BETA-BLOCKING AGENTS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

KEY
Beta1 = beta-1 antagonist (cardiac receptors)
Beta2 = beta-2 antagonist (bronchial, vascular
        receptors)
ISA = intrinsic sympathomimetic activity
MSA = membrane stabilizing activity
Alpha = alpha receptor antagonist
Drug name    Beta1    Beta2     ISA    MSA  alpha
-------------------------------------------------
acebutolol     +        0        +      +     0
atenolol       +        0        0      0     0
betaxolol      +        0        0      +     0
bisprolol      +        0        0      0     0
bucindolol     +        +        0            +
carteolol      +        +        ++     0     0
esmolol        +        0        0      0     0
labetalol      +        +        0      0     +
landiolol      +        0        0      0     +
levobunolol    +        +        0      0     0
metipranolol   +        +        0      0     0
metoprolol     +        0        0      0     0
nadolol        +        +        0      0     0
penbutolol     +        +        +      0     0
pindolol       +        +       +++     +     0
propranolol    +        +        0      ++    0
timolol        +        +        0      0     0

Specific Substances

1) Acebutolol (synonym)
2) Adimolol
3) Alprenolol (synonym)
4) Amosulalol
5) Arotinolol
6) Atenolol (synonym)
7) Befunolol (synonym)
8) Betaxolol (synonym)
9) Bevantolol
10) Bisoprolol (synonym)
11) Bopindolol
12) Bucindolol (synonym)
13) Bufetolol
14) Bufuralol
15) Bunitrolol
16) Bupranolol
17) Butofilolol
18) Carazolol
19) Cartiolol
20) Carvedilol (synonym)
21) Celiprolol (synonym)
22) Cetamolol
23) Coloranolol
24) Cycloprolol
25) Divelalol
26) Draquinolol
27) Espanolol
28) Esmolol (synonym)
29) Flestolol
30) Indenolol
31) Labetalol (synonym)
32) Landiolol (synonym)
33) Levobetaxolol (synonym)
34) Levobunolol (synonym)
35) Levomoprolol
36) Medroxalol
37) Mepindolol (synonym)
38) Metipranolol (synonym)
39) Metoprolol (synonym)
40) Nadolol (synonym)
41) Nebivolol (synonym)
42) Nifenalol
43) Nipradilol
44) Oxprenolol (synonym)
45) Penbutolol
46) Pindolol (synonym)
47) Practolol
48) Propranolol (synonym)
49) Teratolol
50) Tilisolol
51) Timolol (synonym)

1) BLOCKERS, BETA

1.2.1) MOLECULAR FORMULA
1) ATENOLOL: C14H22N2O3
2) BETAXOLOL HYDROCHLORIDE: C18H29NO3-HCl
3) BISOPROLOL FUMARATE: (C18H31NO4)2-C4H4O4
4) CARTEOLOL HYDROCHLORIDE: C16H24N2O3-HCl
5) CARVEDILOL: C24H26N2O4
6) ESMOLOL HYDROCHLORIDE: C16H26NO4Cl
7) LABETALOL HYDROCHLORIDE: C19H24N2O3-HCl
8) LEVOBETAXOLOL HYDROCHLORIDE: C18H29NO3-HCl
9) NADOLOL: C17H27NO4
10) NEBIVOLOL HYDROCHLORIDE: C22H25F2NO4-HCl
11) PENBUTOLOL SULFATE: C36H60N2O8S
12) PINDOLOL: C14H20N2O2
13) PROPRANOLOL HYDROCHLORIDE: C16H21NO2-HCl
14) TIMOLOL MALEATE: C13H24N4O3S-C4H4O4

Available Forms Sources

1) AVAILABLE BETA-BLOCKERS

Drug	Strength
Acebutolol	200, 400 mg cap
Atenolol	25, 50, 100 mg tab, 5 mg/10 mL amp
Betaxolol	2.5, 5 mg/mL ophthalmic 10, 20 mg tab
Bisprolol	5, 10 mg tablet
Carteolol	2.5, 5 mg tab
Carvedilol (Extended Release formulation)	10, 20, 40 and 80 mg capsules
Esmolol	250 mg/mL inj
Labetalol	100,200,300 mg tab 5 mg/mL inj
Levobunolol	0.5% ophthalmic
Metipranolol	0.3% ophthalmic
Metoprolol	50, 100 mg tab 1 mg/mL inj
Nadolol	20, 40, 80, 120, and 160 mg tab
Nebivolol	2.5, 5, and 10 mg
Penbutolol	20 mg tab
Pindolol	5, 10 mg tablets
Propranolol	10, 20, 40, 60, 80, 90 mg tab 60, 80, 120, 160 mg sustained-release cap; 1 mg/mL inj 80 mg/mL oral solution
Timolol	0.25, 0.5% ophth 5,10,20 mg tab

a) Other beta adrenergic blocking agents not available in the US include alprenolol, bupranolol, disoprolol, oxprenolol, practolol, and tolamolol.
b) COMBINATION PRODUCTS: Bimatoprost 0.3 mg/mL/timolol 5 mg/mL (as 6.8 mg of timolol maleate) and travoprost 40 mcg/mL/timolol 5 mg/mL (as timolol maleate) combinations are available as ophthalmic solution (Prod Info GANFORT ophthalmic solution, 2011; Prod Info DuoTrav ophthalmic solution, 2012). Brinzolamide/timolol is available as a combination product containing 10 mg/mL brinzolamide and 5 mg/mL timolol (as timolol acetate) (Prod Info AZARGA ophthalmic suspension, 2012)

1) Beta-blockers are used in the treatment of hypertension, angina, dysrhythmias, cardiomyopathy, migraine headaches, and thyrotoxicosis. Ophthalmic products are used in the treatment of glaucoma (Frishman et al, 1979; Frishman, 1981; Dollery & Patterson, 1969; Abrams et al, 1985; Anon, 1972; Gray, 1988).
2) COMBINATION PRODUCTS: Bimatoprost or travoprost in combination with timolol are used to reduce intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues (Prod Info DuoTrav ophthalmic solution, 2012; Prod Info GANFORT ophthalmic solution, 2011). Brinzolamide in combination with timolol is used for treatment of open-angle glaucoma or ocular hypertension in adults who did not sufficiently respond to monotherapy (Prod Info AZARGA ophthalmic suspension, 2012).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Used primarily to treat hypertension. Also used as a treatment for akathisia, essential tremor, hypertrophic subaortic stenosis, pheochromocytoma, stable angina, tachydysrhythmias, thyrotoxicosis, congestive heart failure, congenital heart conditions, and for migraine headache prophylaxis and variceal hemorrhage prophylaxis. Bimatoprost/timolol and travoprost/timolol ophthalmic combinations are indicated for the reduction of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma. Refer to beta-blocking agents document for more information.
B) PHARMACOLOGY: Inhibition/competitive blockade of beta-adrenergic receptors.
C) TOXICOLOGY: The toxicity of beta-blockers is an extension of their therapeutic effects. They cause bradycardia, heart block, and hypotension. Propranolol has sodium channel blocking properties and may cause ventricular dysrhythmias.
D) EPIDEMIOLOGY: Poisoning is uncommon but can be very severe. May occur via oral, intravenous, or ophthalmic administration.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Hypotension, bradycardia, first-degree heart block, dizziness, fatigue, depression, pruritus, rash, diarrhea, dyspnea, bronchospasm, hypoglycemia, and seizures are among the adverse effects. Superficial punctate keratitis, corneal erosion, burning sensation, eyelid pruritus, eye dryness, eye pain, photophobia, eye discharge, visual disturbances, eyelid erythema, and blepharal pigmentation have been reported in up to 10% of patients receiving bimatoprost/timolol ophthalmic solution. Eye pain, ocular discomfort, dry eye, and eye pruritus have been reported in up to 10% of patients receiving travoprost/timolol maleate (polyquaternium-1-preserved).

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Decreased heart rate and hypotension.
2) SEVERE POISONING: Atrioventricular blocks, intraventricular conduction delays, and congestive heart failure can occur with more severe poisoning. Coma and cardiopulmonary arrest can develop secondary to severe hypotension/bradycardia. Bronchospasm may develop, particularly in patients with asthma or COPD, and respiratory depression may develop in patients with severe hypotension. Propranolol is highly lipid-soluble and may cross the blood brain barrier and cause seizures. Propranolol may cause QRS widening resulting in ventricular dysrhythmias due to sodium channel blockade. Renal failure and pulmonary edema may develop in patients with prolonged hypotension. Hypoglycemia may develop in diabetics or in those with decreased glycogen stores (eg, children, fasting, exercising); manifestations of hypoglycemia (tremor, tachycardia) may be masked by clinical effects of beta-blocker toxicity.
3) OCULAR EXPOSURE: Ophthalmic preparations containing beta-blockers may cause systemic manifestations.
4) ONSET: Symptoms usually occur within 6 hours, but can be as early as 20 minutes and may be delayed with sustained release products.

0.2.3)

A) WITH THERAPEUTIC USE

1) Bradycardia and hypotension are common.

B) WITH POISONING/EXPOSURE

1) Respiratory depression may occur with severe poisoning.

0.2.20)

A) Atenolol is classified by the manufacturer as FDA pregnancy category D. Betaxolol, bisoprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, propranolol, propranolol/hydrochlorothiazide, and timolol are classified as FDA pregnancy category C. Acebutolol and pindolol are classified as FDA pregnancy category B. Beta blocking agents can decrease placental perfusion, which may result in intrauterine fetal death or immature or premature delivery. Fetal adverse effects, particularly hypoglycemia and bradycardia, may also occur. The action of maternal beta-blocker use continues in the neonate for several days after delivery. During the postnatal period, there is an increased risk of neonatal cardiac and pulmonary complications. Bradycardia, respiratory distress, and hypoglycemia have also been reported. Acebutolol, atenolol, betaxolol, labetalol, metoprolol, nadolol, propranolol, and timolol are excreted in human breast milk.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Place patient on a cardiac monitor, give fluids for hypotension, and atropine for bradycardia.

B) MANAGEMENT OF SEVERE TOXICITY

1) Perform early orotracheal intubation for airway protection if the patient has altered mental status. Initially manage hypotension with intravenous fluids (500 mL boluses up to 2L) and atropine for symptomatic bradycardia. Glucagon should be considered if patient does not respond appropriately to intravenous fluids. Give catecholamines to those who do not respond to intravenous fluids and glucagon. No one catecholamine has been shown to be consistently effective; dopamine, norepinephrine and epinephrine may be considered. High doses may be required. If catecholamines are required despite glucagon and intravenous fluids, high-dose insulin euglycemia should be considered. Catecholamines should be titrated down when high-dose insulin euglycemia therapy starts to take effect. Intravenous lipid emulsion should be considered in patients with refractory hypotension. Other non-pharmacological therapies include: cardiac pacing, placement of an intraaortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO). Seizures (rarely progress to status epilepticus) may require aggressive use of benzodiazepines (e.g. 1 to 2 mg lorazepam IV and increase as needed) and/or propofol. Monitor for dysrhythmias and treat accordingly.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway.
2) HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway. After airway protection consider gastric lavage in recent, large ingestion, or whole bowel irrigation.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (depressed mental status, seizures or dysrhythmias).

E) HYPOTENSION

1) Initially manage hypotension with intravenous fluids (500 mL boluses up to 2L) and atropine for symptomatic bradycardia.

a) ANTIDOTE: GLUCAGON: Patients who do not respond to intravenous fluids (500 mL boluses up to 2L) and atropine should be treated with glucagon. Initial dosing is 5 to 15 mg slow IV push with an infusion rate of 5 to 15 mg/hour. Glucagon may also induce nausea/vomiting, as well as elevate blood glucose.
b) CATECHOLAMINES: Give catecholamines to those who do not respond to intravenous fluids (500 mL boluses up to 2L), atropine, glucagon. No one agent has been shown to be consistently effective; dopamine, norepinephrine, and epinephrine may be considered. High doses may be required. Initiating high-dose insulin euglycemia therapy should be considered in patients who require catecholamines despite treatment with intravenous fluids, atropine, and glucagon.
c) HIGH DOSE INSULIN EUGLYCEMIA: Is another potential therapy with some positive animal data and case-based human evidence. Administer a bolus of 1 unit/kilogram of insulin followed by an infusion of 0.1 to 1 unit/kilogram/hour, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to titrate insulin infusion. High-dose euglycemia therapy may allow the practitioner to decrease the dose of catecholamines and avoid the adverse effects of prolonged high-dose catecholamines. Before, during, and after the therapy, monitor for hypoglycemia and hypokalemia.

1) Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (Adults: 25 to 50 mL dextrose 50%; Children: 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hour in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. As the patient improves, insulin resistance abates and dextrose requirements will increase. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued.
2) Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L

d) LIPID EMULSION THERAPY: Patients who develop significant cardiovascular toxicity may be treated with intravenous lipids. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
e) CALCIUM: Calcium chloride has been effective for propranolol, concurrent administration of atenolol and verapamil, and a mixed metoprolol/verapamil overdose that were refractory to conventional therapy. Administer calcium chloride 0.2 mL/kg or calcium gluconate 0.6 mL/kg intravenously.
f) INAMRINONE: A phosphodiesterase inhibitor which also has theoretical benefit via decreasing breakdown of myocardial cAMP. The dosing is 1 mg/kg bolus then 3 to 6 mcg/kg/minute. It is very rarely used because, although it increases inotropy, it may induce peripheral vasodilatation and is difficult to titrate due to a relatively long half-life.
g) OTHER NON-PHARMACOLOGICAL THERAPIES: Include cardiac pacing, placement of an intraaortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO).

F) BRADYCARDIA

1) Atropine, glucagon (50 to 150 mcg/kg bolus followed by an infusion of 1 to 5 mg/hr), pacemaker.

G) SEIZURES

1) Seizures (rarely progress to status epilepticus) may require aggressive use of benzodiazepines (eg, 1 to 2 mg lorazepam IV and increase as needed) and/or propofol.

H) DYSRHYTHMIAS

1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeat as needed; endpoints include resolution of dysrhythmias, narrowing of QRS complex and blood pH 7.45 to 7.55. Use lidocaine (1 mg/kg intravenous bolus followed by 20 to 50 mcg/kg/minute intravenous infusion) if sodium bicarbonate is not successful.

I) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion may be useful for beta blockers with small volumes of distribution such as atenolol, sotalol and nadolol; experience is limited to a few case reports. Hemodialysis and hemoperfusion are not useful for beta-blockers with large volumes of distribution.

J) PATIENT DISPOSITION

1) HOME CRITERIA: According to the AAPCC guidelines, healthy, asymptomatic patients with the following inadvertent single substance ingestions may be monitored at home (IR = immediate release, SR = sustained release):

a) ACEBUTOLOL: ADULT: 600 mg or less; CHILD: 12 mg/kg or less
b) ATENOLOL: ADULT: 200 mg or less; CHILD: 2 mg/kg or less
c) CARVEDILOL: ADULT: 50 mg or less; CHILD: 0.5 mg/kg or less
d) LABETALOL: ADULT: 400 mg or less; CHILD: 20 mg/kg or less
e) METOPROLOL: ADULT: 450 mg or less IR or 400 mg or less SR; CHILD: 2.5 mg/kg or less IR or 5 mg/kg or less SR
f) NADOLOL: ADULT: 320 mg or less; CHILD: 2.5 mg/kg or less
g) PROPRANOLOL: ADULT: 240 mg or less; CHILD: 4 mg/kg or less IR, or 5 mg/kg or less SR
h) TIMOLOL: ADULT: 30 mg or less (tablets); CHILD: No safe dose

2) OBSERVATION CRITERIA: Patients with underlying cardiovascular or respiratory disease, those who co-ingest calcium channel blockers, and those with deliberate overdose of beta-blocking agents should have a baseline ECG and be monitored for a minimum of 6 hours (at least 8 hours if a sustained release formulation is involved) . According to the AAPCC guidelines, patients with the following inadvertent single substance ingestions should be referred to a healthcare facility (IR = immediate release, SR = sustained release):

a) ACEBUTOLOL: ADULT: greater than 600 mg; CHILD: greater than 12 mg/kg
b) ATENOLOL: ADULT: greater than 200 mg; CHILD: greater than 2 mg/kg
c) CARVEDILOL: ADULT: greater than 50 mg; CHILD: greater than 0.5 mg/kg
d) LABETALOL: ADULT: greater than 400 mg; CHILD: greater than 20 mg/kg
e) METOPROLOL: ADULT: greater than 450 mg IR or greater than 400 mg SR; CHILD: greater than 2.5 mg/kg IR or greater than 5 mg/kg SR
f) NADOLOL: ADULT: greater than 320 mg; CHILD: greater than 2.5 mg/kg
g) PROPRANOLOL: ADULT: greater than 240 mg; CHILD: greater than 4 mg/kg IR, or greater than 5 mg/kg SR
h) TIMOLOL: ADULT: greater than 30 mg (tablets); CHILD: any amount

3) ADMISSION CRITERIA: Symptomatic patients with cardiovascular symptoms (ie, hypotension, bradycardia) or central nervous system toxicity (ie, somnolence, seizures, coma) should be admitted to an intensive care setting for further observation/treatment and monitored until they are asymptomatic for a period of several hours without therapy.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with toxicity (hypotension, seizures, dysrhythmias), or in whom the diagnosis is not clear.

K) PITFALLS

1) These patients may require early aggressive treatment to stave off potentially severe sequelae from an overdose. Toxicity may be delayed and prolonged after overdose of sustained release formulations. Patients who co-ingest other cardiovascular medications often develop more severe toxicity.

L) PHARMACOKINETICS

1) Onset of action depends on formulation and route of administration (oral versus intravenously). Duration depends on particular medication and formulation – long-acting formulations do exist for these medications. Elimination primarily by hepatic metabolism for those with high lipid solubility, renal elimination for those with poor lipid solubility.

M) DIFFERENTIAL DIAGNOSIS

1) Other antihypertensive or antidysrhythmic medications (calcium channel blockers, digoxin, clonidine), infections/sepsis, other toxic ingestions may present with some similar clinical features (e.g. some antipsychotics may cause some hypotension and depressed mental status).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Bradycardia and hypotension are common.

B) WITH POISONING/EXPOSURE

1) Respiratory depression may occur with severe poisoning.

3.3.2)

A) WITH THERAPEUTIC USE

1) BRONCHOSPASM: Therapeutic doses of beta adrenergic blocking agents may cause bronchospasm in susceptible patients (Botet et al, 1986; Nelson et al, 1986; Prince & Carliner, 1983; Charan & Lakshminarayan, 1980) .

B) WITH POISONING/EXPOSURE

1) RESPIRATORY DEPRESSION, apnea, and respiratory arrest may develop in patients with severe intoxication Petti et al, 1990; (Peterson et al, 1984; Shore et al, 1981; Mattingly, 1977) .

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA (temperature 28.9 degrees C) developed in a woman with mental status depression after overdose with atenolol 1000 mg and diazepam 200 mg (Hagemann, 1986).

a) Mild hypothermia (34 degrees C) developed in a woman with cardiovascular collapse after atenolol overdose (Saitz et al, 1991).

3.3.4)

A) WITH THERAPEUTIC USE

1) Hypotension may develop after therapeutic doses (Allin et al, 1986)Michelson et al, 1986; (Abrams et al, 1985; Greenblatt & Koch-Weser, 1973) .

B) WITH POISONING/EXPOSURE

1) Severe hypotension may develop after overdose (Lane et al, 1987; Agura et al, 1986) .

3.3.5)

A) WITH THERAPEUTIC USE

1) Bradycardia is a common effect at therapeutic doses (Love & Howell, 1997; Weinstein et al, 1985; Kulling et al, 1983; Eibs et al, 1982; Elkharrat & Bismuth, 1982).

B) WITH POISONING/EXPOSURE

1) Severe bradycardia may develop after overdose (Weinstein et al, 1985; Kulling et al, 1983; Eibs et al, 1982; Elkharrat & Bismuth, 1982). An irregular pulse may be a sign of conduction defects or dysrhythmias. Asystole has also been reported (Amundson & Brodine, 1988).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) DIPLOPIA has been reported after therapeutic use of beta-blocking agents and appears to be dose related (Weber, 1982).
2) IRRITATION: Conjunctival suffusion and erythematous swelling of the eyelids was reported in a man using practolol (Kirkham & Holt, 1976).

a) Ocular pruritus, edema and rash developed in a patient with allergic contact dermatitis to timolol (Fernandez-Vozmediano et al, 1986).
b) Ocular pain and burning and punctate keratopathy have been reported in patients using timolol ophthalmic drops (McMahon et al, 1979).

3) BIMATOPROST/TIMOLOL: CONJUNCTIVAL HYPEREMIA: Based on 12-month clinical data, conjunctival hyperemia was the most common adverse effect, reported in approximately 26% of patients treated with bimatoprost/timolol ophthalmic solution. Discontinuation of therapy due to conjunctival hyperemia occurred in 1.5% of patients (Prod Info GANFORT ophthalmic solution, 2011).
4) BIMATOPROST/TIMOLOL: In clinical trials, superficial punctate keratitis, corneal erosion, burning sensation, eyelid pruritus, eye dryness, eye pain, photophobia, eye discharge, visual disturbances, eyelid erythema, and blepharal pigmentation were reported in up to 10% of patients who received bimatoprost/timolol maleate ophthalmic solution (Prod Info GANFORT ophthalmic solution, 2011).

a) The preservative benzalkonium chloride has been reported to cause punctate keratopathy and toxic ulcerative keratopathy (Prod Info GANFORT ophthalmic solution, 2011).

