Chapter 36
Drugs Affecting Renin-Angiotensin System and Plasma Kinins
ANGIOTENSIN
Circulating renin-angiotensin system The generation and metabolism of A-II in circulation is depicted in Fig. 36.1. Normally, the amount of renin in plasma acts as the limiting factor for A-II generation. The plasma t½ of renin is 15 min. The biological potency of A-I is only 1/100 that of A-II, but it is rapidly converted into the latter by ACE which is a dipeptidyl carboxypeptidase located primarily on the luminal surface of vascular endothelial cells (especially in lungs). Circulating.
A-II also has a very short t½ (1 min); the first degradation product termed Angiotensin-III (A-III) is 2–10 times less potent than A-II, except in stimulating aldosterone secretion, in which it is equipotent. A-III is further acted upon by a variety of peptidases, collectively termed angiotensinases, to inactive fragments.
Tissue (local) renin-angiotensin systems Apart from the A-II generated in circulation as described above, blood vessels capture circulating renin and angiotensinogen and produce A-II within or at the surface of their wall (extrinsic local RAS). Many tissues, especially heart, blood vessels, brain, kidneys, adrenals possess all components of the renin-angiotensin system and generate A-II inside their cells (intrinsic local RAS). Thus, local renin angiotensin systems appear to operate in several organs in addition to the circulating one.
ACTIONS
coronary vessels. A-II induced vasoconstriction promotes movement of fluid from vascular to extravascular compartment. BP rises acutely. As a pressor agent, A-II is much more potent than NA. No tachyphylaxis is seen in the pressor action of A-II; rather long-term infusion of low concentration of A-II produces sustained rise in BP by its renal effects promoting salt and water reabsorption, as well as by enhancing endothelin generation.
A-II increases force of myocardial contraction by promoting Ca2+ influx. Though, it can increase heart rate by enhancing sympathetic activity, reflex bradycardia predominates in the intact animal. Cardiac output is often reduced and cardiac work is increased (due to rise in peripheral resistance). In contrast to NA, A-II does not activate latent pacemakers—little arrhythmogenic propensity.
A-II acting on a chronic basis induces hypertrophy, hyperplasia and increased intercellular matrix production in the myocardium and vascular smooth muscle by direct cellular effects involving expression of proto-oncogenes and transcription of several growth factors. Indirectly, volume overload and increased t.p.r. caused by A-II contributes to the hypertrophy and remodeling (abnormal redistribution of muscle mass) in heart and blood vessels. Long standing hypertension increases vessel wall + intimal thickness and causes ventricular hypertrophy. Fibrosis and dilatation of infarcted area with hypertrophy of the noninfarcted ventricular wall is seen after myocardial infarction. Progressive cardiac myocyte death and fibrotic transformation occurs in CHF. These changes are important risk factors for cardiovascular morbidity and mortality. ACE inhibitor therapy retards/reverses many of these changes imparting a pivotal role to A-II in vascular and ventricular hypertrophy, apoptosis and remodeling.
2. Smooth muscles A-II contracts many visceral smooth muscles in vitro, but in vivo effects are insignificant.
3. Adrenal cortex A-II and A-III are trophic to the zona glomerulosa of the adrenal cortex— enhance synthesis and release of aldosterone which acts on distal tubule to promote Na+ reabsorption and K+/H+ excretion. These effects are exerted at concentrations lower than those required to cause vasoconstriction.
4. Kidney In addition to exerting indirect effect on kidney through aldosterone, A-II promotes Na+/H+ exchange in proximal tubule → increased Na+, Cl– and HCO3¯ reabsorption. Further, it reduces renal blood flow and produces intrarenal haemodynamic effects which normally result in Na+ and water retention. However, an opposite effect has been observed in cirrhotics and renovascular disease patients.
5. CNS It has been noted that systemically administered A-II can gain access to certain periventricular areas of the brain to induce drinking behaviour and ADH release—both of which would be conducive to plasma volume expansion. It also increases central sympathetic outflow —contributes to the pressor response.
5. CNS It has been noted that systemically administered A-II can gain access to certain periventricular areas of the brain to induce drinking behaviour and ADH release—both of which would be conducive to plasma volume expansion. It also increases central sympathetic outflow —contributes to the pressor response.
Angiotensin receptors and transducer mechanisms Specific angiotensin receptors are present on the surface of target cells. Two subtypes (AT1 and AT2) have been differentiated pharmacologically: Losartan is a selective AT1 antagonist, while PD 123177 is a selective AT2 antagonist. Both subtypes are G-protein coupled receptors. However, all known effects of A-II appear to be mediated by AT1 receptor. The AT2 receptor is abundantly expressed in foetal tissues. In adults, it has been demonstrated in vascular endothelium, adrenal medulla, kidney and some brain areas. The functional role of AT2 receptor is not clearly defined, but is generally opposite to that of AT1 receptor. Activation of AT2 receptor causes NO-dependent vasodilatation, promotes apoptosis, myocardial fibrosis and inhibits cell proliferation.
