Drugs Used in the Treatment of Cardiovascular Disorders
These drugs are used in the treatment of conditions such as:
- Hypertension
- Angina pectoris
- Heart failure
- Hyperlipidemia
- Arrhythmias
Drugs Used in the Treatment of Hypertension
Hypertension
Hypertension is the persistent elevation of blood pressure higher than normal (140/90 mmHg).
Common Terms Used in Hypertension
- Blood Pressure: This is the pressure of blood against the walls of the main arteries.
- Diastolic Blood Pressure: This is the pressure exerted in the vessels when the ventricles are relaxing and refilling.
- Systolic Pressure: This is the pressure exerted in the vessels when the ventricles are contracting.
- Orthostatic Hypotension (Postural Hypotension): This is the decrease in blood pressure that occurs when a person stands erect.
- Peripheral Vascular Resistance: This is the pressure that blood must overcome as it flows in the vessels.
- Isolated Systolic Hypertension: This is defined as systolic blood pressure greater than or equal to 140 mmHg with diastolic blood pressure less than 90 mmHg. It is common in elderly patients.
- Malignant Hypertension: This is a rapidly progressing, potentially fatal form of hypertension with diastolic pressure exceeding 120 mmHg.
- Hypertensive Emergency: This is characterized by severe elevation in blood pressure > 180/120 mmHg complicated by target organ dysfunction. These situations require immediate reduction of blood pressure to limit target organ damage.
- Hypertensive Urgency: This is a situation with severe elevation of blood pressure without target organ dysfunction.
Table 1: Stages of Hypertension
Classification of Hypertension
Hypertension may be classified as:
- Essential (Primary) Hypertension
- Secondary Hypertension
Essential Hypertension
Essential hypertension is the most common type of hypertension, contributing to over 90% of the cases of hypertension encountered in medical practice. The cause of essential hypertension is not known.
Secondary Hypertension
Secondary hypertension is an elevation of blood pressure due to an identifiable cause such as:
- Renal disease
- Drugs like oral contraceptives
- Pre-eclampsia
- Renovascular disease
Treatment is directed at elimination of the cause.
Management of Hypertension
Non-Pharmacological Measures
- Encourage regular exercise (e.g., walking, jogging)
- Advise the patient to lose weight (if overweight)
- Advise the patient to limit alcohol intake
- Advise the patient to restrict salt intake
- Advise the patient to stop smoking
- Encourage a diet high in fruits and vegetables
- Advise the patient to relax and manage stress
- Diet should be low in saturated fats and cholesterol
Note: Non-pharmacological measures may be employed alone in pre-hypertension or in combination with drugs in mild to severe hypertension.
Drugs used in the treatment of hypertension may be classified as follows:
- Beta blockers
- ACE inhibitors
- Alpha-II blockers
- Diuretics
- Centrally acting antihypertensives
- Calcium channel blockers
- Angiotensin II antagonists
- Direct vasodilators
Table 2: Choice of Antihypertensives in Different Conditions
Beta Blockers
These drugs are recommended in the treatment of hypertension, angina pectoris, and post-myocardial infarction.
Beta blockers are classified as follows:
Non-selective beta blockers
- Propranolol
- Sotalol
Selective beta-1 blockers
- Atenolol
- Bisoprolol
- Metoprolol
Alpha and beta blockers
- Carvedilol
- Labetalol
Mode of Action
Beta blockers competitively block the response to beta receptors, resulting in a decrease in heart rate and heart contractility, thereby lowering blood pressure.
Atenolol
Available Preparations:
- Tablets: 25 mg, 50 mg, 100 mg
Available Brands: Tenormin®, Totamol®, Velorin®, Atelor®, Betagard®, Cardinol®, Tensimin®
Combinations:
- Tenoret® (Atenolol/Chlorthalidone) 50/12.5 mg
- Tenoretic® (Atenolol/Chlorthalidone) 100/25 mg
Pharmacokinetics
About half of the dose is absorbed following oral administration, crosses the placenta, and is distributed into breast milk. Atenolol undergoes little or no hepatic metabolism and is excreted unchanged in the urine.
Indications
- Hypertension
- Angina pectoris
- Cardiac arrhythmias
- Prophylaxis in migraine
- Acute myocardial infarction
Contraindications
- Hypersensitivity to atenolol
- Sinus bradycardia
- Second and third-degree heart block
- Symptomatic heart failure
Dosage
- Hypertension: 25-100 mg once daily (100 mg is only slightly better than 50 mg)
- Angina: 100 mg once daily or 50 mg twice daily
- Arrhythmias: 50-100 mg daily
- Migraine Prophylaxis: 50-100 mg daily
Side Effects
- Fatigue
- Hypotension
- Impotence
- Muscle ache
- Dizziness
- Wheezing
- Insomnia
Drug Interactions
- Cimetidine may increase atenolol blood concentration
- Diuretics and other antihypertensives may increase the hypotensive effect of atenolol
- Atenolol may mask the symptoms of hypoglycemia and prolong the hypoglycemic effect of insulin and oral hypoglycemics
- NSAIDs may decrease the antihypertensive effects of atenolol
- Alcohol enhances the hypotensive effect of atenolol
- Concurrent use with digoxin increases the risk of AV block and bradycardia
- Oral contraceptives antagonize the hypotensive effect of atenolol
- Concurrent use with verapamil results in severe hypotension and heart failure
Key Issues to Note
- Atenolol should be used with caution in patients with diabetes since it may mask symptoms of hypoglycemia
- Atenolol may be administered with or without food
- Abrupt withdrawal of the drug should be avoided; it should be discontinued over 1-2 weeks through gradual reduction of the dose
Calcium Channel Blockers
These drugs are used in the treatment of hypertension and angina pectoris and are safe for patients with asthma, hyperlipidemia, diabetes, and renal dysfunction. They are subdivided into two groups:
Dihydropyridines
- Non-dihydropyridines
Dihydropyridines: Drugs in this group produce significant blockage of calcium channels in blood vessels and minimal in the heart.