5) BRINZOLAMIDE/TIMOLOL: During clinical trials, blurred vision, eye pain, and eye irritation were reported in up to 10% of patients receiving brinzolamide/timolol ophthalmic solution (Prod Info AZARGA ophthalmic suspension, 2012).
6) TRAVOPROST/TIMOLOL: CONJUNCTIVAL HYPEREMIA: In 3 clinical studies (n=372), 11.8% of patients who received travoprost/timolol maleate (polyquaternium-1-preserved) for up to 12 months experienced hyperemia of the eye, including conjunctival or ocular hyperemia. In the majority of cases (91%), hyperemia of the eye did not result in discontinuation of therapy (Prod Info DuoTrav ophthalmic solution, 2012).
7) TRAVOPROST/TIMOLOL: Eye pain, ocular discomfort, dry eye, and eye pruritus were reported in up to 10% of patients who received travoprost/timolol maleate (polyquaternium-1-preserved) in clinical studies (Prod Info DuoTrav ophthalmic solution, 2012).

B) WITH POISONING/EXPOSURE

1) MYDRIASIS

a) MYDRIASIS: Dilated pupils with sluggish reaction to light may develop in patients with severe hypotension, bradycardia, and CNS depression (McVey & Corke, 1991; Perrot et al, 1988; Freestone et al, 1986; Freysz et al, 1986; Lindvall et al, 1985; Weinstein et al, 1985; Kulling et al, 1983; Halloran & Phillips, 1981; Shore et al, 1981) .

2) ISCHEMIC OPTIC NEUROPATHY

a) Two patients experienced vision loss approximately 3 days following overdose ingestions of verapamil and metoprolol (Senthilkumaran et al, 2011).

1) The first patient, a 55-year-old woman, ingested 30 verapamil 40 mg tablets and 35 metoprolol 50 mg tablets. Three days postingestion, the patient was not able to see. Examination of the patient revealed a visual acuity of light perception in both eyes, dilated pupils that were nonreactive to light, and normal optic discs without disc swelling or evidence of pallor. A diagnosis of posterior ischemic optic neuropathy was made, believed to be secondary to hypoperfusion resulting from a combined beta-blocker and calcium antagonist overdose ingestion. With supportive therapy, including high-dose steroid administration, the patient's vision gradually improved, although a 6-month follow-up examination revealed that she continued to experience bilateral loss of the nasal half of the visual field.
2) The second patient, a 25-year-old woman, ingested 25 verapamil 40 mg tablets and 20 metoprolol 50 mg tablets. Three to four days postingestion, the patient experienced vision loss. An ophthalmic examination revealed fixed and dilated pupils in both eyes with no light perception. Ocular motility, intraocular pressures, anterior segments, and fundoscopy were normal. The patient was diagnosed as having ischemic optic neuropathy. Two days later, with supportive care, the patient's vision gradually improved, although she continued to experience bilateral loss of the nasal half of the visual field at the 6 month follow-up visit.

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypotension may develop after therapeutic doses of beta-blockers (Allin et al, 1986)Michelson et al, 1986; (Abrams et al, 1985; Greenblatt & Koch-Weser, 1973) .
b) ATENOLOL: A 20-year-old woman, with a history of end-stage renal disease and who was receiving peritoneal dialysis, presented to the emergency department with abdominal pain, bradycardia (59 bpm) and hypotension (65/45 mmHg). Her current medication list included atenolol 12.5 mg daily, doxazosin 4 mg daily, amlodipine 10 mg daily, and valsartan 160 mg daily, with the patient reporting no excess ingestion or recent dosing changes. After non-drug-related causes for her clinical signs and symptoms were ruled out, and her hypotension persisted despite administration of IV fluids and vasopressors, 10 mg (2 5-mg IV bolus doses) of glucagon was administered, followed by a glucagon infusion of 5 mg/hour, resulting in hemodynamic stability (heart rate of 90 bpm and a blood pressure of 120/67 mmHg), thereby suggesting a primary diagnosis of unintentional atenolol toxicity. Transient withdrawal of glucagon therapy resulted in a rapid decrease in blood pressure (76/32 mmHg) and restarting the glucagon resulted in blood pressure normalization (112/72 mmHg), thus supporting the primary diagnosis (Hoot et al, 2013). It is believed that decreased clearance of atenolol due to the patient's end-stage renal disease and subsequent peritoneal dialysis may have resulted in toxicity.
c) ESMOLOL: Hypotension has been reported in 13% to 39% of patients treated with esmolol for supraventricular tachycardia (Allin et al, 1986; Anderson et al, 1986)Michelson et al, 1986; (Abrams et al, 1985; Gray et al, 1985) and resolved within 30 minutes after esmolol was discontinued (Allin et al, 1986).
d) NADOLOL: A 57-year-old woman who was taking therapeutic doses of diltiazem developed hypotension after nadolol overdose (Ehgartner & Zelinka, 1988).
e) TIMOLOL: Hypotension has been reported after therapeutic use and inadvertent overuse of timolol ophthalmic drops (Hayes et al, 1989; McMahon et al, 1979) .

2) WITH POISONING/EXPOSURE

a) Severe hypotension may develop after overdose (Lane et al, 1987; Agura et al, 1986; Weinstein et al, 1985; Kulling et al, 1983; Lewis et al, 1983; Eibs et al, 1982) .

1) Hypotension and bradycardia have been infrequently reported in children following accidental ingestions of beta-blocking agents, according to a 7-year retrospective review of acute beta-blocking agent exposures in children less younger than 7 years (Belson et al, 2001).

b) ACEBUTOLOL: Severe hypotension has been reported in acebutolol intoxication (Love, 2000; Donovan et al, 1999; Oppenheim, 1991; Nicolas et al, 1987; Sangster et al, 1983). Hypotension may occur without significant bradycardia (Nicolas et al, 1987; Sangster et al, 1983) .
c) ATENOLOL

1) Profound hypotension has also been reported after atenolol overdose (Huang et al, 2013; Salhanick & Wax, 2000; Snook et al, 2000; Kalman et al, 1998)Stintson et al, 1992; (Saitz et al, 1991; Freestone et al, 1986) .
2) CASE REPORT: A 20-year-old woman ingested multiple drugs, including atenolol (1800 mg to 2500 mg) in a suicide attempt and experienced severe hypotension (systolic BP of 40 mmHg), bradycardia (38 beats/min), and ECG abnormalities. Lab results revealed a serum atenolol concentration of 32,000 ng/mL (Pertoldi et al, 1998).
3) CASE REPORT: A 72-year-old woman, who was on verapamil therapy for treatment of recurrent supraventricular dysrhythmias, developed cardiogenic shock within hours after adding atenolol 25 mg daily to the verapamil regimen. She became hypotensive, developed pulmonary congestion, loss consciousness, and was subsequently mechanically ventilated. Arterial blood gases showed severe hypoxemia with metabolic acidosis. The patient recovered without neurological sequelae following intravenous administration of calcium chloride (Sakurai et al, 2000).

d) LABETALOL: Two cases of hypotension after labetalol overdose have been described (Hicks & Rankin, 1991; Smit et al, 1986) . Severe hypotension can develop without bradycardia (Hicks & Rankin, 1991; Korzets et al, 1990; Smit et al, 1986)because of labetalol's alpha-blocking activity.
e) METOPROLOL: Profound hypotension has been reported after metoprolol overdose (Escajeda et al, 2015; Barton et al, 2015; Tai et al, 1990; Bekes & Scott, 1985; Lindvall et al, 1985; Wallin & Hulting, 1983; Shore et al, 1981; Moller, 1976) .
f) OXPRENOLOL: Severe hypotension developed in 4 patients after oxprenolol overdose (O'Mahony et al, 1990) (Schofield et al, 1985) (Khan & Muscat-Baron, 1977) (Mattingly, 1977) . Hypotension may develop without bradycardia (O'Mahony et al, 1990) (Schofield et al, 1985).
g) PROPRANOLOL: Numerous reports describe profound hypotension after propranolol overdose.

1) References: Brimacome et al, 1991; (McVey & Corke, 1991) (Petti et al, 1990)(Warwick & Boulton-Jones, 1989; Amundson & Brodine, 1988; Kenyon et al, 1988; Lane et al, 1987; Agura et al, 1986; Cox & Starbuck, 1986; Wilkinson, 1986; Chen et al, 1985; Khan & Miller, 1985; Smith et al, 1985; Peterson et al, 1984; Soni et al, 1983; Halloran & Phillips, 1981; Salzberg & Gallagher, 1980; Buiumsohn et al, 1979; Frishman & Silvermon, 1979; Lagerfelt & Matell, 1976; Kosinski & Malindzak, 1973)

B) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) Bradycardia is a common effect at therapeutic doses(Love & Howell, 1997; Weinstein et al, 1985; Kulling et al, 1983; Eibs et al, 1982; Elkharrat & Bismuth, 1982) .
b) ESMOLOL: Bradycardia has been reported after therapeutic use (Anderson et al, 1986).
c) TIMOLOL: Bradycardia has been reported after therapeutic use of timolol ophthalmic preparations (Hayes et al, 1989; Nelson et al, 1986; Linkewich & Merling, 1981; Britman, 1979; McMahon et al, 1979) .
d) A prospective cohort study was conducted to identify factors in exposures to beta-blockers that are associated with the development of cardiovascular morbidity, including bradycardia and hypotension. It was determined that a history of a cardioactive coingestant was the only factor significantly associated with the development of cardiovascular morbidity in beta-blocker exposures. The cardioactive coingestants implicated were calcium channel blockers, cyclic antidepressants, neuroleptics, lithium, procainamide, ACE inhibitors, digoxin and clonidine (Love, 2000). Beta-blockers with membrane stabilizing effects (propranolol, metoprolol, labetalol, acebutolol, and pindolol) were more often associated with significant hypotension and/or bradycardia.

2) WITH POISONING/EXPOSURE

a) Severe bradycardia may develop after overdose (Love & Howell, 1997; Weinstein et al, 1985; Kulling et al, 1983; Eibs et al, 1982; Elkharrat & Bismuth, 1982) .

1) Bradycardia and hypotension have been infrequently reported in children following accidental ingestions of beta-blocking agents, according to a 7-year retrospective review of acute beta-blocking agent exposures in children younger than 7 years (Belson et al, 2001).

b) ACEBUTOLOL: Bradycardia (40 beats per minute) developed in one case of acebutolol overdose (Oppenheim, 1991).
c) ATENOLOL: Severe bradycardia has been reported after atenolol overdose (Huang et al, 2013; Salhanick & Wax, 2000; Snook et al, 2000; Kalman et al, 1998; Pertoldi et al, 1998; Saitz et al, 1991; Gerkin & Curry, 1987; Abbasi & Sorsby, 1986; Freestone et al, 1986) .
d) BETAXOLOL: Severe bradycardia (30 beats per minute) developed after use of betaxolol ophthalmic drops in an 80-year-old man with a history of sick sinus syndrome who was also taking digoxin (Ball, 1987).
e) BISOPROLOL: Asymptomatic bradycardia (42 beats/minute) developed in a 19-year-old man after bisoprolol overdose (Tracqui et al, 1990).
f) LABETALOL: Bradycardia developed in a 43-year-old woman after labetalol overdose (Hicks & Rankin, 1991).
g) METOPROLOL: Severe bradycardia has been reported after metoprolol overdose Beckes & Scott, 1985; (Barton et al, 2015; Lindvall et al, 1985; Wallin & Hulting, 1983; Shore et al, 1981) .
h) NADOLOL: Mild bradycardia (50 to 60 beats per minute) developed in a 57-year-old man after nadolol overdose (Ehgartner & Zelinka, 1988).
i) OXPRENOLOL: Severe bradycardia has been described after oxprenolol overdose Kahn & Muscat-Baron, 1977; (Mattingly, 1977) .
j) PROPRANOLOL: Numerous reports document severe bradycardia after propranolol overdose.

1) (McVey & Corke, 1991; Warwick & Boulton-Jones, 1989; Amundson & Brodine, 1988; Kenyon et al, 1988; Lane et al, 1987; Cox & Starbuck, 1986; Wilkinson, 1986; Chen et al, 1985; Khan & Miller, 1985; Soni et al, 1983; Laake et al, 1981; Lagerfelt & Matell, 1976) .

k) TIMOLOL: Bradycardia has been reported after inadvertent overuse of timolol ophthalmic preparations (Hayes et al, 1989; Nelson et al, 1986; Linkewich & Merling, 1981; Britman, 1979; McMahon et al, 1979) .
l) A prospective cohort study was conducted to identify factors in exposures to beta-blockers that are associated with the development of cardiovascular morbidity, including bradycardia and hypotension. It was determined that a history of a cardioactive coingestant was the only factor significantly associated with the development of cardiovascular morbidity in beta-blocker exposures. The cardioactive coingestants implicated were calcium channel blockers, cyclic antidepressants, neuroleptics, lithium, procainamide, ACE inhibitors, digoxin, and clonidine (Love, 2000). Beta-blockers with membrane stabilizing effects (propranolol, metoprolol, labetalol, acebutolol and pindolol) were more often associated with significant hypotension and/or bradycardia.

C) ATRIOVENTRICULAR BLOCK

1) WITH THERAPEUTIC USE

a) Second-degree AV block has been reported after chronic atenolol therapy in a patient with renal failure (Giang & Isaeff, 1986).

2) WITH POISONING/EXPOSURE

a) First-degree AV block has been reported after overdose with acebutolol, atenolol, labetalol, metoprolol, nadolol, and propranolol (Donovan et al, 1999; Saitz et al, 1991; Ehgartner & Zelinka, 1988; Nicolas et al, 1987; Smit et al, 1986; Sangster et al, 1983; Shore et al, 1981; Buiumsohn et al, 1979; Frishman & Silvermon, 1979) .
b) Second-degree AV block has been reported after metoprolol and propranolol overdose (Tynan et al, 1981; Hesse & Pedersen, 1973).
c) Atrioventricular dissociation has been described after overdose with metoprolol, and oxprenolol (Bekes & Scott, 1985; Schofield et al, 1985).
d) Nodal rhythms and ventricular standstill have also been reported (Love & Howell, 1997; Stinson et al, 1992; Hicks & Rankin, 1991; Warwick & Boulton-Jones, 1989; Lane et al, 1987; Freestone et al, 1986; Salzberg & Gallagher, 1980; Lagerfelt & Matell, 1976) .

D) BUNDLE BRANCH BLOCK

1) WITH POISONING/EXPOSURE

a) Prolongation of the QRS interval has been described after overdose with acebutolol, atenolol, oxprenolol, and propranolol (Pertoldi et al, 1998; Brimacombe, 1992; Brimacombe et al, 1991; McVey & Corke, 1991; Oppenheim, 1991; Pettei et al, 1990; Nicolas et al, 1987; Schofield et al, 1985; Sangster et al, 1983; Tynan et al, 1981; Buiumsohn et al, 1979; Frishman & Silvermon, 1979)Khan & Muscat-Baron, 1977 .

E) VENTRICULAR ARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Ventricular tachycardia or fibrillation may develop with severe beta-blocker overdoses (Love & Howell, 1997; Brimacombe et al, 1991; Kenyon et al, 1988; Lane et al, 1987; Agura et al, 1986; Freysz et al, 1986) .
b) CASE REPORT: A 48-year-old man developed ventricular tachycardia after a concomitant ingestion of ethanol and approximately 6.4 g acebutolol. The patient recovered after administration of sodium bicarbonate 50 mg IV push (Donovan et al, 1999).
c) CASE REPORTS: Ventricular tachycardia and QTc interval prolongation were reported in 2 patients following intentional ingestions of 4 to 6 grams of acebutolol. Despite aggressive resuscitative measures, both patients died within 4 hours postingestion (Love, 2000).

F) RIGHT HEART FAILURE

1) WITH THERAPEUTIC USE

a) Worsening congestive heart failure has been described in patients taking therapeutic doses of beta-blockers (Ball, 1987; Khan & Miller, 1985; Linkewich & Merling, 1981; Britman, 1979) .

G) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) LABETALOL

1) INTRATHECAL/CASE REPORT: A 25-year-old pregnant woman presented in early labor and, in preparation for an emergent cesarean section, inadvertently received labetalol intrathecally instead of the intended bupivacaine 0.5%. Immediately after administration, the patient experienced acute pain with a burning sensation in her lower extremities. She was also restless, tachycardic (150 beats/minute) and hypertensive (190/110 mmHg). Following administration of general anesthesia, the delivery was uneventful, with no evidence of adverse effects in the infant. The patient's pulse and blood pressure decreased to 86 beats/minute and 130/80 mmHg, respectively, remaining stable throughout the procedure, and her leg pain and burning sensation resolved. Following a normal hospital course, the patient was discharged without neurologic sequelae (Laha & Hazra, 2015).

b) PINDOLOL

1) Pindolol has greater beta-agonist properties and overdoses have been associated with hypertension and tachycardia (Offenstadt et al, 1976; Thorpe, 1971) .

H) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An ingestion of 640 mg of propranolol over 24 hours in a 58-year-old man produced ECG changes including bradycardia with early repolarization, ST-segment elevation, and peaked T waves (Gwinup, 1988).
b) CASE REPORT: A 20-year-old woman ingested multiple drugs including atenolol (1800 mg to 2500 mg) in a suicide attempt. Sixteen hours after ingestion, the ECG showed junctional rhythm, left bundle branch block, and a prolonged QTc interval. At 48 hours the patient developed electromechanical dissociation (EMD), which was corrected by repeated doses of calcium chloride. Complete recovery occurred after supportive care and the temporary insertion of a transvenous pacemaker (Pertoldi et al, 1998).
c) CASE REPORT: A 27-year-old woman with a DDD pacemaker developed a cardiac arrest along with prolonged EMD following the ingestion of verapamil (2 times the therapeutic level) and propranolol. The patient required multiple pressor agents, but regained hemodynamic stability within 10 hours of exposure (Waxman et al, 1997).
d) CASE REPORT: A 15-year-old girl developed mild bradycardia and hypotension, prolonged QRS and QTc intervals (500 to 530 msec) after ingesting 1600 mg propranolol. ECG normalized within 14 hours of ingestion (Farhangi & Sansone, 2003).
e) CASE REPORT: A 57-year-old man presented to the emergency department with hypotension and bradycardia approximately 2 hours after ingesting 500 mg of atenolol. An ECG showed sinus bradycardia (53 beats/min) and inferior ST-segment elevations, which resolved after about 20 minutes. Subsequent coronary angiography revealed no significant stenosis, so the transient ST elevation was attributed to vasospasm induced by the atenolol (Petrov et al, 2007).

I) TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) LABETALOL

J) BRUGADA SYNDROME

1) WITH POISONING/EXPOSURE

a) A 24-year-old man ingested 57 propranolol 40 mg tablets. His first ECG 15 minutes after ingestion showed a sinus rate of 63 bpm with a type 2 pattern of Brugada syndrome (incomplete right bundle branch block pattern and discrete saddle-back-type ST-segment elevation in leads V1-V2). The PR, QRS, and QTc intervals were 150, 100, and 420 ms, respectively. Approximately 70 minutes after the ingestion, a second ECG showed sinus rhythm with a typical coved-type pattern of Brugada syndrome; the PR, QRS, and QTc intervals were 190, 110, and 405 ms, respectively. Following treatment with atropine and glucagon, partial ECG normalization was observed within 12 hours, with a persistence of a discrete saddleback-type ECG pattern in leads V1-V2. An ajmaline test 5 days later confirmed Brugada syndrome. The authors concluded that these ECG changes may be explained by the stabilizing membrane effect of high levels of propranolol and/or inhibition of inward calcium current (Aouate et al, 2005).
b) CASE REPORT: A 34-year-old woman presented to the emergency department unresponsive, bradycardic, and hypotensive after ingesting an unknown amount of clonazepam and propranolol. Because of shallow respirations, the patient was intubated and mechanically ventilated. An ECG revealed wide QRS complex with right bundle branch block and coved ST-segment elevation with negative T waves in leads V1 and V2, indicative of a type I Brugada pattern. With supportive care, the patient was extubated and her cardiac abnormalities resolved as indicated on a repeat ECG (Rennyson & Littmann, 2010).

K) CARDIOMYOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute dilated cardiomyopathy was reported in a 16-year-old boy who ingested 3200 mg propranolol in a suicide attempt. Echocardiography revealed a dilated left ventricle with poor contraction. The patient recovered following treatment with isoprenaline and glucagon (Lifshitz et al, 1999).

L) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) METOPROLOL: A 19-year-old woman ingested 7.5 grams metoprolol and developed mechanical asystole and respiratory arrest (Lindvall et al, 1985). Prenalterol was administered every 6 hours for the first 24 hours after a total of 420 mg along with epinephrine. The patient completely recovered.
b) PROPRANOLOL: Two patients developed cardiac arrest following exposure to propranolol. The first patient, a 38-year-old woman, developed sinus bradycardia and became unresponsive and apneic after receiving a 1.5 mg IV bolus of propranolol for treatment of refractory supraventricular tachycardia. Following intravenous administration of enoximone, the patient gradually recovered and was subsequently discharged without neurologic sequelae. The second patient, a 50-year-old man, developed sinus bradycardia that progressed to asystole after intentionally ingesting 1.6 grams of propranolol, 150 milliliters of hydrochloric acid, and an unknown amount of oxazepam. Following prolonged intravenous administration of enoximone, dopamine, and norepinephrine, the patient's hemodynamic status improved and he was eventually discharged (Sandroni et al, 2006).
c) METOPROLOL: A 54-year-old man presented to the emergency department with a recent history of chest pain that began approximately 4 hours earlier after using approximately 1 gram of cocaine. On presentation, the patient did not have any pain. Vital signs indicated hypertension (145/95 mmHg), and sinus tachycardia (114 bpm). Over the next 2 hours, the patient continued to have persistent tachycardia and was given metoprolol 2.5 mg IV. After 5 minutes, there was no change in heart rate and a second dose of metoprolol was given. Approximately 10 minutes later, the patient developed severe chest pain, diaphoresis, nausea, and subsequently, became unresponsive with a systolic blood pressure of 50 mmHg and a pulse of 120 bpm that rapidly deteriorated to asystole. Despite intensive resuscitative measures, the patient died approximately 1 hour later. In this case, a close temporal relationship between the administration of a beta-blocker in a patient with chest pain associated with cocaine use exacerbated coronary vasoconstriction (Fareed et al, 2007).
d) METOPROLOL: After ingesting 80 tablets of metoprolol 25 mg and buPROPion 150 mg, a 50-year-old woman developed severe bradycardia and hypotension (HR 40 beats/min; mean arterial pressure 40 mmHg), refractory to calcium salts, catecholamines, and high-dose insulin. About 30 seconds after receiving 100 mL of 20% intravenous fat emulsion (IFE), she developed brady-asystolic arrest, but her pulse returned to normal after 3 minutes of cardiopulmonary resuscitation (CPR). Despite aggressive supportive care, her condition worsened and she died of multisystem organ failure on day 4. Another patient, a 53-year-old man, developed bradycardia and hypotension (HR 30 beats/min; mean arterial pressure 40 mmHg) after ingesting diltiazem 3600 mg and propranolol 1200 mg. Despite treatment with calcium salts, catecholamines, high-dose insulin, bicarbonate, and atropine, his condition did not improve. Within 1 minute of receiving 150 mL of 20% IFE he developed brady-asystolic arrest, but his pulse returned to normal after 6 minutes of CPR. Despite aggressive supportive care, his condition deteriorated and he died of multisystem organ failure on day 7. Although the exact cause of arrests in these patients is uncertain, several possible causes were suggested: IFE interaction with other resuscitation drugs, a sudden increase in absorption of drug in the GI tract, a brief lack of oxygen in the lipid-laden blood circulating in the coronary vessels contributing to the arrests, fatal ingestions of drugs regardless of therapy (Cole et al, 2014).
e) METOPROLOL: A 59-year-old man, with a medical history of methamphetamine abuse, persistent atrial fibrillation, nonischemic cardiomyopathy, and severe mitral valve regurgitation, developed hypotension and bradycardia after ingesting 7.5 g (75 mg/kg) of metoprolol. Initial treatment included IV atropine 1.5 mg, glucagon 6 mg, and a dopamine infusion of 10 mcg/kg/minute. However, despite treatment, the patient's condition worsened and he developed cardiac arrest. During cardiopulmonary resuscitation, the patient was administered hyperinsulinemia/euglycemia (HIE) therapy, vasopressor therapy with epinephrine and norepinephrine, and an IV lipid emulsion bolus, resulting in return of spontaneous circulation (ROSC). Following ROSC, treatment continued with calcium gluconate administration, HIE therapy, a second IV lipid emulsion bolus, and vasopressor support, with gradual return of hemodynamic stability. He was discharged 5 days post-admission without neurologic sequelae. Urine toxicologic analyses, obtained 48 hours post-ingestion, revealed a metoprolol concentration of 120 ng/mL (reporting limit 5 ng/mL), an amphetamine level of 78 ng/mL (reporting limit 50 ng/mL), and a methamphetamine level of 180 ng/mL (reporting limit of 50 ng/mL) (Barton et al, 2015).
f) METOPROLOL: A 47-year-old man presented to the emergency department with severe hypotension (41/palpable mmHg) and comatose approximately 95 minutes after intentionally ingesting 10 g of metoprolol. Despite IV fluids and vasopressor administration, his hypotension persisted, a cardiac ultrasonography revealed diffuse global hypokinesis. Approximately 40 minutes post-presentation, the patient developed cardiac arrest with narrow-complex pulseless electrical activity (PEA) and CPR was administered. Although the patient developed a transient pulse with minimal improvement in blood pressure, PEA returned. Because of his hemodynamic instability, treatment was initiated with high dose insulin, intralipid therapy, and veno-arterial extracorporeal membrane oxygenation (ECMO) with continued vasopressor support. The patient showed gradual neurologic improvement approximately 8 hours after beginning ECMO (11.5 hours post-ingestion), spontaneously moving his extremities and able to follow commands. ECMO was stopped after 50 hours of treatment, the patient continued to improve, and was discharged to an inpatient psychiatric facility on hospital day 10. Serum metoprolol concentration, obtained 4.5 hours post-ingestion, was 25,000 ng/mL (therapeutic range, 20 to 340 ng/mL) (Escajeda et al, 2015).

M) CARDIOGENIC SHOCK

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 38-year-old woman intentionally ingested 5.32 grams of betaxolol, 30 grams of lorazepam, and an unknown amount of alcohol, and subsequently developed cardiogenic shock that persisted despite treatment with isoproterenol, dobutamine, epinephrine, norepinephrine, and glucagon. Echocardiography revealed diffuse hypokinesia of the left ventricle with no measurable systolic flow. Following extracorporeal membrane oxygenation, the patient's hemodynamic status improved, with gradual recovery of left ventricular function (Bilbault et al, 2007).

N) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 56-year-old man with a previous history of coronary artery disease experienced an acute myocardial infarction after a 1500 mg metoprolol overdose. The patient developed hypotension, bradycardia, ST-segment elevation on ECG, and elevated cardiac markers (Unverir et al, 2007).

Respiratory

3.6.2)

A) BRONCHOSPASM

1) WITH THERAPEUTIC USE

a) Therapeutic doses of beta adrenergic blocking agents may cause bronchospasm in susceptible patients (Gray, 1988; Allin et al, 1986; Botet et al, 1986; Nelson et al, 1986; Prince & Carliner, 1983; Williams & Ginther, 1982; Charan & Lakshminarayan, 1980; McMahon et al, 1979) .
b) Sudden death has been reported in 4 asthmatics after therapeutic doses of beta-blockers (Benatar & Opie, 1982).

2) WITH POISONING/EXPOSURE

a) Bronchospasm has also been reported after overdose (Saitz et al, 1991; Bekes & Scott, 1985; Weinstein et al, 1985) .

B) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) Pulmonary edema has been reported after therapeutic use (Greenblatt & Koch-Weser, 1973).

2) WITH POISONING/EXPOSURE

a) Pulmonary edema has been reported after overdose (Snook et al, 2000; Tai et al, 1990; Amundson & Brodine, 1988; Lane et al, 1987; Frishman & Silvermon, 1979) .

C) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Respiratory depression is common in patients with significant cardiovascular toxicity after overdose (Hicks & Rankin, 1991)O'Mahony et al, 1990; (Pettei et al, 1990; Amundson & Brodine, 1988; Schofield et al, 1985; Peterson et al, 1984; Wallin & Hulting, 1983; Shore et al, 1981) .
b) Apnea develops in severe overdose (Agura et al, 1986; Chen et al, 1985; Lindvall et al, 1985)Kullig et al, 1983; (Halloran & Phillips, 1981; Laake et al, 1981; Mattingly, 1977) .
c) CASE REPORT: Marked suppression of ventilation lasting 2 days despite normal voluntary breathing mechanics and mental status developed in a 42-year-old man after overdose with 5 grams of atenolol and ethanol (Montgomery et al, 1985).
d) CASE REPORT: A 16-year-old boy developed respiratory depression, requiring mechanical ventilation, 3 hours after ingesting 3200 mg propranolol in a suicide attempt. The patient recovered following supportive care (Lifshitz et al, 1999).

D) PULMONARY ASPIRATION

1) WITH POISONING/EXPOSURE

a) Aspiration pneumonia may develop in patients with CNS depression (Tai et al, 1990; Halloran & Phillips, 1981; Mattingly, 1977) .

3.6.3)

A) ANIMAL STUDIES

1) RESPIRATORY DEPRESSION

a) In rat models of severe propranolol and timolol toxicity achieved by continuous infusion, artificial ventilation resulted in an increase in survival time and lethal dose, suggesting that centrally mediated respiratory depression is the usual cause of death in this model (Langemeijer et al, 1986).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) Effects reported at therapeutic doses include sedation, fatigue, and impaired psychomotor performance (Gengo et al, 1987; Allin et al, 1986; McMahon et al, 1979) (Greenblatt & Koch-Weber, 1973).
b) A blinded crossover study comparing lipid-soluble metoprolol and water-soluble atenolol showed no difference in adverse CNS effects (Gengo et al, 1987).

2) WITH POISONING/EXPOSURE

a) While CNS effects at therapeutic doses are more often associated with more lipid soluble agents (propranolol, metoprolol), in overdose all agents may cause significant CNS depression. Effects range from drowsiness and lethargy to obtundation and coma. Severe CNS depression generally develops in patients with hemodynamic instability (Hicks & Rankin, 1991; Saitz et al, 1991; Ehgartner & Zelinka, 1988; Kenyon et al, 1988; Perrot et al, 1988; Edvardsson & Varnauskas, 1987; Agura et al, 1986; Cox & Starbuck, 1986; Freestone et al, 1986; Bekes & Scott, 1985; Lindvall et al, 1985; Schofield et al, 1985; Smith et al, 1985; Peterson et al, 1984; Laake et al, 1981; Salzberg & Gallagher, 1980) (Khan & Muscat-Baron, 1977)(Kosinski & Malindzak, 1973)
b) METOPROLOL: A 47-year-old man presented to the emergency department with severe hypotension (41/palpable mmHg) and comatose approximately 95 minutes after intentionally ingesting 10 g of metoprolol. Despite IV fluids and vasopressor administration, his hypotension persisted, a cardiac ultrasonography revealed diffuse global hypokinesis. Approximately 40 minutes post-presentation, the patient developed cardiac arrest with narrow-complex pulseless electrical activity (PEA) and CPR was administered. Although, the patient developed a transient pulse with minimal improvement in blood pressure, PEA returned. Because of his hemodynamic instability, treatment was initiated with high dose insulin, intralipid therapy, and veno-arterial extracorporeal membrane oxygenation (ECMO) with continued vasopressor support. The patient showed gradual neurologic improvement approximately 8 hours after beginning ECMO (11.5 hours post-ingestion), spontaneously moving his extremities and able to follow commands. ECMO was stopped after 50 hours of treatment, the patient continued to improve, and was discharged to an inpatient psychiatric facility on hospital day 10. Serum metoprolol concentration, obtained 4.5 hours post-ingestion, was 25,000 ng/mL (therapeutic range, 20 to 340 ng/mL) (Escajeda et al, 2015).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures have occasionally been reported after therapeutic use of esmolol (Das & Ferris, 1988).

2) WITH POISONING/EXPOSURE

a) Seizures have occasionally been reported with overdose of alprenolol (Eibs et al, 1982), metoprolol (Wallin & Hulting, 1983; Shore et al, 1981), and oxprenolol (Mattingly, 1977) O'Mahoney et al, 1990.
b) Seizures have been frequently reported after propranolol overdose.

1) (Reith et al, 1996; Brimacombe, 1992; Brimacombe et al, 1991; McVey & Corke, 1991) Petti et al, 1990; (Warwick & Boulton-Jones, 1989; Amundson & Brodine, 1988; Das & Ferris, 1988; Lane et al, 1987; Chen et al, 1985; Kulling et al, 1983; Soni et al, 1983; Artman et al, 1982; Halloran & Phillips, 1981; Laake et al, 1981; Tynan et al, 1981; Buiumsohn et al, 1979; Frishman & Silvermon, 1979; Lagerfelt & Matell, 1976)

C) AMNESIA

1) WITH THERAPEUTIC USE

a) Severe memory impairment developed in an 81-year-old woman taking propranolol 20 mg 3 times/day (Fisher, 1992). Effects were associated with an elevated propranolol blood level (163 mcg/L) and resolved after discontinuation of the drug.

D) PSYCHOTIC DISORDER

1) WITH THERAPEUTIC USE

a) At therapeutic doses, beta-blockers may cause depression, confusion, hallucinations, agitation, delusions, and paranoia (Sklar & Huck, 1983; Petrie et al, 1982; White & Riotte, 1982; Hinshelwood, 1969).

E) SYNCOPE

1) WITH THERAPEUTIC USE

a) Syncope has been described in patients using therapeutic doses of timolol ophthalmic drops (Nelson et al, 1986; McMahon et al, 1979) .

F) SLEEP WALKING DISORDER

1) WITH THERAPEUTIC USE

a) CASE REPORT: Approximately 30 minutes after falling asleep, a 79-year-old man, with a history of myocardial infarction and stent implantation and in the cardiology ward for medication adjustment, experienced sleepwalking (eg, getting dressed, walking around, moving things around, waking up his roommates) until he was woken up by a care worker. The patient's unusual sleep behavior occurred 2 days after beginning metoprolol therapy, 12.5 mg twice daily (total dose taken before occurrence of sleepwalking was 37.5 mg). The sleepwalking recurred two days later, after receiving a total of 7 metoprolol doses (total dose was 87.5 mg). Suspecting an association between the patient's sleepwalking and metoprolol therapy, his physician switched him to carvedilol. Over the next few days, the patient sleepwalked 4 times with a complete disappearance of symptoms 5 days after cessation of metoprolol therapy (Wei et al, 2014).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 77-year-old woman experienced severe nausea and vomiting shortly after initiating timolol therapy for treatment of glaucoma. The nausea and vomiting disappeared after cessation of timolol therapy, but reappeared upon rechallenge with timolol (Wolfhagen et al, 1998).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting have been described in overdose (Warwick & Boulton-Jones, 1989) Lanet et al, 1987.

B) VASCULAR INSUFFICIENCY OF INTESTINE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 19-year-old woman developed mesenteric ischemia after propranolol overdose complicated by hypotension (Pettei et al, 1990).
b) CASE REPORT: Ischemic bowel necrosis developed in a 21-year-old man 19 days after overdose with acebutolol, labetalol, and trimipramine complicated by hypotension requiring isoproterenol and dopamine therapy (Hurwitz et al, 1986).

C) RETROPERITONEAL FIBROSIS

1) WITH THERAPEUTIC USE

a) Drug-induced retroperitoneal fibrosis has been reported following treatment with practolol, atenolol, and oxprenolol (Clark & Terris, 1983). Sclerosing peritonitis has been associated with treatment with practolol and metoprolol (Clark & Terris, 1983).

D) DIFFUSE SPASM OF ESOPHAGUS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 48-year-old woman developed esophageal spasm during orogastric lavage after propranolol overdose (Panos et al, 1986).
b) CASE REPORT: A 39-year-old woman developed possible esophageal spasm preventing passage of a tube for gastric lavage after propranolol overdose (Laake et al, 1981). At autopsy no esophageal or gastric abnormalities were found.

Hepatic

3.9.2)

A) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) Elevated liver enzymes have occurred in patients administered acebutolol. In 6 patients administered 400 mg/day for an average of 22 days, liver enzyme concentrations in all patients and alkaline phosphatase in 4 patients were significantly elevated. Normal hepatic function returned after acebutolol withdrawal (Tanner et al, 1989).
b) Chronic labetalol therapy has also been associated with hepatotoxicity (Hart & Hobdy-Henderson, 1992).
c) CASE REPORT: Atenolol was associated with hepatitis in a 57-year-old woman with a liver transplant 1 month after initiating therapy for treatment of hypertension. Inflammatory infiltrates were seen on the liver biopsy, suggesting an immune-mediated mechanism. Toxicity resolved when atenolol was discontinued (Dumortier et al, 2009).

2) WITH POISONING/EXPOSURE

a) Ischemic hepatitis developed in a 28-year-old woman with prolonged hypotension after acebutolol overdose (Rooney et al, 1996).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute oliguric renal failure has been reported, usually in patients with prolonged hypotension after beta-blocker overdose(Bilbault et al, 2007; Rooney et al, 1996; Saitz et al, 1991; O'Mahony et al, 1990; Warwick & Boulton-Jones, 1989; Perrot et al, 1988; Halloran & Phillips, 1981) .
b) CASE REPORT: Oliguric renal failure developed in a 19-year-old woman who developed moderate hypotension (70/50) lasting approximately 3 hours after labetalol overdose (Smit et al, 1986). This was postulated to have occurred secondary to alpha-blocking effects on renal vasculature.
c) CASE REPORT: Oliguric renal failure developed in a 25-year-old woman who developed severe hypotension after labetalol overdose (Korzets et al, 1990).
d) CASE REPORT: A 27-year-old woman developed acute renal failure secondary to rhabdomyolysis after oxprenolol overdose (Schofield et al, 1985).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis may develop in patients with profound hypotension or seizures (Kalman et al, 1998; Brimacombe et al, 1991; Hicks & Rankin, 1991; McVey & Corke, 1991; Korzets et al, 1990; Pettei et al, 1990; Ehgartner & Zelinka, 1988; Kenyon et al, 1988; Perrot et al, 1988; Agura et al, 1986; Cox & Starbuck, 1986; Wallin & Hulting, 1983; Buiumsohn et al, 1979; Frishman & Silvermon, 1979; Lagerfelt & Matell, 1976) .

Hematologic

3.13.2)

A) AGRANULOCYTOSIS

1) WITH THERAPEUTIC USE

a) A case of agranulocytosis associated with propranolol therapy has been reported (Nawabi & Ritz, 1973).

Dermatologic

3.14.2)

A) NAIL FINDING

1) WITH THERAPEUTIC USE

a) Psoriasiform lesions, conjunctival suffusion, and nail dystrophy have been reported with practolol use (Kirkham & Holt, 1976).

B) CONTACT DERMATITIS

1) WITH THERAPEUTIC USE

a) Contact dermatitis with eyelid erythema and edema has been reported following timolol (Fernandez-Vozmediano, 1986; Romaguera, 1986) and befunolol (Kanzaki et al, 1988).

C) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia associated with propranolol therapy has been reported (Martin et al, 1973).

D) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) Inflammation and induration (8% incidence) have been reported as an infusion site reaction during esmolol therapy (Gray, 1988).

E) LICHENOID DERMATITIS

1) WITH THERAPEUTIC USE

a) Lichen planus-like lesions have been reported following therapy with acebutolol, labetalol, oxprenolol, and propranolol, with the onset of clinical symptoms ranging from 7 weeks to 1 year (Thompson & Skaehill, 1994).

F) VASCULITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 69-year-old man presented to the hospital 48 hours after developing a fever and a rash on both knees. The left knee showed a maculopapular rash and bullous eruptions with ulcerative lesions. The right knee showed a reddish rash with characteristics of palpable purpura. The patient's current medication list included long-term therapy with glibenclamide-phenformin, acarbose, folic acid, spironolactone, and propranolol. Blood tests showed an elevated erythrocyte sedimentation rate (ESR) of 80 mm/hour and skin biopsies determined the rash to be leukocytoclastic vasculitis. It was suspected by a process of elimination that the vasculitis may have been due to propranolol. Propranolol therapy was discontinued and, 10 days later, the patient became afebrile, the ESR decreased, and the rash gradually improved (Iliopoulou et al, 2000).

G) PAIN

1) WITH POISONING/EXPOSURE

a) LABETALOL

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 27-year-old developed rhabdomyolysis after overdose with oxprenolol (Schofield et al, 1985).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) Propranolol can cause hypoglycemia in children after therapeutic use (Artman et al, 1982)Cottrill et al, 1977; (McBride et al, 1973) .
b) Propranolol can cause hypoglycemia and resultant seizures in diabetics treated with oral hypoglycemics or insulin and in nondiabetics who are dieting, fasting, and exercising (Kotler et al, 1966). The clinical effects of hypoglycemia (tachycardia and sweating) may be masked due to the beta-blockade of these agents.
c) In healthy volunteers propranolol causes slight lowering of blood glucose (Allison et al, 1969) and free fatty acid levels (Abramson et al, 1966).
d) CASE REPORT: A 68-year-old woman with IDDM and taking nitroglycerin and propranolol developed asymptomatic hypoglycemia, became comatose, and died. The patient's blood sugar, at the time of her death, was 25 mg/dL (Cooper, 1998).

2) WITH POISONING/EXPOSURE

a) Propranolol can cause hypoglycemia in children after overdose (Hesse & Pedersen, 1973).
b) CASE REPORT: Hypoglycemia developed in a 15-year-old girl after atenolol overdose (Abbasi & Sorsby, 1986).

B) INCREASED THYROXINE LEVEL

1) WITH THERAPEUTIC USE

a) Hyperthyroxinemia has occurred in patients on repeated, high doses (480 mg) of propranolol (Cooper et al, 1982).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Immediate anaphylactoid response to labetalol occurred in a 27-year-old surgical nurse (Bause & Kugelman, 1990).

Reproductive

3.20.1)

3.20.2)

A) PROPRANOLOL

1) No adequate and well-controlled studies of the effects of propranolol in pregnant women are available; however, congenital abnormalities, small placentas, and intrauterine growth retardation were detected in neonates whose mothers were administered propranolol during pregnancy. Bradycardia, hypoglycemia, and respiratory depression were also reported in neonates whose mothers received propranolol while giving birth(Prod Info HEMANGEOL(TM) oral solution, 2014).

B) ANIMAL STUDIES

1) ACEBUTOLOL

a) RATS, RABBITS: No evidence of teratogenicity was seen after the administration of acebutolol at 31.5 and 6.8 times the maximum recommended human dose, respectively (Prod Info acebutolol HCl oral capsules, 2015).

