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Pharmacology and Indications
Propranolol Drug
Propranolol (Inderal®) is a non-selective beta blocker (i.e. it blocks the action of epinephrine on both β1- and β2-adrenoreceptors). It is well and rapidly absorbed after oral dosing with maximal plasma levels observed 1 to 2 hours after application (to fasting patient). Propranolol has a low and variable bioavailability due to extensive first-pass-metabolism. Liver disease will therefore increase bioavailability and pharmacologic actions. The active metabolite 4-Hydroxypropranolol, having a somewhat shorter halflife than the mother-drug, also accounts for the actions of Propranolol. Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of an oral single dose is longer than the halflife indicates and may be up to 12 hours, if the single dose is high enough (e.g. 80mg). Effective plasma-concentrations are between 10 and 100 ng per ml.

It has various uses, such as treatment of high blood pressure, angina, and cardiac arrhythmias, prophylaxis of migraine attacks, controlling essential tremor, suppressing the symptoms of hyperthyroidism (tachycardia, tremor), lowering portal pressure in portal hypertension when this has led to esophageal varices, as well as in the management of anxiety and panic disorders. The treatment of pheochromocytoma together with an alpha-receptor blocking agent is another indication.

A new, and very interesting use, is the co-treatment of chronic heart failure with initially small and slowly increasing doses. Additionally, it can be tried to prevent arrhythmias and reinfarction in patients with recent myocardial infarction after hemodynamic stabilization. Longterm studies combining Propranolol and Aspirin showed a statistically significant reduction of reinfarction and cardiovascular mortality rates.

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder

Contraindications and Precautions
Active Asthma Bronchiale (COLD), History of asthmatic disease
Hypersensitivity to Propranolol
Significant hypotension
Hemodynamic instable acute myocardial infarction
Acute decompensation of chronic heart failure
Bradycardia, AV-Blockage of 2nd. and 3rd. degree
Cardiogenic shock
Prinzmetal-Angina (vasospastic angina)
Severe peripheral arterial circulation disorder
Untreated pheochromocytoma
Metabolic acidosis
Severe liver and renal disease
Caution: unstable Diabetes mellitus (Hypoglycemia may be masked)
Caution: pediatric patients
Caution: preexisting psoriasis (worsening possible)
Caution: preexisting myasthenia gravis (may be worsened)

Side effects
Propranolol is not a harmless drug. A number of unpleasant and/or dangerous side effects may occur. Some of these may be minimized by starting Propranolol treatment with a low initial dose.

Cardiovascular: Bradycardia, worsening of chronic heart failure, AV-Blockage, different arrhythmias, postural hypotension, sometimes with syncope, cold extremities, and Raynaud-Syndrome. A preexisting peripheral arterial circulation disorder may be worsened. As with all antiarrhythmic medications Propranolol may paradoxically cause new arrhythmias.
Central Nervous System: Headaches, dizziness, fatigue, vertigo, depression, hallucinations, psychosis, confusion, emotional instability, vivid dreams, and insomnia. Most central nervous side effects are due to the strong lipophilic properties of Propranolol. If these side effects are bothersome to the patient, the hydrophilic agent Atenolol can be used instead.
Neurology: Paresthesia.
Endocrinous System: Hypoglycemia most often seen in newborns, pediatric patients, the elderly, patients undergoing longterm hemodialysis, drug treated diabetic patients, fasting patients and those with chronic liver disease. Caution: The hypoglycemia may be severe and Propranolol may suppress the typical warning symptoms (tremor, tachycardia, unrest etc.). Irreversible damage or even death is possible.
Bronchial System: Bronchospasm in patients with or without preexisting asthma bronchiale. Fatal cases have been seen. Patients with preexisting asthma, who need beta-blocker treatment should receive a so called cardio-selective agent (e.g. Metoprolol or Atenolol).
Gastrointestinal: Nausea, diarrhea, obstipation and abdominal pain.
Skin: Infrequently skin reactions, psoriasiform skin eruptions, worsening of preexisting psoriasis, and alopecia. If Propranolol is the causing agent, treatment should be withdrawn gradually.
Allergic reactions: Hypersensitivity has been noted including allergic skin reactions (urticaria, photosensitivity), and bradycardia or hypotension. In the latter case consider termination of Propranolol treatment.
Bone marrow: Infrequent cases of agranulocytosis, leukopenia, thrombopenia and purpura.
Miscellaneous: Infrequently, systemic lupus erythematodes or LE-like reactions have been encountered. Blurred vision, dry eyes, impotence, and induratio penis plastica have all been seen. Also, blood tests sometimes showed an increase of anti-nuclear antibodies (ANA) titres. The clinical relevance of this finding is unknown. Rarely the development or worsening of myasthenia gravis has been reported.

Pregnancy and Lactation

Category C. No sufficient studies exist, neither animal studies nor studies in pregnant women. Therefore, the drug should only be given, if the potential benefit to the mother exeeds the risk for the fetus. Beta-blocking agents in general reduce perfusion of the placenta which may lead to intrauterine death, mental and physical retardation of the newborn or to premature birth. The newborn may experience additional side effects such as hypoglycemia and bradycardia. The risk of pulmonal and cardial complications is increased.

Most beta-blocking agents appear in the milk of lactating women. This is especially the case for a lipophilic drug like Propranolol. Therefore, women taking Propranolol regularly should not breast-feed.

Propranolol has quite a number of potentially serious interactions with certain Calcium Antagonists (e.g. Verapamil), certain antiarrhytmic drugs, other antihypertensive drugs, Epinephrine, antidiabetics, cardiac glycosids, Cimetidine and Hydralazine etc.

Hypertension: Usually, the initial dose is 2 times 80 mg, slowly increased to 320 mg. Patients not responsive to 320 mg may receive either combination treatment with a diuretic or/and a vasodilating agent or the dose of Propranolol as single agent is further increased to a maximum of 640 mg daily. To enhance patient compliance long acting formulations for once or twice a day application exist.
Angina pectoris, Anxiety, Prophylaxis of Migraine Attacks, and Essential Tremor: The initial dose is 2 or 3 times 40 mg daily. Increase the dose in weekly intervalls according to the reaction of the patient. Usually, the daily dose for anxiety, prophylaxis of migraine attacks and essential tremor is 80 to 160mg; for angina pectoris 120 to 240 mg daily.
Arrhythmias, psychosomatic complaints and tachycardias, chronic heart failure, hyperthyreodism und thyreotoxic crisis: Usually, 3 to 4 times 10-40 mg starting with low initial doses.
Pheochromocytoma: Preoperatively: 60 mg daily during 3 days before surgery takes place. Propranolol should be given concomitantly with a α-blocking agent only. Maintenance dose is 30 mg daily in patients with inoperable tumor.
Longterm prophylaxis of Reinfarction: Treatment should start between the 5th. and 21st. day after event. Usual dose is 160 mg daily; either given 4 times 40 mg or using the long acting formulations to improve patient compliance. Patient education is very important.
Portal Hypertension / Esophageal Varices: According to special schedule as directed by physician. Usually the dose is determined by the reduction of the pulse rate achieved (not lower than 50 to 55 bpm).
For some indications i.v. treatment may be indicated at the distinction of the physician under close monitoring. The usual dose is 1 mg initially, followed by additional injections, if needed. Oral therapy should substitute i.v.-injections as soon as possible.

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