Examples:
- Nifedipine
- Amlodipine
- Felodipine
Non-Dihydropyridines: These drugs act on vascular smooth muscle and the heart. Since they suppress AV conduction, they are useful in cardiac arrhythmias.
Examples:
- Verapamil
- Diltiazem
Mode of Action
Calcium channel blockers decrease the influx of calcium into smooth muscles, thereby reducing vascular tone, which results in a reduction of peripheral resistance and blood pressure.
Nifedipine
Available Preparations:
- Tablets: 10 mg, 20 mg retard, 30 mg long-acting
Available Brands: Adalat®, Nifelat®, Nifedipine-denk®
Pharmacokinetics
Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract, but bioavailability is reduced by first-pass metabolism. It is extensively metabolized in the liver and excreted in the urine as inactive metabolites.
Indications
- Hypertension
- Prophylaxis of angina pectoris
Contraindications
- Hypersensitivity to nifedipine
- Unstable or acute attacks of angina
- Porphyria
- Cardiogenic shock
Dosage
The dose and frequency of administration vary depending on the preparations used.
- Short-acting nifedipine is given 3 times a day
- Nifedipine retard is given twice daily
- Long-acting nifedipine is given once daily
Hypertension:
- Adults: 10-20 mg twice daily, increased to 20-40 mg twice daily (Nifedipine retard)
- Nifedipine long-acting: 30-90 mg once daily
Angina Pectoris:
- Nifedipine retard: 10-40 mg twice daily or nifedipine long-acting: 30-90 mg once daily
Side Effects
- Oedema of ankle
- Headache
- Flushing
- Dizziness
- Tachycardia
- Palpitations
- Impotence
- Tremors
- Muscle cramps
- Dry mouth
- Constipation
- Nausea
Drug Interactions
- Beta blockers may have additive hypotensive effects when given together with nifedipine
- Nifedipine may increase digoxin blood concentration
- Nifedipine increases the plasma concentration of digoxin
- Rifampicin increases the metabolism of nifedipine, leading to reduced plasma concentrations
Key Issues to Note
- Administer nifedipine with food and swallow sustained-release tablets without chewing
- Advise the patient to avoid alcohol
- Advise the patient to rise slowly from a prolonged sitting or lying position
- Advise the patient not to stop using the drug suddenly
- Inform the patient that excessive hypotension may occur, especially at the beginning of treatment
Amlodipine
Available Preparations:
- Tablets: 5 mg, 10 mg
- Capsules: 5 mg, 2.5 mg
Available Brands: Norvasc®, Amtas®, Asomex®, Amlong®, Lovasc®, Lofral®, Amlodac®, Amedin®
Pharmacokinetics
Amlodipine is well absorbed following oral administration. It is extensively metabolized in the liver and excreted in the urine.
Indications
- Hypertension
- Prophylaxis of angina pectoris
Contraindications
- Unstable angina
- Known hypersensitivity to amlodipine
- Breastfeeding
Dosage
- Hypertension or Angina: Initially 5 mg once daily, increased after 10-14 days to a max of 10 mg once daily if necessary
Side Effects
- Headache
- Dizziness
- Oedema
- Fatigue
- Flushes
- Hypotension
- Malaise
- Bradycardia
- Palpitations
- Taste disturbances
- Abdominal pain
Drug Interactions
- Cimetidine increases serum levels of amlodipine
- Rifampicin may decrease serum concentrations of amlodipine
- Erythromycin may reduce clearance of amlodipine
- Barbiturates reduce plasma concentrations of amlodipine
Key Issues to Note
- Amlodipine may be administered without regard to food but take with caution with grapefruit juice
- Inform the patient not to discontinue the drug abruptly
- Inform the patient to report to the clinician in case of irregular heartbeat, shortness of breath, swelling of the feet and hands, pronounced dizziness, and hypotension
Angiotensin-Converting Enzyme Inhibitors (ACEIs)
These drugs are useful in the treatment of hypertension and heart failure.
Examples:
- Captopril
- Enalapril
- Ramipril
- Lisinopril
- Quinapril
Mode of Action
ACE inhibitors act by inhibiting the conversion of angiotensin I to angiotensin II (a powerful vasoconstrictor). This results in relaxation of blood vessels, which lowers blood pressure.
Captopril
Available Preparation:
- Tablets: 25 mg
Available Brands: Epistron®, Angiopril®
Pharmacokinetics
Captopril is absorbed throughout the GIT, and the presence of food may reduce absorption. It is distributed to body tissues except the CNS, metabolized in the liver, and excreted in the urine and small amounts in feces.