2) BETAXOLOL

a) RATS: In 1 study in which rats were given betaxolol at doses of 4 and 40 mg/kg/day (6 times and 60 times the maximum recommended human dose (MRHD), respectively), there was an increased incidence of incomplete descent of testes and sternebral reductions. In another rat study, there was no evidence of teratogenicity at a betaxolol dose of 200 mg/kg/day (300 times the MRHD). An increased incidence of skeletal visceral abnormalities was reported when pregnant rats were given 400 mg/kg/day (600 times the maximum recommended human dose [MRHD]) (Prod Info Kerlone(R) oral tablets, 2008).
b) RATS, RABBITS: There was no evidence of teratogenicity and no other adverse effects when sub-toxic betaxolol doses were given to rats and rabbits (Prod Info BETOPTIC S(R) ophthalmic suspension, 2007).

3) ESMOLOL

a) RATS, RABBITS: Teratogenicity studies in rats at a daily 30-minute IV dosage of up to 3 mg/kg/min (approximately 10 times the human exposure) resulted in no evidence of teratogenicity. Similar studies in rabbits withdaily 30-minute IV dosages of up to 1 mg/kg/min resulted in no evidence of teratogenicity (Prod Info BREVIBLOC IV injection, 2007).

4) METOPROLOL

a) RATS, MICE: Administration of metoprolol tartrate to pregnant mice demonstrated fetal exposure. There has been no evidence from animal studies that confirm teratogenicity from metoprolol (Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013).

5) NADOLOL

a) RATS, RABBITS, HAMSTERS: Teratogenicity was not observed or reported in any animal reproduction studies (Prod Info CORGARD(R) oral tablets, 2007).

6) NEBIVOLOL/VALSARTAN

a) After the administration of nebivolol at maternally toxic doses (5 and 10 times the maximum recommended human dose) to pregnant rats during organogenesis, reduced fetal weights and reversible sternal and thoracic ossification delays occurred (Prod Info BYVALSON(TM) oral tablets, 2016).

7) PROPRANOLOL

a) RATS, RABBITS: Reduced litter sizes, neonatal deaths, and increased resorption rates were seen in reproductive and developmental studies of propranolol in rats administered doses of 150 mg/kg/day (twice the maximum recommended human dose [MRHD] of 640 mg on a body surface area basis) orally throughout pregnancy and lactation. In contrast, no evidence of embryofetal or neonatal toxicity was reported in rabbits given 5 times the MRHD of propranolol (150 mg/kg/day) (Prod Info HEMANGEOL(TM) oral solution, 2014).

3.20.3)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to esmolol or metoprolol during pregnancy in humans(Prod Info BREVIBLOC IV injection, 2007; Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013).

B) BETA-BLOCKERS

1) A meta-analysis of 13 population-based, case-control, and cohort studies revealed that first-trimester oral beta-blocker use did not increase the risk of major congenital anomalies. However, first-trimester use was associated with a significant 2-fold increase in the risk of cardiovascular defects and a significant greater than 3-fold increases in cleft lip or palate and neural tube defects in studies that detailed organ-specific malformations. Results were similar in studies that used hypertension as the indication compared with studies that used hypertension and cardiovascular disorders for indications as well as studies in which there was no specified indication. A substantial increase was noted in cardiovascular abnormalities in a post hoc secondary analysis of malformations by organ system. Studies with a potential for recall bias showed an association with cardiovascular anomalies, whereas those using prospectively collected data showed no association. Studies that did not exclude or adjust for diabetes mellitus reported no association between beta-blocker use and cardiovascular anomalies (Yakoob et al, 2013).

C) LABETALOL

1) During a retrospective study of women with severe preeclampsia from January 2005 to December 2006, in utero exposure to labetalol had no effect on gestational age, birth weight, or preterm birth. Of 109 infants, 55 were exposed to labetalol during gestation while 54 had no exposure to antihypertensive agents (control group). The incidence of hypotension was significantly greater in infants exposed to labetalol when compared with the control group (29.1% and 7.4%, respectively; p=0.003). Hypotensive infants were treated with crystalloids and/or dopamine/hydrocortisone therapy. Two infants did not receive treatment for hypotension. Incidences of patent ductus arteriosus (PDA), hypoglycemia, and bradycardia were similar amongst both groups. Route of labetalol administration did not have an effect on the rate of hypotension, hypoglycemia, or bradycardia (Heida et al, 2012).

D) PLACENTAL BARRIER

1) ACEBUTOLOL

a) Acebutolol crosses the placental barrier. Neonates exposed to acebutolol during the gestation period have decreased birth weight, blood pressure, and heart rate (Prod Info acebutolol HCl oral capsules, 2015).

2) BETAXOLOL

a) There are no adequate and well-controlled studies of betaxolol use during pregnancy. However, beta blocking agents have been shown to decrease placental perfusion, which may result in intrauterine fetal death and immature and premature deliveries. Fetal adverse effects, particularly hypoglycemia and bradycardia, may also occur. The action of maternal beta-blocker use continues in the neonate for several days after delivery. During the postnatal period, there is an increased risk of neonatal cardiac and pulmonary complications. Bradycardia, respiratory distress and hypoglycemia have also been reported (Prod Info Kerlone(R) oral tablets, 2008).

3) LABETALOL

a) CASE REPORT: Administration of labetalol 50 mg/hr IV for several hours prior to caesarean section resulted in bradycardia, cyanosis, respiratory depression, and hypotonia in a 33-week-gestation neonate. Circulatory collapse and apnea reoccurred 1 hour later (Haraldsson & Geven, 1989).
b) CASE SERIES: Although not statistically significant, neonates born to mothers on labetalol during pregnancy had higher incidences of birth asphyxia and intrauterine growth retardation than mothers on other antihypertensive agents. They also had a significantly increased incidence of hypoglycemia, although most were asymptomatic (Munshi et al, 1992).

4) METOPROLOL

a) CASE REPORT: Metoprolol overdose in a 23-year-old woman at 20 weeks gestation resulted in severe hypotension, pulmonary edema, cardiac arrest and fetal demise. The mother survived (Tai et al, 1990).

5) NADOLOL

a) Neonates whose mothers received nadolol during childbirth have demonstrated evidence of bradycardia, hypoglycemia and related symptoms (Prod Info CORGARD(R) oral tablets, 2007).

6) PROPRANOLOL

a) Propranolol appears to cross the placenta and may result in intrauterine growth retardation, bradycardia, hypoglycemia, respiratory depression(Prod Info HEMANGEOL(TM) oral solution, 2014) and impaired response to anoxic stress (Redmond, 1982; Boice, 1982; O'Connor, 1981; Lydakis et al, 1999).
b) CASE REPORT: An infant born to a woman who received propranolol and digoxin during pregnancy developed apnea, bradycardia, hypoglycemia and acidosis. At birth serum propranolol levels were comparable in maternal and cord blood (venous and arterial) samples (33, 42 and 36 ng/mL respectively) but neonatal levels drawn 4 hours after birth were higher (90 ng/mL) (Cottrill et al, 1977).
c) CASE REPORT: 4 infants born to mothers receiving propranolol developed bradycardia, lethargy and hypoglycemia (Habib & McCarthy, 1977).
d) CASE REPORT: An infant born to a mother taking propranolol 240 mg/day developed polycythemia, hypoglycemia and bradycardia (Gladstone et al, 1975).

E) PREGNANCY CATEGORY

1) The manufacturer has classified atenolol as FDA pregnancy category D (Prod Info TENORMIN(R) oral tablets, 2005).
2) The manufacturers have classified betaxolol, bisoprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, propranolol, propranolol/hydrochlorothiazide, and timolol manufacturer as FDA pregnancy category C (Prod Info HEMANGEOL(TM) oral solution, 2014; Prod Info BYSTOLIC(TM) oral tablets, 2007; Prod Info Kerlone(R) oral tablets, 2008; Prod Info BETOPTIC S(R) ophthalmic suspension, 2007; Prod Info ZEBETA(R) oral tablets, 2004; Prod Info BREVIBLOC IV injection, 2007; Prod Info TRANDATE(R) oral tablets, 2002; Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013; Prod Info CORGARD(R) oral tablets, 2007; Prod Info LEVATOL(R) oral tablets, 2004; Prod Info INDERAL(R) oral tablets, 2007; Prod Info INDERIDE(R) oral tablets, 2011; Prod Info BLOCADREN(R) oral tablets, 2002).
3) The manufacturer has classified acebutolol and pindolol as FDA pregnancy category B (Prod Info acebutolol HCl oral capsules, 2015; Prod Info VISKEN(R) oral tablets, 2007).
4) NEBIVOLOL/VALSARTAN: The use of nebivolol/valsartan and other drugs that act on the renal-angiotensin system during pregnancy can reduce fetal renal function and increase fetal morbidity and mortality rates (Prod Info BYVALSON(TM) oral tablets, 2016).
5) Propranolol is not intended for use during pregnancy (Prod Info HEMANGEOL(TM) oral solution, 2014).

F) ANIMAL STUDIES

1) BETAXOLOL

a) In animal studies, there was evidence of drug-related postimplantation loss in rabbits and rats at betaxolol doses greater than 12 mg/kg and 128 mg/kg, respectively (Prod Info BETOPTIC S(R) ophthalmic suspension, 2007).
b) Maternal toxicity, an increase in resorptions, increased postimplantation loss, and reduced litter size and weight were observed when pregnant rats or rabbits were given betaxolol doses up to 400 mg/kg/day (600 times the maximum recommended human dose [MRHD]). In a peri- and postnatal study in rats, there was a marked increase in total litter loss within 4 days postpartum following a betaxolol dose of 256 mg/kg/day (380 times the MRHD). Growth and development were also affected in the surviving offspring (Prod Info Kerlone(R) oral tablets, 2008).

2) ESMOLOL

a) RATS, RABBITS: Teratogenicity studies in rats at a daily 30-minute IV dosage of up to 3 mg/kg/min (approximately 10 times the human exposure) resulted in no evidence of maternal toxicity, or embryotoxicity. However, a daily 30-minute IV dosage of up to 10 mg/kg/min resulted in maternal toxicity and death. Similar studies in rabbits with daily 30-minute IV dosages of up to 1 mg/kg/min resulted in no evidence of maternal toxicity, or embryotoxicity. Rabbits given a daily 30-minute IV dosage of up to 2.5 mg/kg/min resulted in minimal maternal toxicity and increased fetal resorptions (Prod Info BREVIBLOC IV injection, 2007).

3) METOPROLOL

a) Increased postimplantation loss and decreased neonatal survival were observed in rats given doses up to 11 times the maximum human dose of 450 mg/day based on surface area (Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013).

4) NADOLOL

a) RATS, RABBITS, HAMSTERS: In nadolol reproduction studies, rabbits given doses 5 to 10 times greater (based on mg/kg) than the maximum human exposure showed evidence of embryo- and fetotoxicity. Rats and hamsters given the same doses (on a mg/kg basis) did not demonstrate any embryo- or fetotoxicities (Prod Info CORGARD(R) oral tablets, 2007).

5) NEBIVOLOL

a) RATS: In studies in pregnant rats, oral nebivolol doses of 1.25 mg/kg and 2.5 mg/kg during the perinatal period (late gestation, parturition, and lactation) led to decreased body weights. Doses of 5 mg/kg or higher (1.2 times the maximum recommended human dose [MRHD]) led to prolonged gestation, dystocia, and reduced maternal care, with corresponding increases in late fetal deaths and stillbirths, and decreased birth weight, live litter size, and pup survival. Reproductive performance of offspring was not evaluated at the 5-mg/kg dose due to insufficient numbers of surviving pups. Maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD, respectively) during organogenesis in pregnant rats resulted in reduced fetal body weights. Additionally, sternal and thoracic ossification associated with the reduced fetal body weights and slightly increased resorption occurred at the 40-mg/kg/day dose (Prod Info BYSTOLIC(TM) oral tablets, 2007).
b) RABBITS: Pregnant rabbits treated with oral nebivolol 20 mg/kg/day (10 times the maximum recommended human dose) demonstrated no adverse effects on embryofetal viability, sex, weight, or morphology (Prod Info BYSTOLIC(TM) oral tablets, 2007).

6) NEBIVOLOL/VALSARTAN

a) The nebivolol/valsartan combination has not been tested in reproductive animal toxicity studies, but the individual agents have been tested. Embryofetal and perinatal lethality were observed after the administration of nebivolol to pregnant rats during organogenesis at doses 1.2 times the maximum recommended human dose (MRHD) on a body surface area basis. After the administration of nebivolol at maternally toxic doses (5 and 10 times the maximum recommended human dose) to pregnant rats during organogenesis, reduced fetal weights and reversible sternal and thoracic ossification delays occurred. No adverse effects on embryofetal morphology, sex, viability or weight were noted after the administration of nebivolol to pregnant rabbits at doses 10 times the MRHD. The administration of valsartan to rats and rabbits at maternally toxic doses (approximately 9 times the MRHD) during organogenesis or late gestation resulted in decreased fetal and birth weights as well as decreased pup survival rates and slight developmental delays (Prod Info BYVALSON(TM) oral tablets, 2016).

7) PROPRANOLOL

a) RATS: Reduced litter sizes, neonatal deaths, and increased resorption rates were seen in reproductive and developmental studies of propranolol in rats administered doses of 150 mg/kg/day (twice the maximum recommended human dose [MRHD] of 640 mg on a body surface area basis) orally throughout pregnancy and lactation (Prod Info HEMANGEOL(TM) oral solution, 2014).

3.20.4)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects of exposure to carteolol, carvedilol, esmolol, nebivolol, penbutolol, or pindolol during lactation in humans (Prod Info BYVALSON(TM) oral tablets, 2016; Prod Info BREVIBLOC IV injection, 2007; Prod Info BYSTOLIC(TM) oral tablets, 2007; Shannon et al, 2000; Briggs et al, 1998).

B) BREAST MILK

1) Acebutolol, atenolol, betaxolol, labetalol, metoprolol, nadolol, propranolol, and timolol are excreted in human breast milk (Prod Info acebutolol HCl oral capsules, 2015; Prod Info HEMANGEOL(TM) oral solution, 2014; Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013; Prod Info CORGARD(R) oral tablets, 2007; Shannon et al, 2000; Briggs et al, 1998; Devlin et al, 1981; Bauer et al, 1979).
2) Avoid the use of acebutolol during breastfeeding (Prod Info acebutolol HCl oral capsules, 2015).
3) Propranolol is not intended for use in nursing women (Prod Info HEMANGEOL(TM) oral solution, 2014)
4) It is unknown whether carteolol, carvedilol, esmolol, nebivolol, penbutolol or pindolol are excreted in human breast milk (Prod Info BREVIBLOC IV injection, 2007; Prod Info BYSTOLIC(TM) oral tablets, 2007; Shannon et al, 2000; Briggs et al, 1998).
5) ACEBUTOLOL

a) Acebutolol and its major metabolite diacetolol are concentrated in breast milk at milk:plasma ratios of 7.1 and 12.2, respectively (Prod Info acebutolol HCl oral capsules, 2015). Symptoms of beta blockade (hypotension, bradycardia, and tachypnea) were reported in a breastfed infant whose mother was treated with acebutolol 400 mg/day (Boutroy et al, 1986).

6) ATENOLOL

a) CASE REPORT: The breast fed infant of a woman taking atenolol 100 mg/day developed cyanosis, bradycardia and mild hypothermia. Concentration of atenolol in breast milk 1.5 hours after a 50 mg dose was 469 nanograms (ng)/mL. Atenolol concentration in infant serum 48 hours after feeding was 2010 ng/mL and half life was 6.4 hours (Schmimmel et al, 1989).

7) BETAXOLOL

a) Betaxolol is excreted in human breast milk (Prod Info Kerlone(R) oral tablets, 2008). Concentrations of betaxolol in breast milk are high, being about 3 times greater than in blood (Beresford & Heel, 1986). The milk to plasma ratio ranges from 2.5 to 3 (Morselli et al, 1989).

8) BISOPROLOL

a) CASE REPORT: Measurable amounts of amiodarone and desethylamiodarone were found in the milk of a lactating 30-year-old woman following treatment with IV amiodarone, magnesium sulfate, isoproterenol and lidocaine for ventricular tachycardia and ventricular fibrillation. The patient presented with syncope and complete heart block at 36-weeks gestation. A few hours postpartum, the patient developed ventricular tachycardia and fibrillation. Treatment with IV amiodarone, magnesium sulfate, and isoproterenol was initiated. Lidocaine was added to treatment due to recurrent episodes. A transvenous pacemaker was inserted and treatment with amiodarone, magnesium sulfate, isoproterenol, and lidocaine were gradually discontinued. The patient was administered bisoprolol orally 5 mg/day following insertion of the pacemaker. During treatment the patient pumped and discarded her breast milk at which point aliquots of the expressed milk were saved. When assayed, bisoprolol was not detected in the patient samples, however, amiodarone and desethylamiodarone were found. The patient was discharged on postpartum day 9 on bisoprolol 5 mg/day (Khurana et al, 2014).

9) METOPROLOL

a) Metoprolol is a weak base that is concentrated in breast milk. There have been no reports of adverse effects in infants exposed to metoprolol through breast milk. If the lactating mother nurses during treatment with metoprolol, observation of the infant for signs of beta-blockade is advised. The WHO Working Group on Drugs and Human Lactation suggests that metoprolol would be more likely to produce effects in slow metabolizers (mother or infant) of the drug (Bennett PN and the WHO Working Group, 1988).
b) The concentration of metoprolol in 9 lactating patients was about 3.5 times higher in breast milk than in maternal blood samples (Sandstrom & Regardh, 1980). The authors concluded that a 4 kg infant consuming 1 liter of breast milk daily would ingest 20 to 40 times less than the normal daily antihypertensive dose (on a mg/kg basis).
c) Three healthy volunteers were given metoprolol for 4 days at doses ranging from 50 mg twice daily to 100 mg twice daily . Peak breast milk concentrations were 3 times that measured in serum; AUC values were 2.6 to 3.7 times greater in milk than plasma. An infant consuming 75 mL of breast milk at the time of peak maternal milk concentration (2.58 mcmol/L) would receive a dose of less than 0.05 mg. (Liedholm et al, 1981) The authors suggest that unless the breastfed infant had impaired hepatic function or the mother was receiving high doses of metoprolol, breastfeeding need not be stopped during maternal medication.
d) Very small amounts of metoprolol are excreted in human breast milk. An infant would receive a dose of less than 1 mg of metoprolol by consuming 1 liter of breast milk daily (Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013). Metoprolol is considered compatible with breastfeeding by the American Academy of Pediatrics (Anon, 2001). Although metoprolol is concentrated in breast milk, achieving higher levels than in plasma, the concentration in infant plasma is negligible (Shannon et al, 2000).

10) NADOLOL

a) Twelve lactating patients were given nadolol 80 mg daily for 5 days. Steady state serum levels were achieved by the third day. The mean steady state nadolol concentration in breast milk was 357 nanograms (ng)/mL; the simultaneously measured mean serum concentration was 77 ng/mL (mean milk: plasma ratio of 4.6). The calculated amount of nadolol ingested by a 5 kg nursing infant would be about 2% to 7% of the adult therapeutic dose (Devlin et al, 1981a).
b) Nadolol is considered compatible with breastfeeding by the American Academy of Pediatrics (Anon: Committee on Drugs & American Academy of Pediatrics, 1994). Although nadolol is concentrated in breast milk, achieving higher levels than in maternal plasma, the concentration is not expected to result in a pharmacologically significant dose, and the oral bioavailability to the breastfeeding infant is only low to moderate (Devlin et al, 1981a; Bennett PN and the WHO Working Group, 1988a; Atkinson et al, 1988; Anderson, 1991).

11) PROPRANOLOL

a) In nursing mothers, peak breast milk levels were obtained approximately 2 hours after an oral dose and were approximately 50% of the peak plasma concentration. Assuming an average maternal propranolol serum level of 40 ng/mL and ingestion of 1000 mL of breast milk/day by the neonate, a dose of 0.015 to 0.020 mg/day may be ingested by a nursing infant (Levitan & Manion, 1973; Anderson & Salter, 1976; Coltart & Shand, 1970; Taylor & Turner, 1981).
b) Breast milk concentrations of propranolol have been reported as less than 40% of peak plasma concentrations after a single 40-mg dose and approximately 64% of peak plasma after continuous dosing of 40 mg 4 times daily. The authors calculate that the maximal cumulative load ingested by a breastfed infant would be 21 mcg daily, after a maternal dose of 160 mg daily (Bauer et al, 1979a).
c) Other data report higher milk:plasma ratios. Two subjects received single oral doses of 20 to 160 mg at intervals of several days. Plasma concentrations of approximately 150 ng/mL were observed 3 hours after administration of 160 mg. At all doses administered, propranolol breast milk concentrations were about equal to the corresponding plasma concentration (mean milk to plasma ratio of 1) (Karlberg et al, 1974).

C) ANIMAL STUDIES

1) NEBIVOLOL

a) In rat studies, nebivolol or its metabolites cross the placenta and are excreted in breast milk (Prod Info BYSTOLIC(TM) oral tablets, 2007).

2) NEBIVOLOL/VALSARTAN

a) Nebivolol was detected in the milk of lactating rats and levels peaked at 4 hours after single and repeat doses of 2.5 mg/kg/day. Rat pups were exposed to a daily dose of 0.3% of the administered dose. Fifteen minutes after the administration of valsartan 3 mg/kg to pregnant female rats, the drug was detected in the milk (Prod Info BYVALSON(TM) oral tablets, 2016).

