[DRUG INTERACTIONS ANALYSIS AND

MANAGEMENT]

Drug Interactions Analysis and

Management
I.

Acetazolamide and Methenamine:

Risk Factors:
No specific risk factors are known

Mechanism:

Acetazolamide tends to render the urine alkaline. During therapy with

methenamine compounds, the urine must be kept at a pH level of
approximately 5.5or lower to effect proper conversion of methenamine to
free formaldehyde.
Acetazolamide administration could increase the urine pH and prevent the
conversion of methenamine to formaldehyde.

Clinical Evaluation:

Acetazolamide is an effective urine alkalinizer and would be expected to

antagonize the effect of methenamine compounds.
Although little clinical evidence exists, acetazolamide could alkalinize the
urine effectively and would be expected to inhibit the effect of
methenamine compounds that require a urine pH less than 5.5 for optimal
effect.

Related Drugs:
Other drugs that alkalinize the urine such as
Sodium bicarbonate
Large doses of antacids
These two drugs would be expected to have a similar effect on methenamine
compounds.

Management options:
Monitor:

Monitor patients to keep the urine pH at approximately 5.5 or lower during

methenamine use

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II.

Acetazolamide and Quinidine:

Risk Factors:
No specific risk factors are known.

Mechanism:
Acetazolamide tends to render the urine alkaline, resulting in an increased
proportion of non ionized quinidine. Thus renal tubular reabsorption of quinidine
increased and serum concentrations may be increased.

Clinical Evaluation:

In a study of 4 subjects, the average quinidine excretion was 115mg/L when

urine pH was less than 6, but only 13mg/L when urine was more than 7.5.
Because up to 50%of quinidine is cleared by kidneys, quinidine toxicity may
result when co administered with agents that increase urine pH, particularly
in patients with acidic urine.

Related Drugs:
Other drugs that alkalinize the urine are
sodium bicarbonate would produce similar effects on quinidine serum
concentrations.
Acetazolamide may increase quinidine concentration.

Management options:

Monitor:

Initiation, discontinuation, or a change in dose of acetazolamide in a patient

receiving quinidine may necessitate a change in the quinidine dose.
Monitor for altered quinidine response of urine changes.

III.

Acetylcysteine with Nitroglycerin

Risk Factors:
No specific risk factors are known.
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Mechanism:

Nitrates cause vasodilation by interacting with sulfhydryl groups to increase

cyclic guanylic acid, which induces vascular smooth muscle relaxation.
Acetylcysteine is a sulfhydryl group donor and may enhance the activity of
nitrates.

Clinical Evaluation:

Acetylcysteine 100mg/kg IV increased the peripheral and coronary dilation

caused by nitroglycerin.
Acetylcysteine also can reverse nitrate tolerance in patients with coronary
artery disease and congestive heart failure. However, Acetylcysteine 200400mg orally 3 times a day did not prevent the attenuation of transdermal
nitroglycerin induced hemodynamic changes over 4 days.
The IV infusion of Acetylcysteine 225mg/kg/day did not alter the
development of tolerance to an IV infusion of nitroglycerin 1.5mcg/kg/min
over 24 hours in 13 patients with heart failure.
The differences in the effect of acetylcysteine on nitroglycerin tolerance
between these reports may be caused by the large differences in
acetylcysteine dosage regimens. The effects may be more prominent when
large concentrations of both nitroglycerin and acetylcysteine are present.
The clinical significance of these effects are unknown.

Related Drugs:

A similar reaction may occur with all hypoglycemic agents.

Management options:
Monitor:

The effect of potassium on the response to antidiabetic agents is unlikely to be

large enough to warrant any precautionary measures. However , monitor
hypokalemic diabetic patients treated with potassium supplements for reduced
blood glucose.

IV.

Acyclovir with Cimetidine

Risk Factors:
No specific risk factors are known.

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Mechanism:

Cimetidine reduces the rate but not extent of the conversion of valacyclovir
to acyclovir. Acyclovir renal clearance is reduced by cimetidine
coadministration.

Clinical Evaluation:

12 healthy subjects received valacyclovir, a pro drug of acyclovir, 1g alone

and again following 800mg doses of cimetidine given 8 hours and 1 hour
before the dose of valacyclovir. The area under the concentration time
curve of valacyclovir during the 3 hours after its administration was
increased more than 80% following cimetidine.
The area under the concentration time curve of acyclovir was increased
23% following cimetidine. Cimetidine reduced the renal clearance of
acyclovir 22%
On the basis of this preliminary report, it is unlikely that these changes in
valacyclovir pharmacokinetics would alter patient response. This is because
of wide therapeutic range of acyclovir. The effects of chronic cimetidine
dosing await further studies.

Related Drugs:

Other H2 -receptor antagonists would theoretically be les likely to interact

with acyclovir.

Management options:

V.

No specific action is required, but be alert for evidence of the interaction.

Adenosine with theophylline

Risk Factors:
No specific risk factors are known.