The AT1 receptor utilizes different transducer mechanisms in different tissues. The phospholipase C–IP3/DAG–intracellular Ca2+ release mechanism underlies vascular and visceral smooth muscle contraction by activating myosin light chain kinase (MLCK). In addition, membrane Ca2+ channels are activated. Enhanced Ca2+ movement also induces aldosterone synthesis/release, cardiac inotropy, depolarization of adrenal medullary/autonomic ganglionic cell resulting in CA release/ sympathetic discharge. DAG activates protein kinase C (PKC) which phosphorylates several intracellular proteins and augments the above responses as well as participates in promotion of cell growth. In liver and kidney, A-II inhibits adenylyl cyclase. The intrarenal homeostatic action involves phospholipase A2 activation and PG/LT production.
In many tissues, especially myocardium, vascular smooth muscle and fibroblasts, AT1 receptor also mediates long-term effects of A-II on cell growth. A-II activates MAP kinase, TAK2 tyrosine protein kinase and PKC which together enhance expression of proto-oncogenes, transcription factors and growth factors. As a result, cell growth is promoted and more intercellular matrix is synthesized.
PATHOPHYSIOLOGICAL ROLES
2. Electrolyte, blood volume and pressure homeostasis The RAS plays an important role in maintaining electrolyte composition and volume of extracellular fluid (see Fig. 36.1). Changes that lower blood volume or pressure, or decrease Na+ content induce renin release by—
(i) Decreasing tension in the afferent glomerular arterioles: the intrarenal baroreceptor pathway: possibly operates through increasing local production of prostaglandins (PGs).
(ii) Low Na+ concentration in the tubular fluid sensed by macula densa cells: the macula densa pathway. It has been found that COX-2 and neuronal nitric oxide synthase (nNOS) are induced in macula densa cells by Na+ depletion → release of PGE2 and PGI2 is enhanced both due to increased amount of COX-2 as well as its activation by NO. The locally released PGs act on juxtaglomerular cells to promote renin secretion.
(iii) Baroreceptor and other reflexes which increase sympathetic impulses to JG cells— activated through β1 receptors: the β adrenoceptor pathway.
Increased renin is translated into increased plasma A-II which produces acute rise in BP by vasoconstriction, and more long-lasting effects by directly as well as indirectly increasing Na+ and water reabsorption in the kidney. Rise in BP in turn inhibits renin release : the long-loop negative feedback mechanism. It has been recently shown that A-II can be formed within the kidney and exerts important local regulatory effects. A shortloop negative feedback mechanism operates within the kidney : activation of AT1 receptors on JG cells inhibits renin release. Long-term stabilization of BP despite varying salt and water intake appears to be achieved through these mechanisms.
The mechanisms of regulation of renin release have important pharmacological implications:
ACE inhibitors and AT1 antagonists enhance renin release by interfering with both the short-loop and long-loop negative feedback mechanisms.
Vasodilators and diuretics stimulate renin release by lowering BP.
Loop diuretics increase renin production by reducing entry of Na+ into macula densa cells.
Central sympatholytics and β blockers decrease renin release by depressing the β adrenoceptor pathway.
NSAIDs, including selective COX-2 inhibitors, and nNOS inhibitors decrease renin release by inhibiting PG production → cause Na+ and water retention.
3. Development of hypertension The RAS is directly involved in renovascular hypertension: plasma renin activity (PRA) is raised in most patients. In essential hypertension also it appears to have a permissive role, though PRA may be raised or low. Since ACE inhibitors consistently lower BP in hypertensives, the involvement of this system appears to be more widespread. A positive correlation between circulating angiotensinogen levels and essential hypertension has also been found. Several genetic evidences point to causation of pregnancy-induced hypertension (preeclampsia) by production of AT1 receptor agonistic autoantibodies. The role of A-II in hypertrophy/remodeling of heart and blood vessels is now well recognized (see above).
4. Secondary hyperaldosteronism The RAS is instrumental in the development of secondary hyperaldosteronism.
5. CNS A-II can be formed locally in the brain and may function as transmitter or modulator. Regulation of thirst, hormone release and sympathetic flow may be the responses mediated. A-II is not available commercially, and not used clinically.
Inhibition of renin-angiotensin system It can be achieved by:
1. Sympathetic blockers (β blockers, adrenergic neurone blockers, central sympatholytics)— decrease renin release.
2. Renin inhibitory peptides and renin specific antibodies block renin action—interfere with generation of A-I from angiotensinogen (rate limiting step).
3. Angiotensin converting enzyme inhibitors— prevent generation of the active principle A-II.
4. Angiotensin receptor (AT1) antagonists— block the action of A-II on target cells. 5. Aldosterone antagonists—block mineralocorticoid receptors.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Captopril, an orally active dipeptide analogue was introduced in 1977 and quickly gained wide usage. A multitude of ACE inhibitors have since been added, of which—captopril, enalapril, lisinopril, benazepril, ramipril, fosinopril, trandolapril, imidapril and perindopril are available in India. Some others like quinapril, cilazapril zofenopril, etc. are marketed in other countries. The pharmacology of captopril is described as prototype, since most of its effects are class effects common to all ACE inhibitors.