Indications
- Mild to moderate hypertension
- Congestive heart failure
- Diabetic nephropathy
- Prophylaxis after infarction
Contraindications
- Hypersensitivity to captopril and other ACE inhibitors
- Pregnancy
- Hereditary or idiopathic angioedema
- Bilateral or single renal artery stenosis
Dosage
- Hypertension: Initially 12.5 mg twice daily. Maintenance dose: 25 mg twice daily, max 50 mg twice daily in severe hypertension
- Heart Failure (Adjunct): Initially 6.25-12.5 mg under close supervision. Maintenance dose: 25 mg 2-3 times daily, max 150 mg daily
- Diabetic Nephropathy: 75-100 mg daily in divided doses
Side Effects
- Hypotension
- Chest pain
- Palpitations
- Fatigue
- Non-productive cough
- Tachycardia
- Dyspepsia
- Hyperkalemia
- Taste disturbances
- Malaise
Drug Interactions
- Alcohol, diuretics may increase the effect of captopril
- NSAIDs may decrease the effect of captopril
- Potassium-sparing diuretics, potassium supplements may cause hyperkalemia
Key Issues to Note
- Advise the patient to rise slowly to sitting or standing position to minimize orthostatic hypotension
- Inform the patient that dizziness, fainting, lightheadedness may occur during the first few days of treatment
- Advise the patient to take the drug on an empty stomach about one hour before food
- Captopril should not be administered together with antacids because they hinder its absorption
- The dose administered and frequency of administration should be reduced in renal impairment
Angiotensin II Receptor Antagonists
These drugs include:
- Losartan
- Valsartan
- Telmisartan
They are normally used as an alternative in patients who cannot tolerate side effects such as dry cough associated with ACE inhibitors.
Mode of Action
They produce a fall in blood pressure by direct antagonism of the vasoconstrictor angiotensin II at the AT1 receptor site.
Losartan
Available Preparations:
- Tablets: 50 mg, 100 mg
Available Brands: Losacar®, Tozaar®, Losartec®, Losartas®
Combinations:
- Presartan-H50® (Losartan/Hydrochlorothiazide)
- Tozaar-H®
Pharmacokinetics
Losartan is readily absorbed from the gastrointestinal tract following oral administration, undergoes first-pass metabolism forming active and inactive metabolites. Losartan is excreted in the urine and feces.
Indications
- Hypertension
- Diabetic nephropathy
Contraindications
- Known hypersensitivity to losartan
- Pregnancy (2nd and 3rd trimester)
- Lactation
Dosage
- Usually 50 mg once daily, increased after several weeks to 100 mg once daily if necessary
Side Effects
- Dizziness
- Taste disturbance
- Myalgia
- Fatigue
- Diarrhea
- Urticaria
- Vertigo
- Migraine
Drug Interactions
- Fluconazole may decrease conversion of losartan to active metabolites resulting in loss of anti-hypertensive effects
- NSAIDs may reduce the hypotensive effect of losartan
- Potassium-sparing diuretics may increase the risk of hyperkalemia when given together with losartan
- Cimetidine may increase the effect of losartan
- Alcohol may potentiate the hypotensive effect of losartan
Key Issues to Note
- Avoid tasks that require alertness until response to drug is established (possible dizziness effect)
- Advise the patient not to take any OTC preparations or nasal decongestants without recommendation of a clinician
- Advise the patient not to stop taking the medication unless told by the clinician
- The drug may be taken with or without meals
Direct-Acting Vasodilators
These drugs are rarely used as first-line drugs and are reserved for resistant cases of hypertension and for treatment of hypertensive emergencies. These drugs also cause sodium and water retention; therefore, they are useful when combined with diuretics to counteract the sodium retention. They are also combined with beta blockers to prevent the reflex tachycardia.
Examples:
- Hydralazine
- Minoxidil
Mode of Action
Hydralazine reduces blood pressure by acting directly on the arterial smooth muscle to cause vasodilation and reduction in total peripheral vascular resistance.
Hydralazine
Available Preparations:
- Injection: 20 mg/ml
- Tablets: 25 mg
Available Brands: Apresoline®
Pharmacokinetics
Orally administered hydralazine is rapidly and completely absorbed from the gastrointestinal tract but undergoes considerable first-pass metabolism in the gastrointestinal mucosa and liver. It is widely distributed, metabolized in the liver by acetylation, and excreted in the urine as metabolites.
Indications
- Hypertensive crisis
- Moderate to severe hypertension
- Moderate to severe chronic congestive heart failure (in combination with long-acting nitrates)
- Hypertension secondary to pre-eclampsia/eclampsia
Contraindications
- Known hypersensitivity to hydralazine
- Severe tachycardia
- Heart failure with high cardiac output
- Myocardial insufficiency due to mechanical obstruction
- Idiopathic systemic lupus erythematosus
- Porphyria
Dosage
- Hypertension: By mouth 25 mg twice daily, increased to usual max 50 mg twice daily
- Heart Failure: 25 mg 3-4 times daily, increased every 2 days if necessary. Maintenance dose: 50-75 mg 4 times daily
- By Intravenous Infusion, Hypertension with Renal Complications and Hypertensive Crisis: Initially 200-300 micrograms/minute, maintenance 50-150 micrograms/minute
Side Effects
- Headache
- Severe tachycardia
- Hypotension
- Angina
- Oedema
- Heart failure
- Dizziness
- Flushing
- Palpitations
- Joint swelling
- Anorexia
- Gastrointestinal disturbances
Drug Interactions
- Diuretics, other antihypertensives may increase hypotensive effects of hydralazine
- Indomethacin may decrease hypotensive effects of hydralazine
Key Issues to Note
- Prolonged treatment of more than 6 months may induce lupus-like syndrome
- Beta blockers and thiazides are often used with hydralazine to prevent tachycardia and fluid retention
- Advise the patient to avoid driving until the effect of the drug is established
Centrally Acting Antihypertensive Drugs
These drugs are effective antihypertensives but are no longer considered drugs of choice as they are less tolerated than other antihypertensives. Methyldopa is a drug of choice in the treatment of hypertension in pregnancy.
