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Beta-adrenergic Blockers Drug Interaction

1-Atenolol- Ampicillin
 Atenolol is a selective B1-Blocker and used as antihypertensive agent

 Ampicillin is an orally active penicillin (aminopenicillin) and used in the treatment of upper
respiratory tract infections and urinary tract infections, meningitis, salmonella infections.
 Patients under atenolol therapy show marked decrease in the antihypertensive effect of atenolol
when given ampicillin concurrently.
 This interaction result in:

atenolol bioavailability (24%)

atenolol plasma peak level (33%)
atenolol area under curve (41%)
atenolol steady state level.
 Other B-Blockers do not show such interaction with ampicillin.

 The mechanism of this interaction is Unknown

Recommendation:
1- Patients should be monitored for the loss of therapeutic effect of atenolol.
2- The dose, accordingly, should be increased

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2-Atenolol-Calcium carbonate
Calcium carbonate is an insoluble ca-salt but after oral ingestion, it is converted to soluble ca in the gut
and made available for absorption.

Ca-carbonate is used as antacid and other ca-salt for the treatment of Ca-deficiency and dietary
supplement.

Ca-salts are specific for immediate treatment of low calcium tetany.

Concurrent administration of Ca-salts with atenolol results in:

atenolol peak plasma concentration (51%)
atenolol area under curve (33%)
reduction in B-Blockade is seen after 12 hrs.

The mechanism of this interaction was postulated that Ca-salts impair the GIT absorption of Atenolol.

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Other Ca-salts interact with atenolol and B-Blockers (pindolol, propranolol, nadolol)

Recommendation:

1- Patient monitoring for the loss of therapeutic effect of atenolol.

2-The dose may be required to be adjusted

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Metoprolol-Oral Contraceptives:
Metoprolol is a selective B1-Blocker and used as antihypertensive agent, prophylaxis of Anginal attackes,
reduce recurrent myocardial infarction and arrhythmias.

Oral contraceptives inhibit hepatic microsomal enzymes leading to a reduction in the first pass effect of the
liver.

Metoprolol is metabolized by liver microsomal enzymes to inactive metabolites.

Concurrent administration of Oral contraceptives with oral metoprolol will result in increased bioavailability
of metoprolol. This result in:  metoprolol area under the curve.
but elimination t½ is not changed

There were no observations of increased therapeutic effects of metoprolol BUT the potential exists.
Propranolol (significant metabolism by the liver) interacts similarly but other B-Blockers which do not
undergo significant liver metabolism do not (Pindolol, atenolol, nadolol).

Recommendations:
1- Patient monitoring for the  in therapeutic effects of metoprolol or propranolol and their dose should be
decreased accordingly.
2-Other forms of contraception may be used.
3-Other non-interacting B-Blockers may be used.
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Metoprolol -pentobarbital
 Pentobarbital decreases the plasma concentration and bioavailability of orally absorped
metoprolol and propranolol.
 Pentobarbital and other barbiturate, (amobarbital, secobarbctal, Phenobarbital) induce liver
microsomal drug metabolizing enzymes. So, orally absorbed metoprolol and propranolol will
be metabolized more  plasma concentration.
 It also increase plasma protein binding of propranolol ( protein synthesis)

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For a barbiturate to participate in this interaction, it has to be given for 10 days before this interaction
is seen (induction period).

Other B-Blockers which are not metabolized extensively by the liver, do not interact with barbiturates.
Ex atenolol, nadolol, pindolol.

On the other hand, Propranolol potentiates the sedative effects of barbiturates. This is due to the
metabolite of propranolol,naphthyl oxyl acetic acid, which has CNS depressive effect due to the
presence of “naphthyl” gp.
B-Blockers with no “naphthyl” gp result in CNS stimulation.