3.20.5)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to esmolol, metoprolol, nadolol, or propranolol (Prod Info BREVIBLOC IV injection, 2007; Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013; Prod Info CORGARD(R) oral tablets, 2007; Prod Info HEMANGEOL(TM) oral solution, 2014).

B) ANIMAL STUDIES

1) ACEBUTOLOL

a) RATS: Reproductive performance and fertility were not affected in male and female rats administered acebutolol at doses equivalent to 12 times the maximum recommended human dose. Similar results were found when diacetolol, its active metabolite, was administered to two generations of male and female rats at doses up to 1000 mg/kg/day (Prod Info acebutolol HCl oral capsules, 2015).

2) BETAXOLOL

a) RATS: When betaxolol was given to male and female rats at doses up to 256 mg/kg/day (380 times the maximum recommended human dose), fertility and mating performance were not adversely effected (Prod Info Kerlone(R) oral tablets, 2008).

3) METOPROLOL

a) RATS: Oral doses of metoprolol 3.5 mg/kg (approximately 0.1 times the human dose based on surface area) in rats was associated with reversible adverse effects on spermatogenesis. However, other studies in rats have shown no effect on male fertility (Prod Info Lopressor(R) oral tablets, 2013; Prod Info Lopressor(R) intravenous injection, 2013).

4) NADOLOL

a) RATS: In fertility studies in rats, nadolol did not cause any adverse effects (Prod Info CORGARD(R) oral tablets, 2007).

5) NEBIVOLOL

a) MICE, RATS: In studies of male rats and mice, oral nebivolol doses of 40 mg/kg/day or greater (10 and 5 times the maximum recommended human dose) affected spermatogenesis. In rats, the effects on spermatogenesis were not reversed and possibly worsened during a 4-week recovery period. In mice, the effects were partially reversible (Prod Info BYSTOLIC(TM) oral tablets, 2007).

6) NEBIVOLOL/VALSARTAN

a) The administration of nebivolol to male rats and mice at doses 10 and 5 times the maximum recommended human dose (MRHD), respectively, had irreversible and partially reversible effects on spermatogenesis, respectively. However, valsartan had no adverse reproductive effects when administered at oral doses up to 6 times the MRHD on a body surface area basis (Prod Info BYVALSON(TM) oral tablets, 2016).

7) PROPRANOLOL

a) RATS: One study of both male and female adult rats showed no fertility effects with doses approximately 50 mg/kg or less (up to 0.05% the maximum recommended human dose [MRHD] in adults of 640 mg propranolol) given for 2 generations, starting 60 days prior to mating, and continued throughout pregnancy and lactation. Likewise, juvenile rats experienced no reproductive effects after receiving daily oral dose levels up to 45.6 mg/kg/day (3 times the exposure observed in children at the MRHD) from post-natal day 4 to 21 (Prod Info HEMANGEOL(TM) oral solution, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Specific beta-blocker plasma concentrations are not clinically useful or readily available.
C) No specific lab work is needed in most patients. Beta-blocker toxicity is clinically diagnosed. Obtain an ECG and institute continuous cardiac monitoring. Monitor serum electrolytes and renal function in patients with significant hypotension or dysrhythmias. Monitor blood glucose in children, diabetics, and patients with altered mentation.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor blood glucose in all symptomatic children and diabetic adults or those with altered mental status. Monitor renal function and electrolytes in patients with significant hypotension.
2) SERUM LACTATE: May be elevated in overdose, but it is not an accurate way to predict survival. An 8-year retrospective case review was conducted to determine the utility of a serum lactate concentration as a prognostic indicator for mortality in beta-blocker poisoning. The study included 110 patients with symptomatic beta-blocker poisoning. Of the 110 patients, there were 101 survivors and 9 fatalities. Serum lactate concentrations differed significantly between the survivors and non-survivors, with mean concentrations of 1.6 (0.8 to 4.7) mmol/L and 3.1 (2.2 to 23.3) mmol/L, respectively (p=0.0008). However, there was significant overlap and a cutoff could not be identified that predicted mortality(Megarbane et al, 2010).

4.1.3)

A) OTHER

1) Monitor urine output in hypotensive patients.

4.1.4)

A) OTHER

1) MONITORING

a) Institute continuous cardiac monitoring and follow serial ECGs.
b) Transthoracic electrical bioimpedance (TEB) monitoring was useful in guiding appropriate resuscitation measures in a 61-year-old woman following a severe metoprolol overdose ingestion (Bass et al, 1999).

Radiographic Studies

1) Obtain a chest x-ray in patients with respiratory depression, significant hypotension or evidence of pulmonary edema (secondary to acute lung injury or cardiogenic shock).

Methods

1) ACEBUTOLOL: An HPLC method for determining acebutolol concentration in plasma has been described (Sangster et al, 1983).
2) ALPRENOLOL: A gas liquid chromatographic method for determining alprenolol concentrations in plasma has been described (Rawlins et al, 1974).
3) BISOPROLOL: An HPLC method for determining bisoprolol concentration in plasma has been described (Tracqui et al, 1990).
4) METOPROLOL: A gas chromatographic method with UV spectrophotometry and a GCMS method for determining metoprolol concentrations in biological samples have been described (Rohrig et al, 1987; Riker et al, 1987).
5) OXPENOLOL: A gas chromatographic method with a tritium radio-tracer has been used for determining oxprenolol concentrations in biological fluids (Riess et al, 1970).
6) PROPRANOLOL: Gas chromatographic, gas-liquid chromatographic, and ultraviolet spectrophotometric methods for determining propranolol concentrations in biological fluids have been described (Gault et al, 1977; Jones et al, 1982).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Symptomatic patients should be admitted for further observation/treatment until they are asymptomatic for a period of several hours without therapy. Patients with cardiovascular symptoms (hypotension, bradycardia) or central nervous system toxicity (somnolence, seizures, coma) should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Healthy, asymptomatic patients with the following inadvertent single substance ingestions may be monitored at home (IR = Immediate Release, SR = Sustained Release) (Wax et al, 2005):

1) ACEBUTOLOL: ADULT; 600 mg or less; CHILD: 12 mg/kg or less
2) ATENOLOL: ADULT: 200 mg or less; CHILD: 2 mg/kg or less
3) CARVEDILOL: ADULT: 50 mg or less; CHILD: 0.5 mg/kg or less
4) LABETALOL: ADULT: 400 mg or less; CHILD: 20 mg/kg or less
5) METOPROLOL: ADULT: 450 mg or less IR or 400 mg or less SR; CHILD: 2.5 mg/kg or less IR or 5 mg/kg SR
6) NADOLOL: ADULT: 320 mg or less; CHILD: 2.5 mg/kg or less
7) PROPRANOLOL: ADULT: 240 mg or less; CHILD: 4 mg/kg or less IR or 5 mg/kg or less SR
8) TIMOLOL: ADULT: 30 mg or less (tablets); CHILD: No safe dose

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (hypotension, seizures, dysrhythmias), or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) OBSERVATION CRITERIA: Patients with underlying cardiovascular or respiratory disease, those who co-ingest calcium channel blockers, and those with deliberate overdose of beta-blocking agents should have a baseline ECG and be monitored for a minimum of 6 hours (at least 8 hours if a sustained release formulation is involved). Patients with the following inadvertent single substance ingestions should be referred to a healthcare facility (IR = immediate release, SR = sustained release) (Wax et al, 2005):

1) ACEBUTOLOL: ADULT: greater than 600 mg; CHILD: greater than 12 mg/kg
2) ATENOLOL: ADULT: greater than 200 mg; CHILD: greater than 2 mg/kg
3) CARVEDILOL: ADULT: greater than 50 mg; CHILD: greater than 0.5 mg/kg
4) LABETALOL: ADULT: greater than 400 mg; CHILD: greater than 20 mg/kg
5) METOPROLOL: ADULT: greater than 450 mg IR or greater than 400 mg SR; CHILD: greater than 2.5 mg/kg IR or greater than 5 mg/kg SR
6) NADOLOL: ADULT: greater than 320 mg; CHILD: greater than 2.5 mg/kg
7) PROPRANOLOL: ADULT: greater than 240 mg; CHILD: greater than 4 mg/kg IR, or greater than 5 mg/kg SR
8) TIMOLOL: ADULT: greater than 30 mg (tablets); CHILD: any amount

Monitoring

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) GASTRIC LAVAGE

1) Gastric lavage, followed by activated charcoal, may be considered following beta-blocker overdose. Because gastric lavage may increase vagal tone, it has been recommended that atropine be administered prior to gastric lavage or intubation (Soni et al, 1983).
2) Pretreatment with atropine is NOT recommended routinely. An intravenous line should be established, and atropine should be readily available for administration if bradycardia occurs during the lavage procedure.
3) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

4) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

5) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

6) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

7) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

B) ACTIVATED CHARCOAL

1) EFFICACY

a) Activated charcoal (3 grams administered over 9 hours) reduced the area under the curve in healthy subjects ingesting nadolol (Du Souich et al, 1983).
b) CHARCOAL ADMINISTRATION

1) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

c) CHARCOAL DOSE

1) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

a) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

2) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) WHOLE BOWEL IRRIGATION

1) Consider whole bowel irrigation in patients with ingestion of large amounts of sustained release products.

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

6.5.3)

A) MONITORING OF PATIENT

1) Institute continuous cardiac monitoring and obtain serial ECGs. Monitor vital signs frequently. Administer oxygen and evaluate for the need for endotracheal intubation. Obtain intravenous access.

B) HYPOTENSIVE EPISODE

1) Administer intravenous fluids judiciously to avoid volume overload. Glucagon, calcium, catecholamines, insulin/dextrose, and phosphodiesterase inhibitors should be considered in patients who do not respond to intravenous fluids.
2) INTRAVENOUS FLUIDS

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer glucagon.

3) GLUCAGON

a) Glucagon is considered a first-line antidotal therapy for beta-blocker poisoning (Shepherd, 2006). Administer an initial bolus of 50 to 150 micrograms/kilogram (usually about 10 milligrams in adults) over 1 minute; follow this with a continuous intravenous infusion of 50 to 100 micrograms/kilogram/hour (DeWitt & Waksman, 2004). Alternatively, administer a 5 mg glucagon bolus, and repeat every 5 to 10 minutes for up to 3 doses if necessary. If the patient has a response at a particular dose, start an hourly infusion of glucagon at the response dose (eg, if a patient responds to 10 mg, then start an infusion at 10 mg per hour).
b) Glucagon may produce a positive chronotropic and inotropic cardiac effect, which occurs despite beta-blockage. The drug has been reported to increase myocardial contractility in patients refractive to isoproterenol. Glucagon is thought to activate the adenylate cyclase system at a different site than isoproterenol (Kosinski & Malindzak, 1973).
c) Numerous case reports describe hemodynamic improvement in patients treated with glucagon following beta blocker overdose (Ward & Jones, 1976; Illingsworth, 1979; Chen et al, 1985; Khan & Miller, 1985; Kosinski, 1971; O'Mahony et al, 1990; Ehgartner & Zelinka, 1988; Agura et al, 1986; Kenyon et al, 1988; Peterson et al, 1984; Wilkinson, 1986; Vadhera, 1992).

1) Most of these patients were receiving multiple therapeutic interventions at the time of hemodynamic improvement (e.g. fluids, atropine, dopamine, epinephrine, isoproterenol, and pacing).
2) Continuous intravenous infusion of 10 milligrams/hour of glucagon was associated with improvement in systolic blood pressure to normal levels during a 2 hour period in a 16-year-old girl following an 8 gram ingestion of oxprenolol (O'Mahony et al, 1990).
3) Glucagon has also been used to treat patients who developed symptomatic bradycardia while taking therapeutic doses of beta blocking drugs (Love & Howell, 1997).

d) ANIMAL STUDIES

1) In a canine model of severe propranolol toxicity, glucagon infusion increased cardiac output, heart rate and stroke volume, and decreased arteriolar resistance and left ventricular end diastolic pressure compared with controls, without affecting mean arterial pressure or QRS duration (Love et al, 1992).
2) In a canine model of severe propranolol toxicity, glucagon increased cardiac output and heart rate without correcting the decreased stroke volume, increased central venous pressure, or increased capillary wedge pressure induced by propranolol (Sato et al, 1994).
3) In a canine model of severe propranolol toxicity glucagon increased heart rate and myocardial contractility and decreased coronary vascular resistance without increasing mean arterial pressure (Kosinski & Malindzak, 1973).

4) CATECHOLAMINES

a) Consider catecholamines in patients who do not respond to intravenous fluids, glucagon, and calcium.
b) DOPAMINE

1) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
2) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

c) NOREPINEPHRINE

1) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
2) DOSE

a) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
b) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
c) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

5) INSULIN/DEXTROSE

a) Consider high-dose insulin euglycemia therapy in patients who require catecholamines despite treatment with intravenous fluids, glucagon, and calcium. High-dose insulin euglycemia therapy may allow the practitioner to decrease the dose of catecholamines and avoid the adverse effects of prolonged high-dose catecholamines.
b) DOSE

1) Intravenous insulin infusion with supplemental dextrose, and potassium as needed, is recommended in patients with severe or persistent hypotension after calcium channel blocker overdose, and may also be effective for beta blocker overdose. Before, during, and after the therapy, monitor for hypoglycemia and hypokalemia.
2) Administer a bolus of 1 unit/kilogram of insulin followed by an infusion of 0.1 to 1 units/kilogram/hour, titrated to a systolic blood pressure of > 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to determine the need for higher rates of insulin infusion.

a) In some refractory cases, more aggressive high-dose insulin protocols have been suggested, starting with a 1 unit/kg insulin bolus, followed by a 1 unit/kg/hour continuous infusion. If there is no clinical improvement in the patient, the infusion rate may be increased by 2 units/kg/hour every 10 minutes, up to a maximum of 10 units/kg/hour (Engebretsen et al, 2011).

3) Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (adults 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hour in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued
4) Administer supplemental potassium initially if patient is hypokalemic (serum potassium <2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L.
5) CASE REPORT: Use of high-dose insulin (10 International Units/kg) was successful in a 5-gram metoprolol ingestion. Hypotension was unresponsive to conventional therapies (Page et al, 2009).
6) CASE REPORT: Administration of intravenous fat emulsion (IFE) combined with high-dose insulin was successfully used in a 48-year-old man who developed cardiac arrest following a suspected ingestion of nebivolol (300 mg), baclofen, and diazepam, as well as cocaine use. On presentation to the ED (approximately 3 hours postingestion), the patient was unresponsive with a Glasgow Coma score of 3, blood pressure of 92/52 mmHg, and a heart rate of 72 bpm. Approximately 5 hours later, the patient's heart rate decreased to 35 bpm, his systolic blood pressure decreased to 50 mmHg, and he developed bradyasystolic cardiac arrest. Resuscitative measures included CPR, 2 boluses each of atropine 1 mg and epinephrine 1 mg, administered 4 minutes apart, and 100 mL bolus of 20% IFE. Approximately 1 minute later, the patient's heart rate and blood pressure increased to 123 bpm and 251/162 mmHg, respectively, however bradycardia and hypotension recurred within 20 minutes, necessitating initiation of a 20% IFE infusion of 0.25 mL/kg/min continued over an hour, along with administration of an IV bolus of 100 units regular insulin, followed by a high-dose insulin infusion (up to 21.8 units/kg/hour). Supportive care included calcium (117 mEq) and dextrose (485 g) in order to maintain euglycemia. Over the next several days, the patient's hemodynamic status gradually normalized, and he was discharged on hospital day 11 without neurologic sequelae (Stellpflug et al, 2010).
7) CASE REPORT: A 59-year-old man developed hypotension and bradycardia after ingesting 7.5 g (75 mg/kg) of metoprolol. Initial treatment included IV atropine 1.5 mg, glucagon 6 mg, and a dopamine infusion of 10 mcg/kg/minute. However, despite treatment, the patient's condition worsened and he developed cardiac arrest. During cardiopulmonary resuscitation, the patient was administered hyperinsulinemia/euglycemia (HIE) therapy (a 100 international unit (1-international unit/kg) bolus of regular insulin and a 100 mL bolus of dextrose 50%), vasopressor therapy with epinephrine and norepinephrine, and a 20% IV lipid emulsion bolus of 150 mL (1.5 mL/kg), resulting in return of spontaneous circulation (ROSC). Following ROSC, treatment continued with calcium gluconate administration, HIE therapy (a regular insulin infusion of 100 international units/hour (1 international unit/kg/hour) titrated to 250 international units/hour, and a 10% dextrose infusion at 200 mL/hour, along with 2 bolus doses of regular insulin at 100 international units each), a second IV lipid emulsion bolus (150 mL), and vasopressor support, with gradual return of hemodynamic stability. He was discharged 5 days post-admission without neurologic sequelae (Barton et al, 2015).
8) CASE REPORT: A 47-year-old man presented to the emergency department with severe hypotension (41/palpable mmHg) and comatose approximately 95 minutes after intentionally ingesting 10 g of metoprolol. Despite IV fluids and vasopressor administration, his hypotension persisted, a cardiac ultrasonography revealed diffuse global hypokinesis. Approximately 40 minutes post-presentation, the patient developed cardiac arrest with narrow-complex pulseless electrical activity (PEA) and CPR was administered. Although the patient developed a transient pulse with minimal improvement in blood pressure, PEA returned. Because of his hemodynamic instability, treatment was initiated with high dose insulin (IV bolus of 250 units regular insulin), intralipid therapy (100 mL IV bolus following by a 200 mL/30 minute infusion), and veno-arterial extracorporeal membrane oxygenation (ECMO), at a flow rate of 5 L/minute, with continued vasopressor support. The patient showed gradual neurologic improvement approximately 8 hours after beginning ECMO (11.5 hours post-ingestion), spontaneously moving his extremities and able to follow commands. After 50 hours of treatment, ECMO was stopped. The patient continued to improve and was discharged to an inpatient psychiatric facility on hospital day 10. Serum metoprolol concentration, obtained 4.5 hours post-ingestion, was 25,000 ng/mL (therapeutic range, 20 to 340 ng/mL) (Escajeda et al, 2015).
9) CASE REPORT/INFANT: A 7-month-old girl, receiving propranolol therapy to treat a hemangioma, was inadvertently administered 36 mg for 3 doses (17 mg/kg) instead of the prescribed 3.6 mg three times daily, and presented with bradycardia and lethargy. Her peripheral pulses were weak and a blood pressure was unable to be obtained after 7 attempts. Following administration of IV fluids, her systolic blood pressure was in the 80s; however, her bradycardia persisted despite an IV infusion of 20% lipid emulsion at a dose of 1.5 mL/kg. High dose insulin was then started with boluses of 1 unit/kg regular insulin and 1 g/kg dextrose, resulting in blood pressure and heart rate measurements of 85/46 mmHg and 111 beats/minute, respectively, although weak peripheral pulses persisted. Infusions of insulin at 1 unit/kg/hour and dextrose at 0.5 g/kg/hour were then initiated, resulting in an improvement in her peripheral pulses and increasing alertness. Other than one episode of hypoglycemia (30 mg/dL) that resolved quickly, she recovered uneventfully. The insulin and dextrose infusions were discontinued 3 hours and 7 hours, respectively, after the initial boluses, and she was discharged the following day (Montague et al, 2015).
10) CASE SERIES: A single center, retrospective case review was conducted of patients who received high-dose insulin (HDI) therapy following intentional overdoses (n=11) or for treatment of multifactorial shock (n=3). The patients had either taken beta-blockers as a single agent (n=9), calcium channel blockers as a single agent (n=2), or a combination of beta blockers and calcium channel blockers (n=3). The average age of patients was 54 years (range 24 to 87 years). Of the 14 patients, 11 received dual therapy with HDI and vasopressor/inotrope support, and 3 patients received HDI only. The mean maximum HDI infusion dose was 6 units/kg/hour (range 0.5 to 10 units/kg/hour) with a mean duration of 22 hours (range 1 to 75 hours), and the vasopressor/inotropes administered included norepinephrine (n=9; mean maximum dose (MMD) 0.32 mcg/kg/min), dopamine (n=6; MMD 15 mcg/kg/min), phenylephrine (n=2; MMD 2.3 mcg/kg/min), vasopressin (n=5; MMD 0.04 unit/min), epinephrine (n=2; MMD 0.2 mcg/kg/min), and methylene blue (n=1; MMD 0.75 mg/kg/hour). Adverse effects of therapy included hypoglycemia (n=7), hypokalemia (n=5), and pulmonary edema (n=3). Of the 14 patients, 11 patients survived and the 3 deaths were from elderly patients who had developed multifactorial shock after receiving beta blockers during hospitalization (Robinson et al, 2015).
11) TISSUE PERFUSION MONITORING: A 51-year-old man presented to the emergency department after ingesting 40 25-mg metoprolol tablets and an unknown amount of 5 mg amlodipine tablets. The patient was obtunded with vital signs indicating hypotension (systolic blood pressure in the 50s) and bradycardia (heart rate in the 20s). The patient was intubated and treatment included IV epinephrine and calcium gluconate boluses, and high dose insulin started at 1 unit/kg/hour. Repeat vital sign measurements demonstrated a blood pressure of 79/49 and a heart rate of 39. Tissue perfusion monitoring was started with an initial reading of 69% (normal 75% to 85%). An epinephrine infusion was initiated at 0.1 mcg/kg/hour and his high dose insulin infusion was increased to 10 units/kg/hour, resulting in an increase in the tissue perfusion monitoring measurements to 73% to 75% in direct correlation with mean arterial pressure (MAP) measurements ranging from 56 to 64 mmHg. Following transfer to an intensive care setting, tissue perfusion monitoring was used over the next 2 days to guide resuscitative efforts, with monitor readings increasing to the high 70s resulting in discontinuation of epinephrine and high dose insulin therapy. It is suggested that tissue perfusion monitoring correlates well with MAP measurements, used as a surrogate measure of tissue perfusion, and may be helpful in guiding high dose insulin therapy in patients with beta blocker and calcium channel blocker overdoses (Paetow et al, 2015).

c) ANIMAL STUDIES

1) In a canine model of propranolol toxicity, insulin infusion (4 IU/minute with sufficient 50% dextrose administered to maintain blood glucose within 10% of baseline values) was associated with improved survival, contractility, and blood pressure (Kerns et al, 1997).
2) A study in pigs was conducted, comparing the efficacy of using insulin and dextrose versus vasopressin and epinephrine as resuscitative agents in the treatment of beta-blocker toxicity. The primary outcome measure was survival over 4 hours. Secondary endpoints that were measured included cardiac output (CO), heart rate (HR), mean arterial pressure (MAP), systemic vascular resistance (SVR), and central venous pressure (CVP).

a) In the group who received insulin and dextrose , 100% of the pigs (n=5) survived 4 hours as compared with the vasopressin/epinephrine group where there was 0% survival (n=5), with all of the pigs dying within 1.6 hours from the start of resuscitation. Measurement of the secondary endpoints showed that, in the insulin/dextrose group, HR increased, SVR decreased, there was continued maintenance of MAP over time, and a marked increase in CO. With the vasopressin/epinephrine group, there was a marked increase in MAP until 30 minutes after receiving medication, followed by a significant decrease until death. SVR showed similar results, and CO and HR continuously decreased until death (Holger et al, 2007).