Examples:
- Methyldopa
- Clonidine
Mode of Action
These drugs reduce blood pressure by acting in the CNS to reduce the activity of the sympathetic nervous system.
Methyldopa
Available Preparations:
- Tablets: 250 mg
Available Brands: Aldomet®, Medopress®
Pharmacokinetics
Methyldopa is variably absorbed from the gastrointestinal tract when taken orally, crosses the blood-brain barrier, is extensively metabolized in the liver, and excreted in urine.
Indications
- Hypertension, especially in pregnancy
Contraindications
- Hypersensitivity to methyldopa
- Active liver disease
- Depression
- Phaeochromocytoma
- Porphyria
Dosage
- Adult: Initially 250 mg 2-3 times daily, increased gradually at an interval of at least 2 days until the desired response is obtained, max 3 g daily
- Elderly: Initially 125 mg twice daily, increased gradually, max 2 g daily
Side Effects
- Sedation
- Dry mouth
- Stomatitis
- Myalgia
- Impaired mental acuity
- Impotence
- Hemolytic anemia
- Dizziness
- Constipation
- Oedema
- Postural hypotension
- Decreased libido
- Bradycardia
Drug Interactions
- Enhanced hypotensive effect when methyldopa is given with ACE inhibitors, alcohol, atenolol, or propranolol
- Methyldopa may impair tolbutamide metabolism, enhancing its hypoglycemic effects
- Hypotensive effect of methyldopa is antagonized by NSAIDs
- Hypotensive effect of methyldopa is antagonized by estrogen
- Oral iron therapy reduces the bioavailability of methyldopa
Key Issues to Note
- Methyldopa may be administered with or without regard to food
- Advise the patient to avoid alcohol during treatment
- Warn the patient that methyldopa may cause drowsiness and impair activities requiring mental alertness
- Advise the patient to rise slowly from a prolonged sitting or lying position
- Inform the patient that transient sedation or depression may occur
- Advise the patient not to stop the drug abruptly
Alpha Adrenoceptor Blocking Drugs
These drugs may be used in combination with other drugs in the treatment of resistant hypertension. In addition to lowering blood pressure, they also improve urinary flow rates in benign prostatic hypertrophy.
Examples:
- Prazosin
- Doxazosin
- Terazosin
Mode of Action
These drugs competitively inhibit postsynaptic alpha receptors, which results in vasodilation of veins and arterioles. This leads to a decrease in total peripheral resistance and blood pressure. They also block alpha receptors in non-vascular smooth muscle (e.g., the bladder neck), where alpha-blockade reduces resistance to urinary flow.
Prazosin
Available Preparations:
- Tablets: 1 mg, 2 mg, 5 mg
Available Brands: Hypovase®, Minipress®
Pharmacokinetics
Prazosin is well absorbed after oral administration, extensively metabolized in the liver, and excreted in urine.
Indications
- Hypertension
- Congestive heart failure
- Benign prostatic hyperplasia
- Raynaud’s syndrome
Contraindications
- Hypersensitivity to quinazolines
- Congestive heart failure due to mechanical obstruction
Dosage
- Hypertension: 0.5 mg twice daily, increased to 1 mg 2-3 times daily after 3-7 days, maintenance dose 20 mg daily in 2-3 divided doses
- Heart Failure: 0.5 mg 2-4 times daily, increased to 4 mg daily in divided doses, maintenance dose 4-20 mg daily in divided doses
- Benign Prostate Hyperplasia: Initially 0.5 mg twice daily for 3-7 days, maintenance dose 2 mg twice daily
- Raynaud’s Syndrome: Initially 0.5 mg twice daily, increased if necessary after 3-7 days to the usual maintenance dose 1-2 mg twice daily
Side Effects
- Headache
- Dry mouth
- Drowsiness
- Oedema
- Postural hypotension
- Urinary incontinence
- Priapism
- Urinary frequency
- Weakness
- Palpitations
- Nausea
- Somnolence
Drug Interactions
- Estrogen, NSAIDs may decrease the effect of prazosin
- Concomitant use with propranolol or other beta blockers may cause severe hypotension
Key Issues to Note
- Advise the patient to avoid alcohol
- Inform the patient that prazosin may cause dizziness or drowsiness and impair the ability to perform activities requiring alertness
- Advise the patient to rise slowly from sitting or lying position
- Advise the patient to take the first dose of prazosin at bedtime to avoid dizziness
Drugs for Heart Failure
Heart failure is a clinical syndrome caused by the inability of the heart to pump sufficient blood to meet the metabolic demands of the body. Inadequate perfusion of the tissues leads to a variety of symptoms such as breathlessness, fatigue, and oedema. Drugs used in the treatment of heart failure include:
Diuretics
Cardiac glycosides
ACE inhibitors
- Beta blockers
Diuretics
Diuretics are the first-line drugs in the treatment of heart failure. They are recommended in all patients with clinical evidence of fluid retention.
Classification of Diuretics
Diuretics are classified as follows:
- Loop diuretics
- Thiazide diuretics
- Potassium-sparing diuretics
- Carbonic anhydrase inhibitors
Loop Diuretics
Loop diuretics are potent diuretics used in the treatment of moderate to severe heart failure. They may be used alone or in combination with thiazides, especially metolazone, to achieve a profound diuresis.
Examples:
- Frusemide
- Bumetanide
Mode of Action
Loop diuretics inhibit reabsorption of sodium chloride from the ascending limb of the loop of Henle.
