This review focuses on the crucial role of the most appropriate antihypertensive combination- lowdose reserpine + lowdose co-amilozide (amiloride + hydrochlorothiazide HCT) – against sudden death from sympathetic overload arrhythmia and cardiomyonecrosis, not just against the traditional targets of hypertensive brain, heart, kidney and vision failure.
We all know that after >50 years of use, lowdose reserpine (the extract of the ancient medicinal plant rauwolfia) is a good peripheral vasodilator (Scalfil 1956) with beneficial heart-slowing, metabolic and mood effects – and when combined with lowdose co-amilozide (40 years in use) – is a slow powerful antihypertensive without postural hypotension; whereas betablockers may do the opposite, cause cold extremities, adverse respiratory, mood, sexual, fatigue, bradycardia and metabolic- lipid/diabetic- effects especially with thiazide..
In 2004, Bacaner M ea from Univ Minnesota noted: “It is widely but mistakenly believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD) (see Wikipedia for this surgical view). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death occur in 15%-20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally under-appreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomical obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction”.
“The clinical data suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic cardiovascular heart disease (AdHD or ACVHD)- appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. This vicious cycle, which explains the frequent parallel occurrence of arteriosclerosis and IHD, an association that appears to be linked by the same cause, comprises a common vulnerability to deleterious adrenergic actions on the myocardium, lipid metabolism, and vascular system alike, rather than viewing CAD and IsHD as having a putative cause and effect relationship as commonly thought. Adrenergic actions can also cause the abnormal lipid metabolism that is associated with CAD and IsHD… . This may also be part of toxic catecholamine hypermetabolic actions by enhancing deleterious cholesterol and lipid actions in damaging coronary vessels by plaque formation as well as inducing obstructive coronary spasm and platelet aggregation. This may also cause direct toxic necrosis on the myocardium as well as atherosclerosis in blood vessels. In fact, drugs that inhibit adrenergic actions like reserpine, propranolol and guanethidine all inhibit arteriosclerosis induced by hypercholesterolemia in experimental animals and prevent carotid vascular disease (associated with stroke) in humans. … Thus, like myocardiopathy, CAD and atherosclerosis in general may be the consequences of or a complication of catecholamine actions rather than its putative cause”..
But for good reason, only reserpine is still is used (not guanethedine or beta-blockade) in the firstline treatment of essential hypertension. .
In 1990 Gubner (American Society of Actuaries ) noted that ”Long-term trials employing a combination of drugs, i.e diuretics, vasodilators, reserpine and beta-blockers, almost without fail have not shown that treatment with these agents significantly reduces heart disease mortality and sudden death, attributed both to poor control of hypertension and to unfavorable metabolic effect of diuretics – increased lipid levels, hyperglycemia, worsening diabetes, hyperuricemia, hypokalemia and depletion of body magnesium. Left ventricular hypertrophy greatly increases the propensity to ventricular arrhythmias and sudden death, and is a prime cause of cardiac mortality and sudden death not only in hypertension, but also in obesity, aging and diabetes, in which conditions left ventricular hypertrophy also is very common.”.
But until the 1980s, unnecessarily high dose diuretics and reserpine were in use – and we did not abandon digoxin or prednisone or lithium because high doses are dangerous, we just use lower doses with more respect.
And already in 1973 Edward Freis’ group in Washington DC had shown that (compared to placebo) the combination of reserpine up to 0.2mg + HCT 100mg/day +- hydralazine for about 3 years normalized bloodpressure and abnormal ECG in the great majority of hypertensives, without any effect on conduction or arrhythmia.
In 1981 Lathers ea in Texas showed that reserpine pretreatment increases by 2/3 resistance to digitalis-induced fatal ie ventricular arrhythmia.
In 1995 Kostis ea in the SHEP trial reported that when medium-dose thiazide- chlorthalidone- up to 25mg/d was not enough to control systolic hypertension, and where atenolol was contraindicated as the second drug, the addition of reserpine up to 0.1mg/d for a mean of 1.7years lowered risk (relative to atenolol) for death by 25%, for stroke by 80%, and for CVD by 50%. Thus reserpine as the last-ditch drug far exceeded the benefits of atenolol.
And in 2007 Barzilay, Grimm ea (from Kaiser Permanente and a number of USA Universities) explained “Why Reserpine Deserves a Second Look”, that whereas betablockade is undesirable in a stressed aging smoking or fattening population with metabolic syndrome insulin resistance, reserpine by lowering both central and peripheral sympathetic vasoconstriction is highly effective antihypertensive when combined with lowdose diuretic (and if third add-on is needed a CCB- amlodipine). They showed that (in the MRFIT trial in the 1980s), addition of reserpine to diuretic lowered hypertension by a further 7.8/6.5mm.
And this month Southward ea report from Atlanta the apparent 7th case of amlodipine-induced angioedema.
THE TRIALS EVIDENCE SHOWING THE SUPREMACY OF RESERPINE AND THIAZIDE: The following table (ndburman 2004) shows the comparison of trials and studies of reserpine and thiazide compared to other agents: COMPARISON OF RESERPINE AND THIAZIDE TRIALS (PDF)
Reserpine +HCT each separately thus equal or outdo the benefits of any single other safe antihypertensive drug; and combined with amiloride they outdo all others- because the metabolic profile of reserpine plus amiloride counterbalances any adverse metabolic effect of HCT- and reserpine also has a duration of action of weeks whereas other agents act for barely a day. ie lowdose Reserpine + thiazide is equal to or better than alpha-/Bblocker/CCB/ACEI etc in 100%.
