NITROJECT INJ 1MG/ML SOLUTION

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Active ingredient:
NITROGLYCERIN
Available from:
OMEGA LABORATORIES LTD
ATC code:
C01DA02
INN (International Name):
GLYCERYL TRINITRATE
Dosage:
10MG
Pharmaceutical form:
SOLUTION
Composition:
NITROGLYCERIN 10MG
Administration route:
INTRAVENOUS
Units in package:
10ML
Prescription type:
Ethical
Therapeutic area:
NITRATES AND NITRITES
Product summary:
Active ingredient group (AIG) number: 0103615004; AHFS: 24:12.08
Authorization status:
MARKETED
Authorization number:
00614262
Authorization date:
1990-12-31

Documents

PRODUCT MONOGRAPH

NITROJECT®

(Nitroglycerin for Injection,USP)

Sterile

For Intravenous Infusion

10 mg/10 mL

(1 mg/mL)

&

50 mg/10 mL

(5 mg/mL)

VASODILATOR

Omega Laboratories, Ltd.

11 177, Hamon

Montreal, Canada

H3M 3E4

Control Number: 153511

Date of Revision:

June 26, 2012

NITROJECT®

(Nitroglycerin for Injection, USP)

Sterile

For Intravenous Infusion

1 mg/mL (10 mg/10 mL)

&

5 mg/mL (50 mg/10 mL)

CAUTION:

SEVERAL

PREPARATIONS

OF

NITROGLYCERIN

FOR

INJECTION

ARE AVAILABLE. THEY DIFFER IN CONCENTRATION AND/OR VOLUME PER

VIAL. WHEN SWITCHING FROM ONE PRODUCT TO ANOTHER ATTENTION

MUST BE PAID TO DILUTION AND TO THE DOSAGE AND ADMINISTRATION

INSTRUCTIONS.

THERAPEUTIC CLASSIFICATION

Vasodilator

ACTIONS AND CLINICAL PHARMACOLOGY

The principal pharmacological action of NITROJECT® (Nitroglycerin for Injection, USP) is the

relaxation of vascular smooth muscle. Nitrates probably act primarily by reducing oxygen

demand rather than increasing myocardial oxygen supply. Although venous effects predominate,

nitroglycerin produces, in a dose-related manner, dilatation of both arterial and venous beds.

Dilation of the postcapillary vessels, including large veins, promotes peripheral pooling of blood

decreases

venous

return

heart,

reducing

left

ventricular

end-diastolic

pressure

(preload).

Arteriolar

relaxation

reduces

systemic

vascular

resistance

arterial

pressure

(afterload). Left ventricular end diastolic pressure and volume are decreased, resulting in

reduction of ventricular wall tension results in a net decrease in myocardial oxygen consumption

(as measured by the pressure-rate product, tension time index and stroke work index). A

favorable net balance between myocardial oxygen supply and demand is achieved. Elevated

central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and

systemic vascular resistance are also reduced by nitroglycerin therapy.

Therapeutic doses of intravenous nitroglycerin reduce systolic, diastolic and mean arterial blood

pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if

blood pressure falls excessively or increased heart rate decreases the diastolic filling time.

Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure.

Nitroglycerin is widely distributed in the body with an apparent volume of distribution of

approximately 200 litres in adult male subjects and is rapidly metabolized to dinitrates and

mononitrates, with a short half-life, estimated at 1 to 4 minutes. This results in a low plasma

concentration after intravenous infusion. At plasma concentrations of between 50 and 600

ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while those of the

metabolites 1,2-dinitroglycerin and 1,3-dinitroglycerin are 60% and 30% respectively. The

activity and half-life of 1,2-dinitroglycerin and 1,3-dinitroglycerin are not well characterized.

The mononitrate is not active.

INDICATIONS

NITROJECT® (Nitroglycerin for Injection, USP) is indicated for:

CONTROL OF BLOOD PRESSURE IN PERIOPERATIVE HYPERTENSION, i.e.,

hypertension associated with surgical procedures, especially cardiovascular procedures,

such as the hypertension seen during intratracheal intubation, anesthesia, skin incision,

sternotomy, cardiac bypass, and in the immediate postsurgical period.

CONGESTIVE HEART FAILURE ASSOCIATED WITH ACUTE MYOCARDIAL

INFARCTION.