Frusemide
Available Preparations:
- Tablets: 40 mg
- Injection: 20 mg/ml
Available Brands: Lasix®, Agomide®, Frusina®
Pharmacokinetics
Frusemide is well absorbed from the GIT and excreted in the urine and partially metabolized in the liver and feces.
Indications
- Oedema
- Hypertension
Contraindications
- Renal failure with anuria
- Dehydration
- Known hypersensitivity to frusemide
- Hyponatraemia
- Severe hypokalaemia
- Severe hypernatraemia
- Hypercalcaemia
- Associates with liver cirrhosis
Dosage
Adult:
- Oedema: Oral, initially 40 mg in the morning, maintenance 20-40 mg, 80 mg or more in resistant oedema
- Children: 1-3 mg/kg daily, max 40 mg daily
Hypertension: 20-40 mg twice daily
Slow IV/IM: Initially 20-50 mg, increased if necessary in steps of 20 mg, not less than every 2 hours, doses greater than 50 mg by IV infusion only, max 20 mg daily
Side Effects
- Gout
- Rash
- Nausea
- Hypotension
- Hypokalaemia
- Hyponatraemia
- Hypomagnesaemia
- Hyperglycaemia
- Tinnitus
- Deafness
- Dehydration
- Abdominal cramps
- Diarrhoea or constipation
Drug Interactions
- Amphotericin B may increase the risk of nephrotoxicity caused by frusemide
- Frusemide may decrease the effect of anticoagulants
- Frusemide may increase the risk of lithium toxicity
- Gentamycin may increase the risk of ototoxicity when given concurrently with frusemide
- Cephalosporins enhance the nephrotoxicity caused by frusemide
- Frusemide may increase the risk of digoxin toxicity
Key Issues to Note
- Frusemide may be administered with food or milk to minimize GI distress
- Frusemide may cause photosensitivity reactions (e.g., exposure to sunlight may cause severe sunburn)
Thiazide and Related Diuretics
Thiazide diuretics are used in the treatment of mild heart failure and are the diuretics of choice in the treatment of hypertension. They are relatively weak to be used alone in heart failure.
Examples:
- Bendrofluazide
- Hydrochlorothiazide
- Chlorthalidone
- Metolazone
Mode of Action
They act by inhibiting sodium and chloride reabsorption at proximal sites of the distal convoluted tubule. Excretion of potassium and magnesium is also enhanced, while calcium excretion is diminished.
Bendrofluazide
Available Preparations:
- Tablets: 5 mg
Available Brands: Aprinox®, Benduric®
Pharmacokinetics
Bendrofluazide is completely absorbed from the gastrointestinal tract, a small percentage is metabolized in the liver, and is excreted unchanged in the urine.
Indications
- Oedema
- Hypertension
Contraindications
- Hypersensitivity to bendrofluazide
- Refractory hypokalaemia
- Hyponatraemia
- Symptomatic hyperuricaemia
- Hypercalcaemia
- Addison’s disease
Dosage
- Oedema: Initially 5-10 mg daily in the morning or on alternate days, maintenance 5-10 mg 1-3 times weekly
- Hypertension: 2.5 mg daily in the morning, higher doses rarely necessary
Side Effects
- Gout
- Fatigue
- Impotence
- Hypokalaemia
- Hyperglycaemia
- Hyponatraemia
- Nausea
- Dizziness
- Postural hypotension
- Hypomagnesaemia
Drug Interactions
- The effects of digoxin may be increased by bendrofluazide
- NSAIDs may reduce the diuretic effect of bendrofluazide
- Bendrofluazide may increase lithium levels in the blood
Potassium-Sparing Diuretics
These drugs are relatively weak diuretics as single drugs for heart failure and are not effective for use alone in heart failure. They are used in combination with other diuretics to prevent loss of potassium caused by thiazide or loop diuretics.
Example:
- Spironolactone
Mode of Action
They inhibit sodium reabsorption in the distal tubule by antagonizing aldosterone. As a result, distal tubule sodium-potassium exchange is reduced.
Spironolactone
Available Preparations:
- Tablets: 25 mg, 50 mg
Available Brands: Aldactone®
Pharmacokinetics
Spironolactone is well absorbed from the gastrointestinal tract, metabolized in the liver, and excreted in urine and feces.
Indications
- Liver cirrhosis associated with refractory oedema and ascites
- Ascites associated with malignancy
- Oedema in congestive heart failure
- Nephrotic syndrome
- Hypertension
- Primary hyperaldosteronism
Contraindications
- Pregnancy
- Hyperkalaemia
- Addison’s disease
- Breastfeeding
- Hyponatraemia
- Severe renal impairment
Dosage
- Congestive Heart Failure: 100 mg daily, increased to 400 mg daily in severe cases, maintenance dose 25-200 mg/day
- Oedema: Initially 100 mg daily, maintenance 25-200 mg daily
- Hypertension: 25-100 mg once daily
- Nephrotic Syndrome: 100-200 mg/day
Side Effects
- Ataxia
- Nausea and vomiting
- Confusion
- Diarrhoea
- Dehydration
- Deepening of the voice
- Menstrual irregularities
- Hyperkalaemia
- Hyponatraemia
- Fever
- Weakness
- Headache
- Impotence
- Skin rash
- Drowsiness
- Renal impairment
- Gynaecomastia
Drug Interactions
- Serum concentration of digoxin may be increased when given together with spironolactone
- NSAIDs may decrease the antihypertensive effects of spironolactone
- Potassium supplements, ACE inhibitors, angiotensin II antagonists may increase the risk of hyperkalaemia caused by spironolactone
- Spironolactone may decrease the anticoagulant effect of heparin
Key Issues to Note
- Spironolactone may be administered with food
- It may cause drowsiness and impair the ability to perform activities requiring mental alertness
Osmotic Diuretics
These drugs include:
- Mannitol
Mode of Action
Osmotic diuretics induce diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the tubular reabsorption of water. Excretion of sodium and chloride is increased.
