Ramipril and hydrochlorothiazide are two different medications commonly used to treat various cardiovascular conditions, including hypertension (high blood pressure) and heart failure. They are often prescribed separately or in combination, as they can complement each other's effects in managing these conditions.

Ramipril hydrochlorothiazide is available as a combination product. It is a combination of an ACE inhibitor and a thiazide diuretic.

• It is used for the treatment of hypertension

Ramipril hydrochlorothiazide Dose in Adults

This medication isn't usually the first choice. The amount you take depends on your specific needs and can replace separate medications if you're already taking both or if one alone isn't working for you.

Ramipril hydrochlorothiazide Dose in the treatment of Hypertension:

Usual Dosage:

• The usual starting dose of this combination medication for treating hypertension is Ramipril 2.5 mg/hydrochlorothiazide 12.5 mg taken once daily.

Maximum Dosage:

• Your healthcare provider may increase the dose gradually if needed, up to a maximum of Ramipril 10 mg/hydrochlorothiazide 50 mg taken once daily.

Transitioning from Diuretics:

• If you were previously taking diuretics (water pills), it's recommended to try stopping or reducing them 2 to 3 days before starting this medication. If you can't stop the diuretic, your doctor may begin with the lowest possible dose of Ramipril (e.g., 1.25 mg daily) and adjust it as needed. In some cases, the initial dose may be Ramipril ≤2.5 mg/hydrochlorothiazide 12.5 mg once daily based on clinical judgment.

Ramipril hydrochlorothiazide Dose in Children:

The usual initial dose is 2.5 mg/5 ml of oral solution daily.

Pregnancy Risk Factor: D

• Medications that affect the renin-angiotensin system can be harmful and even life-threatening to a developing fetus.
• If you discover that you're pregnant, it's crucial to stop taking these drugs as soon as you can.
• They should not be used at all during pregnancy, as they can be harmful to the baby.
• It's essential to consult with your healthcare provider to discuss alternative treatments and ensure the safety of both you and your unborn child.
• Please refer to the specific medication instructions and warnings for more information on individual drugs.

Ramipril and hydrochlorothiazide use during breastfeeding:

• Both Ramipril and thiazide diuretics can be present in breast milk, which makes their use in breastfeeding women contraindicated.
• It is essential to avoid taking these medications while breastfeeding, as they can potentially harm the nursing infant.

Ramipril hydrochlorothiazide Dose in kidney disease:

The dosage of Ramipril and hydrochlorothiazide should be adjusted based on your kidney function, as measured by your creatinine clearance (CrCl) rate:

• CrCl >60 mL/minute/1.73 m: No dosage adjustment is needed, and the standard dose can be used.
• CrCl 30 to 60 mL/minute/1.73 m: The initial dose should be Ramipril 2.5 mg/hydrochlorothiazide 12.5 mg once daily. The maximum allowable dose is Ramipril 5 mg/hydrochlorothiazide 25 mg once daily.
• CrCl <30 mL/minute/1.73 m: These medications are contraindicated (not recommended) for individuals with severe kidney dysfunction.
• Dialysis: The use of these medications is contraindicated for individuals on dialysis.

Ramipril hydrochlorothiazide Dose in Liver disease:

• For individuals with mild-to-moderate kidney impairment, the maximum recommended dose of the combination medication Ramipril and hydrochlorothiazide is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide taken once daily. It's important to initiate this treatment under the close supervision of a healthcare provider to monitor its effects and ensure safety.
• For individuals with severe kidney impairment, the use of this combination medication is contraindicated, meaning it should not be used due to the increased risk of complications in this population.

Side Effects of Ramipril hydrochlorothiazide:

• Neuromuscular & skeletal:
  • Back pain
• Respiratory:
  • Bronchitis
  • Cough increased

Contraindications to Ramipril hydrochlorothiazide:

This medication, a combination of Ramipril and hydrochlorothiazide, should not be used in individuals who have:

