The P-I-E-N-O Parkinsn's List Drug Database
propranolol / InderalTM
ANTIHYPERTENSIVE:
Non-selective beta blockers
Description: Propranolol is the prototype of the œ-adrenergic receptor antagonists. It is a competitive, nonselective œ-blocker without intrinsic sympathomimetic activity, similar to nadolol. Although propranolol has membrane-stabilizing effects on the action potential, these effects are clinically insignificant except in overdose situations. Propranolol is a racemic compound, with only its l-isomer having any adrenergic blocking activity. Propranolol was approved by the FDA in 1967. An intranasal dosage form for the treatment of migraine is currently under investigation.
Mechanism of Action: Like other œ-adrenergic antagonists, propranolol competes with adrenergic neurotransmitters (e.g., catecholamines) for binding at sympathetic receptor sites. Similar to atenolol and metoprolol, propranolol blocks sympathetic stimulation mediated by œA-adrenergic receptors in the heart and vascular smooth muscle. Pharmacodynamic consequences of œA-receptor blockade include a decrease in both resting and exercise heart rate and cardiac output, and a decrease in both systolic and diastolic blood pressure. Propranolol may reduce reflex orthostatic hypotension. The fall in cardiac output induced by œA effects is often countered by a moderate reflex increase in peripheral vascular resistance that can be magnified by œA blockade (unmasked › stimulation). As a result, nonselective œ-blocking agents can produce a more modest decrease in (diastolic) blood pressure compared with selective œA-antagonists. In addition, propranolol also can competitively block œA-adrenergic responses in the bronchial muscles, potentially inducing bronchospasm.
Actions that make propranolol useful in treating hypertension include a negative chronotropic effect that decreases heart rate at rest and after exercise; a negative inotropic effect that decreases cardiac output; reduction of sympathetic outflow from the CNS; and suppression of renin release from the kidneys. Thus, propranolol, like other œ-blockers, affects blood pressure via multiple mechanisms.
Actions that make propranolol useful in treating hypertension also apply to managing chronic stable angina. The reduction in myocardial oxygen demand induced by propranolol results in decreases in the frequency of anginal attacks and requirements of nitrate, and increases exercise tolerance. Other postulated anti-anginal actions include an increase in oxygen delivery to tissues, due to propranolol-induced lowering of hemoglobin's affinity for oxygen, and a reduction of platelet aggregation, postulated to be related to interference with calcium ion flux.
Propranolol has been used to treat portal hypertension and to prevent bleeding of esophageal varices. Nonselective œ-blockers decrease portal venous pressure, decrease blood flow in the superior portosystemic collateral circulation, and decrease blood flow in the splanchnic region. œ-blockade decreases cardiac output reducing hepatic arterial and portal venous perfusion. Activation of unopposed ›-receptors lead to splanchnic vasoconstriction, thus decreasing portal perfusion.
Propranolol is used to treat hypertension and the subsequent decline of renal function in patients with scleroderma renal crisis (SRC). SRC is associated with elevated peripheral renin concentrations. Propranolol blocks œ-receptors located on the surface of the juxtaglomerular cells which decreases the release of renin. In turn, this affects the renin-angiotension-aldosterone system reducing blood pressure.
Numerous mechanisms may contribute to the efficacy of propranolol in preventing migraine headaches. œ-blockade can prevent arterial dilation, inhibit renin secretion, and can interfere with catecholamine-induced lipolysis. A decrease in lipolysis decreases arachidonic acid synthesis and, subsequent, prostaglandin production. Inhibition of platelet aggregation is due to this decrease in prostaglandins and blockade of catecholamine-induced platelet adhesion. Other actions include increased oxygen delivery to tissues and prevention of coagulation during epinephrine release.
Propranolol has two roles in the treatment of thyrotoxicosis; these actions are determined by the different isomers of propranolol. L-propranolol causes œ-blockade and can ameliorate the symptoms associated with thytotoxicosis such as tremor, palpitations, anxiety, and heat intolerance. D-propranolol blocks the conversion of TA to TA, but the therapeutic effect of this action is minimal.