Mannitol
Available Preparation:
- Intravenous infusion: 20%
Pharmacokinetics
Following intravenous infusion, mannitol is excreted rapidly by the kidneys before any significant metabolism can take place in the liver.
Indications
- Cerebral oedema
- Acute anuria
- Acute renal failure due to massive haemorrhage, trauma, shock, and major surgery
- To promote urinary excretion of toxic substances (e.g., lithium and salicylates)
Contraindications
- Pulmonary oedema
- Intracranial bleeding
- Congestive heart failure
- Hypersensitivity to mannitol
- Severe dehydration
- Renal failure (anuria)
Dosage
- Cerebral Oedema: By IV infusion 1 g/kg as a 20% solution
- Diuresis: By IV infusion 50-200 g over 24 hours, preceded by a test dose of 200 mg/kg by slow intravenous injection
Side Effects
- Oedema
- Thrombophlebitis
- Chills
- Hypotension
- Headache
- Fever
- Thirst
- Electrolyte imbalance
- Circulatory overload
- Nausea and vomiting
- Increased urinary frequency and urine volume
Drug Interactions
- Mannitol may increase the risk of digoxin toxicity associated with mannitol-induced hypokalaemia
Hyperlipidaemia
Hyperlipidaemia refers to the presence in the blood of an abnormally high concentration of cholesterol and/or triglycerides in the form of lipoproteins. It may be divided into two:
- Primary hyperlipidaemia
- Secondary hyperlipidaemia
Primary hyperlipidaemia is where the raised plasma lipid concentration is the result of a genetic defect.
Secondary hyperlipidaemia may be due to metabolic problems such as diabetes mellitus, chronic renal failure, excessive alcohol intake, hypothyroidism, etc.
The main risk is atherosclerosis, in which fatty deposits called atheroma build up in the arteries, restricting and disrupting the flow of blood. The restriction of blood flow may lead to the formation of blood clots resulting in a stroke or heart attack.
Drugs used in the treatment of hyperlipidaemia include:
- Statins
- Bile acid binding resins
- Fibrates
- Nicotinic acid and its derivatives
- Others (omega-3)
Statins
Statins include drugs such as:
- Simvastatin
- Atorvastatin
- Fluvastatin
- Pravastatin
Mode of Action
Statins competitively inhibit 3-hydroxy methylglutaryl co-enzyme (HMG-CoA) reductase enzyme, the rate-limiting enzyme in cholesterol synthesis, especially in the liver.
Atorvastatin
Available Preparations:
- Tablets: 10 mg, 20 mg
Available Brands: Lipitor®, Atorva®, Atostin®, Lipiget®
Pharmacokinetics
Atorvastatin is rapidly absorbed from the gastrointestinal tract, undergoes first-pass metabolism, is metabolized in the liver, and excreted as metabolites in bile.
Indications
- Combined or mixed hyperlipidaemia
- Prevention of cardiovascular events in patients with type 2 diabetes
- Primary hypercholesterolemia
Contraindications
- Hypersensitivity to atorvastatin
- Active liver disease
- Pregnancy
- Lactation
Dosage
- Adults: Initially 10 mg daily, adjusted according to response at intervals of 4 weeks to 40 mg/day max
- Children (10-17 years): 10 mg once daily
- Prevention of Cardiovascular Events: 10 mg once daily
Side Effects
- Insomnia
- Weight gain
- Back pain
- Nausea
- Skin rash
- Impotence
- Anorexia
- Dizziness
- Chest pain
- Malaise
- Headache
- Muscle pain or weakness
- Tinnitus
- Peripheral neuropathy
- Angina
Drug Interactions
- Atorvastatin may increase the anticoagulant effect of warfarin, digoxin, itraconazole, oral contraceptives
- May increase atorvastatin blood concentration resulting in severe muscle inflammation, pain, and weakness
- Antacids and propranolol decrease atorvastatin activity
- Clarithromycin and erythromycin elevate plasma concentrations of atorvastatin
Key Issues to Note
- Take atorvastatin with or without regard to meals but preferably in the evening
- Advise the patient to report symptoms of myalgia, muscle tenderness, weakness, or gastric upset
- Female patients of childbearing age should be advised to use effective contraception
Blood and Blood Forming Organs
Anticoagulants
These are drugs that prevent the clotting of blood. Anticoagulants help to maintain normal blood flow in people who are at risk of clot formation. They can either prevent the formation of blood clots or stabilize an existing clot so that it does not break.
Anticoagulants are divided into two categories:
- Parenteral anticoagulants
- Oral anticoagulants
Parenteral Anticoagulants
These drugs are normally used when immediate action is required.
Examples:
- Heparin
- Enoxaparin (low molecular weight heparin)
Heparin
Available Preparations:
- Injection: 5000 IU/ml
Available Brands: Cal-heparin®, Heparen®
Pharmacokinetics: After intravenous or subcutaneous injection, the onset of action is immediate, within 1-2 hours. Heparin is extensively bound to plasma proteins and is excreted in the urine mainly as metabolites.