Captopril
It is a sulfhydryl containing dipeptide surrogate of proline which abolishes the pressor action of A-I but not that of A-II: does not block A-II receptors.
Captopril can also increase plasma kinin levels and potentiate the hypotensive action of exogenously administered bradykinin. Pretreatment with B2 kinin receptor antagonist has shown that kinins do contribute to the acute vasodepressor action of ACE inhibitors, but they appear to have little role in the long-term hypotensive effect, probably because kinins play only a minor role, if at all, in BP regulation, and another enzyme ‘Kininase I’ (which also degrades bradykinin) is not inhibited. Nevertheless, elevated kinins (and PGs whose synthesis is enhanced by kinins) may be responsible for cough and angioedema induced by ACE inhibitors in susceptible individuals. ACE inhibitors interfere with degradation of substance P also.
Captopril lowers BP, but in the short-term, magnitude of response is dependent on Na+ status and the level of renin-angiotensin activity. In normotensive Na+ replete individuals, the fall in BP attending initial few doses of ACE inhibitors is modest. This is more marked when Na+ has been depleted by dietary restriction or diuretics. A greater fall in BP occurs in renovascular, accelerated and malignant hypertension. In essential hypertension it has been found that RAS is overactive in 20%, normal in 60% and hypoactive in the rest. Thus, it contributes to maintenance of vascular tone in over 80% cases and its inhibition results in lowering of BP. However, in the long-term no correlation has been observed between plasma renin activity (PRA) and magnitude of fall in BP due to captopril.
Captopril induced hypotension is a result of decrease in total peripheral resistance. The arterioles dilate and compliance of larger arteries is increased. Both systolic and diastolic BP fall. It has no effect on cardiac output. Cardiovascular reflexes are not interfered with and there is little dilatation of capacitance vessels. As such, postural hypotension is not a problem. Reflex sympathetic stimulation does not occur despite vasodilatation. They can be safely used in patients with ischaemic heart disease. The renal blood flow is not compromized even when BP falls substantially. This is due to greater dilatation of renal vessels (A-II markedly constricts them). Cerebral and coronary blood flow are also not compromized.
Reflex (postural) changes in plasma aldosterone are abolished and basal levels are decreased as a consequence of loss of its regulation by A-II. However, physiologically sufficient mineralocorticoid is still secreted under the influence of ACTH and plasma K+. Levels of plasma renin and A-I are increased as a compensatory measure, but the physiological significance of this appears to be minor (most actions are exerted through generation of A-II).
Pharmacokinetics About 70% of orally administered captopril is absorbed. Presence of food in stomach reduces its bioavailability. Penetration in brain is poor. It is partly metabolized and partly excreted unchanged in urine. The plasma t½ is ~2 hours, but actions last for 6–12 hours.
Adverse effects The adverse effect profile of all ACE inhibitors is similar. Captopril is well tolerated by most patients, especially if daily dose is kept below 150 mg.
Hypotension: an initial sharp fall in BP occurs especially in diuretic treated and CHF patients; persistent hypotension may be troublesome in MI patients.
Hyperkalaemia: more likely in patients with impaired renal function and in those taking K+ sparing diuretics, NSAIDs or β blockers. In others significant rise in plasma K+ is rare.
Cough: a persistent brassy cough occurs in 4–16% patients within 1–8 weeks, often requires discontinuation of the drug—subsides 4– 6 days thereafter. It is not dose related and appears to be caused by inhibition of bradykinin/substance P breakdown in the lungs of susceptible individuals.
Rashes, urticaria: occur in 1–4% recipients; does not usually warrant drug discontinuation.
Angioedema: resulting in swelling of lips, mouth, nose, larynx may develop within hours to few days in 0.06–0.5% patients; may cause airway obstruction; treat with Adr, antihistaminics, corticosteroids according to need.
Dysgeusia: reversible loss or alteration of taste sensation due to captopril has an incidence of 0.5–3%; lower incidence with other ACE inhibitors has been noted.
Foetopathic: foetal growth retardation, hypoplasia of organs and foetal death may occur if ACE inhibitors are given during later half of pregnancy. A recent report indicates 2.7-fold higher malformation rate in foetuses exposed to ACE inhibitors in the first trimester. ACE inhibitors must be stopped when the woman conceives.
Headache, dizziness, nausea and bowel upset: each reported in 1–4% patients.
Granulocytopenia and proteinuria: are rare, but warrant withdrawal. Renal disease predisposes to these adverse effects. However, ACE inhibitors retard diabetic nephropathy, reduce attendant proteinuria, and are renoprotective.
Acute renal failure: is precipitated by ACE inhibitors in patients with bilateral renal artery stenosis due to dilatation of efferent arterioles and fall in glomerular filtration pressure. ACE inhibitors are contraindicated in such patients.
Interactions Indomethacin (and other NSAIDs) attenuate the hypotensive action. Incidents of renal failure have been reported when a NSAID was given to patients (especially elderly) receiving ACE inhibitor + diuretic. Hyperkaliemia can occur if K+ supplements/K+ sparing diuretics are given with captopril. Antacids reduce bioavailability of captopril, while ACE inhibitors reduce Li+ clearance and predispose to its toxicity.