Propranolol has been used in the management of hereditary or familial essential tremor. œ-blockade controls the involuntary, rhythmic and oscillatory movements of essential tremor. Tremor amplitude is reduced, but not the frequency of tremor. The mechanism of action is unclear, but the antitremor effect may be mediated by blockade of peripheral œA receptor mechanisms.
Propranolol can dampen the peripheral physiologic symptoms of anxiety. œ-blockade can attenuate somatic symptoms of anxiety such as palpitations and tremor, but it is less effective in controlling psychologic components, such as intense fear. These effects are thought to be due to improvement in somatic symptoms secondary to œ-blockade, although the mechanism of action is unclear.
Pharmacokinetics: Propranolol is administered orally or intravenously. After oral administration of immediate-release propranolol, the dose is almost completely absorbed, and peak concentrations are achieved within 60-90 minutes. Food can increase the time to peak levels but does not affect the peak concentration. After oral administration of a sustained-release formulation, absolute bioavailability is decreased, absorption is slowed, and peak concentrations occur within 6 hours. After IV administration of propranolol, pharmacodynamic effects are seen immediately and maintained for 2-4 hours.
Propranolol is highly lipophilic and, as a result, is widely distributed throughout the body. It readily crosses the blood-brain barrier and the placenta, and is distributed into breast milk. Propranolol is greater than 90% bound to plasma proteins, primarily albumin. Propranolol is not appreciably removed by hemodialysis. Propranolol is extensively metabolized upon first pass through the liver, and the extent of metabolism is dependent on liver blood flow. The drug also binds to and saturates nonspecific hepatic binding sites before the drug reaches the systemic circulation. An equipotent, pharmacologically active metabolite, 4-hydroxypropranolol, is produced with the initiation of oral therapy, but it is eliminated faster than the parent drug. With chronic or IV therapy, this metabolite is produced to a lesser degree. Overall, at least eight metabolites of propranolol have been identified. Important differences may exist among ethnic groups in the ability to metabolize propranolol, which can affect the overall efficacy of the drug in some instances.
Excretion of propranolol occurs renally, primarily as metabolites, with only 1-4% of a dose excreted fecally as unchanged drug. The elimination half-life of propranolol ranges from 2-6 hours, with chronic administration yielding longer half-lives, possibly due to saturation of liver binding sites and/or systemic clearance. In patients with severe renal dysfunction, fecal elimination can increase to compensate for decreased renal excretory processes.
CONTRAINDICATIONS/PRECAUTIONS: Abrupt discontinuation of any œ-adrenergic blocking agent, including propranolol, can result in the development of myocardial ischemia, infarction, ventricular arrhythmias, or severe hypertension, particulary in patients with preexisting cardiac disease. In addition, rapid discontinuation of œ-blocking therapy can precipitate thyroid storm in patients with hyperthyroidism or thyrotoxicosis.
Propranolol should be used with caution in patients with hyperthyroidism because the drug can mask the tachycardia that occurs in this condition. Abrupt withdrawal of propranolol in patients with hyperthyroidism can precipitate a thyroid storm. Note, however, that œ-blockers are, in general, useful in treating hyperthyroid-related states.
Because these drugs depress conduction through the AV node, œ-blockers are contraindicated in patients with severe bradycardia or advanced AV block. In general, œ-blockers should not be used in patients with cardiogenic shock or systolic congestive heart failure, particularly in those with severely compromised left ventricular dysfunction, because the negative inotropic effect of these drugs can further depress cardiac output. In some patients with heart failure, however, œ-blockers given in low doses have been beneficial. Many œ-blockers are used in the treatment of hypertrophic cardiomyopathy. œ-blocker monotherapy should be used with caution in patients with a pheochromocytoma or vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed ›-receptor stimulation. In the treatment of myocardial infarction, œ-blockers are contraindicated in patients with hypotension (SBP < 100 mmHg).