TREATMENT

ANGINA

PECTORIS

patients

have

responded

recommended doses of conventional antianginal agents.

PRODUCTION

CONTROLLED

HYPOTENSION

DURING

SURGICAL

PROCEDURES.

CONTRAINDICATIONS

NITROJECT® (Nitroglycerin for Injection, USP) should not be administered to individuals

with:

A known hypersensitivity to nitroglycerin or a known idiosyncratic reaction to organic

nitrates.

Hypotension or uncorrected hypovolemia, as the use of nitroglycerin for injection in such

states could produce severe hypotension or shock.

Increased intracranial pressure (e.g., head trauma or cerebral hemorrhage).

Constrictive pericarditis and pericardial tamponade.

WARNINGS

NITROGLYCERIN

READILY

MIGRATES

INTO

MANY

PLASTICS.

AVOID

ABSORPTION

NITROGLYCERIN

INTO

PLASTIC

PARENTERAL

SOLUTION

CONTAINERS, THE DILUTION AND STORAGE OF NITROJECT® (NITROGLYCERIN

for INJECTION, USP) SHOULD BE MADE ONLY IN GLASS PARENTERAL SOLUTION

BOTTLES.

Some filters absorb nitroglycerin; therefore all filters should be avoided.

Important: Prior to the initiation of infusion check carefully which type of infusion set is going to

be used:

A conventional administration set with absorbable tubing (most frequently made of

polyvinyl chloride); or

A special administration set which will not absorb any significant amount of nitroglycerin

from the infusion solution.

Please read carefully points A and B below taking into account the highly significant difference

in the amount of nitroglycerin being delivered depending on the type (A or B) of the set used.

A.

Forty to 80% of the total amount of nitroglycerin in the final diluted solution for infusion

is absorbed by polyvinyl chloride (PVC) intravenous administration sets. The higher rates of

absorption occur when flow rates are low, nitroglycerin concentrations are high, and the

administration set is long. Although the rate of loss is highest during the early phase of infusion

(when flow rates are lowest), the loss is neither constant nor self-limiting. Consequently, no

simple calculation or correction can be performed to convert the theoretical infusion rate (based

on the concentration of the infusion solution) to the actual delivery rate.

B.

Because of this problem, special administration sets in which loss of nitroglycerin is

minimal have been developed. When these sets are used the calculated dose will be delivered,

because the loss of nitroglycerin due to absorption into the set will be negligible. Because the

tubing of such infusion sets may be less pliable than conventional PVC tubing, occlusion of the

infusion set by some pumps may not be complete. The result may be excessive flow at low

infusion rate settings, causing alarms, or unregulated gravity flow when the infusion pump is

stopped which could lead to over-infusion of nitroglycerin. To minimize the potential for such

occurrence, one should consider the following before using an infusion pump:

All infusion pumps should be tested with an appropriate infusion set to ensure their

ability to deliver nitroglycerin accurately at low flow rates, and to occlude the infusion

set properly when the infusion pump is stopped.

If the infusion pump alarms frequently, the tubing may be made more pliable by

manipulating and warming the tubing with your hands before installing the i.v. set into

the unit.

To prevent the possibility of a runaway infusion, locate the set's roller clamp above the

pump unit, and use it to establish the approximate desired drip rate manually. Then insert

the infusion set into the unit, setting the unit at the desired drip rate. (It should be noted

that this procedure may be contrary to usually recommended procedures with some

infusion pumps).

In accordance with good operating practices, when turning off the pump, close the roller

clamp to assure complete occlusion.

Hospitals that use volumetric pumps for infusion of nitroglycerin should note that some

volumetric pumps require a special cassette or special integrated administration set with

disposal pump components made of assorted nitroglycerin-absorbing materials. If such

pump is used with the set connected from the bottle to the pump, you should be aware

that some loss of nitroglycerin will occur.

Additionally, care should be taken to fill the set drip chamber at least half full to prevent the

aspiration of air bubbles into the line during the fill cycle of the volumetric cassette.

As with all potent drugs, no matter what means for infusion of nitroglycerin is chosen, critical

care personnel must carefully monitor the patient's status. Due to variation in the responsiveness

individual

patients

drug,

each

patient

must

titrated

desired

level

hemodynamic function. Therefore, continuous monitoring of physiologic parameters (e.g. blood

pressure and heart rate in all patients, other measurements such as pulmonary capillary wedge

pressure, as appropriate) must be performed to achieve the correct dose. Adequate blood pressure

and coronary perfusion pressure must be maintained.

