Propranolol

C07A - Beta blocking agents ATC C07AA05 Small molecule approved 1967 Oral Parenteral Natural product Black-box warning

JFDA label: Indicardin Tablets

⚠ Black-Box Warning

Cardiac ischemia after abrupt discontinuation (Inderal LA, Inderal XL, Innopran XL):

Mechanism of Action

Nonselective beta-adrenergic blocker (class II antiarrhythmic); competitively blocks response to beta1- and beta2-adrenergic stimulation which results in decreases in heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand. Nonselective beta-adrenergic blockers (propranolol, nadolol) reduce portal pressure by producing splanchnic vasoconstriction (beta2 effect) thereby reducing portal blood flow.

Indications

Approved

Chronic kidney disease (CKD) and hypertension
Coronary artery disease (CAD) and hypertension
Hypertension

Off-label

Akathisia, antipsychotic-induced
Performance anxiety
Tetralogy of Fallot (TOF) hypercyanotic spells
Thyroid storm
Thyrotoxicosis
Thyrotoxicosis/thyroid storm (pediatric patients)
Tremor, lithium-induced
Variceal hemorrhage (prophylaxis)

Contraindications

Source: Lexicomp · Curated

Additional contraindications (not in US labeling): Cor pulmonale Absolute
Hypersensitivity to propranolol, beta-blockers, or any component of the formulation Absolute
Severe reactive airway disease (may precipitate life-threatening bronchospasm) Absolute
Uncompensated heart failure Absolute
allergic rhinitis during pollen season Absolute
bronchial asthma Hemangeol (additional contraindications): Premature infants with corrected age Absolute
hypotension (blood pressure parameters not specified in labeling) Absolute
metabolic acidosis Absolute
patients prone to hypoglycemia Absolute
severe peripheral arterial circulatory disturbance Hemangiol (additional contraindications): Infants weighing Absolute
severe sinus bradycardia, sick sinus syndrome, or heart block greater than first-degree (except in patients with a functioning artificial pacemaker) Absolute
uncompensated congestive heart failure (unless the failure is due to tachyarrhythmias being treated with propranolol), cardiogenic shock Absolute
vasospastic angina (also referred to as Prinzmetal angina or variant angina) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (10)

Common Bradycardia

Not Known angina pectoris · atrioventricular conduction disturbance · bradycardia · cardiac failure · cardiogenic shock · Cold extremities · hypotension · ineffective myocardial contractions · syncope

Vascular disorders (1)

Common Cold extremities

Nervous system disorders (17)

Not Known agitation · amnesia · carpal tunnel syndrome (rare) · catatonia · cognitive dysfunction · confusion · dizziness · drowsiness · fatigue · hypersomnia · irritability · lethargy · nightmares · paresthesia · psychosis · Sleep disorder · vertigo

Hepatobiliary disorders (2)

Not Known Increased serum alkaline phosphatase · increased serum transaminases

Renal and urinary disorders (4)

Not Known Increased blood urea nitrogen · interstitial nephritis (rare) · Oliguria (rare) · proteinuria (rare)

Blood and lymphatic system disorders (2)

Not Known Immune thrombocytopenia · thrombocytopenia

Metabolism and nutrition disorders (4)

Not Known Hyperglycemia · hyperkalemia · hyperlipidemia · hypoglycemia

Gastrointestinal disorders (6)

Not Known abdominal pain · anorexia · constipation · decreased appetite · Diarrhea · stomach discomfort

Skin and subcutaneous tissue disorders (8)

Not Known Changes in nails · contact dermatitis · dermal ulcer · eczematous rash · erosive lichen planus · hyperkeratosis · pruritus · skin rash

Musculoskeletal and connective tissue disorders (3)

Not Known Arthropathy · oculomucocutaneous syndrome · polyarthritis

Psychiatric disorders (2)

Common Sleep disturbance / nightmares

Uncommon Depression

Eye disorders (3)

Not Known Conjunctival hyperemia · decreased visual acuity · mydriasis

Reproductive system and breast disorders (1)

Common Erectile dysfunction

General disorders and administration site conditions (2)