Propranolol should be used with caution in patients with diabetes mellitus because the drug can mask symptoms of hypoglycemia such as tachycardia, palpitations, blood pressure changes, tremor, and anxiety. However, propranolol usually does not mask other symptoms of hypoglycemia (sweating and dizziness), nor does it, in usual doses, cause insulin-induced hypoglycemia. In addition, œ-blockers can precipitate hyperglycemia via inhibition of glycogenolysis. While œ-blockers probably should not be used in patients with brittle diabetes, they can be used cautiously in more stable patients.
Patients receiving propranolol before or during surgery involving general anesthetics that have negative inotropic effects (e.g., ether, cyclopropane, or trichlorethylene) should be monitored closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery on patients receiving œ-blockers. If discontinuation of the drug is indicated, therapy should be stopped 2 days prior to surgery.
Propranolol is relatively contraindicated in patients with hepatic disease because of possible decreased clearance of the drug, since it is principally metabolized by the liver. Dosage adjustment may be necessary in such cases.
Propranolol is classified as a pregnancy category C drug by the FDA, so appropriate consideration of risks/benefits of its use is prudent; the clinican also can consider switching the patient to acebutalol or pindolol, both of which fall under FDA category B and may be safer for use during pregnancy.
Propranolol is distributed into breast milk and should not be used in women breast-feeding their infants.
Propranolol is contraindicated in patients with bronchial asthma. Caution should be exercised when administering propranolol to patients with nonallergic bronchospastic disease (e.g., COPD, emphysema, bronchitis) because bronchodilation can be inhibited.
Propranolol is relatively contraindicated in patients with Raynaud's disease or peripheral vascular disease because reduced cardiac output and the relative increase in › stimulation can exacerbate symptoms.
The actual relationship between depression and œ-blockers has not been definitively established. œ-blockers should be used with caution in patients with major depression.
œ-blockers may exacerbate conditions such as psoriasis.
œ-blockers may potentiate muscle weakness and double vision in patients with myasthenia gravis.
œ-blockers can be used safely in elderly patients, however these patients may have unpredictable responses to œ-blockers. They may be less sensitive to the antihypertensive effects of the drug, however, reduced excretion may increase the potency of œ-blockers in this population. The elderly have age-related peripheral vascular disease and the relative increase in › stimulation can exacerbate symptoms. Geriatric patients are at increased risk of œ-blocker-induced hypothermia.
Propranolol is contraindicated in patients exhibiting hypersensitivity to the drug or any of its excipients.
DRUG INTERACTIONS: The hypotensive effects of œ-blockers are additive with other antihypertensive agents. This interaction is often used advantageously in treating hypertension, however, lower doses of one or more agents may be necessary. Blood glucose and serum triglyceride concentrations appear to increase significantly when œ-blockers are used with thiazide diuretics. Orthostatic hypotension may be more likely if œ-blockers are coadministered with dihydropyridine calcium-channel blockers such as nifedipine; nifedipine and propranolol may each increase the bioavailability of the other. If a œ-blocker is to be substituted for clonidine, clonidine should be gradually tapered and the œ-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of œ-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed › stimulation. It is possible to administer clonidine and œ-blockers concurrently without sequelae, although hypotensive effects can be additive. In general, œ-blockers can be administered safely with most other antihypertensives although it may be wise to avoid using œ-blockers with agents that cause catecholamine depletion such as guanethidine, reserpine, or other rauwolfia alkaloids. œ-blockers can interfere with reflex tachycardia, worsening orthostatic hypotension.
While additive effects are possible if a œ-blocker is administered with any other antiarrhythmic agent, particular attention should be given to using œ-blockers in combination with cardiac glycosides, diltiazem, verapamil, or other antiarrhythmics that significantly depress AV nodal conduction. When used with œ-blockers, these agents can cause complete AV block. In addition, diltiazem and verapamil decrease propranolol clearance. Amiodarone also appears to decrease the clearance of œ-blockers eliminated by hepatic metabolism (e.g., metoprolol, propranolol) and severe cardiovascular reactions have occurred when propranolol was administered to patients receiving amiodarone. Propafenone has been shown to increase the plasma concentrations and prolong the elimination half-life of propranolol. Additive negative inotropic effects are possible if œ-blockers are used with diltiazem, disopyramide, quinidine, or verapamil. Quinidine may also inhibit the clearance of propranolol. Propranolol and flecainide each appear to inhibit the clearance of the other and both drugs also possess negative inotropic activity. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction.