DOSING INSTRUCTIONS MUST BE FOLLOWED WITH CARE. IT SHOULD BE NOTED

THAT WHEN SPECIAL NON-ABSORBING TYPE OF SET (TYPE B) IS USED THE

CALCULATED DOSE WILL BE DELIVERED TO THE PATIENT BECAUSE THE LOSS

OF NITROGLYCERIN DUE TO ABSORPTION IN STANDARD PVC TUBING WILL BE

KEPT

MINIMUM.

NOTE

THAT

DOSAGES

COMMONLY

USED

PUBLISHED STUDIES UTILIZED GENERAL-USE PVC ADMINISTRATION SETS, AND

RECOMMENDED

DOSES

BASED

THIS

EXPERIENCE

HIGH

WHEN

SPECIAL NON-ABSORBING TYPE OF SET (TYPE B) IS USED.

PRECAUTIONS

NITROJECT® (Nitroglycerin for Injection, USP) should be used with caution in patients who

have severe hepatic or renal disease.

Nitroglycerin can

cause sudden severe hypotension. Excessive

hypotension,

especially for

prolonged periods of time, must be avoided because of possible deleterious effects on the brain,

heart, liver and kidney from poor perfusion and the attendant risk of ischemia, thrombosis, and

altered function of these organs. Paradoxical bradycardia and increased angina pectoris may

accompany nitroglycerin-induced hypotension. Patients with depleted blood volumes such as

those with dehydration due to vomiting, diarrhea, or GI fluid loss, significant hemorrhage or

intensive diuretic therapy may be subject to hypotensive crises with i.v. nitroglycerin. The

hypovolemic state should be corrected prior to therapy to ensure that adequate ventricular filling

is maintained. Patients with normal or low pulmonary capillary wedge pressure are especially

sensitive to the hypotensive effects of intravenous nitroglycerin. If pulmonary capillary wedge

pressure is being monitored, it will be noted that a fall in wedge pressure precedes the onset of

arterial hypotension, and the pulmonary capillary wedge pressure is thus a useful guide to safe

titration of the drug.

Tolerance to nitroglycerin and cross tolerance to other nitrates may occur. Nitrate tolerance and

dependence in patients with chronic use of nitrates has been well documented. Tolerance to

nitroglycerin has been readily produced in animals and it was reported that even a single dose of

nitroglycerin in rats can produce some tolerance.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No long term studies in animals were performed to evaluate the carcinogenic potential of

nitroglycerin.

Pregnancy:

Animal reproduction studies have not been conducted with nitroglycerin. It is not known whether

nitroglycerin can cause fetal harm when administered to a pregnant woman or can affect

reproduction capacity. Nitroglycerin should be given to a pregnant woman only if clearly

needed.

Nursing Mothers:

It is not known whether nitroglycerin is excreted in human milk. Because many drugs are

excreted

human

milk,

caution

should

exercised

when

intravenous

nitroglycerin

administered to a nursing woman.

Pediatric Use:

The safety and effectiveness of nitroglycerin in children have not been established.

Drug Interactions:

Nitroglycerin prolongs pentobarbital sleep time. Nitroglycerin potentiates the hypotensive and

anticholinergic effects of tricyclic antidepressants. Patients receiving hypotensive agents and

nitroglycerin should be observed for possible additive hypotensive effect. If nitroglycerin is used

surgical

procedures,

choice

anesthetic

agents

influence

response

nitroglycerin.

ADVERSE REACTIONS

The most frequent adverse reaction in patients treated with NITROJECT® (Nitroglycerin for

Injection, USP) by intravenous infusion is headache, which occurs in approximately 14.5% of

patients. However, considerable variation in frequency is observed according to the indication

and dosage utilized. Symptomatic hypotension (2.7%) is the second most common adverse

reaction. Other adverse reactions occurring in less than 1% of patients are:

Cardiovascular:

Reflex tachycardia, paradoxical increase of anginal pain, palpitations and

bradycardia may also occur, the incidence again depending on the indication and on the dosage

utilized. These effects can be reversed or minimized by discontinuing the drug or by carefully

adjusting the rate of infusion with constant hemodynamic monitoring of the patient.