6) LIPID EMULSION THERAPY

a) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
b) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):

1) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
2) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
3) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
4) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

c) HUMAN CASE REPORTS

1) Administration of intravenous fat emulsion (IFE) combined with high-dose insulin was successfully used in a 48-year-old man who developed cardiac arrest following a suspected ingestion of nebivolol (300 mg), baclofen, and diazepam, as well as cocaine use. On presentation to the ED (approximately 3 hours postingestion), the patient was unresponsive with a Glasgow Coma score of 3, blood pressure of 92/52 mmHg, and a heart rate of 72 bpm. Approximately 5 hours later, the patient's heart rate decreased to 35 bpm, his systolic blood pressure decreased to 50 mmHg, and he developed bradyasystolic cardiac arrest. Resuscitative measures included CPR, 2 boluses each of atropine 1 mg and epinephrine 1 mg, administered 4 minutes apart, and 100 mL bolus of 20% IFE. Approximately 1 minute later, the patient's heart rate and blood pressure increased to 123 bpm and 251/162 mmHg, respectively, however bradycardia and hypotension recurred within 20 minutes, necessitating initiation of a 20% IFE infusion of 0.25 mL/kg/min continued over an hour, along with administration of an IV bolus of 100 units regular insulin, followed by a high-dose insulin infusion (up to 21.8 units/kg/hour). Supportive care included calcium (117 mEq) and dextrose (485 g) in order to maintain euglycemia. Over the next several days, the patient's hemodynamic status gradually normalized, and he was discharged on hospital day 11 without neurologic sequelae (Stellpflug et al, 2010).
2) A 27-year-old woman presented to the ED approximately 1 hour after intentionally ingesting 7 g propranolol. She was comatose (GCS 3) with hypotension, bradycardia, and generalized tonic-clonic seizures. An ECG indicated severe sinus broad complex bradycardia. Despite supportive therapies, including administration of glucagon, insulin, and vasopressors, her hypotension and bradycardia persisted. IV lipid emulsion therapy was then initiated, 100 mL bolus of 20% intralipid followed by an infusion of 400 mL over 20 minutes. Following intralipid therapy, the patient recovered, with gradual discontinuation of vasopressor and glucagon therapy, and was referred for psychiatric care (Dean et al, 2010).
3) A 31-year-old woman presented to the ED comatose and hypotensive (80/45 mmHg), with generalized seizures, approximately 2 hours after ingesting 3.6 g propranolol and an unknown amount of ethanol. An ECG showed nonspecific intraventricular conduction delay followed by supraventricular tachycardia with wide QRS complex. Toxicological analysis of the patient's blood revealed a propranolol concentration of 4.21 mg/L and an ethanol concentration of 2.42 g/L. Despite treatment with glucagon, insulin, sodium bicarbonate, diazepam and dopamine, the patient continued to deteriorate clinically, prompting a decision to start IV lipid emulsion therapy, with a 100 mL bolus of 20% intralipid followed by an infusion of 400 mL over a 20-minute period. Following intralipid therapy, the patient's condition improved with discontinuation of seizures and an increase in blood pressure (110/50 mmHg); however, within 30 minutes after cessation of intralipid treatment, her blood pressure once again decreased to 70/30 mmHg. Intralipid therapy was restarted 60 minutes after the first dose, with an infusion of 500 mL 20% intralipid at a rate of 10 mL/min. The patient rapidly improved with a return of sinus rhythm and an increase in blood pressure to 120/60 mmHg. The patient remained stable, and was transferred to the psychiatric unit the next day (Jovic-Stosic et al, 2011).
4) A 32-year-old woman developed hypotension and sinus bradycardia after intentionally ingesting 475 mg of metoprolol in a suicide attempt. IV lipid emulsion (ILE) therapy was initiated with a 100 mL bolus dose followed by a 0.5 mL/kg/min infusion for 2 hours (total dose 3100 mL). The patient's blood pressure and heart rate increased 2 hours following therapy. Although her urine color was red, suspected to be due to ILE therapy, she had no signs and symptoms related to metoprolol intoxication, and she was discharged 24 hours post-admission following psychiatric consultation. Four days later, she presented to the emergency department with elevated pancreatic enzymes (amylase 249 units/L, lipase 438 units/L) leading to a diagnosis of minimal change pancreatitis, a complication related to ILE therapy (Eren Cevik et al, 2014).
5) After ingesting 80 tablets of metoprolol 25 mg and buPROPion 150 mg, a 50-year-old woman developed severe bradycardia and hypotension (HR 40 beats/min; mean arterial pressure 40 mmHg), refractory to calcium salts, catecholamines, and high-dose insulin. About 30 seconds after receiving 100 mL of 20% intravenous fat emulsion (IFE), she developed brady-asystolic arrest, but her pulse returned to normal after 3 minutes of cardiopulmonary resuscitation (CPR). Despite aggressive supportive care, her condition worsened and she died of multisystem organ failure on day 4. Another patient, a 53-year-old man, developed bradycardia and hypotension (HR 30 beats/min; mean arterial pressure 40 mmHg) after ingesting diltiazem 3600 mg and propranolol 1200 mg. Despite treatment with calcium salts, catecholamines, high-dose insulin, bicarbonate, and atropine, his condition did not improve. Within 1 minute of receiving 150 mL of 20% IFE he developed brady-asystolic arrest, but his pulse returned to normal after 6 minutes of CPR. Despite aggressive supportive care, his condition deteriorated and he died of multisystem organ failure on day 7. Although the exact cause of arrests in these patients is uncertain, several possible causes were suggested: IFE interaction with other resuscitation drugs, a sudden increase in absorption of drug in the GI tract, a brief lack of oxygen in the lipid-laden blood circulating in the coronary vessels contributing to the arrests, fatal ingestions of drugs regardless of therapy (Cole et al, 2014).
6) A 59-year-old man developed hypotension and bradycardia after ingesting 7.5 g (75 mg/kg) of metoprolol. Initial treatment included IV atropine 1.5 mg, glucagon 6 mg, and a dopamine infusion of 10 mcg/kg/minute. However, despite treatment, the patient's condition worsened and he developed cardiac arrest. During cardiopulmonary resuscitation, the patient was administered hyperinsulinemia/euglycemia (HIE) therapy vasopressor therapy with epinephrine and norepinephrine, and a 20% IV lipid emulsion bolus of 150 mL (1.5 mL/kg), resulting in return of spontaneous circulation (ROSC). Following ROSC, treatment continued with calcium gluconate administration, HIE therapy, a second IV lipid emulsion bolus (150 mL), and vasopressor support, with gradual return of hemodynamic stability. He was discharged 5 days post-admission without neurologic sequelae (Barton et al, 2015).
7) A 47-year-old man presented to the emergency department with severe hypotension (41/palpable mmHg) and comatose approximately 95 minutes after intentionally ingesting 10 g of metoprolol. Despite IV fluids and vasopressor administration, his hypotension persisted, a cardiac ultrasonography revealed diffuse global hypokinesis. Approximately 40 minutes post-presentation, the patient developed cardiac arrest with narrow-complex pulseless electrical activity (PEA) and CPR was administered. Although the patient developed a transient pulse with minimal improvement in blood pressure, PEA returned. Because of his hemodynamic instability, treatment was initiated with high dose insulin (IV bolus of 250 units regular insulin), intralipid therapy (100 mL IV bolus following by a 200 mL/30 minute infusion), and veno-arterial extracorporeal membrane oxygenation (ECMO), at a flow rate of 5 L/minute, with continued vasopressor support. The patient showed gradual neurologic improvement approximately 8 hours after beginning ECMO (11.5 hours post-ingestion), spontaneously moving his extremities and able to follow commands. After 50 hours of treatment, ECMO was stopped. The patient continued to improve and was discharged to an inpatient psychiatric facility on hospital day 10. Serum metoprolol concentration, obtained 4.5 hours post-ingestion, was 25,000 ng/mL (therapeutic range, 20 to 340 ng/mL) (Escajeda et al, 2015).

7) CALCIUM

a) Calcium chloride has been effective for propranolol, concurrent administration of atenolol and verapamil, and a mixed metoprolol/verapamil overdose that were refractory to conventional therapy (Sakurai et al, 2000; Koppel et al, 1995; Brimacombe et al, 1991). At high doses, propranolol blocks the calcium channels that may induce the asystole, AV block, and depressed myocardial contraction (Smith, 1991) .
b) Administer calcium chloride 0.2 mL/kg or calcium gluconate 0.6 mL/kg intravenously (DeWitt & Waksman, 2004). May repeat every 10 to 20 minutes for 3 or 4 doses, consider an infusion if patient responds.
c) In a canine model of severe propranolol toxicity calcium chloride (0.125 milliliters/kilogram of 10% CaCl bolus followed by an infusion of 0.375 milliliters/kilogram for 30 minutes) improved cardiac index and stroke volume, and induced earlier recovery of mean arterial pressure and peripheral vascular resistance (Love et al, 1996).
d) CASE REPORT: Calcium chloride was successfully used in a 56-year-old woman with shock and first-degree heart block after an intentional atenolol overdose. The following were administered without effect: glucagon, epinephrine, atropine, ephedrine, and high-dose dopamine. After 1 gram of calcium chloride, blood pressure improved. Recurrence of hypotension resolved after a second dose of calcium chloride (O'grady et al, 2001).

8) PHOSPHODIESTERASE INHIBITORS

a) INAMRINONE

1) CASE REPORT: A 37-year-old woman developed hypotension, bradycardia, depressed mental status, decreased cardiac index and seizures after receiving 800 mg labetalol for severe hypertension. Treatment with intravenous fluids, dopamine, phenylephrine and glucagon was associated with an increase in blood pressure without improvement in mental status. Amrinone infusion was successful in increasing cardiac index, decreasing pulmonary capillary wedge pressure, and improved mental status (Kollef, 1994).
2) STUDY: In a canine model of severe propranolol toxicity, amrinone infusion increased cardiac output and stroke volume, and decreased arteriolar resistance and left ventricular end diastolic pressure compared with controls, without affecting heart rate, mean arterial pressure or QRS duration (Love et al, 1992).

b) MILRINONE

1) STUDY: In a canine model of severe propranolol overdose, milrinone increased cardiac output, mean arterial pressure, and stroke volume and decreased central venous pressure and pulmonary capillary wedge pressure without affecting heart rate (Sato et al, 1994).
2) In a similar study, the combination of milrinone and glucagon increased cardiac output and mean arterial pressure but induced severe tachycardia in dogs with severe propranolol toxicity (Sato et al, 1995).

c) ENOXIMONE

1) ATENOLOL/VERAPAMIL: After ingesting 2800 mg of atenolol and 1600 mg of verapamil, a 57-year-old man with a history of an ischemic heart disease (two previous acute MIs) developed hypotension (BP 80/50 mmHg), and bradycardia (40 beats/min). An ECG revealed a sinus bradycardia with a first-degree heart block, previously absent. A chest X-ray revealed interstitial pulmonary edema. Despite treatment with fluid resuscitation, calcium salts, and norepinephrine/epinephrine inotropic support, only a modest hemodynamic improvement was observed. Following treatment with a bolus of enoximone 1 mg/kg and a continuous infusion at 0.5 mcg/kg/min, his hemodynamic status improved (Sandroni et al, 2004).
2) METOPROLOL: A 55-year-old man who ingested 10 grams of metoprolol developed bradycardia and hypotension refractory to epinephrine, calcium, glucagon, and atropine. Right heart catheterization revealed depressed cardiac output (1.3 liters/minute) and stroke volume (19 milliliters). She was treated with a bolus of 0.5 milligrams of enoximone followed by an infusion of 15 micrograms/kilogram/minute with subsequent improvement in her cardiac output and stroke volume, and her clinical status improved over 48 hours (Hoeper & Boeker, 1996).
3) PROPRANOLOL: Two patients developed cardiac arrest following propranolol exposure and recovered uneventfully following enoximone administration. The first patient, a 38-year-old woman, developed sinus bradycardia progressing to cardiac arrest following a 1.5 milligram IV bolus dose of propranolol. Despite aggressive cardiac resuscitative measures for 15 minutes, the patient's condition did not improve. Following administration of a 100-milligram IV bolus of enoximone, the patient's hemodynamic status improved and she was subsequently discharged without sequelae. The second patient, a 50-year-old man, developed cardiac arrest, after intentionally ingesting 1.6 grams of propranolol, as well as 150 milliliters of hydrochloric acid and an unknown amount of oxazepam. The patient gradually recovered following administration of a 100-milligram IV bolus dose of enoximone followed by an infusion of 5 micrograms/kilogram/minute, as well as inotropic support with dopamine and norepinephrine (Sandroni et al, 2006).

9) SODIUM/SODIUM BICARBONATE

a) CASE REPORT/MIXED INGESTION: A 24-year-old woman ingested 7360 mg propranolol LA, 1350 mg paroxetine and 140 mg diazepam. She developed CNS depression, hypotension, metabolic acidosis, and cardiorespiratory arrest. She was treated with intravenous bicarbonate (100 mL 8.4% sodium bicarbonate), isoprenaline, epinephrine, glucagon and intravenous fluids, but continued to have recurrent cardiac arrest (primarily pulseless electrical activity) and a widening QRS complex. She was then given a 300 mL bolus of 8.4% sodium bicarbonate with narrowing of the QRS complex and return of cardiac output. She went on to recover completely (Shanker et al, 2003).
b) CASE REPORT: A 48-year-old man developed ventricular tachycardia after ingesting approximately 6.4 grams of acebutolol and ethanol (Donovan et al, 1997). He converted to sinus rhythm after receiving 50 mEq of sodium bicarbonate as an intravenous bolus.
c) ANIMAL STUDY: The effect of sodium bicarbonate on propranolol-induced cardiovascular toxicity in canines was evaluated. A Propranolol infusion of 10 milligrams/kilogram was given, resulting in a decrease in heart rate and mean arterial pressure, and a prolonged QRS interval. Two minutes after completion of the propranolol infusion was given, a bolus of 1.5 mEq/kg of sodium bicarbonate solution, followed by an infusion of 1.5 mEq/kg over the next 26 minutes, was given. There appeared to be no improvement in the cardiovascular parameters, of the canines, following administration of the sodium bicarbonate solution (Love, 2000).
d) In an isolated rat heart model, hypertonic saline and dantrolene restored the ability to pace hearts after propranolol intoxication (Kerns et al, 1997).

10) ISOPROTERENOL

a) MECHANISM OF ACTION: Is a beta agonist which will competitively antagonize the effect of the beta-blocker.
b) CAUTION: Hypotension may be aggravated by isoproterenol necessitating careful monitoring of blood pressure and titration of dose (norepinephrine or dopamine may be preferable in severely hypotensive patients). A combination infusion of dopamine and isoproterenol seemed to be more effective than glucagon alone in treating beta-blocker toxicity in the dog model (Dymowski & Turnbull, 1986).
c) ISOPROTERENOL INDICATIONS

1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) Massive beta-blocker ingestions have been reported to require up to 200 micrograms/minute or more along with glucagon for effective treatment (Agura et al, 1986; Hicks & Rankin, 1991).

11) PRENALTEROL

a) Prenalterol (a beta agonist) has been used successfully in high doses for the treatment of atenolol, propranolol and metoprolol poisoning (Wallin & Hulting, 1983; Kulling, 1982; Kulling et al, 1983; Lindvall et al, 1985; Freestone et al, 1986). Its actual role is yet to be determined, since these patients were also treated with conventional therapy. Prenalterol is not available in the USA.
b) In a canine model of severe metoprolol toxicity prenalterol increased blood pressure, cardiac output and stroke volume, and decreased central venous pressure, pulmonary capillary wedge pressure and peripheral resistance (Andersson et al, 1982).

12) INTRA-AORTIC BALLOON PUMP

a) Intra-aortic balloon pump has been used successfully after pharmacologic therapy failed in cases of severe propranolol and atenolol poisoning (Lane et al, 1987; Koppel et al, 1994).

13) EXTRACORPOREAL CIRCULATION

a) CASE REPORT: Extracorporeal support and hemoperfusion were used to treat a 20-year-old woman with bradycardia and hypotension unresponsive to fluids, atropine, glucagon, isoproterenol, epinephrine and cardiac pacing after propranolol overdose (McVey & Corke, 1991). She survived neurologically intact.
b) CASE REPORT: Extracorporeal membrane oxygenation (ECMO) was used to provide hemodynamic support for a 28-year-old woman with dysrhythmias, hypotension and heart failure unresponsive to glucagon, dopamine, norepinephrine, epinephrine, and a pacemaker (Rooney et al, 1996). The patient's course was complicated by ischemic hepatitis, acute tubular necrosis and intravenous catheter related deep vein thrombosis, but she survived.
c) CASE REPORT: A 38-year-old woman, who intentionally ingested 5.32 grams of betaxolol, 30 grams of lorazepam, and an unknown amount of alcohol, was treated with ECMO after developing cardiogenic shock unresponsive to isoproterenol, dobutamine, epinephrine, norepinephrine, and glucagon. The patient's hemodynamic status improved, but her clinical course was complicated by development of a hematoma of her thigh, resulting in ischemia of the leg requiring surgical intervention (Bilbault et al, 2007).
d) CASE REPORT: Extracorporeal life support (ECLS) was used successfully in a 15-year-old girl with a mixed verapamil and propranolol ingestion. The patient presented to the hospital with asystole and, after 70 minutes of cardiopulmonary resuscitation, there was no clinical improvement. Cardiac arrest persisted and ECLS was initiated. Various dysrhythmias were observed while on ECLS. At approximately 70 hours, ECLS was terminated and the patient had a perfusing sinus rhythm with normal QRS and QTc. The patient made a complete recovery (Kolcz et al, 2007).
e) CASE REPORT: A 36-year-old man presented to the ED with decreased level of consciousness, dyspnea, hypoxemia (O2 sat 91%), and hypotension (80/40 mmHg) approximately 2 hours after intentionally ingesting 10 g atenolol and an unknown amount of nifedipine, lacidipine, fluoxetine, and sertraline. An ECG indicated prolonged QT interval and QRS widening. The patient rapidly deteriorated hemodynamically, developed cardiac arrest (successfully resuscitated), and persistent metabolic acidosis and shock with multiple organ failure despite aggressive decontamination and supportive therapies. ECMO was initiated 2 hours post-admission along with high-volume continuous veno-venous hemofiltration (HV-CVVH). Over the next 48 hours, the patient became hemodynamically stable and was weaned from ECMO; however, the patient's clinical course was complicated by the development of progressive neurologic impairment, resulting in a persistent reduction in motor skills, impaired coordination, gait ataxia, and mild aphasia (Rona et al, 2011).
f) CASE REPORT: A 47-year-old man presented to the emergency department with severe hypotension (41/palpable mmHg) and comatose approximately 95 minutes after intentionally ingesting 10 g of metoprolol. Despite IV fluids and vasopressor administration, his hypotension persisted, a cardiac ultrasonography revealed diffuse global hypokinesis. Approximately 40 minutes post-presentation, the patient developed cardiac arrest with narrow-complex pulseless electrical activity (PEA) and CPR was administered. Although the patient developed a transient pulse with minimal improvement in blood pressure, PEA returned. Because of his hemodynamic instability, treatment was initiated with high dose insulin (IV bolus of 250 units regular insulin), intralipid therapy (100 mL IV bolus following by a 200 mL/30 minute infusion), and veno-arterial extracorporeal membrane oxygenation (ECMO), at a flow rate of 5 L/minute, with continued vasopressor support. The patient showed gradual neurologic improvement approximately 8 hours after beginning ECMO (11.5 hours post-ingestion), spontaneously moving his extremities and able to follow commands. On hospital day 3, the flow rate was decreased to 4 L/minute, and after 50 hours of treatment, ECMO decannulation occurred. The patient continued to improve and was discharged to an inpatient psychiatric facility on hospital day 10. Serum metoprolol concentration, obtained 4.5 hours post-ingestion, was 25,000 ng/mL (therapeutic range, 20 to 340 ng/mL) (Escajeda et al, 2015).