œ-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, œ-blockers may cause a pharmacodynamic interaction with antidiabetic agents. œ-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Also, œ-blockers can blunt the tachycardic response to and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between œ-blockers and antidiabetic agents, patients receiving œ-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective œ-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia.
Concurrent use of œ-blocking agents with sympathomimetics or adrenergic agonists can result in antagonism of the desired therapeutic effect(s) of either agent (e.g., œA-and/or œA-agonism or antagonism) and/or may lead to excessive › pharmacodynamic effects. Concomitant use of epinephrine and œ-blockers can lead to excessive › tone which may cause a hypertensive response. In addition, local anesthetics that contain epinephrine or other vasoconstrictor should be used cautiously in patients receiving œ-blockers. Beta-blockade may intensify the localized vasoconstriction from these local anesthetics.
Athough œ-blocking agents are used to treat or reduce the signs and symptoms of cocaine intoxication and the subsequent cardiovascular manifestions of cocaine withdrawal, care must be exercised that excessive ›-agonism -either secondary to cocaine or due to endogenous catecholamines -does not result.
Beta-blockers may increase the risk of hypotension and/or heart failure from diethyl ether or other general anesthetics that depress the myocardium.
Glucagon has positive inotropic properties and may be a useful alternative for treating œ-blocker-induced heart failure unresponsive to œ-agonists. Further, œ-blockade can blunt the hyperglycemic response to glucagon by interfering with glucagon-induced catecholamine release. Clinicians should be aware of these opposing pharmacologic actions of glucagon and œ-blockers.
Simultaneous use of antimuscarinic anticholinergic agents, such as atropine or some tricyclic antidepressants, with œ-blockers can antagonize œ-blocker-induced bradycardia.
Propranolol can potentiate the effects of neuromuscular blockers, such as tubocurarine, possibly by interfering with the ionic permeability of the postjunctional membrane.
Simultaneous use of œ-blockers with some ergot alkaloids such as ergotamine or ergonovine can cause severe peripheral vasoconstriction with pain and cyanosis. The combination of œ-blockade with the ›-agonism of ergot alkaloids can lead to excessive › effects.
Cimetidine interferes with the hepatic metabolism of propranolol, causing reduced clearance and increased serum concentrations of propranolol. Fluvoxamine can also inhibit hepatic cytochrome P-450 isoenzymes and has been shown to interfere with propranolol clearance however clinical symptoms of excessive œ-blocker effects were not seen.
Several interactions can occur between levodopa and œ-blockers. Levodopa is metabolized to dopamine. œ-blockers can antagonize the œ-adrenergic actions (e.g., positive inotropic action; tremor; hypotensive action) of levodopa but may potentiate the dopaminergic actions of levodopa on growth hormone release.
NSAIDs can reduce the hypotensive effects of œ-blockers however the mechanism of this interaction is not well defined. Therapy with NSAIDs for not more than several days would not be expected to produce substantial changes in blood pressure.
Propranolol has been shown to inhibit the metabolism of chlorpromazine and of thioridazine. Since chlorpromazine is also known to possess hypotensive activity, additive hypotension is possible if propranolol is used with chlorpromazine.
Propranolol can inhibit the hepatic metabolism and subsequent clearance of theophylline. In addition, because of the potential for œ-blockers to induce bronchospasm in predisposed individuals, it would be illogical for patients to be receiving theophylline and œ-blockers simultaneously.
Rifampin, a potent inducer of hepatic enzymes, has been shown to alter the pharmacokinetics of propranolol. Although the clinical significance of this pharmacokinetic interaction is uncertain, patients should be monitored for loss of propranolol effects if rifampin is added. Barbiturates may also accelerate the hepatic metabolism of propranolol.
Propranolol has been shown to raise warfarin AUC however, no changes in prothrombin times have been observed. Although a clinical interaction does not appear to exist, clinicians should always be cautious when administering drugs that can affect warfarin clearance to patients stabilized on warfarin.
ADVERSE REACTIONS: The adverse effects of propranolol are generally mild and temporary; they usually occur at the onset of therapy and diminish over time.
Most adverse reactions of propranolol are manifestations of its therapeutic effect. Sinus bradycardia and hypotension are rarely serious and can be reversed with IV atropine if necessary. AV block, secondary to depressed conduction at the AV node, may necessitate sympathomimetic and/or pressor therapy or use of a temporary pacemaker.
Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of propranolol therapy.
Adverse CNS effects of œ-blockers include dizziness, fatigue, and depression and are more common with lipophilic agents such as propranolol. Other CNS-related side effects include nightmares and hallucinations, which may occur more frequently in elderly patients.
Diarrhea and nausea/vomiting are propranolol's most common GI adverse effects.
Patients with preexisting bronchospastic disease are at high risk for exacerbation of asthma, dyspnea, or bronchospasm.
Both hypoglycemia and hyperglycemia can occur during propranolol therapy. Propranolol can interfere with glycogenolysis to cause hyperglycemia, and it also can mask signs of hypoglycemia. Propranolol should be used cautiously in brittle diabetics.
Rare but severe hematologic side effects, such as agranulocytosis, have been reported with propranolol therapy.
œ-blockers have been shown to cause hypertriglyceridemia and decrease plasma HDLs during therapy. The clinical implications of these effects, in light of other cardivascular advantages of œ-blockers, is unknown.
Myalgias and musculoskeletal pain can occur with propranolol therapy.
Propranolol has been associated with increases in hepatic enzymes.
Sexual dysfunction, impotence, and libido decrease are less frequent adverse effects of beta-blocker therapy than is generally perceived.
Dermatologic reactions with œ-blockers are usually mild and transient. Some of these reactions include pruritus, skin hyperpigmentation, reversible alopecia, xerosis, and exfoliative dermatitis.
PATIENT INFORMATION:
What do propranolol tablets or extended-release capsules do?
Propranolol (InderalTM ) belongs to a group of medicines called beta-blockers. Beta-blockers reduce the workload on the heart and help it to beat more regularly. Propranolol controls, but does not cure, high blood pressure (hypertension). Hypertension may not make you feel sick, but it can lead to serious heart problems. Propranolol has a number of other uses, for some of these the sustained-release capsules are not suitable. Propranolol steadies irregular heart rhythms (arrhythmias) and relieves chest pain (angina), and it may be helpful after a heart attack. Propranolol can help prevent migraine headaches; relieve serious tremors (uncontrollable shaking); and help certain problems related to the thyroid gland and adrenal gland. Generic propranolol tablets and extended-release capsules are available.
What should my doctor, dentist, or pharmacist know before I take propranolol?
They need to know if you have any of these conditions:
How should I take this medicine?
Take propranolol tablets or extended-release capsules by mouth. Follow the directions on the prescription label. Swallow the tablets or capsules with a drink of water; do not crush or chew the capsules. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Elderly patients may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose (less than 4 hours for regular tablets, or less than 8 hours for extended-release capsules), take only that dose. Do not take double or extra doses.
What other medicines can interact with propranolol?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking propranolol?
Serious side effects with propranolol include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with propranolol include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take propranolol?
Check your heart rate and blood pressure regularly while you are taking propranolol. Ask your doctor what your heart rate and blood pressure should be, and when you should contact him or her.
Do not stop taking this medicine suddenly. This could lead to serious heart-related side effects.
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how propranolol affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Alcohol can make you more drowsy, and increase flushing and rapid heartbeats. Avoid alcoholic drinks.
Propranolol can affect blood sugar levels. If you are diabetic check with your doctor before you change your diet or the dose of your diabetic medicine.
If you are going to have surgery, tell your doctor or dentist that you are taking propranolol.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature approximately 25C (77F). Protect from light and moisture. Throw away any unused medicine after the expiration date.
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