CNS:

Weakness, dizziness, apprehension and restlessness.

Gastrointestinal:

Nausea, vomiting, abdominal pain.

Metabolic:

Methemoglobinemia

especially

presence

methemoglobin

reductase

deficiencies or in congenital M hemoglobin variants (for treatment see Overdosage).

Miscellaneous:

Muscle twitching and retrosternal discomfort.

The following additional adverse reactions have been reported with the oral and/or topical use of

nitroglycerin: cutaneous flushing, weakness, and occasionally drug rash or exfoliative dermatitis.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms of overdosage include headache, dizziness, flushing of skin, vomiting, marked fall in

blood pressure, methemoglobinemia and coma. Most of these effects can be obviated by

discontinuing the drug immediately. Reflex tachycardia can be treated by elevating the legs and

decreasing or temporarily terminating the infusion until the patient's condition stabilizes. Since

the duration of the hemodynamic effects following nitroglycerin administration is quite short,

additional corrective measures are usually not required.

However, if further therapy is indicated, administration of an intravenous alpha adrenergic

agonist (eg, methoxamine or phenylephrine) should be considered. Methemoglobinemia has been

reported following the use of nitroglycerin. The diagnosis of methemoglobinemia must be

considered in any cyanotic patient. Methylene blue 1-2 mg/kg as a 1% solution should be given

intravenously only if stupor or coma occurs.

DOSAGE AND ADMINISTRATION

General information:

Adequate facilities and personnel should be available for monitoring of the ECG and the blood

pressure. In addition, whenever possible, the pulmonary capillary wedge pressure should be

monitored to aid in the safe and effective infusion of nitroglycerin. Because of the rapid onset of

action

potency

NITROJECT®

(Nitroglycerin

Injection,

USP),

should

administered with the use of an infusion pump in order to allow precise measurement of the flow

rate.

BECAUSE OF THE LIKELY ALTERATIONS TO THE AMOUNT OF NITROGLYCERIN

DELIVERED TO THE PATIENT CAUSED BY ADMINISTRATION SETS, PUMPS, ETC.

AND THE GREAT VARIATIONS IN RESPONSIVENESS OF INDIVIDUAL PATIENTS TO

NITROGLYCERIN,

THERE

FIXED,

OPTIMUM

DOSE

NITROGLYCERIN.

EACH PATIENT MUST BE TITRATED TO THE DESIRED LEVEL OF HEMODYNAMIC

FUNCTION (SEE WARNINGS).

NOT FOR DIRECT INTRAVENOUS INJECTION. NITROJECT® (NITROGLYCERIN for

INJECTION, USP IS A CONCENTRATED, POTENT DRUG WHICH MUST BE DILUTED

IN DEXTROSE (5%) INJECTION, USP, OR SODIUM CHLORIDE (0.9%) INJECTION, USP,

PRIOR TO ITS INFUSION. THE RESULTANT SOLUTION SHOULD BE USED WITHIN 24

HOURS.

NITROJECT®

(NITROGLYCERIN

INJECTION,

USP)

SHOULD

ADMIXED WITH OTHER DRUGS.

Dilution:

It is important to consider the fluid requirements of the patient as well as the expected duration

of infusion in selecting the appropriate dilution of nitroglycerin.

Dosage:

IMPORTANT NOTICE

Dosage is affected by the type of infusion set used (see WARNINGS). Although the usual

starting adult dose range reported in clinical studies was 25 µg/min or more, those studies used

PVC tubing.

NONABSORBING

TUBING

WILL

RESULT

NEED

REDUCED DOSAGE.

The recommended dosage should initially be 5 µg/min delivered through an infusion pump

capable of exact and constant delivery of the drug, such as a properly calibrated peristaltic-action

pump which has been checked to determine proper operation with the appropriate infusion set.

Subsequent titration must be adjusted to the clinical situation, with dose increments becoming

more cautious as partial response is seen. Initial titration should be 5 µg/min increments, with

increases every 3 to 5 minutes until some response is noted. If no response is seen at 20 µg/min,

increments of 10 and later 20 µg/min can be used. Once a partial blood pressure response is

observed, the rate of dose increase should be reduced and the interval between increments should

be lengthened.

