Propranolol and hydrochlorothiazide

Uses

Hydrochlorothiazide is used for-

• Edema associated with congestive heart failure, hepatic cirrohosis, various forms of renal dysfunction and corticosteroid and estrogen therapy
• Management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe form of hypertension
• Management of diabetes insipidus
• Management of proximal renal tubular acidosis
• Idiopathic hypercalciuria and calcium nephrolithiasis, osteoporosis and exercise induced hyperkalemia

Propranolol is used for:

• essential and renal hypertension
• angina pectoris
• long term prophylaxis after recovery from acyte myocardial infarction
• cardiac dysrhythmia
• prophylaxis of migraine
• essential tremor
• anxiety and anxiety tachycardia
• adjunctive management of thyrotoxicosis and thyrotoxic crisis
• hypertrophic obstructive cardiomyopathy
• phaeochromocytoma (with α-blocker)

Propranolol and hydrochlorothiazide is also used to associated treatment for these conditions: Acidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsiaAkathisia caused by antipsychotic use, Angina Pectoris, Atrial Fibrillation, Cardiovascular Mortality, Gastroesophageal variceal hemorrhage prophylaxis, Hemangiomas, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Obstructive Hypertrophic Cardiomyopathy, Performance Anxiety, Pheochromocytomas, Proliferating Infantile Hemangioma, Supraventricular Arrhythmias, Tachyarrhythmia caused by Digitalis intoxication, Tachyarrhythmia caused by catecholamine excess, Thyroid Crisis, Thyrotoxicosis, Tremor caused by lithium, Tremor, Essential, Ventricular Tachycardia (VT)

How Propranolol and hydrochlorothiazide works

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.

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.

Dosage

Propranolol and hydrochlorothiazide dosage

Adults-

For Edema: The usual adult dosage is 25 to 100 mg daily as a single or divided dose.

For Control of Hypertension: The usual initial dose in adults is 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium. In some patients (especially the elderly) an initial dose of 12.5 mg daily may be sufficient.

Infants and children-

For diuresis and for control of hypertension: The usual pediatric dosage is 1 to 2 mg/kg/day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 3 mg/kg/day in two divided doses may be required.

Tablet:

Adults:

• Hypertension: A starting dose of 80 mg twice a day may increased at weekly intervals according to response. The usual dose range is 160-320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.
• Angina, anxiety, migraine and essential tremor: A staring dose of 40 mg two or three times daily may be increased by the same amount at weekly intervals according to patients response. An adequate response in anxiety, migraine and essential tremor is usually seen in the range 80-160 mg/day and an angina in the range 120-240 mg/day.
• Situational and generalized anxiety: A dose of 40 mg daily may provide short term relief of acute situational anxiety. Generalized anxiety require long term therapy, usually responds adequately to 40 mg twice daily which ,which individual cases, may be increased to 40 mgthree times daily. Treatment should be continued according to responses. Patients should reviewed after 6 to 12 months treatment.
• Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: A dosage range of 10-40 mg three or four times a day usually achieves the required response.
• Post myocardial infarction: Treatment should be started between days 5 and after 21 after myocardial infarction, with an initial dose of 40 mg four times a day for 2 or 3 days. In order to improve compliance the total daily doses three after be given as 80 mg twice a day. Phaeochromocytoma (Used only with an alpha receptor blocking drug).
• Pre-operative: 60 mg daily for three days.
• Non-operable malignant cases: 30 mg daily.
• Migraine: Under 12 years: 20 mg two or three times daily.Over 12 years : The adult dose.

Children:

• Sysrhythmias, Phaeochromocytoma, Thyrotoxicisis: Dosage should be individually determined and the following is only a guide 0.25-0.5 mg/kg three or four times daily as required.

Sustained Release Capsule:

Adult:

• Hypertension: The usual initial dose is 80mg Propranolol SR once daily, whether used alone or added to a diuretic. The usual maintenance dosage is 120 to 160 mg once daily.
• Angina pectoris: Starting with 80mg Propranolol SR once daily, dosage should be gradually increased three to seven day intervals until optimum response is obtained.
• Migraine: The initial oral dose is 80 mg Propranolol SR once daily. T he usual effective dose range is 160 to 240 mg once daily. It may be advisable to withdraw the drug gradually over a period of several weeks.
• Hypertrophic subaortic stenosis: 80 mg Propranolol SR once daily

Injection:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The usual dose is 1 to 3 mg administered under careful monitoring, such as electrocardiography and central venous pressure. The rate of administration should not exceed 1 mg (1 mL) per minute to diminish the possibility of loweringblood pressureand causing cardiac standstill.

Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present. If necessary, a second dose may be given after two minutes. Thereafter, additional drug should not be given in less than four hours. Additional propranolol hydrochloride should not be given when the desired alteration in rate or rhythm is achieved.

Transfer to oral therapy as soon as possible.

Side Effects

Generally, Hydrochlorothiazide is well tolerated. However, a few side effects may occur like weakness, restlessness, dizziness, headache, fever, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia, and hypotension. In rare case hyperglycemia, glycosuria, hyperuricemia and muscle spasm may occur.

Propranolol is usually well tolerated. Minor side effects such as cold extremities, nausea, diarrhea, sleep disturbances and lassitude are often transient. There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs.

Toxicity

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

Symptoms of overdose include hypotension, hypoglycemic seizure, restlessness, euphoria, insomnia. Patients with asthma may develop bronchospasm. In case of overdose, monitor vital signs, mental status, and blood glucose. Treat hypotension with intravenous fluids, bradycardia with atropine, and isoproterenol and aminophylline for bronchospasm. If patients do not respond to intravenous fluids, follow up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour, followed by catecholamines. Dialysis will not be useful as propranolol is highly protein bound.

Precaution

Thiazides should be used with caution in patients with severe renal disease, impaired hepatic function or progressive liver disease and gout.

Beta-adrenoceptor blocking drugs should be avoided in over heart failure. Propranolol modifies the tachycardia of hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.

Interaction

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin): Thiazides can impair control of diabetes mellitus by diet and antidiabetic Drugs. Antihypertensive Drugs: Additive effect or potentiation.

Beta-adrenoceptor blocking drugs interact with clonidine.If beta-adrenoceptor blocking drugs and clonidine are given concurrently, clonidine should be discontinued until several days after withdrawal of beta-adrenoceptor blocking drug. Care should be taken in prescribing a beta-adrenoceptor blocking drugs with class 1 antidysrhythmic agents (disopyramide).Beta-adrenoceptor blocking drugs should be used with caution in combination with verapamil in patients with impaired ventricular function.

Volume of Distribution

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

The volume of distribution of propranolol is approximately 4L/kg or 320L.

Elimination Route

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

Patients taking doses of 40mg, 80mg, 160mg, and 320mg daily experienced C_max values of 18±15ng/mL, 52±51ng/mL, 121±98ng/mL, and 245±110ng/mL respectively. Propranolol has a T_max of approximately 2 hours, though this can range from 1 to 4 hours in fasting patients. Taking propranolol with food does not increase T_max but does increase bioavailability.

Half Life

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

The elimination half life of propranolol is approximately 8 hours. The plasma half life of propranolol is 3 to 6 hours.

Clearance

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

The clearance of propranolol is 2.7±0.03L/h/kg in infants 90 days. Propranolol clearance increases linearly with hepatic blood flow. Propanolol has a clearance in hypertensive adults of 810mL/min.

Elimination Route

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

91% of an oral dose of propranolol is recovered as 12 metabolites in the urine.

Pregnancy & Breastfeeding use

Pregnancy: Evidence of fetal risk in hydrochlorothiazide therapy is found, but it is indicated if benefits outweigh risks. Thiazides are indicated in pregnancy when edema is due to pathologic causes.\

Lactation: Neonatal side effects have been seen incase of hydrochlorothiazide therapy and therefore it is not recommended.

There are no adequate and controlled studies in pregnant women. Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing mother.

Contraindication

Hydrochlorothiazide is contraindicated to the patients of anuria and those who are sensitive to hydrochlorothiazide or to other sulfonamide-derived drugs. Therapy is not to be initiated in diabetes mellitus.

Propranolol Hydrochloride is contraindicated in patients with known Hypersensitivity to any component of the formulation. If there is a history of bronchial asthma of bronchospasm.

Special Warning

Elderly: in some patients specially the elderly an initial dose of 12.5 mg daily may be sufficient.

Children: An initial dose for children has been 1 to 2 mg per kg body-weight in 2 divided doses. Infants under 6 months may need doses upto 3 mg per kg daily.

Acute Overdose

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Rarely, autoimmune hemolytic anemia and other hypersensitivity reactions may complicate the picture.

In the event of over dosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. Hemodialysis can be used successfully to treat severe intoxication.

The symptoms of over dosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm. Treatment of over dosage include close supervision, treatment in an intensive care ward, he use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Storage Condition

Store between 15-30°C. Protect from light, moisture and freezing.

Store in a cool dry place. Protect from light.

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