional advantage of Bosentan is the absence of reflex increase in heart rate, norepinephrine blood level, plasma renin activity or angiotensin II. This could have important useful implications in cardiovascular disease particularly in patients with heart failure. The main adverse effects were headache, flushing and lower limb oedema. No serious side effects were reported. New ET receptor antagonists are being developed, some of which like BQ-123 are specific to the ETa receptor which is likely to make them more potent hypotensive agents (Fig 2). ET antagonists are likely to create a new class of hypotensive drugs, which will widen the range of our armamentarium for the treatment of hypertension.

(ii) ECE inhibitors: Phosphoramidon is the first ECE inhibitor but has other non-specific actions. More selective agents are being developed by a number of pharmaceutical firms.

Genetics and Hypertension

With the development in molecular biology, the field of genetics is progressing rapidly. Some developments are helping in the understanding of the pathophysiology and management of hypertension. Examples of such developments are:

 A. ACE Gene and I/D Polymorphism With DNA cloning it was possible to identify the structure of the ACE gene with 26 exons and spans 21 Kb on chromosome 17. I/D polymorphism consists of the presence (Insertion -I-) or absence (Deletion - D -) of 287 base pair fragments in intron 16 resulting in 3 genotypes: Insertion homozygotes (II), Insertion/Deletion heterozygotes (ID) and Deletion homozygotes (DD).

II individuals have relatively low plasma concentrations of ACE compared to DD individuals who have high levels, while the heterozygotes ID have intermediate plasma ACE levels.

The DD genotype has been linked to essential hypertension, left ventricular hypertrophy and development of nephropathy in insulin and non-insulin-dependent diabetes mellitus. It may also be a potential genetic marker in hypertensives at risk of renal complications  .

Unlike the DD geneotype, which has good antiproteinuric response to ACE inhibitors, the II genotype response is limited. This could be explained by the fact that the II has naturally low plasma ACE levels allowing no significant drop with the use of ACE inhibitors.

AT II Type 1 Receptor (AT₁) Polymorphism

Recently AT II type 1 receptor (AT₁) polymorphism has been described in which there is either an adenine (A) or cytosine (C) base at position 1166 in the 3' untranslated region of the gene according to which persons can be typed as AA or AC/CC. Recent studies have suggested a predictive value of those types to the effect of AT II receptor antagonists. Losartan was found to increase the GFR and lower the mean arterial pressure in the AC/AA group but did not influence these parameters in the AA group.

{mospagebreak}SURVEYED DATA

 

 

CATEGORY	NO OF STRIPS SOLD IN A MONTH
B Blockers	92
Ace inhibitors	198
Ca++ Channel blockers	190
Total	480

 

RESULTS

After the survey , from the data collected it was concluded that

 

      ACE inhibitors > Ca++Channel Blockers > B-blockers

Among ACE inhibitors category wise sale is

    Ramipril >Enalapril >lisinopril

Among B-Blockers the Market leader is

   Atenolol

Among Ca++channel Blockers the Market leader is

    Amlodipine

 

REFRENCES

 

1. Tortora J. Gerard “Principles of Anatomy & Physiology”. 8^thedition Harper Collins college publisher page no 578.

 

2. Ross & Wilson “Anatomy & Physiology in Health & Illness”.9^th edition page    no105

 

3. Howland D. Richard “Pharmacology” 3^rd edition Lippincott Williams & Wilkins

Page no 213

 

4. Tripathi KD “Essentials of Medical Pharmacology”.5^th  edition jaypee publishers

page no 450

 

5. www.pharmacology insight .com