Patients with normal or low left ventricular filling pressure or pulmonary capillary wedge

pressure (e.g., angina patients without other complications) may be hypersensitive to the effects

of nitroglycerin and may respond fully to doses as small as 5 µg/min. These patients require

especially careful titration and monitoring.

There is no fixed optimum dose of nitroglycerin. Due to variations in the responsiveness of

individual patients to the drug, each patient must be titrated to the desired level of hemodynamic

function. Therefore, continuous monitoring of physiologic parameters (blood pressure and heart

rate

patients,

other

measurements

such

pulmonary

capillary

wedge

pressure,

appropriate) MUST BE PERFORMED to achieve the correct dose. Adequate systemic blood

pressure and coronary perfusion pressure must be maintained.

Nitroject® I.V. ADMINISTRATION TABLE

NITROJECT® 1 mg/mL

EACH 10 mL VIAL = 10 mg NITROGLYCERIN

Mixing

Instructions:

10 mL in 250 mL

20 mL in 250 mL

30 mL in 250 mL

Concentration:

40 µg/mL (approx.)

75 µg/mL (approx.)

110 µg/mL (approx.)

µg/min

µg/min

µg/min

µdrops/min(=mL/hour)

(60 microdrops=1 mL)

Nitroject® I.V. ADMINISTRATION TABLE

NITROJECT® 5 mg/mL

EACH 10 mL VIAL = 50 mg NITROGLYCERIN

Mixing

Instructions:

10 mL in 1000 mL

10 mL in 500 mL

20 mL in 1000 mL

10 mL in 250 mL

20 mL in 500 mL

40 mL in 1000 mL

Concentration:

50 µg/mL (approx.)

100 µg/mL

(approx.)

200 µg/mL (approx.)

µg/min

µg/min

µg/min

µdrops/min(=mL/hour)

(60 microdrops=1 mL)

Invert the glass parenteral bottle several times following admixture to ensure uniform dilution of

NITROJECT® IV. As with all intravenous admixtures, dilution should be made just prior to

administration and the solution used within 24 hours.

NOTE: If the concentration is adjusted, it is imperative to flush or replace the nitroglycerin

infusion set before a new concentration is utilized. Depending on the length of the dead space

and the flow rate, the time required for the new concentration to reach the patient may vary (e.g.

if the dead space of the set is approximately 15 mL and depending on the flow rate, it could take

from 9 minutes to 3 hours for the new concentration to reach the patient if the set has not been

flushed or replaced).

PHARMACEUTICAL INFORMATION

Drug substance:

Proper name:

Nitroglycerin, USP

Chemical name:

1,2,3-Propanetriol, trinitrate

Structural formula:

Molecular weight:

227.09

Physical form:

A colourless, slightly volatile, odourless, oily liquid, with a sweet,

aromatic and pungent taste.

Solubility:

1 g in 800 mL of water, 1 g in 4 g of alcohol, 1 g in 18 g methanol,

1 g in 120 g of carbon disulphide, and 1 g in 6 g of almond oil;

miscible with acetone, chloroform, ether glacial acetic acid, ethyl

acetate,

benzene,

nitrobenzene,

pyridine,

ethylene

bromide,

dichloroethylene; sparingly soluble in glycerol and light petroleum.

Melting point:

Crystallizes in 2 forms: labile form, mp + 2.8°C; stable form, mp +

13.5°C.

Composition:

NITROJECT® 1 mg/mL (Nitroglycerin for Injection, USP) is a clear, colorless solution for

intravenous infusion after dilution. Each mL contains 1.0 mg of nitroglycerin, 10% ethanol v/v

and Water for Injection, USP, q.s. to 1 mL.

NITROJECT® 5 mg/mL (Nitroglycerin for Injection, USP) is a clear, colorless solution for

intravenous infusion after dilution. Each mL contains 5.0 mg of nitroglycerin, 30% ethanol v/v,

30% propylene glycol v/v and Water for Injection, USP, q.s. to 1 mL.

These solutions are sterile, non-pyrogenic and non-explosive.

Stability and storage recommendations:

Store between 15 and 30°C. Protect from freezing. Protect from light.

Under these storage conditions NITROJECT® 1 mg/mL (Nitroglycerin for Injection, USP) is

stable for 18 months.

