CO-PRITOR

Indications

• Hypertension
• Angina pectoris
• Arrhythmias
• Migraine prophylaxis
• Thyrotoxicosis (adjunct therapy)
• Phaeochromocytoma (with an alpha-blocker)
• Prophylaxis of variceal bleeding in portal hypertension

Dosage

Adults: Initially 80 mg once daily, increased as needed in steps of 80 mg weekly

Mechanism of action

Propranolol acts by competitively inhibiting beta-adrenergic receptors, both beta-1 (located in the heart) and beta-2 (located in the lungs and vascular smooth muscle). This blockade decreases the effects of sympathetic stimulation, resulting in lowered heart rate, reduced myocardial contractility, and vasodilation, which collectively contribute to its antihypertensive and antianginal effects.

Pharmacodynamics

Propranolol exhibits dose-dependent effects on heart rate and blood pressure. At therapeutic doses, it reduces cardiac output and lowers blood pressure through decreased cardiac contractility and heart rate. It also has antiarrhythmic properties, preventing abnormal heart rhythms. Additionally, it may have central nervous system effects, contributing to its efficacy in migraine prophylaxis by inhibiting vasodilation and suppressing the release of inflammatory mediators.

Pharmacokinetics

Propranolol is well absorbed from the gastrointestinal tract, but it undergoes extensive first-pass metabolism in the liver, leading to variable bioavailability (approximately 25-35%). It is highly protein-bound (90-95%) and has a relatively short half-life of about 3-6 hours. Propranolol is metabolized primarily by CYP2D6 and CYP1A2, and its elimination half-life may be prolonged in patients with hepatic impairment. Renal function does not significantly affect the pharmacokinetics of propranolol.

Contra-indications

• Asthma or severe chronic obstructive pulmonary disease
• Bradycardia
• Heart block greater than first degree
• Cardiogenic shock
• Severe peripheral arterial disease
• Phaeochromocytoma (without an alpha-blocker)
• Hypersensitivity to propranolol or any of its components

Adverse effects

• Fatigue
• Hypotension
• Bradycardia
• Dizziness
• Nausea
• Vomiting
• Diarrhea
• Insomnia
• Nightmares
• Depression
• Sexual dysfunction
• Cold extremities
• Peripheral vasoconstriction
• Worsening of asthma
• Agranulocytosis
• Thrombocytopenia
• Psoriasis exacerbation

Interactions

• Other antihypertensives
• Calcium channel blockers (e.g., verapamil, diltiazem)
• Digoxin
• Insulin and oral hypoglycemics
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Rifampicin
• Cimetidine
• Clonidine

Precautions

• Caution in patients with diabetes mellitus due to potential hypoglycemia
• Caution in patients with hepatic impairment
• Monitor patients with a history of depression
• Use with caution in patients with peripheral vascular disease
• May mask signs of hyperthyroidism or hypoglycemia
• Gradual withdrawal is recommended to avoid rebound hypertension

Pregnancy

Propranolol should only be used during pregnancy if the benefits outweigh the risks. It can affect fetal development and may cause bradycardia or respiratory issues in the neonate.

Breast-feeding

Propranolol is excreted in breast milk. Caution is advised when administered to a nursing mother, as it may affect the infant.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• 5 mg/1 ml solution for injection
• 40 mg tablets
• 80 mg tablets

Indications

• Hypertension
• Edema associated with congestive heart failure
• Edema due to renal dysfunction

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: 2.5 mg daily, taken in the morning for hypertension; higher doses may be used for other indications.

Mechanism of action

Hydrochlorothiazide is transported into epithelial cells of the distal convoluted tubule via organic anion transporters OAT1, OAT3, and OAT4. It inhibits the sodium-chloride symporter (SLC12A3), preventing sodium reabsorption. This action reduces the concentration gradient that promotes water reabsorption, leading to increased urine production.

Pharmacodynamics

Hydrochlorothiazide increases the excretion of sodium and water, thereby promoting diuresis. It is effective in lowering blood pressure and has a wide therapeutic range, with doses typically ranging from 25 to 100 mg. The drug exhibits a greater antihypertensive effect at lower doses due to enhanced vasodilation, while higher doses primarily exert their effects through diuresis. Caution is advised in patients with renal or hepatic impairment.