Indications:
- Deep vein thrombosis
- Pulmonary embolism
- Prophylaxis in general and gynecological surgery
- Prophylaxis in orthopedic surgery
- Myocardial infarction
- Unstable angina
Contraindications:
- Hemophilia
- Severe hypertension
- Recent eye surgery
- Peptic ulcers
- Known hypersensitivity to heparin
- Acute bacterial endocarditis
- Thrombocytopenia
- Severe liver disease
Dosage:
Deep Venous Thrombosis, Pulmonary Embolism, and Unstable Angina:
- Adults: By IV injection, loading dose of 5000 units (10,000 units in severe pulmonary embolism), followed by continuous infusion of 18 units/kg/hour or by SC injection of 15,000 units every 12 hours.
- Children and small adults: Loading dose 50 units/kg, then 15-25 units/kg/hour by intravenous infusion or subcutaneous injection of 250 units/kg every 12 hours.
Side Effects:
- Hemorrhage
- Hyperkalemia
- Chills
- Epistaxis
- Thrombocytopenia
- Anaphylaxis
- Headache
- Nausea and vomiting
- Urticaria
Drug Interactions:
- Heparin increases the risk of hemorrhage when given together with oral anticoagulants like warfarin.
Key Issues to Note:
- Advise the patient to report any signs of bleeding from the gums, under the skin, urine, or stool.
- Advise the patient to limit alcohol intake during treatment.
- Do not administer IM due to pain, irritation, and hematoma formation.
- When given together with oral anticoagulants, heparin should be withdrawn once effective oral anticoagulation is established.
Oral Anticoagulants
Oral anticoagulants are effective in the primary and secondary prevention of venous thromboembolism.
Examples:
- Warfarin
Warfarin
Available Preparations:
- Tablets: 3 mg, 5 mg
Available Brands: Marevan®
Pharmacokinetics: Warfarin is readily absorbed from the gastrointestinal tract, crosses the placenta but does not occur in significant quantities in breast milk. It is extensively metabolized in the liver and excreted in urine and bile.
Indications:
- Prophylaxis of embolism in rheumatic heart disease and atrial fibrillation
- Prophylaxis after insertion of prosthetic heart valve
- Prophylaxis and treatment of venous thrombosis and pulmonary embolism
- Myocardial infarction
Contraindications:
- Hypersensitivity to the drug
- Peptic ulcer
- Severe hypertension
- Bacterial endocarditis
- Pregnancy
- Alcoholism
- Bleeding disorders
Dosage:
- Initially 5 mg daily for 2-5 days, then adjust according to response to the usual maintenance dose of 3-9 mg daily.
Side Effects:
- Hemorrhage
- Rash
- Jaundice
- Hepatic dysfunction
- Vomiting
- Skin rash
- Nausea and vomiting
- Hypersensitivity
- Diarrhea
- Headache
- Pancreatitis
- Urticaria
- Abdominal cramps
Drug Interactions:
- Drugs that decrease warfarin anticoagulant effect include alcohol, carbamazepine, phenytoin, cholestyramine, rifampicin, oral contraceptives, and vitamin K.
- Concomitant use with amiodarone, metronidazole, cimetidine, and streptokinase may increase the anticoagulant effect of warfarin.
Key Issues to Note:
- Warn the patient that bleeding may occur, especially at the beginning of treatment and with high doses.
- Warfarin may be administered on an empty or full stomach.
- Adequate anticoagulation is not observed until about 3-4 days after initial administration of warfarin; heparin should be used concurrently if immediate effect is required.
Antiplatelet Drugs
Antiplatelet drugs inhibit thrombus formation by decreasing platelet aggregation. They are used to prevent further thromboembolic events in patients who have suffered myocardial infarction, ischemic stroke or transient ischemic attacks, or unstable angina.
Examples:
- Aspirin (low dose)
- Clopidogrel
- Dipyridamole
Aspirin
Available Preparations:
- Tablets: 75 mg, 100 mg
Available Brands: Ecorin®, Aspirem®, Ascard®, Bayer Aspirin Cardio®
Indications:
- Acute myocardial infarction
- Unstable angina
- Primary and secondary prevention of stroke
Contraindications:
- Children and adolescents under 16 years
- Hypersensitivity to aspirin or NSAIDs
- Aspirin-sensitive asthma
- Active peptic ulcer
- Breastfeeding
- Hemophilia
Dosage:
- 75 mg daily. 150-300 mg daily may be required in acute conditions (MI, acute ischemic stroke, unstable angina).
Side Effects:
- Bronchospasms
- Nausea and vomiting
- Increased bleeding time
- Urticaria
- Ringing in the ears
- Dizziness
- Heartburn
- Gastrointestinal bleeding
Drug Interactions:
- Aspirin increases the risk of bleeding when given together with oral anticoagulants and heparin.
- Aspirin decreases the diuretic effect of spironolactone and frusemide.
- Aspirin decreases the antihypertensive effect of captopril and beta-blockers.
Key Issues to Note:
- The drug should be administered with food.
- Avoid alcohol while taking aspirin.
- Avoid use of OTC preparations for pain without recommendation of a clinician.
Thrombolytics
Thrombolytics are drugs used to break up or dissolve blood clots that have already formed. Thrombolytic enzymes are used to lyse the thrombi that obstruct coronary or pulmonary arteries.
Examples:
- Streptokinase
- Urokinase
Mode of Action: They act by converting plasminogen to plasmin, which catalyzes the breakdown of fibrin and therefore is able to dissolve blood clots.
Streptokinase
Available Preparations:
- Injection: 1,500,000 IU
Available Brands: Stpase®
Indications:
- Acute myocardial infarction
- Deep vein thrombosis
- Pulmonary embolism
- Acute arterial thromboembolism
Contraindications:
- Active internal bleeding
- Recent trauma to the head
- Severe uncontrollable hypertension
- Uncontrollable clotting disorders
- Intracranial surgery
- Recent cerebral vascular accident
- Severe allergic reactions
- Recent abortion or delivery
Dosage:
- Myocardial Infarction: IV infusion 1,500,000 units over 30-60 minutes.
- Deep Vein Thrombosis, Pulmonary Embolism, Acute Arterial Thromboembolism, Arterial Thrombosis: By IV infusion 250,000 units infused over 30 minutes, then 100,000 units/hour for up to 12-72 hours according to the patient’s condition.
Side Effects:
- Fever
- Headache
- Skin rash and itching
- Vomiting
- Convulsions
- Nausea
- Nephritis
- Hypotension
- Malaise
- Superficial bleeding at puncture site
Drug Interactions:
- Heparin, oral anticoagulants, aspirin, dipyridamole may increase the risk of bleeding when given together with streptokinase.
Antifibrinolytic Drugs
These drugs inhibit the dissolution of blood clots.
Examples:
- Tranexamic acid
Tranexamic Acid
Available Preparations:
- Tablets/Capsules: 500 mg
Available Brands: Tranlok®, Hemsamic®
Combinations: Tranfib-MF® (tranexamic acid/mefenamic acid) 500/250
Mode of Action: Tranexamic acid acts primarily by blocking the binding of plasminogen and plasmin to fibrin.
Pharmacokinetics: Tranexamic acid is rapidly and completely absorbed from the GIT, crosses the placenta, distributes into breast milk. It is metabolized in the liver and excreted in urine.
Indications:
- Menorrhagia
- Prevention of bleeding in prostatectomy and dental extraction in patients with hemophilia
- Epistaxis
- Thrombolytic overdose
- Prophylaxis of hereditary angioedema
Contraindications:
- Hypersensitivity to tranexamic acid
- Severe renal impairment
- Thromboembolic disease
Dosage:
Oral:
- Menorrhagia (inhibited when menstruation has started): 1 g 3 times daily for 3-4 days
- Hereditary Angioedema: 1-1.5 g 2-3 times daily
- Epistaxis: 1 g 3 times daily for 7 days
Side Effects:
- Nausea
- Diarrhea
- Thrombosis
- Vomiting
- Hypotension
- Disturbances in color vision
Drug Interactions:
- Heparin, oral anticoagulants, aspirin, dipyridamole may increase the risk of bleeding when given together with tranexamic acid.
Drugs Used in the Treatment of Anaemia
Anaemia is defined as a decrease in hemoglobin concentration below that necessary for tissue oxygenation. It may be caused by increased RBC loss, decreased production of RBCs, or increased destruction of RBCs.
Ferrous Sulphate
Available Preparations:
- Tablets: 200 mg
Available Brands: Cyano Iron®, Ferol®
Indications:
- Iron deficiency anaemia
Contraindications:
- Haemolytic anaemias
- Peptic ulcer disease
- Patients receiving blood transfusion
- Hemosiderosis
- Haemochromatosis
Dosage:
- Iron Deficiency Anaemia: 200 mg 2-3 times daily
- Prophylaxis of Anaemia: 200 mg daily
Side Effects:
- Constipation
- Diarrhea
- Anorexia
- Epigastric pain
- Dark stool
- Gastrointestinal irritation
- Nausea
Drug Interactions:
- Antacids and cimetidine decrease the absorption of ferrous sulphate
- Chloramphenicol may increase the serum levels of ferrous sulphate
- Ferrous sulphate decreases the anti-infective effect of quinolones when given concurrently
- The drug may be given with meals
Folic Acid
Available Preparations:
- Tablets: 5 mg
Available Brands: Folacid®, Asflic®, Folon®
Pharmacokinetics: Folic acid is rapidly absorbed from the gastrointestinal tract, distributed to all body tissues, metabolized in the liver to the active form, and excreted in urine.
Indications:
- Folate-deficient megaloblastic anaemia
- Prophylaxis in chronic hemolytic states or renal dialysis
- Prevention of neural tube defects in pregnancy
- Nutritional supplement
Contraindications:
- Folate-dependent malignant disease
- Aplastic anaemia
- Hypersensitivity to folic acid
Dosage:
- Megaloblastic Anaemia: 5 mg once daily for 4 months, up to 15 mg daily may be given in malabsorption states
- Prevention of Neural Tube Defect: 400 micrograms daily before conception and during the first 12 weeks of pregnancy
- Prevention of Recurrence of Neural Tube Defect: 5 mg daily from at least 4 weeks before conception until 12 weeks of pregnancy
- Children (Folic Acid Deficiency): 1-2 mg daily
Side Effects:
- Nausea
- Headache
- Insomnia
- Irritability
- Skin rash
- Fever
- Diarrhea
- Bronchospasm
Drug Interactions:
- Folic acid may decrease serum phenytoin concentrations
- Antifolate drugs such as trimethoprim may interfere with folic acid metabolism and may cause deficiency in patients with low folic acid stores
- Chloramphenicol may antagonize the hematologic response to folic acid
Combination Preparations: Ferrous Salts with Folic Acid
Available Preparations:
- Capsules
- Suscaps
- Tablets
Available Brands: Aktiferrin-F®, Fefol®, Fef®, Fefan®
Indications:
- Prevention of iron and folic acid deficiencies in pregnancy, after delivery, and lactation
Contraindications:
- Known hypersensitivity to any of the ingredients
Dosage:
- One capsule/suscap/tablet once daily
Side Effects:
- Sensation of fullness
- Nausea and vomiting
- Diarrhea
- Constipation