C) HYPOGLYCEMIA

1) HYPOGLYCEMIA should be managed with intravenous dextrose (Frishman & Silvermon, 1979).

D) BRONCHOSPASM

1) BRONCHOSPASM SUMMARY

a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.

2) ALBUTEROL/ADULT DOSE

a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

3) ALBUTEROL/PEDIATRIC DOSE

a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

4) ALBUTEROL/CAUTIONS

a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.

5) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).

E) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Enhanced Elimination

1) SUMMARY: Hemodialysis may be useful in severe cases of atenolol overdoses since atenolol is less than 5% protein bound and 40% to 50% is excreted unchanged in urine. Nadolol, sotalol, and atenolol reportedly are removed by hemodialysis. Acebutolol is dialyzable. Propranolol, metoprolol, and timolol are NOT removed by hemodialysis.
2) ATENOLOL

a) Hemodialysis was begun 6 hours after ingestion of atenolol 3 grams and ethanol in a 61-year-old man with renal insufficiency (BUN 30, serum Cr 2.3 milligrams/deciliter). An atenolol concentration obtained after the first 4-hour run of dialysis was 2.5 micrograms/milliliter; the level was undetectable after a second run of dialysis performed two hours later. A predialysis level was not available. The neurologic status improved after the first dialysis session, enabling extubation. Cardiac dysfunction (sinus bradycardia, heart block) requiring a pacemaker normalized after the second dialysis session (Saitz et al, 1991).
b) Atenolol half life during dialysis was 3 hours compared with 35 hours after dialysis in another case (Bouffard et al, 1984).
c) Serial hemodialysis with charcoal hemoperfusion was successfully used in a patient with end stage renal failure, who was inadvertently given 900 milligrams of atenolol within 24 hours (the recommended atenolol dose is 50 to 100 milligrams daily). With the dialysis treatments, the patient's plasma atenolol levels decreased from 7.4 milligrams/liter to 2.1 milligrams/liter, although significant rebound did occur between dialyses (Salhanick & Wax, 2000).
d) CASE REPORT: A 57-year-old man, with chronic kidney disease, developed bradycardia and hypotension after intentionally ingesting 50 50-mg atenolol tablets. Despite administration of IV fluids, vasopressors, glucagon, and insulin, hypotension and bradycardia persisted. His urine output was 100 to 125 mL/hour. Due to his persistent hypotension and decreased renal function, a trial of hemodialysis was initiated approximately 11 hours post-ingestion. During the 5-hour session, his systolic and diastolic pressures ranged from 90 to 101 mmHg and 49 to 52 mmHg, respectively. Ten hours after completing the first session, his blood pressure and heart rate were 105/50 mmHg and 60 bpm, necessitating continued vasopressor therapy. A second hemodialysis session was then initiated. At the end of the second session, glucagon therapy was discontinued and vasopressor therapy was discontinued approximately 15 to 20 hours later. His heart rate and blood pressure were 70 bpm and 120/50 mmHg, respectively (Huang et al, 2013).

3) NADOLOL: A 61-year-old man with renal insufficiency developed bradycardia (20 bpm) and hypotension (50 mmHg) while taking nadolol and verapamil. Bradycardia and hypotension did not respond to atropine, isoproterenol, dopamine or transcutaneous pacing. Hemodialysis was initiated and calculated nadolol clearance was 37 to 100 milliliters/minute (McKinney & Lawrence, 1995).
4) ACEBUTOLOL: Use of hemodialysis and ECMO were associated with clinical improvement in a patient with severe dysrhythmias, hypotension and heart failure after acebutolol overdose (Rooney et al, 1996). The patient was also treated with isoproterenol, epinephrine, glucagon, dopamine, norepinephrine, and a pacemaker. Acebutolol half life and clearance during dialysis were not determined.

1) A case was reported on the use of charcoal hemoperfusion in the treatment of a mixed-drug ingestion involving metoprolol. Clearance due to hemoperfusion was 81 to 106 milliliters/minute, baseline clearance was not determined (Anthony et al, 1986).
2) There is, however, no evidence that a significant proportion of the total amount of metoprolol ingested can be removed. Hemoperfusion is most likely to be effective in nadolol, atenolol, and sotalol overdose. It should be considered only when treatment with glucagon and other pharmacotherapy fails.
3) Extracorporeal support and hemoperfusion were used to treat a 20-year-old woman with bradycardia and hypotension unresponsive to fluids, atropine, glucagon, isoproterenol, epinephrine and cardiac pacing after propranolol overdose (McVey & Corke, 1991). She survived neurologically intact. No data were provided on the hemoperfusion clearance of propranolol.

1) CASE REPORT: Continuous veno-venous hemodiafiltration (CVVHDF) was utilized in a 45-year-old man who ingested atenolol with an atenolol blood concentration of 69.6 mcg/mL. Atenolol concentrations in the dialysate fluid ranged from 35 mcg/mL on the first day of CVVHDF to 5 mcg/mL on the last day. Clinical toxicity subsided after day 5 (Pfaender et al, 2008).

Abstracts

Case Reports

1) ACEBUTOLOL: Intentional overdose with 8 g acebutolol resulted in fatality (Jean et al, 1984). One hour following ingestion, severe hypotension ensued, followed in 2 hours by cardiovascular collapse and respiratory arrest. Plasma concentrations at 4 hours following overdose were 13,400 ng/mL of acebutolol and 2,000 ng/mL of the acetylated metabolite; serum concentrations of the amine metabolite were 25,000 ng/mL. Despite intensive therapy, the patient died 30 hours postingestion.
2) OXPRENOLOL: Overdose of oxprenolol has produced bradycardia and circulatory collapse (Russo & Covinsky, 1983).
3) TIMOLOL: Acute bronchospasm in an asthmatic, CHF in an elderly patient with known rheumatic disease, bradycardia, palpitations, hypotension, syncope, lightheadedness, mental depression, fatigue, disorientation and loss of libido have been reported following ocular instillation of timolol maleate (Fraunfelder, 1986) Nelson, 1986;(Alder et al, 1982; Charan & Lakshminarayan, 1980; Britman, 1979; McMahon et al, 1979) .

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) ACEBUTOLOL

1) ANGINA PECTORIS

a) INITIAL: The recommended dose is 200 mg orally twice daily. If an adequate response is not observed within 2 weeks, the dose may be increased to 300 mg twice daily. MAX dose: 300 mg twice daily (Prod Info SECTRAL(R) oral tablets, 2009).
b) MAINTENANCE: The recommended dose is between 200 and 600 mg orally daily divided into 2 doses. If a patient is adequately controlled on 400 mg/day, a maintenance dose of 100 mg/day may be used (Prod Info SECTRAL(R) oral tablets, 2009).

2) HYPERTENSION

a) INITIAL: The recommended dose is 100 mg orally twice daily. If an adequate response is not observed within one week, the dose may be increased to 200 mg twice daily. Additional increases of 100 mg twice daily at intervals not less than 2 weeks are permitted if adequate response has not been achieved. MAX dose 400 mg twice daily (Prod Info SECTRAL(R) oral tablets, 2009).
b) MAINTENANCE: The recommended dose is between 400 and 800 mg/day orally (Prod Info SECTRAL(R) oral tablets, 2009).

B) ATENOLOL

1) ANGINA PECTORIS

a) The recommended dose is 50 mg/day orally. If an adequate response is not achieved within one week, the dose may be increased to 100 mg/day. A dosage of 200 mg/day may be required for some patients (Prod Info TENORMIN(R) oral tablets, 2012).

2) HYPERTENSION

a) The recommended dose is 50 mg/day orally. If an adequate dose is not achieved within 2 weeks, the dose may be increased to 100 mg/day (Prod Info TENORMIN(R) oral tablets, 2012).

3) MYOCARDIAL INFARCTION

a) INITIAL: The recommended dose is 5 mg IV over 5 minutes followed by 5 mg IV 10 minutes later (Prod Info TENORMIN(R) oral tablets, 2012).
b) MAINTENANCE: If the full IV dose is tolerated, administer 50 mg orally 10 minutes after the last IV dose. An additional 50 mg should be administered orally 12 hours later. The recommended dose thereafter is 100 mg once daily or 50 mg twice daily for 6 to 9 days or until discharged from the hospital (Prod Info TENORMIN(R) oral tablets, 2012).

C) BETAXOLOL

1) The recommended dose is 10 mg orally once daily. If an adequate response is not achieved within 14 days, the dose can be doubled (Prod Info Kerlone(R) oral tablets, 2011).

D) BISOPROLOL

1) The recommended initial dose is 2.5 to 5 mg/day orally. If an adequate response is not achieved, the dose may be increased up to 20 mg/day. MAX dose: 20 mg/day (Prod Info Zebeta(R) oral tablets, 2010).

E) CARTEOLOL

1) The recommended dose is one drop in the affected eye twice daily (Prod Info carteolol hcl ophthalmic solution, 2004)

F) ESMOLOL

1) SUPRAVENTRICULAR OR SINUS TACHYCARDIA

a) LOADING: The recommended loading dose is 500 mcg/kg/min followed by 50, 100, or 150 mcg/kg/min for 4 minutes. If necessary, the dose may be increased to 200 mcg/kg/min. The loading dose is optional (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
b) MAINTENANCE: The recommended dose is 50 to 200 mcg/kg/min IV for up to 48 hours. If necessary, doses as low as 25 mcg/kg/min may be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

2) INTRA-/POST-OPERATIVE TACHYCARDIA/HYPERTENSION

a) IMMEDIATE CONTROL: The recommended dose is 1 mg/kg IV bolus over 30 seconds followed by 150 mcg/kg/min IV infusion as necessary. MAX dose, 200 mcg/kg/min for treatment of tachycardia, 300 mcg/kg/min for treatment of hypertension (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
b) GRADUAL CONTROL: The recommended dose is 500 mcg/kg IV bolus over one minute followed by 50 mcg/kg/min IV infusion for 4 minutes. MAX dose: 200 mcg/kg/min for treatment of tachycardia, 300 mcg/kg/min for treatment of hypertension (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

G) LABETALOL

1) INITIAL: The recommended dose is 100 mg orally twice daily. If necessary, the dosage may be titrated every 2 to 3 days in increments of 100 twice daily (Prod Info TRANDATE(R) oral tablets, 2010).
2) MAINTENANCE: The recommended dose is between 200 and 400 mg twice daily; for severe hypertension, 1200 to 2400 mg/day, in 2 or 3 divided doses, may be required (Prod Info TRANDATE(R) oral tablets, 2010).

H) METIPRANOLOL

1) The recommended dose is one drop in the affected eye(s) twice daily (Prod Info metipranolol 0.3% ophthalmic solution, drops, 2007).

I) METOPROLOL

1) ANGINA PECTORIS

a) The recommended dose is 100 mg/day in 2 divided doses. If an adequate response is not achieved, the dose may be increased weekly until optimum response. MAX dose: 400 mg/day (Prod Info Lopressor(R) oral tablets, IV injection, 2011).

2) HYPERTENSION

a) The recommended dose is 100 mg/day orally. If an adequate response is not achieved, the dose may be increased weekly. MAX dose 450 mg/day (Prod Info Lopressor(R) oral tablets, IV injection, 2011)

3) MYOCARDIAL INFARCTION

a) EARLY TREATMENT: The recommended dose is three bolus injections of 5 mg administered at 2 minute intervals. If patients tolerate the full IV dose (15 mg), administer 50 mg orally every 6 hours, starting 15 minutes after the last IV dose, for up to 48 hours. If patients are unable to tolerate the full IV dose (15 mg), administer 25 to 50 mg every 6 hours starting 15 minutes after the last IV dose (Prod Info Lopressor(R) oral tablets, IV injection, 2011).
b) LATE TREATMENT: The initial recommended dose is 100 mg twice daily orally for a minimum of 3 months (Prod Info Lopressor(R) oral tablets, IV injection, 2011).

J) NADOLOL

1) ANGINA PECTORIS

a) INITIAL: The recommended dose is 40 mg orally once daily. If adequate response is not achieved, the dose may be increased by 40 to 80 mg every 3 to 7 days. MAX dose: 240 mg/day (Prod Info CORGARD(R) oral tablets, 2011).
b) MAINTENANCE: The recommended dose is 40 to 80 mg once daily. Doses up to 240 mg once daily may be required for some patients. MAX dose: 240 mg/day (Prod Info CORGARD(R) oral tablets, 2011).

2) HYPERTENSION

a) INITIAL: The recommended dose is 40 mg once daily. If adequate response is not achieved, the dose may be increased by 40 to 80 mg/day. MAX dose: 320 mg/day (Prod Info CORGARD(R) oral tablets, 2011).
b) MAINTENANCE: The recommended dose is 40 to 80 mg/day. Doses up to 320 mg/day may be required in some patients. MAX dose: 320 mg/day (Prod Info CORGARD(R) oral tablets, 2011).

K) NEBIVOLOL

1) The recommended dose is 5 mg/day orally. If adequate response is not achieved, the dose may be increased at 2-week intervals. MAX dose: 40 mg/day (Prod Info BYSTOLIC(R) oral tablets, 2011).

L) NEBIVOLOL/VALSARTAN

1) The recommended dose is one tablet (nebivololol 5 mg/valsartan 80 mg) orally once daily (Prod Info BYVALSON(TM) oral tablets, 2016).

M) PENBUTOLOL

1) The recommended dose is 20 mg orally once daily. If necessary, doses up to 80 mg/day may be administered (Prod Info levatol(R) oral tablets, 2010).

N) PINDOLOL

1) The recommended dose is 5 mg twice daily by mouth. If an adequate response is not achieved within 4 weeks, the dose may be increased by 10 mg/day. MAX dose: 60 mg/day (Prod Info VISKEN(R) oral tablets, 2007).

O) PROPRANOLOL

1) ANGINA PECTORIS

a) The recommended dose is between 80 and 320 mg/day orally. Doses may be administered 2, 3, or 4 times daily (Prod Info Inderal(R) oral tablets, 2011).

2) ATRIAL FIBRILLATION

a) The recommended dose between 10 and 30 mg/day orally administered 3 to 4 times per day before meals and at bedtime (Prod Info Inderal(R) oral tablets, 2011).

3) HYPERTENSION

a) INITIAL: The recommended dose is 40 mg twice daily by mouth. If adequate response is not achieved, the dose may be increased gradually. MAX dose: 640 mg/day (Prod Info Inderal(R) oral tablets, 2011).
b) MAINTENANCE: The recommended dose is 120 to 240 twice daily by mouth. Doses up to 640 mg/day may be required for some patients. MAX dose: 640 mg/day (Prod Info Inderal(R) oral tablets, 2011).

4) HYPERTROPHIC SUBAORTIC STENOSIS

a) The recommended dose is 20 to 40 mg 3 or 4 times daily before meals and at bedtime (Prod Info Inderal(R) oral tablets, 2011).

5) MIGRAINE

a) INITIAL: The recommended dose is 80 mg/day orally in divided doses (Prod Info Inderal(R) oral tablets, 2011).
b) MAINTENANCE: The recommended dose is between 160 and 240 mg/day orally in divided doses (Prod Info Inderal(R) oral tablets, 2011).

6) MYOCARDIAL INFARCTION

a) INITIAL: The recommended dose is 40 mg 3 times daily by mouth. If adequate response is not achieved within one month, the dose may be titrated between 60 and 80 mg 3 times daily (Prod Info Inderal(R) oral tablets, 2011).
b) MAINTENANCE: The recommended dose is between 180 and 240 mg/day by mouth in divided doses (Prod Info Inderal(R) oral tablets, 2011).

7) PHEOCHROMOCYTOMA

a) The recommended dose is 60 mg/day orally in divided doses for 3 days prior to surgery as adjunct therapy to alpha-blockers (Prod Info Inderal(R) oral tablets, 2011).
b) INOPERABLE TUMORS: The recommended dose is 30 mg/day orally in divided doses as adjunct therapy to alpha-blockers (Prod Info Inderal(R) oral tablets, 2011).

8) TREMOR

a) INITIAL: The recommended initial dose is 40 mg orally twice daily (Prod Info Inderal(R) oral tablets, 2011).
b) MAINTENANCE: The recommended dose is between 120 and 320 mg/day (Prod Info Inderal(R) oral tablets, 2011).

P) TIMOLOL

1) OPHTHALMIC The recommended dose is one drop of 0.25% solution in affected eye(s) twice daily. If an adequate response is not achieved, the dose may be changed to one drop of 0.5% solution in affected eye(s) twice daily (Prod Info TIMOPTIC(R) ophthalmic solution, 2011)
2) ORAL

a) HYPERTENSION: Initially, 10 mg orally twice daily; maintenance dose is 20 to 60 mg/day in 2 divided doses (Prod Info Timolol Maleate oral tablets, 2006).
b) MIGRAINE: 10 to 20 mg/day, as a single dose or in 2 divided doses; MAX: 30 mg/day in divided doses (Prod Info Timolol Maleate oral tablets, 2006).
c) MYOCARDIAL INFARCTION: For long-term prophylactic use after an acute myocardial infarction, 10 mg orally twice daily (Prod Info Timolol Maleate oral tablets, 2006).

7.2.2)

A) SPECIFIC SUBSTANCE

1) ACEBUTOLOL

a) The safety and effectiveness of acebutolol have not been established in pediatric patients (Prod Info SECTRAL(R) oral tablets, 2009).

2) ATENOLOL

a) The safety and effectiveness of atenolol have not been established in pediatric patients (Prod Info TENORMIN(R) oral tablets, 2012).
b) HYPERTENSION

1) 1 year of age and older: Initially, 0.5 to 1 mg/kg/day orally in 1 to 2 divided doses. May titrate up to a maximum dose of 2 mg/kg/day, up to 100 mg/day (NoneListed, 2004).

c) SUPRAVENTRICULAR TACHYCARDIA

1) Initial dose: 0.5 to 1 mg/kg orally once daily (Ko et al, 2004; Luedtke et al, 1997; Mehta et al, 1996).
2) Maintenance dose: May increase by 0.5 mg/kg/day increments orally every 3 to 4 days up to a maximum dose of 2 mg/kg/day (Ko et al, 2004; Luedtke et al, 1997; Mehta et al, 1996; Trippel & Gillette, 1989) in 1 to 2 divided doses (Ko et al, 2004).

3) BETAXOLOL

a) The safety and effectiveness of betaxolol have not been established in pediatric patients (Prod Info Kerlone(R) oral tablets, 2011).

4) BISOPROLOL

a) The safety and effectiveness of bisoprolol have not been established in pediatric patients (Prod Info Zebeta(R) oral tablets, 2010).

5) CARTEOLOL

a) The safety and effectiveness of carteolol have not been established in pediatric patients (Prod Info carteolol hcl ophthalmic solution, 2004).

6) ESMOLOL

a) The safety and effectiveness of esmolol have not been established in pediatric patients (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
b) ACUTE MANAGEMENT OF POSTOPERATIVE HYPERTENSION

1) Loading dose: 100 to 500 mcg/kg IV bolus over 1 minute (Tabbutt et al, 2008; Tabbutt et al, 2008a; Fivush et al, 1997; Cuneo et al, 1994; Vincent et al, 1990).
2) Maintenance infusion: Initial, 25 to 150 mcg/kg/minute continuous infusion. Increase in increments of 25 to 50 mcg/kg/minute every 5 to 10 minutes until desired blood pressure is achieved (Tabbutt et al, 2008; Tabbutt et al, 2008a; Wiest et al, 1998; Fivush et al, 1997; Cuneo et al, 1994; Vincent et al, 1990). Usual maintenance dose range is 50 to 500 mcg/kg/minute (Flynn & Tullus, 2009; Fivush et al, 1997; Cuneo et al, 1994; Vincent et al, 1990).

c) SUPRAVENTRICULAR TACHYCARDIA (SVT)/VENTRICULAR TACHYCARDIA (VT)

1) Loading dose: 500 to 1000 mcg/kg IV bolus over 1 to 2 minutes (Ratnasamy et al, 2008; Adamson et al, 2006; Trippel et al, 1991).
2) Maintenance infusion: Initial, 25 to 300 mcg/kg/minute continuous IV infusion. Increase in increments of 50 to 100 mcg/kg/minute every 5 to 10 minutes until control of the ventricular rate is achieved (Ratnasamy et al, 2008; Adamson et al, 2006; Balcells et al, 2004; Trippel et al, 1991).

7) LABETALOL

a) The safety and effectiveness of labetalol have not been established in pediatric patients (Prod Info TRANDATE(R) oral tablets, 2010).

8) METIPRANOLOL

a) The safety and effectiveness of metipranolol have not been established in pediatric patients (Prod Info metipranolol 0.3% ophthalmic solution, drops, 2007).

9) METOPROLOL

a) The safety and effectiveness of metoprolol have not been established in pediatric patients (Prod Info Lopressor(R) oral tablets, IV injection, 2011).

10) NADOLOL

a) The safety and effectiveness of nadolol have not been established in pediatric patients (Prod Info CORGARD(R) oral tablets, 2011).

11) NEBIVOLOL

a) The safety and effectiveness of nebivolol have not been established in pediatric patients (Prod Info BYSTOLIC(R) oral tablets, 2011).

12) NEBIVOLOL/VALSARTAN

a) Safety and effectiveness have not been established in pediatric patients (Prod Info BYVALSON(TM) oral tablets, 2016)

13) PENBUTOLOL

a) The safety and effectiveness of penbutolol have not been established in pediatric patients (Prod Info levatol(R) oral tablets, 2010).

14) PINDOLOL

a) The safety and effectiveness of pindolol have not been established in pediatric patients (Prod Info VISKEN(R) oral tablets, 2007).

15) PROPRANOLOL HYDROCHLORIDE

a) USUAL DOSE

1) Intravenous: 0.01 to 0.15 mg/kg IV every 6 to 8 hours. Maximum 1 to 3 mg/dose (Luedtke et al, 1997; Prod Info propranolol hydrochloride IV injection, 2008).

b) CONGESTIVE HEART FAILURE, HYPERTENSION, TACHYDYSRHYTHMIAS

1) Oral: Initially, 0.5 to 1 mg/kg/day orally in 3 to 4 divided doses (divided every 6 to 8 hours; extended-release capsules dosed every 12 to 24 hours) (Drago et al, 2008; Ratnasamy et al, 2008; Robinson et al, 2005; Buchhorn et al, 2001; Ross, 2001; Buchhorn et al, 2000; Paul et al, 2000; Luedtke et al, 1997; Berenson et al, 1990; Gillette et al, 1978; Griswold et al, 1978). Higher initial doses (2 mg/kg/day) have also been used for the treatment of supraventricular tachycardias and long QT syndrome (Etheridge et al, 2001; Moss et al, 2000; Drago et al, 1998; Gillette, 1981; Pickoff et al, 1979)
2) Oral: Maintenance: May increase by 1 mg/kg/day increments every 3 to 4 days up to a maximum of 6 mg/kg/day. Usual maintenance dose is 1 to 4 mg/kg/day orally in 3 to 4 divided doses (divided every 6 to 8 hours; extended-release capsules dosed every 12 to 24 hours) (Drago et al, 2008; Ratnasamy et al, 2008; Robinson et al, 2005; Erkan et al, 2003; Tortoriello et al, 2003; Buchhorn et al, 2001; Chou et al, 2001; Etheridge et al, 2001; Ross, 2001; Buchhorn et al, 2000; Moss et al, 2000; Paul et al, 2000; Drago et al, 1998; Luedtke et al, 1997; Berenson et al, 1990; Gillette et al, 1978; Griswold et al, 1978). Doses as high as 14 to 16 mg/kg/day have been used in children to control supraventricular tachycardias (Ratnasamy et al, 2008; Luedtke et al, 1997a; Gillette, 1981; Pickoff et al, 1979).

c) INFANTILE HEMANGIOMAS

1) Usual maintenance doses have been 2 to 3 mg/kg/day orally in 3 divided doses (Buckmiller et al, 2010; Rosbe et al, 2010; Fay et al, 2010; Marsciani et al, 2010; Truong et al, 2010; Sans et al, 2009; Buckmiller et al, 2009; Denoyelle et al, 2009; Jephson et al, 2009; Lawley et al, 2009; Vanlander et al, 2010; Leaute-Labreze et al, 2008; Siegfried et al, 2008). Initial doses of 2 mg/kg/day orally in 3 divided doses have been used while some authors recommend starting at 0.3 to 1 mg/kg/day to assess tolerability and then increasing to 2 mg/kg/day incrementally over several days (Schiestl et al, 2011; Rosbe et al, 2010; Denoyelle et al, 2009; Lawley et al, 2009; Siegfried et al, 2008). Continuation of therapy until full involution of the lesion has occurred or until 1 year of age has been recommended (Tan et al, 2011). Recurrences have been reported with early discontinuation of therapy (Leboulanger et al, 2010). Tapering periods have ranged from 2 weeks to 1 month (Buckmiller et al, 2010; Fay et al, 2010; Vanlander et al, 2010; Lawley et al, 2009; Siegfried et al, 2008).

d) MIGRAINE PROPHYLAXIS

1) 3 years of age and older: Doses of 1 to 3 mg/kg/day orally in 2 divided doses have been used in clinical trials (Bidabadi & Mashouf, 2010; Ashrafi et al, 2005; Olness et al, 1987). In one clinical trial, a maximum dose of 30 mg twice daily and 60 mg twice daily were used for children less than or equal to 35 kg and greater than 35 kg, respectively (Bidabadi & Mashouf, 2010).

e) TIMOLOL

1) The safety and effectiveness of timolol have not been established in pediatric patients (Prod Info TIMOPTIC(R) ophthalmic solution, 2011).

Minimum Lethal Exposure

1) GENERAL: Patient response can be quite variable, depending upon the other medical problems of the patient.
2) ACEBUTOLOL: Fatalities were reported in 2 of 9 patients who overdosed, (one took 8.6 g, the other unknown), with postmortem blood levels of 3.3 mg/dL in one (Auzepy et al, 1983).
3) ALPRENOLOL: Fatalities have been reported from 12.8 g of alprenolol (Prichard et al, 1984).
4) METOPROLOL: Death has been reported following metoprolol 7.5 g and 10 g (Shore et al, 1981; Riker et al, 1987). However, an adult survived a 10 g ingestion of metoprolol tartrate following intensive clinical care including vasopressors, high-dose insulin, intralipid therapy, and veno-arterial extracorporeal membrane oxygenation (Escajeda et al, 2015).
5) PROPRANOLOL

a) Ingestion of about 2060 mg was fatal in a 30-year-old woman who received no medical care (Suarez et al, 1988).
b) Ingestion of 9600 mg was fatal in a 60-year-old man (Jones et al, 1982).
c) Ingestion of 3200 to 8000 mg was fatal in a 39-year-old woman (Laake et al, 1981).

Maximum Tolerated Exposure

1) Patients with the following inadvertent single substance ingestions should be considered to have the potential to develop toxicity and be referred to a healthcare facility (IR = immediate release, SR = sustained release) (Wax et al, 2005):

1) ACEBUTOLOL

a) A 15-year-old developed hypotension, AV block and QRS widening after ingesting 7600 mg of acebutolol (Sangster et al, 1983).

2) ATENOLOL

a) One case of a woman ingesting 1200 mg of atenolol without major complications (Shanahan & Counihan, 1978) and another after 1000 mg (Weinstein et al, 1985) have been reported.
b) Atenolol has been used therapeutically in dosages up to 1800 mg/day with favorable outcomes (Abbasi & Sorsby, 1986).
c) A 15-year-old girl ingested 10 50-mg tablets of atenolol by history survived the suicide attempt and required support with atropine for 36 hours (Abbasi & Sorsby, 1986).
d) A 61-year-old man survived ingestion of 3000 mg of atenolol, in combination with ethanol. A temporary pacemaker and high-dose vasopressor therapy were required (Saitz et al, 1991).

3) BETAXOLOL

a) A 38-year-old woman developed cardiogenic shock with acute renal failure after intentionally ingesting 5.32 g of betaxolol, 30 g of lorazepam, and an unknown amount of alcohol. She recovered following treatment with extracorporeal membrane oxygenation and hemodialysis (Bilbault et al, 2007).

4) BISOPROLOL

a) A 19-year-old man tolerated an overdose of 140 mg with minimal clinical effects (Tracqui et al, 1990).

5) ESMOLOL

a) Adverse effects occurred in 18% of patients receiving 200 mcg/kg/minute or more in a double-blind, placebo-controlled crossover study of 71 patients with supraventricular tachycardia (Anderson et al, 1986).

6) LABETALOL

a) Acute oliguric renal failure occurred following an overdose of 19 g labetalol in a 19-year-old in a suicide attempt. Glomerular filtration rate had increased from 19 milliliters/minute 15 days postingestion to 102 milliliters/minute at 4 months postingestion (Smit et al, 1986).
b) INFANT: An 8-month-old child on labetalol therapy, at a dose of 0.9 mg/kg/dose (5 mg) twice daily via a nasogastric tube, inadvertently received 95 mg as an intravenous bolus immediately following receipt of 5 mg given enterally (total dose 17.2 mg/kg). Following the overdose, the patient experienced only transient hypotension and a mild decrease in heart rate. An echocardiogram, performed 100 minutes post-overdose, did not indicate any abnormalities (Thorsteinsson et al, 2008).

7) METOPROLOL

a) A 31-year-old man ingested 4.8 g of metoprolol without any clinical effects other than asymptomatic bradycardia (Love, 1994). Blood metoprolol level 2 hours after ingestion was 7,140 ng/mL.
b) A 34-year-old man developed seizures, hypotension, bradycardia, and acidosis after ingesting 50 g of metoprolol but survived with aggressive supportive care (Wallin & Hulting, 1983).
c) A 59-year-old man developed hypotension, bradycardia, and subsequent cardiac arrest after ingesting 7.5 g (75 mg/kg) of metoprolol, but survived without neurologic sequelae following aggressive treatment, including hyperinsulinemia/euglycemia therapy, vasopressor administration, and IV lipid emulsion therapy (Barton et al, 2015).
d) A 47-year-old man developed hypotension, coma, and cardiac arrest after intentionally ingesting 10 g of metoprolol, but survived following treatment with vasopressors, high-dose insulin, intralipid therapy, and veno-arterial extracorporeal membrane oxygenation (Escajeda et al, 2015).

8) NEBIVOLOL

a) Ingestion of up to 500 mg of nebivolol as well as several 100-mg tablets of acetylsalicylic acid in a patient resulted in hyperhidrosis, pallor, a decreased consciousness level, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure, and vomiting. The patient recovered with supportive care (Prod Info BYSTOLIC(TM) oral tablets, 2007).

9) OXPRENOLOL

a) An 8 g overdose of oxprenolol produced coma, shallow respirations, severe hypotension, and shock in a 16-year-old girl. High-dose glucagon infusion was associated with improvement of systolic blood pressure to normal levels during the first 2 hours of infusion. Bolus intravenous glucagon (30 milligrams) in divided doses over 80 minutes was ineffective (O'Mahony et al, 1990).
b) A 39-year-old woman developed hypotension, bradycardia, respiratory arrest and seizures after ingesting 2.5 to 3 g of oxprenolol, but survived with aggressive supportive care (Mattingly, 1977).

10) PINDOLOL

a) A 38-year-old woman remained asymptomatic except for hypertension after ingestion of 500 mg of pindolol (Thorpe, 1971).
b) Maximum tolerated intravenous dose in healthy adults was 16 mg over 5 minutes (Boakes & Boeree, 1973).

11) PRACTOLOL

a) Maximum tolerated intravenous dose in healthy adults was 1280 milligrams over 5 minutes (Boakes & Boeree, 1973).

12) PROPRANOLOL

a) Khan & Miller (1985) report survival of a 28-year-old man following ingestion of 3 g propranolol.
b) Survival has been reported after 5.1 g (Lagerfelt & Matell, 1976) and 8 g (Tynan et al, 1981).
c) A 45-year-old man remained asymptomatic after ingesting 2000 mg of propranolol (Wermut & Wojcicki, 1973).
d) Maximum tolerated intravenous dose in healthy adults was 120 mg over 5 minutes (Boakes & Boeree, 1973).
e) A 20-year-old woman developed bradycardia, hypotension and seizures after ingesting 2000 mg (Salzberg & Gallagher, 1980).
f) Two case series suggest that propranolol accounts for a disproportionate number of severe overdoses or fatalities after beta blocker overdose (Reith et al, 1996; Love & Howell, 1997).
g) INFANT: A 7-month-old child inadvertently received 36 mg propranolol for 3 doses (17 mg/kg) instead of the prescribed 3.6 mg 3 times daily and developed bradycardia, hypotension, lethargy, and weak peripheral pulses. Following treatment with high dose insulin therapy, the patient recovered uneventfully (Montague et al, 2015).

13) OXPRENOLOL

a) Maximum tolerated intravenous dose in healthy adults was 160 mg over 5 minutes (Boakes & Boeree, 1973).

14) TIMOLOL

a) Bradycardia, hypotension, bronchospasm, and worsening congestive heart failure have been reported after therapeutic use and inadvertent overuse (3 to 4 drops) of timolol ophthalmic preparations (McMahon et al, 1979; Britman, 1979; Williams & Ginther, 1982; Nelson et al, 1986; Hayes et al, 1989).

15) RISK FACTORS: Adverse effects could occur at lower doses and each patient requires individual evaluation for potential toxic exposures. It has been suggested that patients without heart disease are less likely to develop cardiac toxicity (Shanahan & Counihan, 1978).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) PROPRANOLOL/METOPROLOL: Therapeutic blood concentrations of propranolol and metoprolol for maximum beta-blockade range between 60 and 100 nanograms/mL (231.4 and 385.7 nmol/L) (Salzberg & Gallagher, 1980).
b) NADOLOL: Serum levels of 0.047 to 0.204 nanomole/liter are reported to be in the therapeutic range.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) ACEBUTOLOL

1) Postmortem blood levels of 21.5 micrograms/milliliter were found in one fatal case, with liver levels of 127.8 micrograms/gram (Chaumont et al, 1983).
2) Plasma acebutolol levels were 15 milligrams/liter 1 hour after ingestion of 76000 milligrams in a 15-year-old who developed hypotension and conduction delay but survived (Sangster et al, 1983).

b) ATENOLOL

1) A 44-year-old woman developed coma and hypothermia after overdose with atenolol (1000 mg) and diazepam (200 mg). Blood atenolol level was 250 mg/L (Hagemann, 1986).
2) A serum atenolol level of 35 mcg/mL was reported in a 38-year-old man, who developed hypotension and bradycardia followed by cardiac arrest with successful resuscitation, following an overdose ingestion of an unknown amount (Snook et al, 2000).
3) A woman in her twenties developed cardiorespiratory arrest and died after ingesting 300 mg of atenolol, 300 mg of pilsicainide (a sodium channel blocker), and 800 mg of aspirin. Postmortem atenolol concentrations in the right and left cardiac blood were 4.94 and 5.58 micrograms/mL, respectively (Hikiji et al, 2008).

c) BETAXOLOL

1) A peak serum betaxolol concentration of 11.6 mg/L was reported in a 38-year-old woman who intentionally ingested 5.32 g of betaxolol in a suicide attempt. The patient developed cardiogenic shock and acute renal failure, but recovered following extracorporeal membrane oxygenation and hemodialysis (Bilbault et al, 2007).

d) LABETALOL

1) Greater than 500 ng /mL labetalol serum concentration is reported to be toxic (Smit et al, 1986).
2) INFANT: The serum labetalol concentration in an 8-month-old infant, obtained 1 hour after receiving a labetalol overdose of 17.2 mg/kg (prescribed dose 0.9 mg/kg twice daily), was 0.9 mg/L (Thorsteinsson et al, 2008).

e) METOPROLOL

1) A 57-year-old man found dead had a blood ethanol concentration of 0.25 gram/deciliter and a blood metoprolol concentration of 20 micrograms/milliliter. Therapeutic plasma metoprolol levels range from 0.02 to 0.34 microgram/milliliter (Rohrig et al, 1987).
2) A blood metoprolol level of 75 micrograms/milliliter was reported at autopsy in a 26-year-old man following an ingestion of 100 tablets of metoprolol 100 milligrams in a successful suicide attempt (Riker et al, 1987).
3) A 17-year-old woman was successfully resuscitated after prolonged cardiac arrest following overdose with metoprolol and verapamil. Plasma metoprolol and verapamil levels were 5.3 micrograms/milliliter and 1.25 micrograms/milliliter respectively (Koppel et al, 1995).
4) Two 39-year-old women ingested 2500 mg and 7500 mg of metoprolol. Two hours post-ingestion metoprolol blood levels were 648 and 63,000 ng/mL, respectively. Treatment was directed at maintaining blood pressure and heart rate (Shore et al, 1981).
5) A serum metoprolol level of 0.4 mcg/mL (therapeutic range 0.035 to 0.5 mcg/mL) was reported following a suicidal ingestion of an unknown amount in combination with overdose administration of insulin (Junge et al, 2000).

f) NADOLOL

1) A patient with severe nadolol toxicity had a serum level of 1.25 nanomoles/liter (Ehgartner & Zelinka, 1988).

g) OXPRENOLOL

1) Blood concentrations of oxprenolol were 10.26 and 12.08 milligrams/liter at 4 and 9.5 hours, respectively, following an 8 gram ingestion in a 16-year-old girl (O'Mahony et al, 1990).

h) PINDOLOL

1) 500 milligrams pindolol produced a plasma concentration of 1.5 micrograms/milliliter (Thorpe, 1971).

i) PROPRANOLOL

1) Because of the variability in patient sensitivity, the degree of beta-blockade cannot be accurately related to the propranolol plasma concentration.
2) Propranolol concentrations between 4 to 16 mcg/mL were lethal in 5 patients (Kristinsson & Johannesson, 1977).
3) In other cases postmortem blood propranolol concentrations were 2, 4, 7, 9, 9.7, 20, 20, 28, and 167 mcg/mL (Piper & Smith, 1976; Stevenson, 1979; Laake et al, 1981; Gault et al, 1977; Jones et al, 1982; Suarez et al, 1988; Fucci & Offidani, 2000).
4) In fatal propranolol poisoning, plasma levels at autopsy have ranged from 4000 ng/mL (Piper & Smith, 1976) to 28000 ng/mL (Gault et al, 1977).
5) One case report described a 3-year-old boy who presented to the ED alert and anxious but in no distress 3 to 4 hours following the ingestion of 400 to 1200 mg of propranolol. His plasma concentration 4 hours postingestion was 2289 ng/mL (8827.6 nanomoles/liter). The child was discharged 6 hours after ingestion; his stay and follow-up over the following 2 weeks were uneventful (Artman et al, 1982).
6) Use of serum levels for routine monitoring of therapy and/or toxicity is not advisable. Serum concentrations may not accurately reflect total body concentrations.

Pharmacology Toxicology

Pharmacologic Mechanism

1) The degree of lipid solubility of a beta-blocker is important since it has been associated with the drugs ability to cross the blood-brain barrier, and to result in various CNS adverse effects. The CNS effects of propranolol may be attributed to its lipid solubility which enables it to penetrate the CNS. The CNS effects will theoretically be less of a problem in patients treated with the more hydrophilic B-blocking drugs such as nadolol or atenolol (White & Riotte, 1982).
2) Propranolol and alprenolol have the highest degree of lipid solubility; metoprolol, pindolol and practolol exhibit a moderate degree of lipid solubility; and atenolol, nadolol and timolol have the lowest degree of lipid solubility (Frishman, 1981; Frishman & Silvermon, 1979).

1) Acebutolol, carteolol, penbutolol, and pindolol possess intrinsic sympathomimetic activity (ISA) or partial agonist activity both at therapeutic and high doses (Prod Info levatol(R) oral tablets, 2010; Prod Info SECTRAL(R) oral tablets, 2009; Prod Info VISKEN(R) oral tablets, 2007; Prod Info carteolol hcl ophthalmic solution, 2004).
2) These agents cause less slowing of the heart rate, less depression of atrioventricular conduction, less cardiac insufficiency, and less of an increase in cardiopulmonary blood volume at rest when compared to agents lacking ISA (Frishman, 1981; Frishman & Silvermon, 1979).
3) Pindolol, the beta-blocker which exhibits the most ISA, has been reported to be bronchoprotective (Frishman & Silvermon, 1979).

Table 1- RECEPTOR TYPES (Frishman, 1979)
Type of receptor	Organ	Effect of Blocking
B1	Heart	Decrease rate
B1	Heart	Decrease contractility
B1	Heart	Decrease A-V conduction
B2	Bronchi	Constriction
B2	Blood vessels	Constriction
B2	Stomach	Increased motility
B2	Intestine	Increased motility
B2	Kidney	Decreased renin secretion

Table 2 - POTENCY/CARDIOSELECTIVITY(Frishman, 1979; Koch-Weser & Frishman)
Drug	B-Blocker Potency(propranolol = 1)	Cardioselectivity (B1)
Acebutolol	0.3	+
Alprenolol	0.3	o
Atenolol	1	+
Bisprolol	-	+
Carteolol	-	o
Metoprolol	1	+
Nadolol	1	o
Oxprenolol	0.5-1	o
Pindolol	6	o
Practolol	0.3	+
Propranolol	1	o
Timolol	6	o
d-isoproterenol	0.1	o
Betaxolol	-	+
Levobunolol	-	o
	Partial Agonist Activity	Membrane StabilizingActivity
Acebutolol	+	+
Alprenolol	++	+
Atenolol	o	o
Bisprolol	No data	o
Carteolol	No data	++
Metoprolol	o	+/-
Nadolol	++	+
Oxprenolol	oo	o
Pindolol	+++	+
Practolol	++	o
Propranolol	o	++
Timolol	+/-	o
d-isoproterenol	o	++
Betaxolol	o	o
Levobunolol	o	o

Toxicologic Mechanism

1) An in-vitro study was conducted to determine the effect that modification of extracellular potassium and sodium ions would have on beta-blocker-induced cardiotoxicity. Isolated rat hearts were perfused with propranolol or atenolol. Some of the hearts were then modified by decreasing the extracellular concentration of potassium ions or increasing the extracellular concentration of sodium ions over a 30-minute treatment period. Following perfusion of the hearts with only propranolol or atenolol, the heart rate significantly decreased and pacing did not successfully restore the heart rate to baseline. However, decreasing extracellular potassium concentration or increasing extracellular sodium concentration allowed pacing to increase the heart rate to baseline in the atenolol group. In the propranolol group, modification of the extracellular ions also allowed pacing to increase the heart rate, although not to baseline in the group who received the increase in sodium ions. Based on the results of this study, it is believed that beta-blockers may induce ion dyshomeostasis resulting in cardiac hyperpolarization. Modification of extracellular ions appeared to reverse the hyperpolarization (Kerns et al, 1996).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

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BETA-BLOCKING AGENTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

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Range Of Toxicity

Summary Of Exposure

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General Bibliography