Dose 25 mg BD, increased gradually upto 50 mg TDS according to response. In patients on diuretics and in CHF patients it is wise to start with 6.25 mg BD to avoid marked fall in BP initially. Tablets should be taken 1 hr before or 2 hr after a meal. It has become less popular due
ANGIOPRIL 25 mg tab, ACETEN, CAPOTRIL 12.5, 25 mg tab
OTHER ACE INHIBITORS
Differences among ACE inhibitors are primarily pharmacokinetic reflected in time course of their action; no single drug is superior to others.
Enalapril This is the second ACE inhibitor to be introduced. It is a prodrug—converted in the body to enalaprilat (a tripeptide analogue), which is not used as such orally because of poor absorption, but is marketed as injectable preparation in some countries. Enalapril has the same pharmacological, therapeutic and adverse effect profile as captopril, but may offer certain advantages:
1. More potent, effective dose 5–20 mg OD or BD.
2. Its absorption is not affected by food.
3. Onset of action is slower (due to need for conversion to active metabolite), less liable to cause abrupt first dose hypotension.
4. Has a longer duration of action: most hypertensives can be treated with single daily dose.
5. Rashes and loss of taste are probably less frequent.
ENAPRIL, ENVAS, ENAM 2.5, 5, 10, 20 mg tab.
Lisinopril It is the lysine derivative of enalaprilat: 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. A reduction in venous return, cardiac contractility and cardiac output has been noted after few weeks of lisinopril use.
LINVAS, LISTRIL, LIPRIL 2.5, 5, 10 mg tab, LISORIL 2.5, 5, 10, 20 mg tab
Perindopril Another long-acting ACE inhibitor with a slow onset of action: less chance of first dose hypotension. Though 66–95% of orally administered perindopril is absorbed, only about 20% is converted to the active metabolite perindoprilat. Extensive metabolism to other inactive products occurs. Efficacy and tolerance of perindopril are similar to other ACE inhibitors.
COVERSYL 2, 4 mg tab.
Fosinopril This ACE inhibitor is unique in being a phosphonate compound that is glucuronide conjugated and eliminated both by liver and kidney. The t½ is not altered by renal impairment; dose remains the same. However, like most others, it is a prodrug suitable for once daily administration. First dose hypotension is more likely. Dose: Initially 10 mg (elderly 5 mg) OD; maximum 40 mg/day.
FOSINACE, FOVAS 10, 20 mg tabs.
Trandolapril It is a carboxyl prodrug that is 40–60% bioavailable in the active form. Absorption is delayed but not decreased by food. The peak effect occurs at 4–6 hours. It is partly metabolized and eliminated both in urine and faeces. The plasma t½ of active metabolite is 16– 24 hours, suitable for once daily dosing.
Dose: 2–4 mg (max 8 mg) OD; ZETPRIL 1, 2 mg tabs.
Ramipril The distinctive feature of this longacting ACE inhibitor is its extensive tissue distribution. It may thus inhibit local RAS to a greater extent. Whether this confirs any therapeutic advantage is not known. The plasma t½ of its active metabolite ramiprilat is 8–18 hours, but terminel t½ is longer due to slow release of tissue bound drug.
CARDACE, RAMIRIL, CORPRIL, R.PRIL 1.25, 2.5, 5 mg caps.
Imidapril The oral bioavailability of this longacting prodrug ACE inhibitor is 40%, that is reduced by taking with meals. The peak effect occurs at 6–8 hours and plasma t½ is >24 hours. Dose: Initially 5 mg OD taken 1 hour before food; usual maintenance dose 10 mg OD.
TANATRIL 5, 10 mg tabs.
Benazepril Another no sulfhydryl prodrug ACE inhibitor; has a bioavailability of 37% and is excreted by kidney with a t½ of 10–12 hr. Dose: 10 mg initially, max 20–40 mg/day;
BENACE 5, 10, 20 mg tab.
USES
1. Hypertension The ACE inhibitors are now first line drugs in all grades of hypertension. About 50% patients of essential hypertension respond to monotherapy with ACE inhibitors and majority of the rest to their combination with diuretics or β blockers. The hypotensive effect of lower doses develops gradually over 2–3 weeks. They offer the following advantages:
Lack of postural hypotension, electrolyte disturbances, feeling of weakness and CNS effects.
Safety in asthmatics, diabetics and peripheral vascular disease patients.
Recent evidence indicates that long-term ACE inhibitor therapy has the potential to reduce incidence of type 2 diabetes in high risk subjects.
Prevention of secondary hyperaldosteronism and K+ loss due to diuretics.
Renal blood flow is well maintained.
They reverse left ventricular hypertrophy and the increased wall-to-lumen ratio of blood vessels that occurs in hypertensive patients.
No hyperuricemias, no deleterious effect on plasma lipid profile.
No rebound hypertension on withdrawal.