Pharmacokinetics

Hydrochlorothiazide is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours post-administration. It has a half-life of about 6-15 hours, depending on individual patient factors. The drug is primarily excreted unchanged in the urine. Dosage adjustments may be necessary in patients with renal impairment due to the risk of accumulation.

Contra-indications

• History of hypersensitivity to sulfonamides
• Acute porphyrias
• Severe renal impairment

Adverse effects

• Angina pectoris
• Arrhythmias
• Arthralgia
• Asthenia
• Chest pain
• Confusion
• Dry mouth
• Haemolytic anaemia
• Hepatic disorders
• Hyperkalaemia
• Hypokalemia
• Nausea
• Rhabdomyolysis
• Syncope
• Vertigo

Interactions

• Potassium-sparing diuretics
• Other antihypertensives
• Lithium
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids

Precautions

• Diabetes mellitus
• Elderly patients
• Basal cell carcinoma
• Cutaneous lupus erythematosus
• Patients with hepatic impairment
• Monitoring of electrolytes

Pregnancy

Hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is advisable to avoid use, especially during the first trimester.

Breast-feeding

Hydrochlorothiazide is present in breast milk; however, the amount is probably too small to be harmful. Caution is advised as large doses may suppress lactation.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets: 12.5 mg, 25 mg
• Oral solution
• Combination products with amiloride

Indications

• Hypertension
• Angina pectoris
• Arrhythmias
• Myocardial infarction prophylaxis
• Migraine prophylaxis
• Essential tremor
• Anxiety disorders

Dosage

Children: Refer to the BNF for Children for specific dosing information, as paediatric doses vary based on condition and patient age.

Adults: The usual starting dose for hypertension is 40 mg twice daily, which may be increased based on clinical response. For migraine prophylaxis, the recommended dose is 80 mg daily, which can be divided or taken as a single dose.

Mechanism of action

Propranolol works by blocking β-adrenergic receptors, leading to vasoconstriction and inhibition of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). This action induces apoptosis of endothelial cells and downregulates the renin-angiotensin-aldosterone system, contributing to its antihypertensive effects.

Pharmacodynamics

Propranolol has a long duration of action, allowing for once or twice daily dosing depending on the clinical indication. It effectively lowers blood pressure and heart rate. Abrupt discontinuation may lead to rebound hypertension, exacerbations of angina, or myocardial infarctions due to increased sympathetic activity.

Pharmacokinetics

Propranolol is well-absorbed after oral administration, with a bioavailability of approximately 25% due to first-pass metabolism in the liver. It is extensively metabolized in the liver, and its elimination half-life is about 3 to 6 hours. The drug is primarily excreted in urine as metabolites, and it has a volume of distribution of about 4 L/kg, indicating extensive tissue binding.

Contra-indications

• Severe bradycardia
• Second or third degree heart block
• Cardiogenic shock
• Asthma or history of bronchospasm
• Severe peripheral arterial disease

Adverse effects

• Fatigue
• Dizziness
• Bradycardia
• Hypotension
• Cold extremities
• Sleep disturbances
• Nausea
• Diarrhea

Interactions

• dacomitinib: Severe (increases exposure)
• propafenone: Moderate (increases risk of cardiovascular adverse effects)
• eliglustat: Moderate (increases exposure)
• rifampicin: Moderate (decreases exposure)
• triptans: Unknown (increases exposure)
• rizatriptan: Unknown (increases exposure)
• fluvoxamine: Unknown (increases concentration)

Precautions

• Monitor heart rate and blood pressure regularly
• Use with caution in patients with diabetes as it may mask hypoglycemia
• Taper dosage gradually to avoid acute withdrawal symptoms
• Use cautiously in patients with a history of depression

Pregnancy

Propranolol should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Propranolol is excreted in breast milk, and caution should be exercised when administered to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets (10 mg, 40 mg, 80 mg)
• Oral solution (20 mg/5 ml)
• Injectable solution (1 mg/ml)

Mechanism of action

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

Pharmacodynamics

Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function.

Mechanism of action

Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system.

Pharmacodynamics

Propranolol is a beta-adrenergic receptor antagonist used to treat hypertension. Propranolol has a long duration of action as it is given once or twice daily depending on the indication. When patients abruptly stop taking propranolol, they may experience exacerbations of angina and myocardial infarctions.