Propranolol/ Propranolol Hydrochloride

Propranolol is an antihypertensive agent belonging to the beta-blocker class.

Propranolol is approved for treating hypertension, heart failure, angina, atrial fibrillation, myocardial infarction, prophylaxis of migraine,essential tremor, hypertrophic subaortic stenosis, and pheochromocytoma.

It particularly competes for accessible receptor sites with beta-adrenergic receptor agonists. The chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are diminished proportionately when access to beta-receptor sites is prevented by propranolol. Propranolol also has a quinidine-like or anesthetic-like membrane effect at dosages higher than those needed for beta-blocking, which alters the cardiac action potential.

The common side effects associated with Propranolol are dizziness, tiredness, nausea, vomiting, diarrhea, constipation, stomach cramps, sleep problems (insomnia), runny or stuffy nose, cough, sore throat, hoarse voice, etc.

Propranolol is available in the form of oral solution, injections, tablets, and extended-release capsules.

The propranolol is available in Australia, Germany, Canada, US, India.

• Propranolol is a nonselective beta-adrenoceptor antagonist, also classified as a class II antiarrhythmic. It responds by competitively blocking beta-1 and beta-2 adrenergic stimulation in the heart, which is typically induced by epinephrine and norepinephrine.
• On cardiac myocytes, including the sinoatrial and atrioventricular nodes, there are beta-1 receptors. These receptors are activated, which results in an increase in cyclic AMP and an increase in intracellular calcium. Increased muscle fiber contractility results from this mechanism. Beta-adrenergic receptor blockade causes the heart's total workload to be lowered, which in turn lowers oxygen consumption and causes myocardial remodeling.
• On the other hand, beta-2 receptor activation results in an increase in cyclic AMP, which activates protein kinase A and causes smooth muscle cells in many organs and arteries to relax. Therefore, there is slight vasoconstriction when beta-2 receptors are inhibited.
• Due to this action, it can be difficult for asthmatics to administer emergency epinephrine since it prevents epinephrine from potentially binding to pulmonary receptors. Beta-blockers have a Vd of around 4 to 6 L/kg and are well distributed throughout the body. They are also highly protein-bound.

• Propranolol are available in various dosage forms like- oral solution, injections, tablets, and extended-release capsules.
• The long-acting oral capsules and tablets should be swallowed whole.
• Do not open, crush, chew, or break them.
• Take propranolol extended-release pills before bed. This medicine may be taken with or without food.

Propranolol is used alone or in combination with other medications to treat high blood pressure. Propranolol lowers the heart rate and facilitates simpler blood circulation throughout the body.

It is typically taken for high blood pressure and other cardiovascular issues, but it can also help with the physical sign of anxiety, such as shaking and sweating.

Propranolol is approved for use in the following clinical indications:

• Essential Tremors: Propranolol is the only drug approved by the FDA for Essential Tremor. It is a nonselective beta-blocker that has shown tremor reduction of up to 50%. Propranolol is useful in the reduction of tremor amplitude, but not frequency. Across all therapies, complete suppression of Essential Tremor is rare. Propranolol appears to work best in high-amplitude, low-frequency Essential Tremor. Therapeutic doses seem to be patient-specific, and patient response is variable.
• Angina Pectoris: Propranolol is helpful in the long-term therapy of angina pectoris as it works by relaxing the blood vessels and slowing the heart rate to improve the blood flow and lower its blood pressure.
• Hypertension: Beta-blocking medications' antihypertensive effects still lack a precise mechanism of action. However, several potential methods have been put forth: reduced cardiac output due to competing antagonistic interactions between catecholamines at peripheral (mainly cardiac) adrenergic neuron locations; decreased sympathetic outflow to the periphery due to a significant influence; and suppression of renin activity.
• Migraine: Beta-blockers alleviate that pain by telling the blood vessels to relax so that the blood can flow normally.
• Atrial fibrillation: After coronary artery bypass surgery, beta-adrenoceptor antagonists (b-blockers) are particularly successful at preventing atrial fibrillation.Atrial fibrillation can be treated with propranolol by lowering heart rate, allowing the heart to fully contract and relax while still being able to pump blood throughout the body efficiently.In atrial fibrillation, beta-blockers are useful for preserving sinus rhythm and regulating ventricular pace.
• Hypertrophic subaortic stenosis: A heart condition called hypertrophic subaortic stenosis, also known as hypertrophic obstructive cardiomyopathy (HOCM), is characterized by thickening of the septum, which separates the left and right sides of the heart (hypertrophic). The left ventricle's capacity to pump blood into the aorta, the body's largest artery, may be hindered by this thicker septum.In this condition, propranolol and other beta-blockers are frequently used to improve chest pain, exercise-induced shortness of breath, and the risk of irregular cardiac rhythms. It improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.
• Pheochromocytoma: When combined with other drugs like alpha blockers, propranolol can help lower the high blood pressure caused by pheochromocytoma.In addition to alpha-adrenergic inhibition, propranolol is indicated to manage blood pressure and lessen the symptoms of catecholamine-secreting tumor.
• Some off label indication for Propranolol includes: tachyarrhythmias, treatment of restless leg syndrome, proliferating infantile hemangioma, akathisia, anxiety, and sweating.

