Ramipril dosing

Two cases of severe vomiting, dyspepsia, and headache, with falls in body weight and plasma albumin, have been reported in patients on chronic peritoneal dialysis (2). Both occurred a few days after they started to take ramipril (dose not reported) and totally resolved after withdrawal. Both patients subsequently took losartan, which was well tolerated. This led the authors to suggest that the mechanism was mediated by bradykinin and/or prostaglandins, through an interaction with gastrointestinal motility, which may also be affected by peritoneal dialysis. 

A kidney transplant patient taking sirolimus 9 mg daily developed non-pitting oedema of the eyelid, cheek and lips when he started to take ramipril (dose not specified). Another kidney transplant patient who had taken enalapril 2.5 mg daily for two months developed erythematous skin lesions with non-pitting oedema of the neck, face and chest 9 days after she was switched from tacrolimus to sirolimus 2 mg daily. Symptoms resolved in both patients when the ACE inhibitor was stopped and corticosteroid therapy was increased. ... 

Rubin P, Johnston CJ, Williams JP etal. (1995) A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33 99-109 Ryu S, Kolozsvary A, Jenrow KA et al. (2007) Mitigation of radiation-induced optic neuropathy in rats by ACE inhibitor ramipril importance of ramipril dose and treatment time. J Neurooncol 82 119 124... 

Ramipril 1.25 to 2.5 mg initially target dose 5 mg twice daily or 10 mg once daily. 

Maintenance dosage 2.5 to 20 mg/day as a single dose or in two equally divided doses. If BP is not controlled with ramipril alone, a diuretic can be added. 

Keilani T, Danesh FR, Schlueter WA, Molteni A, Batile D. A sub-depressor low dose of ramipril lowers urinary protein excretion without increasing plasma potassium. Am J Kidney Dis 1999 33 450-7. 

Despite many clinical similarities, these agents differ in their absorption, dosing with other drugs, and duration of actions for example, quinapril has a of 3 hours whereas ramipril has a of 13-17 hours. The quest for ACE inhibitors devoid of the sulfhydryl group also led to the evaluation of phosphonate-containing inhibitors, on the basis of the notion that phosphinic acid is bioisosterically equivalent to sulfhydryl and carboxylate groups in terms of Zn " chelation. This lead to the development of fosinopril... 

With the data included in the overview of Garg et al. (316), it is possible to calculate that 18 patients need to be treated for 90 days to avoid one death or one hospitalization for congestive heart failure (95% confidence interval [Cl] 16-23). This meta-analysis includes 32 trials with the ACE inhibitors captopril, enalapril, lisinopril, quinapril, ramipril, and perindopril. It is likely that high doses (for instance, lisinopril 35 mg daily) are more effective than low doses (lisinopril 5 mg daily) (302). Treating 30 patients for 4 years with a high dose of lisinopril (95% Cl 16-509) will avoid one hospitalization for cardiovascular reasons or one death in comparison with a low dose, without increasing the number of adverse effects requiring withdrawal from treatment. 

The efficacy of aliskiren monotherapy and aliskiren in combination with the diuretic hydrochlorothiazide (HCT), aliskiren in combination with the angiotensin receptor blocker (ARB) valsartan, and aliskiren in combination with the ACE inhibitor ramipril in reducing mean sitting diastolic blood pressure (msDBP) have been reported (Table 3). From a pooled analysis of several placebo-controlled clinical trials, the approved doses of 150 and 300 mg aliskiren provide a placebo-subtracted reduction in msDBP of 3.2 and... 

All patients with heart failure due to left ventricular systolic dysfunction must be initiated on an ACE inhibitor. This should be initiated as soon as the patient s acute symptoms have been controlled at the appropriate dose and then titrated up at short intervals to the target dose or maximum tolerated dose. A suitable agent would be ramipril 2.5 mg once daily, which then could be slowly titrated (e.g. approximately every two weeks) to the target of 10 mg once daily or 5 mg twice daily. Parameters that require regular monitoring are blood pressure, urea and electrolytes (particularly serum potassium) at drug initiation then every week and after each dose increase until stable. 

Profound first-dose hypotension can occur when ACE inhibitors are introduced to patients with heart failure. This effect may be particularly pronounced if the patient is taking a high dose of a loop diuretic. Temporary withdrawal of the loop diuretic could be considered but is not appropriate in this case as it may cause rebound pulmonary oedema. Therefore in this case the steps are to initiate the ACE inhibitor at low dose (e.g. ramipril 1.25 mg daily at night time while the patient is lying down) and then to monitor blood pressure hourly for the first 4 hours. 