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Mechanism:
Theophylline acts as an adenosine antagonist capable of blunting the vasodilation
caused by adenosine.

Related Drugs:
Caffeine produces similar effects on adenosine hemodynamics

Management options:
Circumvent/minimize

Patients maintained on theophylline may require greater than normal doses of

Monitor:

Watch for decreased therapeutic response to adenosine when theophylline is

initiated and for adenosine toxicity( e.g bradycardia) when theophylline is
discontinued.

VI.

Allopurinol with theophylline:

Risk Factors:

Dosage regimen:

Allopurinol doses at least 600mg/day may inhibit the hepatic metabolism

of theophylline.

Mechanism:
Pharmacokinetic studies suggest that allopurinol inhibits the hepatic metabolism
of theophylline. This mechanism is consistent with a 44% increase in aminopyrine
half life in 5 subjects given allopurinol ( aminopyrine is used as a marker for
alteration in hepatic oxidative drug metabolism.) Although allopurinol did not
affect the spectrophotometric determination of theophylline in vitro the possibility
that allopurinol therapy may falsely increase serum concentration has not been
strictly ruled out .

Related Drugs:
No information is available

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Management options:
Monitor:

Monitor for evidence of altered theophylline effect if allopurinol therapy is initiate

for discontinued, especially if large doses of allopurinol are used. Alteration of
theophylline dose may be needed.

VII.

Alprazolam with Erythromycin

Risk Factors:
No specific risk factors are known.

Mechanism:
Erythromycin probably inhibits the hepatic metabolism of alprazolam by
inactivating CYP3A4, which is responsible for its metabolism.

Related Drugs:
Erythromycin is known to increase the plasma concentration of other
benzodiazepines including trizolam and midazolam. Calithromycin or
trolendomycin may produce similar reductions in the clearance of alprazolam

Management options:
Consider alternative:

Selection of non inhibiting macrolides or dirithromycins likely to limit changes in

alprazolam pharmacokinetics. Anxiolytics not metabolized by CYP3A4 such as
lorazepam or temazepam could be substituted for alprazolam.
Monitor:

Monitor patients taking alprazolam chronically for increased sedation during

erythromycin administration.

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VIII.

Amantadine with triamterene

Risk Factors:
No specific risk factor is known.

Mechanism:
Not established. There is some evidence that the combination formulation of
triamterene/hydrocholorothiazide can reduce the renal excretion of amantadine.
Because this interaction has not been reported with thiazides, the triamterene
appears to be responsible.

Related Drugs:
It is possible that rimantadine is similarly affected by triamterene.

Management options:
Circumvent/Minimize:

Amantadine dosage may need to be reduced when triamterene is coadministered.

Monitor:

In patients receiving amantadine, use trimetrene orthiazides with caution and

watch for signs of amantadine toxicity including nausea, dizziness and dry mouth.

IX.

Amiloride with digoxin

Risk Factors:
No specific risk factor is known.

Mechanism:
Amiloride appears to be increase the renal clearance and reduce the non renal
clearance of digoxin. Amiloride also may inhibit the inotropic effect of digoxin.

Related Drugs:
Digoxin may be similarly affected by amiloride.

Management options:
No specific action is required, but be alert for evidence for interaction.

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X.

Amiodarone with grapefruit juice

Risk Factors:
No specific risk factor is known.

Mechanism:
Grapefruit juice inhibits CYP3A4, resulting in a reduction in the first pass
metabolism of Amiodarone and an increase in plasma concentrations.

Related Drugs:
None known

Management options:
Monitor:

Caution patients stabilized on Amiodarone to avoid excessive amounts of

grapefruit juice. Monitor for altered Amiodarone response, if grapefruit juice is
coadministered.

XI.

Carbamazepine with Contraceptives:

Risk Factors:

Dosage regimen:

Oral contraceptives with lower doses of hormones can increase the risk of
interaction

Mechanism:
Anticonvulsant induced enzyme induction probably enhances the metabolism of
oral contraceptives.

Related Drugs:
Carbamazepine decreased the area under the plasma drug concentration curve
of ethinyl estradiol 42% and levonorgestrel 40%. Phenytoin decreased the AUC of
ethinyl estradiol 49% and levonorgesteral 40%.
Clinical evidence and theoretical considerations suggest that benzodiazepines
anticonvulsants would be unlikely to affect oral contraceptive efficacy.

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Management options:
Consider alternative:

Consider an other means of contraceptives instead of , or in addition to oral

contraceptives when pregnancy is to be avoided in women receiving
carbamazepine or other enzyme inducing anticonvulsants such as phenobarbital,
phenytoin and primidone. Although an oral contraceptives with a higher estrogen
content would be preferable for some women who are beaing treated with
enzyme inducing anticonvulsants, individualize based upon patient response.
Monitor:

Spotting or breakthrough bleeding in patients taking oral contraceptives and

enzyme inducing anticonvulsants could indicate that the drugs are interacting,
although lack of breakthrough bleeding does not ensure contraceptive protection.

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