Propranolol is available in oral solution, injections, tablets, and extended-release capsules. The method of administration of Propranolol for various treatment are as follow:

• Tremors: A half to 2 tablets of propranolol (20 mg) can be administered 30 min to 1 h before a social activity or the anxiety-provoking event, which increases tremor.
• Angina pectoris: The extended-release capsule should always be taken with or without food each time. It is typically taken before bed; take immediate-acting propranolol tablets or solution up to four times per day. Every day, take propranolol around the same time(s).
• Migraine: The initial oral dose is 80 mg of Propranolol once daily. The usual effective dose range is 160 to 240 mg once daily. The dosage may be increased gradually in order to achieve optimal migraine prophylaxis.
• High Blood Pressure: It can be ingested or administered intravenously by injection. The oral medication is available in both short-acting and long-acting varieties. When taken orally, propranolol begins to show up in the blood after 30 minutes and reaches its peak effect between 60 and 90 minutes.

Propranolol is available in dosage strength of 1 mg/ml,4.28 mg/ml, 20mg/5ml and 40mg/5ml

Propranolol is available in various dosage form, i.e., oral solution, injections, tablets, and extended-release capsules.

Propranolol should be used in the treatment of high blood pressure, angina pectoris, migraine, and tremor along with appropriate dietary restrictions

• High Blood Pressure: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.
• Angina Pectoris:  Avoid foods that are high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce the intake of dairy products including cheese, cream, and eggs.
• Migraine: Some common triggered diets include: Baked food with yeast, such as sourdough bread, bagels, doughnuts, coffee cake, Chocolate, Cultured dairy products (like yogurt and kefir), Tomatoes, Vegetables like onions, pea pods, some beans, corn, and sauerkraut, Vinegar and Alcohol must be avoided.
• Tremors: Anything that contains caffeine, such as tea, coffee, colas, or chocolate, can temporarily worsen tremors. Some medications, including antidepressants and excessive thyroid replacement, might potentially make tremors worse.

Propranolol's primary side effect is to lower heart rate; patients with bradycardia should avoid taking it (less than 60 beats per minute).

Additionally, propranolol should not be used by patient who have lung diseases such COPD, asthma, or emphysema. This mechanism's pathophysiology is primarily a result of the influence beta-2 receptors have on lung function. The smooth muscle in the lungs is normally vasodilated when beta-2 receptors are activated. The inhibition of beta-2 results in smooth muscle vasoconstriction when drugs like propranolol are administered to individuals with underlying lung conditions, affecting respiratory performance.

Solely selective beta-blockers, with only block beta-1 receptors while leaving beta-2 receptors unaffected, should be prescribed to such patients by doctors.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Patient who is suffering from Asthma, very slow heartbeats, or serious cardiac problem like "sick sinus" or “AV block" shouldn't use propranolol.
• Diabetes patients should not be given propranolol because it may hide some of the warning signs and symptoms of hypoglycemia (low blood sugar levels), such as palpitations and shakiness.
• The oral liquid shouldn't be administered to infants under 4.5 pounds.
• Anaphylaxis, a major allergic reaction that might be life-threatening and necessitate emergency medical intervention, may be brought on by this medication. If any experience any of the following symptoms while taking this medication: rash, itching, hoarseness, difficulty breathing, difficulty swallowing, or any swelling of the hands, face, or lips.
• In some cases, propranolol may result in heart failure, Ischemic Heart Disease.
• Angina Pectoris

Following the abrupt termination of propranolol therapy, reports of angina flare-ups and, in some cases, myocardial infarction have been made. As a result, when stopping propranolol is intended, the dosage should be decreased gradually over at least a few weeks, and the patient should be advised against stopping or interrupting medication without consulting a doctor. It is typically advised to restart propranolol therapy and take further steps necessary for the management of angina pectoris if propranolol therapy is halted and aggravation of angina develops. It may be wise to lead the following advice in individuals thought to be at risk of having occult atherosclerotic heart disease who are receiving propranolol for other purposes since coronary artery disease may go undiagnosed.

