Piramil 5 mg: composition and presentation
Piramil is ramipril in tablets, made in four strengths: 1.25 mg, 2.5 mg, 5 mg and 10 mg. This is not marketing variety: ramipril is almost never prescribed at its final dose from the start, that dose is reached in steps, and each pack corresponds to a step. Piramil 5 mg is the middle rung, reached after roughly a month of stepping up; some patients stay there and others go on to ten milligrams.
The tablet is best taken every day at the same time. Food does not change bioavailability, so it may be taken before, during or after a meal; the tablet is swallowed with liquid and must not be chewed or crushed.
How Piramil 5 mg works
After being swallowed, ramipril is absorbed quickly from the digestive tract and converted in the liver into its active form, ramiprilat. This is a long-acting ACE inhibitor — the enzyme that turns angiotensin I into angiotensin II. As a result the plasma concentration of angiotensin II falls, plasma renin activity rises, aldosterone secretion drops, and the whole renin-angiotensin-aldosterone system is suppressed. Blood pressure falls because the peripheral vessels widen and vascular resistance decreases, not because the heart works less strongly.
The enzyme has a second name as well — kininase II — and it explains the best-known adverse effect of the entire class. By breaking down bradykinin, ACE takes part in the kallikrein-kinin-prostaglandin system; when the enzyme is blocked, bradykinin accumulates, and from that come the dry persistent cough and, occasionally, angioedema. As for the figures, peak plasma concentration of ramiprilat comes 2 to 4 hours after a dose, absorption ranges from 50 to 60%, protein binding is 73% for ramipril and 56% for ramiprilat; the substance is almost fully metabolised and excreted mainly by the kidneys.
Indications
The indications for ramipril fall into four groups of meaning, and only the first is about lowering blood pressure as such; the rest are about protecting the vessels, the kidneys and the heart after a heart attack. Hence the paradox familiar to many patients: the medicine is often prescribed to someone whose blood pressure is already normal.
| Group | For whom exactly |
| Arterial hypertension | treatment of raised blood pressure, alone or together with antihypertensives from other groups |
| Prevention of cardiovascular disease | in manifest atherosclerotic disease — coronary heart disease, a previous stroke, peripheral arterial disease — or in diabetes with at least one risk factor |
| Early diabetic nephropathy | where glomerular damage is confirmed by microalbuminuria |
| Manifest diabetic nephropathy | where there is proteinuria and at least one cardiovascular risk factor |
| Manifest non-diabetic nephropathy | with proteinuria of at least 3 g a day |
| Symptomatic heart failure | treatment where clinical manifestations are present |
| Secondary prevention after a heart attack | reduction of mortality where there are signs of heart failure; the medicine is added after 48 hours |
The meaning of the second group is worth spelling out: it concerns reducing cardiovascular morbidity and mortality, that is, the statistics of outcomes rather than how one feels today. The renal indications work the same way. That is why the course of treatment is long, and breaking it off because "nothing hurts" makes no sense.
Method of use and dosage
One principle holds for every indication: start with a small dose, double it at intervals of a few days to a few weeks, and stop at the target dose, guided by tolerability. In hypertension one starts at 2.5 mg a day and raises the dose every 2 to 4 weeks until the target pressure, with a maximum of 10 mg, usually as a single dose. For cardiovascular prevention the start is also 2.5 mg, doubled after 1 to 2 weeks, with a further 2 to 3 weeks bringing the maintenance dose of 10 mg. In diabetes with microalbuminuria and in non-diabetic nephropathy the start is 1.25 mg, 2.5 mg after two weeks and 5 mg two weeks after that. In diabetes with a risk factor treatment begins at 2.5 mg and moves to 5 mg after 1 to 2 weeks and to 10 mg after a further 2 to 3. In symptomatic heart failure, in patients stabilised on a diuretic, the start is 1.25 mg a day, doubled every 1 to 2 weeks up to the maximum of 10 mg, preferably in two divided doses.