Minimum worsening of quality-of-life parameters like general wellbeing, work performance, sleep, sexual performance, etc.
Large multicentric trials have confirmed that ACE inhibitors reduce cardiovascular morbidity and increase life expectancy of hypertensive patients. It appears that by their specific effect on myocardial and vascular cell growth/remodeling, they have greater protective potential than other classes of antihypertensive drugs.
ACE inhibitors are highly effective and first choice drugs in renovascular and resistant hypertension. They are particularly suitable for diabetic hypertensives in whom they reduce cardiovascular complications more than other antihypertensive drugs, probably by improving endothelial function.
2. CHF ACE inhibitors cause both arteriolar and Veno dilatation in CHF patients: reduce afterload as well as preload. Hemodynamics measurements in severe CHF patients have shown reduction in right atrial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, systemic vascular resistance, systolic wall stress and systemic BP. Though they have no direct myocardial action, stroke volume and cardiac output are increased, while heart rate is reduced. Accumulated salt and water are lost due to improved renal perfusion and abolition of mineralocorticoid mediated Na+ retention. Cardiac work as measured by heart rate × pressure product is reduced; thereby, exercise capacity of CHF patients is enhanced. Beneficial effects are well sustained with chronic therapy and the NYHA functional class of most patients is improved.
Robust multicentric trials have shown that ACE inhibitors retard the progression of left ventricular systolic dysfunction and prolong survival of CHF patients of all grades (I to IV). Unless contraindicated, ACE inhibitors are now advocated by several professional bodies, including American Heart Association and American College of Cardiology, as first line drugs in all patients with symptomatic as well as asymptomatic left ventricular inadequacy. A diuretic, β blocker with or without digitalis may be added according to need. ACE inhibitors reduce episodes of decompensation, myocardial infarction and sudden death. In addition to improved haemodynamics, long-term benefits of ACE inhibitors accrue from withdrawal of A-II mediated ventricular hypertrophy, remodeling, accelerated myocyte apoptosis and fibrosis. Indirect benefits occur due to reduction in sympathetic activation and aldosterone levels.
The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial on 3164 heart failure patients (NYHA class II to IV) has shown that high dose lisinopril (32.5–35 mg/ day) given for 39–58 months was more effective in reducing all cause mortality, hospitalization for heart failure and risk of MI than lower dose (2.5–5 mg/day). To afford maximum protection against progression of heart failure, the dose of ACE inhibitors needs to be titrated to nearly the upper limit of recommended dose range, as shown in other mega trials like GISSI-3, SOLVD, AIRE, etc. as well. ACE inhibitors are effective in reducing development of ventricular dysfunction, heart failure and related mortality in post-MI patients also (SAVE, TRACE, AIRE trials).
3. Myocardial infarction (MI) Several megatrials have established that oral ACE inhibitors administered while MI is evolving (within 24 hr of an attack) and continued for 6 weeks reduce early as well as long-term mortality, irrespective of presence or absence of systolic dysfunction, provided hypotension is avoided. In high risk patients and those with latent or overt ventricular dysfunction (CHF) extension of therapy continues to afford survival benefit over years. In unstable angina/non-ST segment elevation MI, long-term ACE inhibitor therapy reduces recurrent MI and need for coronary angioplasty (SAVE and SOLVD trials), though no benefit was apparent in the short-term (ISIS-4 study). Current evidence shows that if there are no contraindications, all MI patients stand to gain from ACE inhibitor therapy, though magnitude of benefit is greatest in those having associated hypertension and/or diabetes.
4. Prophylaxis in high cardiovascular risk subjects The results of Heart Outcomes Prevention Evaluation (HOPE) study in 9297 post-MI and other high risk subjects, but having no left ventricular dysfunction or heart failure have shown that ramipril reduced cardiac death and MI or stroke by 22% over a period of 4.5 years. Risk of developing heart failure or diabetes was also reduced. These results have been confirmed by the EUROPA trial and appear to hold true even for patients who have undergone coronary revascularization (APRES trial). Thus, ACE inhibitors are protective in high cardiovascular risk subjects even when there is no associated hypertension or left ventricular dysfunction. Protective effect is exerted both on myocardium as well as vasculature, may involve improved endothelial function, and is independent of hypotensive action.
5. Diabetic nephropathy Prolonged ACE inhibitor therapy has been found to prevent or delay end-stage renal disease in type I as well as type II diabetics. Albuminuria (an index of glomerulopathy) remains stable in those treated with ACE inhibitor, but aggravates in untreated diabetics. Treated patients have higher creatinine clearance, require less dialysis and have longer life expectancy. Benefits appear to be due to haemodynamic (systemic and intrarenal) as well as abnormal mesangial cell growth attenuating effects of ACE inhibitors. They reduce intraglomerular pressure and hyperfiltration. ACE inhibitors arrest/partly reverse any degree of albuminuria, but benefits are restricted after macroalbuminuria in type 2 diabetes has set in. The RAS seems to accentuate micro- and macrovascular complications in diabetics, and ACE inhibitors have specific organ protective effect by attenuating the same. Deterioration of retinopathy in diabetics also appears to be retarded by ACE inhibitors. All patients with diabetic nephropathy, whether hypertensive or normotensive, deserve ACE inhibitor therapy.