• Hypersensitivity and Skin Reaction:

Taking propranolol has been linked to hypersensitivity responses, including anaphylactic/anaphylactoid reactions.

Propranolol use has been linked to cutaneous reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria.

PRECAUTIONS:

When administered to patients with impaired renal or hepatic function, propranolol should be used with caution. Hypertensive emergencies should not be treated with propranolol. Reduction of intraocular pressure can result from blocking beta-adrenergic receptors. It is important to inform patients that Propranolol may affect the results of the glaucoma screening test. Redrawal could result in elevated intraocular pressure returning.

Patients who have previously experienced severe anaphylactic reactions to a variety of allergens may be more sensitive to repeated challenges while using beta-blockers, whether they are accidental, diagnostic, or therapeutic. These people might not respond to the standard epinephrine dosages used to treat allergic reactions.

When used with alcohol, Propranolol may cause an increase in plasma levels.

Propranolol is excreted in human milk. Caution must be taken when it is administered to a breastfeeding woman.

This drug is only recommended for use during pregnancy when there are no alternatives and the benefit outweighs the risk.

The food warning while consuming Propranolol that should be taken in concentrations while its consumption:

• Food can enhance the level of propranolol in the body.
• Avoid drinking alcohol, which could increase drowsiness and dizziness while taking propranolol.
• When used with propranolol, caffeine-containing foods and beverages can reduce the drug's effectiveness. Tea and coffee should be avoided while taking propranolol.

The Adverse Reaction of Propranolol for various treatment are as follow:

• Common/Serious Adverse effects of propranolol: Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.
• Moderate Adverse effects: Lightheadedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuro psychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related.
• Lesser Adverse effects: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.

Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol's metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions .

• Substrates or Inhibitors of CYP2D6

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.

• Substrates or Inhibitors of CYP1A2

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.

• Substrates or Inhibitors of CYP2C19

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.

• Inducers of Hepatic Drug Metabolism

Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.

Cardiovascular Drugs

• Antiarrhythmics

The AUC of propafenone is increased by more than 200% by co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two-three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.

• Calcium Channel Blockers

The mean Cmax and AUC of propranolol are increased, respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine.The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol.

Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.

Non-Cardiovascular Drugs

• Migraine Drugs:

• Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively).
• Theophylline

Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.

• Benzodiazepines

Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

• Neuroleptic Drugs

Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.

• Anti-Ulcer Drugs

Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics.

• Lipid Lowering Drugs

Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.

• Warfarin

Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

• Alcohol

Concomitant use of alcohol may increase plasma levels of propranolol.

The common side effects associated with Propranolol are as follows:

Dizziness, tiredness, nausea, vomiting, diarrhea, constipation, stomach cramps; sleep problems (insomnia); runny or stuffy nose, cough, sore throat, hoarse voice, etc.

General:

If ingestion is or may have been recent, remove gastric contents, taking care to prevent pulmonary aspiration.

Supportive Therapy:

Hypotension and bradycardia have been reported following the propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50­- 150 mcg/kg intravenously followed by a continuous drip of 1-5 mg/hour for a positive chronotropic effect. Isoproterenol, dopamine, or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status, and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.

Pharmacodynamics:

A beta-adrenergic receptor antagonist called propranolol is used to treat hypertension. Given once or twice daily, depending on the indication, propranolol has a long duration of action. Patients who quit taking propranolol abruptly risk worsening their angina and myocardial infarctions.

Pharmacokinetics:

PHARMACOKINETICS AND DRUG METABOLISM:

• Absorption

Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentration occurs about 1 to 4 hours after an oral dose. Administration of protein-rich foods increases the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in urine.

• Distribution

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha1 glycoprotein and the R(+)-enantiomer is preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg. Propranolol crosses the blood-brain barrier and the placenta and is distributed into breast milk.

• Metabolism and Elimination

Propranolol is extensively metabolized, with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41%, and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent, by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6. Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-GP). Studies suggest; however that p-GP is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range. In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) concerning oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and of naphthyl oxyacetic acid significantly lower in EMs than PMs. The plasma half-life of propranolol is from 3 to 6 hours.

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