Within the HOPE study ramipril was the agent of choice and this would be an appropriate ACE inhibitor to use post-myocardial infarction. Ramipril is licensed for use post myocardial infarction at a dose of 2.5 mg twice daily initially (started in hospital 3-10 days after infarction), increased after 2 days to 5 mg twice daily. Maintenance doses are 2.5 mg-5 mg twice daily. 

You are a supplementary prescriber working in a diabetes clinic when John Stephens comes in to see you. He is still overweight despite being on the maximum dose of metformin and gliclazide. His HbAlc is 9.0% and on examination he has neuropathy developing in his feet. He is also on ramipril 10 mg, simvastatin 40 mg and aspirin 75 mg daily. His blood pressure was 130/80 mmHg and his total cholesterol was 4.0 mmol/L (reading from three months ago). There is no microalbuminuria present. 

The results of this trial show that ramipril was well tolerated and even protective in cases of advanced renal insufficiency. One major reason for the current practice of underprescription and of prescription of suboptimal doses of ACE inhibitors, especially in patients with heart failure, is the presence of renal insufficiency (16). In such patients, not only should ACE inhibitors no longer be avoided, they are indeed indicated for preservation of renal function. 

Vree, T.B., Dammers, E., Ulc, I., Horkovics-Kovats, S., Ryska, M. and Merkx, I. (2003) Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose. The Scientific Word Journal, 3,1332-1343. 

There is no precisely defined relationship between dose and long-term clinical effectiveness of these drugs, but it is reasonable to use doses comparable to those used in studies that established efficacy in patients with heart failure. On this basis, target doses of these drugs would be 50 mg three times/day for captopril 10 mg twice daily for enalapril 10 mg once daily for lisinopril or 5 mg twice daily for ramipril. In patients who have not achieved an adequate clinical response at these doses, further increases, as tolerated, may be of value high-dose lisinopril (32.5 or 35 mg) reduced the combined endpoint of mortality and hospitalization when compared to lower doses of this agent. 

Scholze J, Bauer B, Massaro J (1999) Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER. Clinical and Experimental Hypertension 21 1447-1462. 

Propranolol 80 mg three times daily did not affect the pharmacokinetics of a single 20-mg dose of quinapril in 10 healthy subjects. The pharmacokinetics of ramipril 5 mg daily were unaffected by propranolol 40 mg twice daily. Similarly, the manufacturer of fosinopril reports that the bioavailability of fosinoprilat, its active metabolite, was not altered by propranolol. Another study found no significant pharmacokinetic interaction between cilazapril 2.5 mg daily and propranolol 120 mg daily in healthy subjects, but the reductions in blood pressure were about doubled and long-lasting in healthy subjects and in patients with hyperten-... 

No pharmacokinetic interaction occurred between single doses of fe-lodipine 10 mg and ramipril 5 mg in healthy subjects. The blood pressure-lowering effect of the eombination was greater, and ramipril attenuated the reflex taehyeardia eaused by felodipine. ... 

Other single-dose studies have shown that food had no statistically significant effect on the pharmacokinetics of lisinopril, or enalapril, and its active metabolite, enalaprilat. Similarly, food had minimal effects on the pharmacokinetics of cilazapril (AUC decreased by only 14%). Food caused small, but statistically significant increases in the time to reach maximum plasma levels of quinapril and its active metabolite. However, as the increase was less than 30 minutes this is not expected to alter the therapeutic effect. Likewise, the manufacturers of spirapril briefly mention in a review that food delayed its absorption by 1 hour, it did not affect the bioavailability of spirapril or spiraprilat, its active metabolite. Other manufacturers state that food had no effect on the absorption of fosinopril 11,12 ramipril, or trandolapril. ... 

Other ACE inhibitors. A placebo-controlled, randomised, crossover study in 16 hypertensive patients found that indometacin 50 mg twice daily reduced the blood pressure-lowering effects of cilazapril 2.5 mg daily. The reduction was greater when cilazapril was added to indometacin than when indometacin was added to cilazapril (approximately 60% versus 30% reduction in hypotensive effect measured 3 hours after the morning dose). The antihypertensive effects of perindopril 4 to 8 mg daily were also found to be reduced by about 30% by indometacin 50 mg twice daily in 10 hypertensive patients. A brief mention is made in a review that the pharmacodynamics of ramipril were unaffected by indometacin (dosage not stated) given to healthy subjects for 3 days. Indometacin 25 mg three times daily did not alter the hypotensive effects of trandolapril 2 mg daily in 17 hypertensive patients. ... 

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