• Hypersensitivity (allergic reactions) to ramipril, hydrochlorothiazide, other ACE inhibitors, thiazides, sulfonamide-derived drugs, or any other component of the medication.
• A history of angioedema (swelling under the skin) with or without previous treatment.
• Anuria (inability to produce urine).
• Significant bilateral or unilateral renal artery stenosis (narrowing of the arteries supplying the kidneys).
• Hypotensive states (very low blood pressure) or hemodynamically unstable conditions.
• Used sacubitril/valsartan within the last 36 hours or are switching to or from it.
• Concurrent use of aliskiren-containing drugs in patients with certain conditions, including diabetes, severe renal impairment, hyperkalemia, and heart failure, who are hypotensive.
• Concurrent use of angiotensin II receptor antagonists (ARBs) in patients with certain conditions, including diabetes with organ damage, severe kidney impairment, hyperkalemia, and heart failure, who are hypotensive.
• Severe hepatic impairment.
• Severe renal impairment (CrCl <30 mL/minute/1.73 m²) or are undergoing dialysis.
• Use in combination with treatments that expose blood to negatively charged surfaces, such as certain types of dialysis or apheresis.
• Clinically significant electrolyte imbalances like hypokalemia, hyponatremia, or hypercalcemia.
• Pregnancy.
• Breastfeeding.

Please note that while the product labeling suggests contraindication with other sulfonamide-containing drug classes, this recommendation has been debated in the scientific community.

Warnings and Precautions

Angioedema:

• Angioedema, although rare, can potentially occur at any time during treatment with ACE inhibitors like ramipril.
• It may manifest as swelling, particularly in the head and neck region, which could potentially obstruct the airway and lead to breathing difficulties.
• In some cases, it may also affect the intestines, causing abdominal pain.
• It's worth noting that Black patients may have an increased risk of experiencing angioedema with ACE inhibitors.
• Additionally, the risk may be elevated when ACE inhibitors are used in conjunction with mTOR inhibitor therapy, such as everolimus.
• If angioedema affects critical areas like the tongue, glottis, or larynx and poses a risk of airway blockage, close and prolonged monitoring is essential.
• Patients with a history of airway surgery are at a higher risk of airway obstruction in the event of angioedema.
• For those with a previous history of angioedema, the use of ACE inhibitors like ramipril is contraindicated (strongly discouraged) due to the increased risk.
• In cases of angioedema, early and appropriate medical intervention is crucial.

Cholestatic jaundice:

• ACE inhibitors, including ramipril, can rarely lead to a condition called cholestatic jaundice, which involves impaired bile flow from the liver and may progress to severe liver damage known as fulminant hepatic necrosis.
• If you experience a significant increase in liver enzyme levels or develop jaundice (yellowing of the skin and eyes), it's important to discontinue the medication.
• Additionally, if you encounter symptoms of liver dysfunction, such as fever, malaise, muscle pain, or rash, within the first few weeks to months of starting ACE inhibitor therapy, it's advisable to consider discontinuing the medication and seek medical attention promptly.

Cough:

• An ACE inhibitor cough is a distinct type of cough characterized by being dry, persistent, and nonproductive.
• It typically develops within the first few months of starting ACE inhibitor treatment and should generally go away within 1 to 4 weeks after stopping the ACE inhibitor.
• However, before discontinuing the medication, it's crucial to consider and rule out other potential causes of cough, especially in patients with heart failure where pulmonary congestion may also lead to cough.

Dermatologic malignancy:

• Hydrochlorothiazide use has been associated with an increased risk of non-melanoma skin cancers, specifically basal cell carcinoma and squamous cell carcinoma.
• This risk may become greater with long-term or cumulative use of the medication.
• Therefore, caution is advised when prescribing hydrochlorothiazide to patients who are at a high risk of developing non-melanoma skin cancer.
• These high-risk individuals may include those with a personal or family history of skin cancer, individuals on immunosuppressive therapy, or those with light-colored skin.
• It's important to monitor the skin for any new or changing lesions while taking hydrochlorothiazide.
• To reduce the risk, it's recommended to limit exposure to sunlight, avoid using sunlamps or tanning equipment, and apply sunscreen with a sun protection factor (SPF) of at least 30 on a daily basis.
• Additionally, wearing sun-protective clothing and hats, along with other protective measures, is advisable to help safeguard against skin cancer.

Electrolyte disturbances:

• Electrolyte imbalances can happen with ACE inhibitors and thiazide diuretics.
• ACE inhibitors can raise potassium levels in the blood, especially in people with kidney problems, diabetes, or those using medications like potassium-sparing diuretics or supplements.
• Thiazide diuretics, on the other hand, may lower potassium levels and cause other imbalances like low chloride, low magnesium, and low sodium levels.
• If you already have significant electrolyte problems, it's not safe to use these medications.
• If you do use them, it should be done cautiously, especially if you have risk factors for high or low potassium, and your potassium levels should be closely monitored.