A separate schedule applies after a heart attack: a stable patient is given, 48 hours on, 2.5 mg twice a day for three days; if that is poorly tolerated, 1.25 mg twice a day for two days and then 2.5 and 5 mg; the dose is doubled at intervals of 1 to 3 days up to the maintenance dose of 5 mg twice a day, and if 2.5 mg twice a day cannot be reached, treatment is stopped. Data on NYHA class IV immediately after a heart attack remain scarce; if the decision is made to treat, one starts at 1.25 mg once a day. The dose is also adjusted to organ function: with a creatinine clearance of 60 ml/min or more the start is the usual one and the maximum 10 mg; between 30 and 60 the maximum is 5 mg; between 10 and 30 the start is 1.25 mg and the maximum 5 mg; on haemodialysis the figures are the same and the tablet is taken several hours after the session, since ramipril is poorly dialysed. In liver disease treatment is begun only under strict medical supervision and does not exceed 2.5 mg a day. In older people the starting dose is reduced to 1.25 mg and raised more slowly; in children safety has not been established.
Contraindications
The list is short and built almost entirely around a single mechanism. The medicine is not used in hypersensitivity to ramipril, to any excipient or to another ACE inhibitor; in angioedema linked to past use of ACE inhibitors; in hereditary or idiopathic angioedema; in haemodynamically significant bilateral renal artery stenosis or stenosis of the artery of a single kidney; and in the second and third trimesters of pregnancy.
Renal artery stenosis is on that list for a reason. A kidney with a narrowed artery holds up its filtration precisely by means of angiotensin II, which constricts the efferent arteriole; by removing it, the medicine takes away the last support. For the same reason any episode of angioedema on an ACE inhibitor closes the door on the whole class: the mechanism of bradykinin accumulation is common to them all, and swapping one drug for another does not protect against a recurrence.
Special warnings and precautions
The kidneys are the main thing to watch. In renal impairment a lower dose or less frequent administration may be needed, and if creatinine exceeds 265 µmol/l, that is 3 mg%, or doubles from the baseline value, withdrawal is considered. Impairment recognised in time is usually reversible. In some patients with renal artery stenosis on ACE inhibitors urea and creatinine rose, and after withdrawal those changes generally passed. In renovascular hypertension the risk of severe hypotension and renal failure is higher: treatment starts at small doses under strict supervision, diuretics are stopped for a time, and renal function is followed in the first weeks.
The second thing to watch is blood pressure in the first days. In uncomplicated hypertension symptomatic hypotension is rare, but it becomes likelier when fluid volume is reduced: on diuretics, a salt-free diet, dialysis, diarrhoea or vomiting. Marked falls in pressure have been described chiefly in severe heart failure on high doses of loop diuretics together with hyponatraemia; once the circulating volume is restored and pressure normalised, treatment is resumed with careful dose adjustment. Caution is needed in aortic ostial stenosis and hypertrophic cardiomyopathy, especially with outflow tract obstruction. Treatment is not started in the early phase of a heart attack complicated by hypotension with a systolic pressure of 100 mm Hg or below, nor in cardiogenic shock. The medicine is not used with dialysis through high-flux membranes such as AN69, or during desensitisation to hymenoptera venom: in both cases the risk of anaphylactoid reactions rises. At the wheel one should allow for occasional dizziness and fatigue — particularly at the start of treatment, after a dose increase and with alcohol.
Interactions with other medicines
Combining ramipril with other blood-pressure-lowering medicines strengthens the antihypertensive effect — sometimes that is the very aim of treatment, but the doctor chooses the combination. The hypotensive effect is also strengthened by alcohol, general anaesthetics, hypnotics, antidepressants and narcotic painkillers. Working the other way are non-steroidal anti-inflammatory drugs and sympathomimetics, and in renal impairment the anti-inflammatories may on top of that worsen kidney function.
Potassium deserves separate attention. Ramipril reduces the likelihood of hypokalaemia and hyperuricaemia caused by thiazides and limits potassium loss with other diuretics, but in renal impairment it can raise plasma potassium. Potassium preparations, potassium-sparing diuretics and other sources of it, including potassium salt in place of table salt, are therefore inadvisable. During treatment with lithium salts the serum lithium level is monitored: ramipril may slow lithium excretion. With medicines that suppress immunity the risk of leukopenia rises. Finally, the medicine strengthens the action of insulin and of oral glucose-lowering drugs, which in diabetes means watching glucose more closely at the start of treatment.