Unsurprisingly, since the table was drawn up in 2004, no significant new trials that change the conclusion justify adding – there have been no striking proven additions to the range of look-alike alpha-and/or-beta-blockers, calcium channel or angiotensin blockers, and no new trials of other drugs against the long-proven gold standard lowdose thiazide-reserpine, and none showing special superiority of newer drugs singly against lower-dose thiazide or coamilozide. .
But a 2008 study from Croatia confirms that anti-inflammatories NSAIDs reverse the antihypertensive effect of ACEI but not of amlodipine.
Whereas higher-dose thiazides, like betablockers, increase insulin resistance, an Indian study in 2004 in mice confirmed that reserpine potentiates insulin ie is an insulin sensitizer.
CO-AMILOZIDE COMBINATION: In 1968 Colin Dollery’s group first (on Pubmed) reported on amiloride being equivalent to thiazide in antihypertensive effect, but the combination of the two neutralizing the potassium-magnesium wasting effect of essential hypertension and thiazide.
Rosenfeld 1980 however found that adding amiloride 10mg/d lowered hypertension by another +- 20/10mm compared to HCT 100mg/day alone.
In 1982 Jaffe ea showed that coamilozide produced both a greater decrease and better control of blood pressure in a greater percentage of patients that did the comparison diuretic with potassium.
In 1987 Kronig & Flygt showed that there was no statistically significant difference in blood pressure reduction between felodipine and co-amilozide . However, more felodipine patients were withdrawn because of adverse effects.
The 2000 INSIGHT trial (Brown ea Cambridge UK) showed that “Nifedipine 30mg and co-amilozide 27.5mg daily were equally effective preventing overall cardio- or cerebro-vascular complications” – but ” in fact primary outcome (CVD death, myocardial infarction, heart failure, or stroke) occurred in 6.3% on nifedipine and 5.8% on co-amilozide ( p= .35)”
In 1994 Avanzini ea in Milan found that after 6 months of therapy, the percentage of hypertensives who had reached target BP was 14.6% in controls, 28.6% on atenolol 50mg/d; and about 53% on coamilozide 27.5mg/d or Nifedipine 20mg/d or Atenolol 25mg + Chlorthalidone 6.25mg/d.
Last year Guerrero ea from Brazil reported that combining thiazide with enalapril gave better bloodpressure control but more cough than coamilozide alone. Much experience confirms that the problem with ACEIs and ARBs are common allergic effects including respiratory, laryngeal and rashes, which thus relegate them (along with betablockers) to last choice for average hypertension. .
No trial has shown superiority of triamterene or spironolactone over amiloride as potassium-sparing agent- and spironolactone has the troublesome breast-enlarging ie estrogenic effect.
The Cache County Study in 2006 reported that potassium-sparing diuretics (but not other diuretics) reduced by 74% the incidence of Alzheimer’s Disease.
And low dose combination co-amilozide has not been shown to impair insulin sensitivity or cause gout.
CONCLUSION: the triple combination of reserpine 0.25mg 1/4 tablet/day plus co-amilozide +- 7 to 14mg/day has solid longstanding evidence that it is the best treatment there is for all grades of hypertension. Only in severe cases with eg heartfailure may it be justified to start with 1 tablet a day of each for a few days, then ½ tablet each for a week or two before dropping to ¼ tablet each daily- if not just Mondays, Wednesdays and Fridays – providing reserpine 0.16mg and coamilozide ~20-40mg/week. . Only in the rare obviously complicated hypertension cases -eg with active uncontrolled ischemic heart disease, diabetes or renal failure- should other newer agents be considered (in addition to just 1/4 tablet each a day of reserpine and co-amilozide) at the outset until response has been tested for a few months.
The ALLHAT 2008 followup report confirms that at best 28% of patients were controlled on a single drug from any antihypertensive category. The average patient required 2 drugs (thiazide plus one other) for good control.
Since hypertension is one of the commonest easily detectable risk factors of middle age- working people, a $multibillion a year industry, economic pressure promotes massive research and marketing of new drugs and especially patented fixed-dose combination pills. But it has been common cause for decades that fixed-dose combinations cannot work for all due to individual metabolic variation.
Hence US$6 a year of separate reserpine and co-amilozide allows simple fine tuning to suit every patient; without the major and multiple adverse effects of angiotensin-, alpha-, beta- and calcium-channel blockers.
This explains why the triple combination lowdose reserpine + amiloride + HCT is unsurpassable for cost-benefit – it addresses many of the mechanisms of hypertension ( sodium overload, peripheral and central sympathetic overload, magnesium-potassium depletion, and thus even insulin resistance).
No traditional antihypertensive drugs significantly address the predominant core problem of atheroma (insulin resistance- AGEs, reactive oxygen species, and depletion of many vitamins, minerals and biologicals including nitric-oxide,) as do metformin and other appropriate supplements eg magnesium, vitamins, chromium, zinc, fish oil, and the human biologicals like coQ10, arginine, carnitine, carnosine, acetylcysteine, appropriate HRT etc– which should always be introduced preventatively long before costly and risk-prone modern antihypertensive and anti-angina drugs become necessary.