Nondiabetic nephropathy There is evidence now that chronic renal failure due to nondiabetic causes may also be improved by ACE inhibitors. They reduce proteinuria by decreasing pressure gradient across glomerular capillaries as well as by altering membrane permeability. This retards disease progression. Among hypertensive nephropathy patients the incidence of doubling of serum creatinine or end stage renal failure is significantly lower in those treated with ACE inhibitors than those treated with other antihypertensives.
6. Scleroderma crisis The marked rise in BP and deterioration of renal function in scleroderma crisis is mediated by A-II. ACE inhibitors produce dramatic improvement and are life saving in this condition.
Captopril test This test has been devised to obviate the need for renal angiography for diagnosis of renovascular hypertension. The basis of the test is—acute blockade of A-II formation by captopril results in a reactive increase in PRA which is much higher in renovascular compared to essential hypertension. However, this test is only of adjunctive value.
ANGIOTENSIN ANTAGONISTS (Angiotensin receptor blockers or ARBs)
Over the past 2 decades, several nonpeptide orally active AT1 receptor antagonists have been developed as alternatives to ACE inhibitors. These include losartan, candesartan, valsartan, telmisartan and irbesartan. Selective antagonists of AT2 receptors as well as combined AT1 + AT2 antagonists have also been produced.
Pharmacologically, AT1 receptor antagonists differ from ACE inhibitors in the following ways:
They do not interfere with degradation of bradykinin and other ACE substrates: no rise in level or potentiation of bradykinin occurs. Consequently, ACE inhibitor related cough is rare.
They result in more complete inhibition of AT1 receptor activation, because alternative pathway of A-II generation and consequent AT1 receptor activation remain intact with ACE inhibitors.
They result in indirect AT2 receptor activation. Due to blockade of AT1 receptor mediated feedback inhibition—more A-II is produced which acts on AT2 receptors that remain unblocked. ACE inhibitors result in depression of both AT1 and AT2 activation.
The impact of these differences on clinical efficacy and therapeutic value of the two classes of RAS inhibitors is not known.
Losartan causes fall in BP in hypertensive patients which lasts for 24 hours, while HR remains unchanged and cardiovascular reflexes are not interfered. No significant effect on plasma lipid profile, carbohydrate tolerance, insulin sensitivity has been noted. It is also a mild uricosuric.
Pharmacokinetics Oral absorption of losartan is not affected by food, but bioavailability is only 33% due to first pass metabolism. It is partially carboxylates in liver to an active metabolite (E3174) which is a 10–30 times more potent noncompetitive AT1 receptor antagonist. After oral ingestion peak plasma levels are attained at 1 hr for losartan and at 3–4 hours for E3174. Both compounds are 98% plasma protein bound, do not enter brain and are excreted by the kidney. The plasma t½ of losartan is 2 hr, but that of E3174 is 6–9 hr. No dose adjustment is required in renal insufficiency, but dose should be reduced in presence of hepatic dysfunction.
Adverse effects Losartan is well tolerated; has side effect profile similar to placebo. Like ACE inhibitors it can cause hypotension and hyperkalemia, but first dose hypotension is uncommon. Though, a few reports of dry cough have appeared, losartan is considered to be free of cough and dysgeusia inducing potential. Patients with a history of ACE inhibitor related cough have taken losartan without recurrence. Angioedema is reported in fewer cases. Headache, dizziness, weakness and upper g.i. side effects are mild and occasional. However, losartan has fetopathic potential like ACE inhibitors—not to be administered during pregnancy.
Dose: 50 mg OD, rarely BD; in liver disease or volume depletion 25 mg OD; addition of hydrochlorothiazide 12.5–25 mg enhances its effectiveness.
LOSACAR, TOZAAR, ALSARTAN 25, 50 mg tabs.
Candesartan It has the highest affinity for the AT1 receptor and produces largely unsurmountable antagonism, probably due to slow dissociation from the receptors or receptor desensitization. Elimination occurs by both hepatic metabolism and renal excretion with a t½ of 8-12 hours: action lasts 24 hours.
Dose: 8 mg OD (max 8 mg BD), liver/kidney impairment 4 mg OD.
CANDESAR 4, 8, 10 mg tab., CANDILONG, CANDESTAN 4, 8 mg tabs.
Irbesartan The oral bioavailability of this AT1 antagonist is relatively high. It is partly metabolized and excreted mainly in bile. The t½ is ~12 hours.
Dose: 150–300 mg OD.
IROVEL, IRBEST 150, 300 mg tabs.
Valsartan The AT1 receptor affinity of valsartan is similar to that of losartan. Its oral bioavailability averages 23% and food interferes with its absorption. Elimination occurs mainly by the liver in unchanged form with a t½ of 6–9 hours; action lasts 24 hours.
Dose: 80–160 mg OD 1 hour before meal (initial dose in liver disease 40 mg).
DIOVAN, STARVAL, VALZAAR 40, 80, 160 mg tabs.