Under these storage conditions NITROJECT® 5 mg/mL (Nitroglycerin for Injection, USP) is

stable for 36 months.

Dilution:

SOLUTION PREPARATION FOR AN INFUSION PUMP

Aseptically transfer 10 mL (10 mg nitroglycerin) of NITROJECT® 1 mg/mL (Nitroglycerin for

Injection, USP) into a glass, IV bottle containing 250 mL of 5% Dextrose Injection, USP or 0.9%

Sodium Chloride Injection, USP, and mix well. The resultant solution will contain approximately

40 µg/mL of nitroglycerin and is stable for at least 24 hours at controlled room temperature (15

to 30°C). For other concentrations, refer to Table. Invert the glass parenteral bottle several times

following admixture to assure uniform dilution.

STABILITY AND STORAGE OF DILUTED SOLUTION

The diluted NITROJECT® (Nitroglycerin for Injection, USP) is stable for at least 24 hours at

controlled room temperature (15 to 30°C). Discard all unused solution after 24 hours.

INCOMPATIBILITIES

NITROJECT® (Nitroglycerin for Injection, USP) is incompatible with alkalies. Nitroglycerin

readily migrates into many plastics (see WARNINGS). Some filters also absorb nitroglycerin

and should be avoided. Forty to 80% of the total amount of nitroglycerin in the final diluted

solution for infusion is absorbed by polyvinyl chloride (PVC) intravenous administration sets

(see WARNINGS).

DOSAGE FORMS

Availability

NITROJECT® 1 mg/mL (Nitroglycerin for Injection, USP) is available in 10 mL single-dose

vials containing 10 mg of nitroglycerin. Each mL contains 1 mg of nitroglycerin. Boxes of 5 x 10

NITROJECT® 5 mg/mL (Nitroglycerin for Injection, USP) is available in 10 mL single-dose

vials containing 50 mg of nitroglycerin. Each mL contains 5 mg of nitroglycerin. Boxes of 5 x 10

The NITROJECT® dosage forms consist of concentrated solutions of nitroglycerin which

must

be diluted

in Dextrose (5%) Injection, USP, or Sodium Chloride (0.9%) Injection, USP, prior to

intravenous infusion.

PHARMACOLOGY

It has been shown that intravenous nitroglycerin in anesthetized dogs produced a significant

dilation of the large coronary arteries. Similarly, a marked dilation of large coronary arteries was

observed in conscious dogs although only a slight effect was seen in the small coronary arteries.

Nitroglycerin caused a decrease in the ST segment elevations which accompany myocardial

ischemia when administered intravenously to dogs with occluded coronary arteries. Although

coronary blood flow was increased by 45% in the subendocardium of the ischemic areas,

prolonged i.v. administration of nitroglycerin did not decrease the size of the infarct.

Nitroglycerin

administered

concentrations

produced

dilation

veins

which

predominated over the arterioles. In anesthetized dogs, nitroglycerin decreased mean arterial

pressure due to vasodilation of peripheral arteries.

CLINICAL PHARMACOLOGY

Studies on blood flow in the human forearm have demonstrated a significant decrease in venous

tone after sublingual administration of nitroglycerin. This caused a pooling of blood in the

peripheral veins and a decrease in venous return to the heart. A slight decrease in systemic

arterial pressure was observed with a corresponding fall in vascular resistance in the forearm.

Administration of nitroglycerin reduced towards normal left ventricular end diastolic pressure

which has been found to be markedly elevated in patients with coronary artery disease. The

result was disappearance of anginal pain. Intravenous nitroglycerin given to patients with

congestive heart failure produced a significant decrease in pulmonary capillary wedge pressure

and an improvement of the cardiac index.

Pharmacokinetics

Nitroglycerin shows essentially single compartment kinetics in rats when administered by the

intracardiac

route;

half-life

about

minutes

mean

apparent

volume

distribution

about

litres/kg.

Intravenous

nitroglycerin

rabbits

second

distribution phase, followed by rapid metabolism with a half-life of about 4 minutes.

In animal studies, nitroglycerin was rapidly degraded in the liver by glutathione-organic nitrate

reductase. The metabolites are 1,3 or 1,2-glyceryl dinitrate, 1 or 2-glyceryl-mononitrate and

oxidized glutathione.

Elimination was by the urine, feces and expired air.

