Chemistry - A non-specific beta-adrenergic blocking agent, propranolol HCl occurs as a bitter-tasting, odorless, white to almost white powder with a pKa of 9.45 and a melting point of about 161°C. One gram of propranolol is soluble in about 20 ml of water or alcohol. At a pH from 4-5, solutions of propranolol will fluoresce. The commercially available injectable solutions are adjusted with citric acid to a pH 2.8 - 3.5.
Storage/Stability/Compatibility - All propranolol preparations should be stored at room temperature (15-30°C) and protected from light. Propranolol solutions will decompose rapidly at alkaline pH. Propranolol injection is reported to be compatible with D5W, 0.9% sodium chloride, or lactated Ringer’s injection. It is also physically compatible with dobutamine HCl, verapamil HCl and benzquinamide HCl.
Pharmacology - Propranolol blocks both beta1 and beta2 adrenergic receptors in the myocardium, bronchi, and vascular smooth muscle. Propranolol does not have any intrinsic sympathomimetic activity (ISA). Additionally, propranolol possesses membrane-stabilizing effects (quinidine-like) affecting the cardiac action potential and direct myocardial depressant effects. Cardiovascular effects secondary to propranolol include: decreased sinus heart rate, depressed AV conduction, diminished cardiac output at rest and during exercise, decreased myocardial oxygen demand, decrease hepatic and renal blood flow, reduced blood pressure, and inhibition of isoproterenol-induced tachycardia. Electrophysiologic effects on the heart include decreased automaticity, increased or no effect on effective refractory period, and no effect on conduction velocity.
Additional pharmacologic effects of propranolol, include increased airway resistance (especially in patients with bronchoconstrictive disease), prevention of migraine headaches, increased uterine activity (more so in the non-pregnant uterus), decreased platelet aggregability, inhibited glycogenolysis in cardiac and skeletal muscle and increased numbers of circulating eosinophils.
Uses/Indications - While propranolol is used for hypertension, migraine headache prophylaxis and angina in human patients, it is used primarily in veterinary medicine for its antiarrhythmic effects. Dysrhythmias treated with propranolol include, atrial premature complexes, ventricular premature complexes, supraventricular premature complexes and tachyarrhythmias, ventricular or atrial tachyarrhythmias secondary to digitalis, atrial tachycardia secondary to WPW with normal QRS complexes, and atrial fibrillation (generally in combination with digoxin). Propranolol reportedly improves cardiac performance in animals with hypertrophic cardiomyopathy. It has been used to treat systemic hypertension and symptoms associated with thyrotoxicosis and pheochromocytoma.
Pharmacokinetics - Propranolol is well absorbed after oral administration, but a rapid first-pass effect through the liver reduces systemic bioavailability to approximately 2-27% in dogs, thereby explaining the significant difference between oral and intravenous dosages. These values reportedly increase with chronic dosing.
Propranolol is highly lipid soluble and readily crosses the blood-brain barrier. The apparent volume of distribution has been reported to 3.3 - 11 L/kg in the dog. Propranolol will cross the placenta and enters milk (at very low levels). In humans, propranolol is approximately 90% bound to plasma proteins.
Propranolol is principally metabolized by the liver. An active metabolite, 4-hydroxypropranolol, has been identified after oral administration in humans. Less than 1% of a dose is excreted unchanged into the urine. The half-life in dogs has been reported to range from 0.77 - 2 hours, and in horses, less than 2 hours.
Contraindications/Precautions - Propranolol is contraindicated in patients with overt heart failure, hypersensitivity to this class of agents, greater than 1st degree heart block, or sinus bradycardia. Non-specific beta-blockers are generally contraindicated in patients with CHF unless secondary to a tachyarrhythmia responsive to beta-blocker therapy. They are also relatively contraindicated in patients with bronchospastic lung disease.
Propranolol should be used cautiously in patients with significant renal or hepatic insufficiency. It should also be used cautiously in patients with sinus node dysfunction.
Propranolol can mask the symptoms associated with hypoglycemia. It can also cause hypoglycemia or hyperglycemia and, therefore, should be used cautiously in labile diabetic patients.
Propranolol can mask the symptoms associated with thyrotoxicosis, but it has been used clinically to treat the symptoms associated with this condition.
Use propranolol cautiously with digitalis or in digitalis intoxicated patients; severe bradycardias may result.