Pregnancy and breastfeeding
The wording of the description is as short as it gets: do not use either in pregnancy or while breastfeeding. The second and third trimesters are set out separately, on the list of outright contraindications, and that reflects the heart of the matter: in the second half of pregnancy ACE inhibitors act on the foetal kidneys, on which the production of amniotic fluid depends, and after oligohydramnios the development of the lungs and the skull bones suffers.
The practical conclusion concerns not so much pregnant women as those planning a pregnancy. Ramipril is taken for years, and hypertension and diabetic nephropathy also occur at childbearing age, so a change of medicine is discussed with the doctor in advance rather than after a positive test. If a pregnancy comes to light during treatment, it must be reported at once: another regimen can usually be found quickly, whereas continuing the previous one is not allowed.
Adverse reactions
On the whole the medicine is well tolerated, and adverse reactions are usually mild and transient. The commonest is a dry, persistent cough that worsens at night and when lying down; it goes away once the medicine is stopped and does not respond to cough remedies. Sore throat, a runny nose, bronchospasm and bronchitis are also possible, and rarely angioedema of the face, limbs, lips, tongue, glottis and larynx. On the circulatory side there is hypotension, palpitations and tachycardia, and very rarely, in patients with significant arterial stenoses, a heart attack or transient cerebral ischaemia caused by a sharp fall in pressure.
The digestive tract responds with occasional dry mouth, epigastric pain and nausea, less often vomiting, diarrhoea and constipation; in isolated cases hepatitis, jaundice and pancreatitis have been described. From the nervous system come headache and dizziness, mood changes, disorientation and paraesthesia, along with the disturbances of taste and sleep typical of the class. The skin answers with sweating, itching, hives, hair loss and light sensitivity, and in isolated cases with psoriasis and severe lesions extending to Stevens-Johnson syndrome and toxic epidermal necrolysis. The kidneys rarely react with the appearance or worsening of existing impairment and, in severe congestive failure, with reduced urine output and rarely proteinuria; erectile disturbance has been noted. In the blood, bone marrow suppression with anaemia, thrombocytopenia or leukopenia has been described, along with rare cases of agranulocytosis. Laboratory tests show transient rises in urea, creatinine, liver enzymes and bilirubin, as well as hyperkalaemia and hyponatraemia.
Overdose
The features of overdose follow directly from the mechanism: a severe fall in blood pressure as far as shock, bradycardia, disturbance of electrolyte balance and renal failure. Treatment is symptomatic, and the measure named for consideration is the administration of angiotensin II — the very substance whose production the medicine suppresses.
In practice this means that accidentally taking one tablet too many calls for observation rather than home remedies: blood pressure and pulse are measured and the person is assessed while standing. Sudden weakness, dizziness on standing, fainting or a markedly slowed pulse are reasons to call for help. This applies above all to older people and to those with impaired kidney function: in them ramipril is cleared more slowly.
How to get a Piramil 5 mg prescription online
Piramil is dispensed on prescription, and at e-zdrowie.com it can be arranged remotely. You fill in a medical questionnaire, the doctor reviews the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and any Polish pharmacy will dispense the tablets against it. For this particular medicine the format suits well: ramipril is taken continuously, the dose is settled once, and after that only a regular supply is needed.
In the questionnaire state who prescribed the medicine and when, what dose you are on now and why you take it — for hypertension, to protect the kidneys or after a heart attack. Recent blood pressure readings will be useful, as will fresh test results: creatinine, potassium and, in nephropathy, protein in the urine. Be sure to report a pregnancy or plans for one, the use of diuretics, potassium preparations, lithium and non-steroidal anti-inflammatory drugs, and any episode of swelling of the face, lips or tongue during treatment — that last one means the whole class of medicines is contraindicated for you.