TOXICOLOGY

Acute Toxicity

The acute intravenous toxicity in various species is summarized below:

Species

Test

Dose (mg/kg)

Guinea pig

83.5

Rabbit

Rabbit

>10

>30

Lethal doses of nitroglycerin in common laboratory animals by other routes of administration

ranged from 80 to 500 mg/kg.

Signs of toxicity included methemoglobinemia and circulatory collapse, leading to convulsions

and death.

It has been reported that most cats receiving 7.5 or 15 mg/kg, subcutaneously, survived 50 daily

doses. Albuminuria and icterus were noted in the animals; and, at sacrifice, hemorrhage of the

cerebellum, heart, liver and spleen were observed. Cats exposed to saturated atmospheres of

nitroglycerin for 68 days developed anemia and moderate leucocytosis. Longer exposures

produced

tolerance

cats.

Methemoglobinemia

peripheral

vasodilation

with

accompanying fall in blood pressure were produced.

BIBLIOGRAPHY

Anjou-Lindskog E, Broman L, Holmgren A: Effects of nitroglycerin on central

haemodynamics and V A/Q distribution early after coronary bypass surgery. Acta

Anaesth Scand 26: 489-497, 1982.

Armstrong PW, Walker DC, et al: Vasodilator therapy in acute myocardial infarction:

A comparison of sodium nitroprusside and nitroglycerin. Circulation 52: 1118-1122,

1975.

Armstrong PW, Watts DG, Moffat JA: Steady state pharmacokinetic haemodynamic

studies of intravenous nitroglycerin in congestive cardiac failure. Brit J Clin Pharmac

16: 385-390, 1983.

Azancot

Masquet

Effets

l'administration

parentérale

trinitroglycérine sur la fonction myocardique, le débit coronaire et la consommation

d'oxygène myocardique chez le coronarien. Nouv Press Méd 8 (4):250-256, 1979.

Baaske DM, Amann AH, et al: Nitroglycerin compatibility with intravenous fluid

filters, containers, and administration sets. Am J Hosp Pharm 37 (2):201-205, 1980.

Bale R, Powles A, Wyatt R: I.V. glyceryl trinitate: haemodynamic effects and clinical

use in cardiac surgery. Br J Anaesth 54 (3):297-301, 1982.

Barnes CD, Eltherington LG: Nitroglycerol, in: Barnes CD, Eltherington LG (Eds):

Drug dosage in laboratory animals. - A handbook. University of California Press,

Berkeley (2 ed), p.174, 1973.

Bayley S, Valentine H, Bennett ED: The haemodynamic responses to incremental

doses of intravenous nitroglycerin in left ventricular failure. Intensive Care Med 10

(3): 139-145, 1984.

Bjoraker DG, Knight PR: Intravenous nitroglycerin administration during infrarenal

aortic clamping. Can Anaesth Soc J 31 (1):44-50, 1984.

Bussmann

Barthe

Controlled

study

intravenous

nitroglycerin

treatment for two days in patients with recent myocardial infarction. Clin Cardio 3

(6):399-405, 1980.

Chestnut JS, Albin MS, et al: Clinical evaluation of intravenous nitroglycerin for

neurosurgery. J Neurosurg 48:704-712, 1978.

Cottrell JE, Turndorf H: Intravenous nitroglycerin. Am Heart J 96 (4):550-553, 1978.

Di Carlo FJ: Nitroglycerin revisited: Chemistry, biochemistry, interactions. Drug

Metab Rev 4:1-38, 1975.

Elliott GT, Quinn SL: Nitroglycerin intravenous infusion. Drug Intell Clin Pharm 16

(3): 211-217, 1982.

Fahmy

Nitroglycerin

hypotensive

drug

during

general

anesthesia.

Anesthesiology 49 (1):17-20, 1978.

Fibuch EE, Cecil WT, Reed WA: Methemoglobinemia associated with organic nitrate

therapy. Anesthesia and Analgesia 58:521-523, 1979.

Flaherty JT: Parenteral nitroglycerin: clinical usefulness and limitations. Cardiovasc

Clin 14 (3):111-118, 1984.

Flaherty JT, Becker LC, et al: A randomized clinical trial of intravenous nitroglycerin

in patients with acute myocardial infarction: benefits of early treatment. ZX Kardiol

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