Gout:

• In some individuals who have a history of gout, a family history of gout, or chronic kidney problems, hydrochlorothiazide can potentially trigger gout attacks.
• The risk of this happening may be higher when using doses of hydrochlorothiazide that are 25 milligrams or more.

Hypersensitivity reactions:

• Hypersensitivity reactions, including severe ones like anaphylactic or anaphylactoid reactions, can occur with ACE inhibitors.
• In some rare cases, these severe reactions may happen during hemodialysis with specific dialysis membranes or during low-density lipoprotein apheresis with dextran sulfate cellulose.
• There have also been reports of anaphylactoid reactions in patients receiving hymenoptera (bee or wasp) venom sensitization treatment while on ACE inhibitors.
• These reactions can sometimes be avoided by temporarily stopping ACE inhibitor therapy for at least 24 hours but may reoccur if the medication is resumed.
• Hydrochlorothiazide, another medication, can also trigger hypersensitivity reactions, with a higher risk in individuals with a history of allergies or bronchial asthma.
• It's crucial to be aware of these risks and seek prompt medical attention if any hypersensitivity reactions occur while taking these medications.

Hypotension/syncope:

• Symptomatic low blood pressure (hypotension) with or without fainting (syncope) can occur, especially with the first few doses of ACE inhibitors.
• This is more likely to happen in people who have low fluid volume in their bodies.
• Before starting the medication, it's important to address any low fluid levels in the body.
• Close monitoring of the patient is necessary, especially when starting the medication or increasing the dose.
• Blood pressure should be lowered at a rate that's suitable for the patient's specific health condition.
• Patients should also be cautious when driving or operating machinery, particularly when they're just starting the medication or when the dose is increased, as low blood pressure may affect their ability to do these tasks safely.
• While it may be necessary to reduce the dose in some cases, low blood pressure is not a reason to stop using ACE inhibitors in the future, especially in patients with heart failure, where lowering systolic blood pressure is a beneficial outcome.

Neutropenia/ agranulocytosis:

• Another ACE inhibitor, captopril, has been linked to bone marrow suppression, including rare instances of agranulocytosis (a severe reduction in white blood cells), neutropenia (low levels of a specific type of white blood cell called neutrophils), or leukopenia (a decrease in overall white blood cell count) with myeloid hyperplasia (abnormal bone marrow growth).
• Patients with conditions like collagen vascular disease (e.g., systemic lupus erythematosus) and/or renal disease are at a higher risk of experiencing bone marrow suppression while using these medications.
• Therefore, it's essential to monitor the complete blood count (CBC) with differential (a blood test that counts different types of white blood cells) in these patients to detect any potential issues early and take appropriate actions as needed.

Ocular effects:

• Hydrochlorothiazide, a medication commonly used as a diuretic, can lead to certain eye problems.
• These issues may include a sudden and temporary nearsightedness called acute transient myopia and a severe eye condition known as acute angle-closure glaucoma.
• These eye problems typically occur within hours to weeks after starting the medication.
• If you experience a sudden decrease in your vision or eye pain, it's crucial to stop taking the medication immediately.
• You may need additional treatments if the high pressure inside your eye (intraocular pressure) remains uncontrolled.
• It's important to note that risk factors for these eye problems may include a history of allergies to sulfonamide or penicillin medications.
• If you notice any changes in your vision or eye discomfort while taking hydrochlorothiazide, seek prompt medical attention.

Photosensitivity:

• Photosensitivity reactions can occur as a side effect of certain medications, including hydrochlorothiazide.
• If you experience photosensitivity reactions, which are skin reactions triggered by sunlight or ultraviolet (UV) light exposure, you should discontinue the use of the medication immediately.
• These reactions can manifest as skin redness, rash, blistering, or other forms of skin irritation when exposed to sunlight.

Renal function deterioration:

• Renal function deterioration can occur with the use of ACE inhibitors like ramipril, particularly in patients with conditions that reduce renal blood flow, such as renal artery stenosis or heart failure, where the kidney's glomerular filtration rate (GFR) relies on angiotensin II-mediated vasoconstriction of the efferent arterioles.
• This deterioration may lead to reduced urine production (oliguria), acute renal failure, and increasing levels of waste products in the blood (progressive azotemia).
• In some cases, there may be slight increases in serum creatinine levels when starting the medication.
• However, discontinuation of the ACE inhibitor should only be considered for patients with a substantial and progressive decline in renal function.