Telmisartan The AT1 receptor blocking action of telmisartan is similar to losartan, but it does not produce any active metabolite. After an oral dose, peak action occurs in 3 hours and action lasts > 24 hours. It is largely excreted unchanged in bile; dose reduction is needed in liver disease.
Dose: 20–80 mg OD
TELMA, TELSAR, TELVAS 20, 40, 80 mg tabs.
Uses of AT1 receptor antagonists (ARBs) The ARBs have the same overall range of clinical utility as ACE inhibitors, but the suitability/ efficacy of one over the other is not clearly defined; may depend on the condition being treated and/ or specific features of the patient. The value of their combination versus monotherapy is also still unsettled.
Hypertension Losartan and other ARBs are now first line drugs, comparable in efficacy and desirable features to ACE inhibitors, with the advantage of not inducing cough and a lower incidence of angioedema, rashes and dysgeusia. As such, their popularity has increased. Like ACE inhibitors, the maximum antihypertensive effect is reached in 2–4 weeks and ventricular/vascular hypertrophy/remodeling is arrested/reversed. The Losartan intervention for endpoint reduction in hypertension (LIFE, 2002) study has found losartan to be more effective than β-blockers in reducing stroke among > 9000 hypertensive patients with left ventricular hypertrophy.
CHF The ARBs afford clear-cut symptomatic relief as well as survival benefit in CHF. However, their relative value compared to ACE inhibitors, especially in long-term morbidity and mortality reduction, is still uncertain. A number of large randomized endpoint trials like Evaluation of losartan in the elderly (ELITE, 1997), ELITEII (2000), OPTIMAAL (2002), Valsartan in acute MI (VALIANT, 2003) have produced contradictory results. Some find ACE inhibitors more effective, others find ARBs more effective, while still others find them equieffective. For CHF, the current consensus is to use ACE inhibitors as the first choice drugs and to reserve ARBs for those who fail to respond well or who develop cough/angioedema/ other intolerance to ACE inhibitors.
Myocardial infarction The evidence so far indicates that utility of ARBs in MI, including long-term survival, is comparable to ACE inhibitors. However, the latter are generally used first, since there is greater experience with them.
Diabetic nephropathy Several studies have confirmed that ARBs are renoprotective in type 2 diabetes mellitus, independent of BP lowering. The magnitude of benefit is comparable to ACE inhibitors, but because of better tolerability profile, many consider ARBs to be the first choice now.
Combination of ACE inhibitors with ARBs There are theoretical reasons to combine an ACE inhibitor with an ARB to obtain more complete suppression of RAS and achieve added cardioprotection in CHF or renoprotection in diabetic nephropathy.
These are:
A-II is generated in several tissues (especially heart and kidney) by non-ACE mechanisms, whose effect can be blocked by ARBs.
ACE inhibitors produce bradykinin related vasodilatation and other effects that are not produced by ARBs.
ARBs cause compensatory increase in A-II production that is checked by ACE inhibitors.
ARBs enhance unblocked AT2 receptor mediated effects that can be prevented by concurrent ACE inhibition.
Additional haemodynamic and symptomatic improvement over short-term has been obtained in CHF with addition of an ARB to exhisting ACE inhibitor therapy. However, several large randomized trials including Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD, 1999), Valsartan heart failure trial (VAL-He FT, 2001), CHARM-added trial (2003) of combinations of ARBs and ACE inhibitors Vs their monotherapy in affording mortality and other end point benefits in CHF have yielded controversial results. The Ongoing Telmisartan alone and in combination with ramipril global endpoint trial (ON TARGET) may clarify whether long-term use of ARB + ACE inhibitor combination is advisable or not.
In non-diabetic renal disease, the Combination treatment of ARB and ACE inhibitor randomized trial (COOPERATE, 2003) has concluded that ARB + ACE inhibitor combination therapy retards progression of non-diabetic renal disease to a greater extent compared with their monotherapy.
PLASMA KININS (Bradykinin and Kallidin)
Plasma kinins are polypeptides split off from a plasma globulin Kininogen by the action of specific enzymes Kallikreins. The two important plasma kinins, Kallidin (decapeptide) and Bradykinin (nonapeptide) were discovered around 1950 by two independent lines of investigation into the hypotensive activity of urine and certain snake venoms. These and other biological fluids were found to act indirectly: they contained enzymes which generated active substances in the plasma.
Generation and metabolism Kininogens are α2 globulins present in plasma which also contains inactive kininogenase prekallikrein. Prekallikrein is activated by Hageman factor (factor XII) which itself is activated by tissue injury and contact with surfaces having negative charge, e.g. collagen, basement membrane, bacterial liposaccharides, urate crystals, etc. Plasmin facilitates contact activation of Hageman factor. Kinins are also generated by trypsin, proteolytic enzymes in snake and wasp venoms and by kallikrein present in kidney, pancreas and other tissues. Bradykinin is generated from high molecular weight (HMW) kininogen by the action of plasma kallikrein, because HMWkininogen does not cross the capillaries. On the other hand, kallidin can be produced from both low molecular weight (LMW) kininogen as well as HMW-kininogen by the action of tissue kallikreins. Bradykinin can also be generated from kallidin on the removal of lysine residue by an aminopeptidase.
Plasma and tissues also contain kininogenase inhibitory factors of which complement (C1) esterase inhibitor is the most important. Moreover, kallikreins are normally present in their inactive forms. Thus, physiologically only small amounts of kinins are generated in plasma and tissues.
Kinins are very rapidly degraded, primarily in lungs, but also in other tissues and have a t½ of < 1 min. The principal degrading enzyme is Kininase II, also known as ‘angiotensin-II converting enzyme’ (ACE) which splits off 2 amino acids from the carboxyterminal of the peptide chain. Another carboxypeptidase Kininase I removes only one amino acid (arginine) producing selective B1 receptor agonistic metabolites (desArg bradykinin and desArg kallidin) which are further degraded by other peptidases.
ACTIONS
1. CVS Kinins are more potent vasodilators than ACh and histamine. The dilatation is mediated through endothelial NO and PGI2 generation, and involves mainly the arterioles. Larger arteries, most veins and vessels with damaged endothelium are constricted through direct action on the smooth muscle. In addition, they can release histamine and other mediators from mast cells. Injected i.v. kinins cause flushing, throbbing headache and fall in BP. They markedly increase capillary permeability due to separation of endothelial cells → exudation and inflammation occurs if they are injected in a tissue. Intradermal injection produces wheal and flare (similar to histamine). Kinins have no direct action on heart; reflex stimulation occurs due to fall in BP.
2. Smooth muscle Kinin induced contraction of intestine is slow (bradys—slow, kinein—to move). They cause marked bronchoconstriction in guineapigs and in asthmatic patients. Action
on other smooth muscles is not prominent, some may be relaxed also.
3. Neurones Kinins strongly stimulate nerve endings that transmit pain and produce a burning sensation. Applied to blister base/injected intraperitoneally or in the brachial artery, bradykinin produces intense, transient pain and has been used in analgesic testing. Kinins release CAs from adrenal medulla. Injected directly in brain they produce a variety of effects including enhanced sympathetic discharge. They increase permeability of the bloodbrain barrier.
4. Kidney Kinins increase renal blood flow as well as facilitate salt and water excretion by action on tubules. The diuretic effect of furosemide is reduced by kinin B2 receptor antagonists, indicating participation of locally generated kinins in this response.
Kinin receptors Existance of two types of kinin receptors (B1, B2) has been established. Most kinin actions in noninflamed tissues are mediated by B2 receptors which are constitutively present on:
(i) Visceral smooth muscle—contraction of intestine, uterus, airway.
(ii) Vascular endothelium—NO release, vasodilatation, increased permeability.
(iii) Sensory nerves—acute pain.
The B2 receptor is a G-protein coupled receptor which utilizes the phospholipaseC—IP3/DAG—intracellular Ca2+ mobilization transducer mechanism. Certain responses to kinins, e.g. bronchoconstriction and renal vasodilatation are attenuated by pretreatment with PG synthesis inhibitors (aspirin). Aspirin injected i.p. before bradykinin through the same cannula blocks its algesic action. These responses are mediated by phospholipase A activation—release of arachidonic acid and generation of PGs.
The B1 receptor is located on the smooth muscle of large arteries and veins—mediates contraction of these vessels, but is expressed minimally in normal tissues. Inflammation induces synthesis of B1 receptors, so that they might play a major role at inflamed sites. Bradykinin has higher affinity for B2 than for B1 receptors, while Kallidin is equipotent on both. The desArg metabolites of bradykinin and kallidin are the natural selective agonists of B1 receptor.
PATHOPHYSIOLOGICAL ROLES
1, TNF-α and other inflammatory mediators.
3. Functional hyperemia (in glands during secretion) and regulation of microcirculation—especially in kidney may be occurring through local kinin production.
4. Production of kinins is integrated with clotting, fibrinolysin and complement systems. Kallikreins may have roles in these systems which are independent of kinin production.
6. Kinins cause closure of ductus arteriosus, dilatation of foetal pulmonary artery and constriction of umbilical vessels—they may be involved in adjusting from foetal to neonatal circulation.
7. Kinins play a major role in the development of angioedema. They also appear to be involved in shock, rhinitis, asthma, ACE inhibitor induced cough, carcinoid, postgastrectomy dumping syndrome, fluid secretion in diarrhoea, acute pancreatitis and certain immunological reactions.
Because of evanescent and unpleasant actions, kinins have no clinical use.
Bradykinin antagonists
After characterization of B1 and B2 kinin receptors, several peptide and nonpeptide kinin antagonists have been produced. The synthetic peptide HOE 140 is a selective B2 antagonist resistant to kinin degrading enzymes and having longer t½, while Icatibant, FR 173657 and some others are orally active nonpeptide B2 antagonists that have helped in defining the pathophysiological roles of kinins and have undergone limited trials as analgesic, antiinflammatory drugs and in pancreatitis, head injury, etc.
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