Recommendation:
1-The dosage of orally administered metoprolol or propranolol should be increased if given
Concomitantly with barbiturate for longer than 10 days.
2-Other B-Blockers could be used, instead.
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Propranolol-Cimetidine
 Cimetidine is H2- receptor antagonist and it is used for the management of peptic ulcer.

 Cimetidine:
1-  hepatic blood flow   extraction ability of the liver to. circulating agents.
2- Binds avidly to Cyt. P450 isozymes  inhibits hepatic microsomal enzymes.
3-  GIT motility  Bioavailability of orally administered drugs

 Cimetidine increases the plasma concentration of propranolol and metoprolol when given
concomitantly with either. But the plasma level of atenolol or pindolol do not change significantly.

 Ranitidine(H2- antagonist):
1- hepatic blood flow
2- GIT motility
3-less bound to hepatic Cyt. P450 less inhibition of hepatic microsomal enzyme.

Recommendations:
1- Patients should be monitored for increased blockade of B-receptors. Accordingly.
2-The dosage of propranolol or metoprolol and/or cimetidine should be adjusted (i.e. decreased).
3-Rantidine could be used instead of cimetidine.
4-Atenolol or pindolol could be used instead of propranolol.

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Epinephrine -propranolol
Epinephrine and other sympathomimetics with alpha-agonist activity such as

phenylephrine, metaraminol, methoxamine, norepinephrine

when administered to patients under propranolol or other non-selective B-Blockers, will result in
considerable increase in systolic and Diastolic blood pressure and marked decrease in heart rate
This results in Hypertensive episode which may results in stroke and several cases of
cardiac arrythmias.
The underlying mechanism is due to the Blockade of B-receptors by propranolol leaving
alpha-receptors >Vasoconstricting effect unopposed.
Bradycardia is attributed to the blockade of B -receptor and reflex stimulation of vagal nerve (cholinergic).
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This interaction is not seen between non-selective B-Blockers and B-agents such as isoproterenol, Albuterol,
terbutaline.
Minimal interaction occurs with B -selective Antagonist (metoprolol, atenolol) and sympathomimetics with alpha-
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agonist activity

Recommendations:
1-Sympathomimetic drugs with alpha-agonist activity should be avoided in patients taking non-selective beta
blockers.
2-Alternatively, B1-selective blockers may be used instead of non-selective B-Blockers.
3- Vasodilators or loap diureties may be used .
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Propranolol- Indomethacin
Indomethacin is a non-steroidal anti-inflammatory drug that inhibits prostaglandins synthesis. Some
prostaglandins are vasodilator and it has been reported that Indomethacin increases blood pressure. It also
 GFR as it  KD perfusion & hence  Bl. Volume and  Bl. Pr.
Several studies indicate that indomethacin reduces the hypotensive effect of propranolol
Other non-steroidal anti-inflammatory drugs such as Ibuprofen and sulindac, and
other B-Blockers are expected to interact similarly, Although no studies have been reported.

1-Patients should be monitored for reduced hypotensive effect of propranolol.

2-Accordingly, propranolol dose should be increased.
3-Indomethacin therapy may be discontinued. May use less potent NSAIDS such as Aspirin, Ibuprofen, ..etc
since they will less affected Bl.pr than Indomethacin.

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Propranolol -tobacco
 Smoking results in:

propranolol steady state plasma concentration

 propranolol clearance

 The effect of smoking on propranolol is greatest in younger patients and minimal in older patients.

 Smoking inhibits the therapeutic effect of propranolol in treatment of angina pectoris.

 Tobacco smoke and some of its components induce hepatic microsomal enzymes and hence

increase the metabolism of propranolol and metoprolol resulting in decreased their respective

plasma concentration.

 Other B-Blockers that are not metabolized mainly by the liver (atenolol, nadolol, pindolol) do not

interact similarly with tobacco.

 Recommendations:
 1-Smokers should receive larger doses of propranolol than non-smokers.

 2-If the patient stop smoking while under propranolol therapy, dose adjustment may be needed.

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