Sulfonamide (“sulfa”) allergy:

• Many medications contain a chemical group called sulfonamides, and the FDA-approved product labeling for these drugs often includes a contraindication for patients with a history of allergic reactions to sulfonamides ("sulfa" drugs).
• There used to be concerns about potential cross-reactivity between different types of sulfonamides, including antibiotics and non-antibiotic medications.
• However, recent research suggests that cross-reactivity is unlikely to occur, especially for allergic reactions involving antibodies like anaphylaxis.
• It's essential to note that the potential for cross-reaction, particularly for T-cell-mediated reactions like maculopapular rashes, is less clear.
• In cases where patients have experienced severe reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN) in response to sulfonamides, some healthcare providers may choose to avoid exposure to both antibiotic and non-antibiotic sulfonamide medications.

Aortic stenosis:

• In patients with severe aortic stenosis, the use of certain medications, including ACE inhibitors like ramipril, should be approached with caution.
• These medications may reduce coronary perfusion (blood flow to the heart muscle), which can potentially lead to ischemia (inadequate blood supply) of the heart tissue.
• Therefore, it's important for healthcare providers to carefully evaluate the risks and benefits of using ACE inhibitors in individuals with severe aortic stenosis.
• Close monitoring and individualized treatment plans may be necessary to ensure the patient's safety and well-being.

Bariatric surgery:

• After bariatric surgery, it's important to avoid diuretic medications in the immediate postoperative period.
• Diuretics can lead to electrolyte imbalances and dehydration, which can be especially concerning during this recovery phase.
• Instead, diuretics may be resumed, if necessary, once you've achieved your oral fluid intake goals as advised,

Cardiovascular disease:

• When starting therapy with medications like ACE inhibitors in patients who have ischemic heart disease or cerebrovascular disease, it's essential to closely monitor them because there is a risk that their blood pressure may drop significantly.
• This drop in blood pressure can have serious consequences, such as a heart attack (MI) or stroke.
• If low blood pressure occurs, it may be necessary to provide fluid replacement to restore blood pressure to a safe level.
• Once blood pressure is stabilized, therapy with the medication may be resumed.
• However, if hypotension (low blood pressure) happens again and poses a risk, it's advisable to discontinue the medication.
• The priority is to maintain blood pressure within a safe range while managing cardiovascular disease

Collagen vascular disease:

• Patients with collagen vascular diseases, particularly when accompanied by renal impairment, should use ACE inhibitors like ramipril with caution.
• They may be at an increased risk for hematologic toxicity (adverse effects on blood cells).
• Additionally, hydrochlorothiazide use may lead to the exacerbation or activation of systemic lupus erythematosus (SLE), a chronic autoimmune disease.
• It's essential for healthcare providers to be aware of these potential risks and carefully evaluate the benefits and potential complications when prescribing these medications to individuals with collagen vascular diseases.
• Patients with these conditions should be closely monitored, and any signs of adverse effects or disease exacerbation should be promptly addressed.

Diabetes:

• If you have prediabetes or diabetes mellitus, it's important to exercise caution when using hydrochlorothiazide, a medication often used as a diuretic.
• This medication may affect your blood glucose control and potentially lead to changes in your blood sugar levels.

Hepatic impairment:

• Severe hepatic (liver) dysfunction is a contraindication for the use of certain medications, including those discussed in your previous questions.
• It's important to avoid using these medications in cases of severe liver impairment.
• Additionally, in progressive liver disease, it's essential to steer clear of any electrolyte or acid-base imbalances that could potentially contribute to hepatic encephalopathy (brain dysfunction due to liver disease) or coma.

Hypercalcemia:

• Thiazide diuretics, like hydrochlorothiazide, can reduce the excretion of calcium by the kidneys.
• Therefore, it's important to consider avoiding the use of these diuretics in patients who already have hypercalcemia (elevated levels of calcium in the blood).
• Using thiazide diuretics in individuals with hypercalcemia may further increase their calcium levels, which can lead to various health complications.

Hypercholesterolemia:

• In patients with moderate or high cholesterol levels (hypercholesterolemia), the use of thiazide diuretics like hydrochlorothiazide should be approached with caution.
• Thiazide diuretics have been associated with increases in cholesterol and triglyceride levels in some individuals.

Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction:

• In patients with hypertrophic cardiomyopathy (HCM) and outflow tract obstruction, caution should be exercised when using certain medications, as these medications can reduce the afterload (the force the heart has to overcome to pump blood), potentially worsening symptoms associated with HCM.