Adverse Effects/Warnings - It is reported that adverse effects most commonly occur in geriatric animals or those that have acute decompensating heart disease. Adverse effects considered to be clinically relevant include: bradycardia, lethargy and depression, impaired AV conduction, CHF or worsening of heart failure, hypotension, hypoglycemia, and bronchoconstriction. Syncope and diarrhea have also been reported in canine patients.
Exacerbation of symptoms have been reported following abrupt cessation of beta-blockers in humans. It is recommended to withdraw therapy gradually in patients who have been receiving the drug chronically.
Overdosage - The most predominant symptoms expected would be hypotension and bradycardia. Other possible effects could include: CNS (depressed consciousness to seizures), bronchospasm, hypoglycemia, hyperkalemia, respiratory depression, pulmonary edema, other arrhythmias (especially AV block), or asystole.
If overdose is secondary to a recent oral ingestion, emptying the gut and charcoal administration may be considered. Monitor ECG, blood glucose, potassium, and, if possible, blood pressure. Treatment of the cardiovascular and CNS effects are symptomatic. Use fluids, and pressor agents to treat hypotension. Bradycardia may be treated with atropine. If atropine fails, isoproterenol given cautiously has been recommended. Use of a transvenous pacemaker may be necessary. Cardiac failure can be treated with a digitalis glycosides, diuretics, oxygen and, if necessary, IV aminophylline. Glucagon (5-10 mg IV - Human dose) may increase heart rate and blood pressure and reduce the cardiodepressant effects of propranolol. Seizures generally will respond to IV diazepam.
Drug Interactions - Sympathomimetics (metaproterenol, terbutaline, betaeffects of epinephrine, phenylpropanolamine, etc.) may have their actions blocked by propranolol. Additive myocardial depression may occur with the concurrent use of propranolol and myocardial depressant anesthetic agents. Phenothiazines given with propranolol may exhibit enhanced hypotensive effects. Thyroid hormones may decrease the effect of beta blocking agents. Propranolol doses may need to be decreased when initiating methimazole or propylthiouracil therapy. Cimetidine may decrease the metabolism of propranolol and increase blood levels. Furosemide and hydralazine may increase the effects of propranolol. Effects of tubocurarine and succinylcholine may be enhanced with propranolol therapy. Hepatic enzyme induction by phenobarbital, rifampin or phenytoin may increase the metabolism of propranolol. Unopposed alpha effects of epinephrine may lead to rapid increases in blood pressure and decrease in heart rate when given with propranolol. Propranolol may prolong the hypoglycemic effects of insulin therapy. Lidocaine clearance may be impaired by propranolol. Effects of theophylline (bronchodilitation) may be blocked by propranolol. Concurrent use of betablockers with calcium channel blockers (or other negative inotropes should be done with caution; particularly in patients with preexisting cardiomyopathy or CHF.
a) 0.1 - 0.3 mg/kg twice a day IV administered over 1 minute (Muir and McGuirk 1987a)
b) Oral: Days 1 & 2: 175 mg tid; Days 3 & 4: 275 mg tid; Days 5 & 6: 350 mg tid.
Intravenous: Days 1 & 2: 25 mg bid; Days 3 & 4: 50 mg bid; Days 5 & 6: 75 mg bid (Hilwig 1987)
Monitoring Parameters -
2) Toxicity (see Adverse Effects/Overdosage)
3) Blood pressure if administering IV
Client Information - To be effective, the animal must receive all doses as prescribed. Notify veterinarian if animal becomes lethargic or becomes exercise intolerant, begins wheezing, has shortness of breath or cough, or develops a change in behavior or attitude.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
Veterinary-Approved Products: None
Propranolol HCl Tablets 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 90 mg; Inderal® (Wyeth-Ayerst), Generic; (Rx)
Propranolol HCl Extended/Sustained-Release capsules 60 mg, 80 mg, 120 mg, 160 mg; Inderal® LA (Wyeth-Ayerst); Betachron E-R® (Inwood); generic, (Rx)
Propranolol for Injection 1 mg/ml in 1 ml amps or vials; Inderal® (Wyeth-Ayerst) (Rx), Generic; (Rx)
Propranolol Oral Solution 4 mg/ml, 8 mg/ml, 80 mg/ml concentrate in 30 ml; Propranolol Intensol® (Roxane); Propranolol HCl® (Roxane) (Rx)
Also, fixed dose combination products containing propranolol and hydrochlorothiazide are available to treat hypertension in humans.
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