Very Common Fatigue

Not Known Ulcer

Respiratory, thoracic and mediastinal disorders (7)

Uncommon Bronchospasm

Not Known bronchiolitis (infants; associated with cough, fever, diarrhea, and vomiting) · Bronchitis · bronchospasm · dyspnea · pulmonary edema · wheezing

Dosing

Source: Lexicomp

Essential tremor: Oral: Immediate-release formulations: 40 mg twice daily initially; maintenance doses: Usually 120 to 320 mg/day Hypertension: Oral: Immediate-release formulations: 40 mg twice daily; increase dosage every 3 to 7 days; usual dose: 120 to 240 mg divided in 2 to 3 doses/day; maximum daily dose: 640 mg; usual dosage range (ASH/ISH [Weber 2014]): 40 to 160 mg twice daily Extended-release formulations: Inderal LA: Initial: 80 mg once daily; usual maintenance: 120 to 160 mg once daily; maximum daily dose: 640 mg Inderal XL, InnoPran XL: Initial: 80 mg once daily at bedtime; if initial response is inadequate, may be increased at 2 to 3 week intervals to a maximum daily dose of 120 mg Migraine headache prophylaxis: Oral: Immediate-release formulations: Initial: 80 mg/day divided every 6 to 8 hours; increase by 20 to 40 mg/dose every 3 to 4 weeks to a maximum of 160 to 240 mg/day given in divided doses every 6 to 8 hours; if satisfactory response not achieved within 6 weeks of starting therapy, drug should be withdrawn gradually over several weeks Inderal LA: Initial: 80 mg once daily; effective dose range: 160 to 240 mg once daily Obstructive hypertrophic cardiomyopathy: Oral: Immediate-release formulations: 20 to 40 mg 3 to 4 times/day Inderal LA: 80 to 160 mg once daily Pheochromocytoma: Oral: Immediate-release formulations: 30 to 60 mg/day in divided doses Post-MI mortality reduction: Oral: Immediate-release formulations: Initial: 40 mg 3 times/day; usual dosage range: 180 to 240 mg/day in 3 to 4 divided doses Stable angina: Oral: Immediate-release formulations: 80 to 320 mg/day in doses divided 2 to 4 times/day Inderal LA: Initial: 80 mg once daily; maximum dose: 320 mg once daily Supraventricular tachycardia: Acute treatment (off-label dose): IV: Initial: 1 mg over 1 minute, may repeat 1 mg after 2-minute intervals, up to 3 doses (ACC/AHA/HRS [Page 2015]) Ongoing management (off-label use): Oral: Initial: 30 to 60 mg daily in divided doses (immediate-release) or once daily (extended-release); maximum maintenance dose: 160 mg daily in divided doses (immediate-release) or once daily (extended-release) (ACC/AHA/HRS [Page 2015]) Tachyarrhythmias: Oral: Immediate-release formulations: 10 to 30 mg/dose every 6 to 8 hours or a usual maintenance dose of 10 to 40 mg three or four times daily for rate control in patients with atrial fibrillation (AHA/ACC/HRS [January 2014]). IV: 1 to 3 mg/dose slow IVP; repeat every 2-5 minutes up to a total of 5 mg; titrate initial dose to desired response. Note: Once response achieved or maximum dose administered, additional doses should not be given for at least 4 hours. or 0.5 to 1 mg over 1 minute; may repeat, if necessary, up to a total maximum dose of 0.1 mg/kg (ACLS guidelines 2010) or 1 mg over 1 minute; may be repeated every 2 minutes up to 3 doses for rate control in patients with atrial fibrillation (AHA/ACC/HRS [January 2014]). Akathisia, antipsychotic-induced (off-label use): Oral: Immediate-rel

(For additional information see "Propranolol: Pediatric drug information") Proliferating infantile hemangioma (Hemangeol): Infants ≥2 kg: Oral: Note: Initiate treatment at age 5 weeks to 5 months; doses should be administered at least 9 hours apart. Refer to product labeling for detailed weight-based dosing tabulation. Dosing expressed in terms of salt. Propranolol hydrochloride 4.28 mg/mL is equivalent to propranolol base 3.75 mg/mL. Week 1: 0.15 mL/kg (~0.6 mg/kg) twice daily Week 2: 0.3 mL/kg (~1.1 mg/kg) twice daily Week 3 (maintenance): 0.4 mL/kg (~1.7 mg/kg) twice daily; maintain this dose for 6 months. Readjust dose periodically as the child's weight increases. Treatment may be reinitiated if hemangiomas recur. Hypertension (off-label use): Children and Adolescents: Oral: Immediate-release formulations: Initial: 1 to 2 mg/kg/day divided in 2 to 3 doses/day; titrate dose to effect; maximum dose: 4 mg/kg/day up to 640 mg/day; sustained-release formulation may be dosed once daily (NHBPEP 2004; NHLBI 2011). Thyrotoxicosis (off-label use): Limited data available: Infants and Children: Oral: Immediate release formulations: 0.5 to 2 mg/kg/day divided every 8 hours; maximum dose: 40 mg/dose (Kliegman 2016) Adolescents: Oral: Refer to adult dosing. Thyroid storm: Limited data available: Infants and Children: Oral: 1 to 4 mg/kg/day divided every 12 hours (Cameron 2012; Fuhrman 2011) Adolescents: Oral: Immediate release formulations: 20 to 40 mg every 4 to 6 hours (Kliegman, 2016); doses as high as 60 to 80 mg every 4 hours have been recommended (ATA [Ross 2016]). IV: 0.5 to 1 mg slow IV push over 10 minutes (Braverman 2013, Kliegman 2016). Dosing interval in adolescents is not defined; in adults, doses may be repeated every several hours with continuous cardiac monitoring; when transitioning to oral therapy, IV therapy may need to be continued until the effects of oral therapy are achieved (Braverman 2013).

IV: Use caution; initiate at lower end of the dosing range. Oral: Hypertension: Consider lower initial doses and titrate to response (Aronow 2011) Tachyarrhythmias: Immediate-release formulations: Initial: 10 mg twice daily; increase dosage every 3 to 7 days; usual dose range: 10 to 320 mg/day given in 1 to 2 divided doses. Refer to adult dosing for additional uses.

There are no dosage adjustments provided in the manufacturer’s labeling. However, renal impairment increases systemic exposure to propranolol. Use with caution. Not dialyzable (0% to 5%); supplemental dose is not necessary. Peritoneal dialysis effects: Supplemental dose is not necessary.

There are no dosage adjustments provided in the manufacturer’s labeling. However, hepatic impairment increases systemic exposure to propranolol. Use with caution.

Warnings & Precautions

Source: Lexicomp

Anaphylactic reactions

Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects. Disease-related concerns:

Bronchospastic disease

In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring.

Conduction abnormality

Consider pre-existing conditions such as sick sinus syndrome before initiating.

Diabetes

Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.

Heart failure (HF)

Use with caution in patients with compensated HF and monitor for a worsening of the condition (efficacy of propranolol in HF has not been demonstrated).

Hepatic impairment

Use with caution in patients with hepatic impairment; dosage adjustment may be required.

Myasthenia gravis

Use with caution in patients with myasthenia gravis.

Peripheral vascular disease (PVD) and Raynaud's disease

Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud's disease. Use with caution and monitor for progression of arterial obstruction.

Pheochromocytoma (untreated)

Adequate alpha-blockade is required prior to use of any beta-blocker.

Prinzmetal variant angina

Beta-blockers without alpha1-adrenergic receptor blocking activity should be avoided in patients with Prinzmetal variant angina since unopposed alpha1-adrenergic receptors mediate coronary vasoconstriction and can worsen anginal symptoms (Mayer 1998).

Psoriasis

Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.

Psychiatric disease

Use with caution in patients with a history of psychiatric illness; may cause or exacerbate CNS depression.

Renal impairment

Use with caution in patients with renal impairment; may have increased side effects.

Thyroid disease

May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm. Alterations in thyroid function tests may be observed. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Infants and children

Considerations when treating infantile hemangioma: - Cardiovascular concerns: Bradycardia and/or hypotension may occur or be worsened; monitor heart rate and blood pressure after propranolol initiation or increase in dose; discontinue treatment if severe (- Hypoglycemia: May potentiate hypoglycemia and/or mask signs and symptoms. Withhold the dose in infants or children who are not feeding regularly or who are vomiting; discontinue therapy and seek immediate treatment if hypoglycemia occurs. - Respiratory concerns: May cause bronchospasm. Interrupt therapy in infants or children with lower respiratory tract infection associated with dyspnea or wheezing.

Elderly

Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary. Smokers: Cigarette smoking may decrease plasma levels of propranolol by increasing metabolism. Patients should be advised to avoid smoking. Other warnings/precautions:

Abrupt withdrawal

Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.

Major surgery

Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

Pregnancy & Lactation

Pregnancy

FDA category C

Caution

Labetalol preferred for hypertension. Propranolol still used for thyrotoxicosis control in T1 before carbimazole effect achieved

Lactation

RID 1.0%

Propranolol is present in breast milk. The relative infant dose (RID) of propranolol is 1% when calculated using the highest breast milk concentration located and compared to an infant therapeutic dose of 1 mg/kg/day. In general, breastfeeding is considered acceptable when the RID is 25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000). Using the highest milk concentration (0.075 mcg/mL), the estimated daily infant dose via breast milk is 11.25 mcg/kg/day. This milk concentr

Monitoring

Clinical pearl	Acute cardiac treatment: Monitor ECG, heart rate, and blood pressure with IV administration; heart rate and blood pressure with oral administration Consult individual institutional policies and procedures. Hemangeol: Monitor heart rate and blood pressure for 2 hours after initiation or dose increases.

Chemistry & Properties

Formula	C16H21NO2
Molecular weight	259.35 g/mol
IUPAC name	1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol
CAS	525-66-6
PubChem CID	4946
InChIKey	`AQHHHDLHHXJYJD-UHFFFAOYSA-N`
logP	2.58 (XLogP 3.0)
Polar surface area	41.49 Å²
H-bond acceptors / donors	3 / 2
Drug-likeness (QED)	0.84
Lipinski violations	0

SMILES

CC(C)NCC(O)COc1cccc2ccccc12

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB 0.64)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	IC₅₀ 4.000000000000001 µM
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	IC₅₀ 2.670511575118003 µM
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
5-HT1B (HTR1B)	Binding	pKi 6.3
HISTAMINE H1 (HRH1)	Binding	pKi 5.2

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)NTCP (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MCT1 (Substrate)MDR1 (Substrate)MRP (Substrate)OATP1B3 (Substrate)OATP2B1 (Substrate)OCT1 (Substrate)OCT2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Aminophylline	major
Ceritinib	major
Dolasetron	major
Dyphylline	major
Epinephrine	major
Fingolimod	major
Formoterol	major
Indacaterol	major
Iobenguane (I-131)	major
Methacholine	major
Olodaterol	major
Orciprenaline	major
Oxtriphylline	major
Pirbuterol	major
Salbutamol	major
Salmeterol	major
Siponimod	major
Terbutaline	major
Theophylline	major
Vilanterol	major
Abiraterone	moderate
Acetohexamide	moderate
Aldesleukin	moderate
Alectinib	moderate
Alimemazine	moderate
Amifostine	moderate
Anagrelide	moderate
Apalutamide	moderate
Atropine	moderate
Betamethasone	moderate
Brigatinib	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Budesonide	moderate
Bupropion	moderate
Calcium Phosphate	moderate
Calcium acetate	moderate
Calcium carbonate	moderate
Calcium citrate	moderate
Calcium glubionate anhydrous	moderate

Showing 40 of 100+.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Indicardin Tablets	Tablet 10 mg	50 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	0.990
Indicardin Tablets	Tablet 40 mg	5x10s pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	1.940
Indicardin Tablets	Tablet 10 mg	1000 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	16.830
Indicardin Tablets	Tablet 40 mg	1000 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	32.260
Pranol	Ampoule 1 mg/ml	6 amp	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Pranol	Ampoule 5 mg/5 ml	5 amp	Hikma Pharmaceuticals Co.Ltd/Jordan	—