Parathyroid disease:

• Thiazide diuretics, such as hydrochlorothiazide, can decrease the excretion of calcium by the kidneys.
• Prolonged use of these diuretics has been associated with changes in the parathyroid glands, leading to conditions like hypercalcemia (elevated blood calcium levels) and hypophosphatemia (low blood phosphate levels).
• Therefore, if you are scheduled to undergo testing for parathyroid function, it's important to discontinue the use of thiazide diuretics prior to the test.
• This allows for accurate assessment of parathyroid function without the potential interference of medication effects.

Renal artery stenosis:

• In patients with hemodynamically relevant bilateral or unilateral renal artery stenosis (narrowing of the arteries supplying the kidneys), the use of certain medications is contraindicated, which means it should be strongly avoided.
• Using these medications in such individuals can lead to complications like reduced urine production (oliguria), progressive elevation of waste products in the blood (progressive azotemia), and, in rare cases, acute renal failure and even death.

Renal impairment:

• Patients with pre-existing renal insufficiency should use ACE inhibitors with caution, as dosage adjustments may be necessary.
• Rapidly increasing the dosage of these medications can potentially worsen renal impairment, so gradual adjustments are recommended.
• Patients with renal impairment may also be at increased risk for hematologic toxicity.
• In the case of hydrochlorothiazide, cumulative effects may develop, leading to conditions like azotemia, especially in patients with impaired renal function.
• However, hydrochlorothiazide is contraindicated (strongly discouraged) in individuals with severe renal disease, as it is ineffective in such cases.
• Additionally, it should be avoided in patients with anuria (inability to urinate) or severe renal impairment, where the glomerular filtration rate (CrCl) is less than 30 mL/minute/1.73 m².

Ramipril hydrochlorothiazide: Drug Interaction

Monitor:

Blood Pressure Monitoring:

• Regularly check and monitor blood pressure.

Kidney Function Tests:

• Periodically measure BUN (blood urea nitrogen), serum creatinine, and electrolyte levels.

Blood Tests:

• Conduct a complete blood count (CBC) with a differential count.

Special Considerations:

• If the patient has collagen vascular disease and/or renal impairment, more frequent monitoring may be needed.
• Keep an eye out for any new or changing skin lesions.

These tests and monitoring are important to assess the patient's overall health and the effects of the medication on their body. They help ensure that the treatment remains safe and effective.

How to administer Ramipril and hydrochlorothiazide?

Timing: Take it in the morning.

With Water: Swallow it with half a glass of water.

Food: You can take it with or without meals.

Do Not Chew or Crush: Do not break, chew, or crush the tablets; swallow them whole.

Mechanism of action of Ramipril and hydrochlorothiazide:

Ramipril:

• Ramipril is an ACE inhibitor that works similarly to captopril in terms of pharmacology and blocks the production of angiotensin II from angiotensin I.
• In the liver, esterases also enzymatically saponify ramipril to create ramiprilat, which is ramipril's physiologically active metabolite.
• The competitive, high-affinity, and reversible binding of ramiprilat to the angiotensin-converting enzyme causes ramipril to have pharmacological effects by inhibiting the production of the potent vasoconstrictor angiotensin II.

Hydrochlorothiazide:

• Hydrochlorothiazide is a thiazide diuretic that exerts its effects by inhibiting the reabsorption of sodium and chloride in the distal tubules resulting in their excretion along with water.
• Potassium, hydrogen ions, magnesium, phosphate, and bicarbonate may also be lost.

International Brands of Ramipril and hydrochlorothiazide:

• Altace HCT
• PMS-Ramipril/HCTZ
• RAN-Ramipril HCTZ
• TEVA-Ramipril/HCTZ
• Altace Plus
• Ampril HD
• Ampril HL
• Cardace-H
• Co-ramipril
• Co-Tritace
• Cotriatec
• Hartil HCT
• Mypril Plus
• Prilen Plus
• Ramace H
• Ramicar 2.5 Plus
• Ramicar 5 Plus
• Ramicard
• Ramimed HCT
• Ramipril Comp
• Ramipril Plus
• Ramiro N
• Ramitas-HT
• Ramizid
• Triatec Comp
• Triatec HCT
• Triatec Plus
• Triltec Plus
• Tritace Comp
• Tritace Max
• Tritace Plus
• Tritace-HCT
• Tritazide

Ramipril hydrochlorothiazide Brand Names in Pakistan: