Atropine
Atropine is commonly classified as an anticholinergic or antiparasympathetic (parasympatholytic) drug. More precisely, however, it is termed an antimuscarinic agent since it antagonizes the muscarine-like actions of acetylcholine and other choline esters.
Atropine inhibits the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves, and on smooth muscles which respond to endogenous acetylcholine but are not so innervated. As with other antimuscarinic agents, the major action of atropine is a competitive or surmountable antagonism which can be overcome by increasing the concentration of acetylcholine at receptor sites of the effector organ (e.g., by using anticholinesterase agents which inhibit the enzymatic destruction of acetylcholine). The receptors antagonized by atropine are the peripheral structures that are stimulated or inhibited by muscarine, (i.e., exocrine glands and smooth and cardiac muscle).
Responses to postganglionic cholinergic nerve stimulation may also be inhibited by atropine but this occurs less readily than with responses to injected (exogenous) choline esters.
Pralidoxime Chloride
The principal action of pralidoxime is to reactivate cholinesterase (mainly outside the central nervous system) which has been inactivated by phosphorylation due to an organophosphorous nerve agent or related compound, although pralidoxime does not reactivate cholinesterase inactivated by all organophosphate nerve agents (e.g. soman). The destruction of accumulated acetylcholine can then proceed and neuromuscular junctions will again function normally. Pralidoxime also slows the process of “aging” of phosphorylated cholinesterase to a non-reactivatable form and detoxifies certain organophosphates by direct chemical reaction.
Atropine
Atropine reduces secretions in the mouth and respiratory passages, relieves the constriction and spasm of the respiratory passages, and may reduce the paralysis of respiration which results from actions of the toxic agent on the central nervous system. Atropine-induced parasympathetic inhibition may be preceded by a transient phase of stimulation, especially on the heart where small doses first slow the rate before characteristic tachycardia develops due to paralysis of vagal control. Although mild vagal excitation occurs, the increased respiratory rate and occasionally increased depth of respiration produced by atropine are more probably the result of bronchiolar dilatation. Accordingly, atropine is an unreliable respiratory stimulant and large or repeated doses may depress respiration.
Adequate doses of atropine abolish various types of reflex vagal cardiac slowing or asystole. The drug also prevents or abolishes bradycardia or asystole produced by injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. Atropine may also lessen the degree of partial heart block when vagal activity is an etiologic factor. In some patients with complete heart block, the idioventricular rate may be accelerated by atropine; in others, the rate is stabilized. Occasionally, a large dose may cause atrioventricular (A-V) block and nodal rhythm.
Atropine in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure. Systemic doses slightly raise systolic and lower diastolic pressures and can produce significant postural hypotension. Such doses also slightly increase cardiac output and decrease central venous pressure. Occasionally, therapeutic doses dilate cutaneous blood vessels, particularly in the “blush” area (atropine flush), and may cause atropine “fever” due to suppression of sweat gland activity in infants and small children.
Pralidoxime Chloride
Pralidoxime chloride has its most critical effect in relieving paralysis of the muscles of respiration. Because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site.
Pralidoxime relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose.
Published reports have established the safety and efficacy of atropine and pralidoxime chloride used separately, as well as the safety and increased efficacy of atropine and pralidoxime chloride when administered concomitantly in the treatment of nerve agent poisoning in humans3.
Atropine
Atropine is rapidly and well absorbed after intramuscular administration. Atropine disappears rapidly from the blood and is distributed throughout the various body tissues and fluids. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine. Traces are found in various secretions, including milk. Atropine readily crosses the placental barrier and enters the fetal circulation.
The Cmax, Tmax, and T½ of atropine following 2.09 mg atropine given intramuscularly by multi-chambered delivery system was 13 ± 3 ng/mL, 31 ± 30 minutes, and 2.4 ± 0.3 hours, respectively. The protein binding of atropine is 14 to 22% in plasma. There are gender differences in the pharmacokinetics of atropine. The AUC(0-inf) and Cmax were 15% higher in females than males. The half-life of atropine is slightly shorter (approximately 20 minutes) in females than males.
Pralidoxime Chloride
Pralidoxime is distributed throughout the extracellular water; it is not bound to plasma protein. The drug is rapidly excreted in the urine partly unchanged, and partly as a metabolite produced by the liver. Consequently, pralidoxime is relatively short acting and repeated doses may be needed, especially where there is any evidence of continuing absorption of the poison.
The Cmax, Tmax, and T½ of pralidoxime following 600 mg pralidoxime given intramuscularly by multi-chambered delivery system was 7 ± 3 mcg/mL, 28 ± 15 minutes, and 2 ± 1 hour, respectively. The Cmax of pralidoxime was about 36% higher in females than males but the AUC was comparable between the two genders.
Atropine
The major side effects of atropine can be attributed to antimuscarinic action. These include dryness of the mouth, blurred vision, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitance or retention, constipation, abdominal distention, nausea, vomiting, loss of libido, and impotency. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Larger or toxic doses may produce such central effects as restlessness, tremor, fatigue, locomotor difficulties, delirium, followed by hallucinations, depression,
and ultimately, medullary paralysis and death. Large doses can also lead to circulatory collapse. In such cases, blood pressure declines and death due to respiratory failure may ensue following paralysis and coma. Hypersensitivity reactions will occasionally occur with atropine; these are usually seen as skin rashes, on occasion progressing to exfoliation.
Pralidoxime Chloride
Pralidoxime may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, decreased renal function, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In actual cases of poisoning, it is very difficult to differentiate some of the toxic effects produced by atropine or the organophosphate compound from those of pralidoxime chloride.
Excitement and manic behavior immediately following recovery of consciousness after organophosphorous poisoning treated with pralidoxime chloride have been reported in several cases. However, similar behavior has occurred in cases that were not treated with pralidoxime. 3,5,6
Elevations in SGOT and/or SGPT enzyme levels were observed in one of six normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about two weeks.
Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. A single intramuscular injection of 330 mg in 1 mL in rabbits caused myonecrosis, inflammation, and hemorrhage.
Atropine and Pralidoxime Chloride
When atropine and pralidoxime are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone.
Atropine
Serious overdosage with atropine is characterized by widespread paralysis of parasympathetically innervated organs. Dry mucous membranes, widely dilated and nonresponsive pupils, tachycardia, fever, and cutaneous flush are especially prominent, as are mental and neurological symptoms.
Disorientation, mania, hallucinations, gait disturbances, and symptoms may last 48 hours or longer. In instances of severe intoxication, respiratory depression, coma, circulatory collapse, and death may occur.
The fatal dose of atropine is not known. In the treatment of organophosphorous poisoning, 200 mg doses have been used and doses as high as 1000 mg have been given.
In children, 10 mg or less may be fatal. With a dose as low as 0.5 mg, undesirable minimal symptoms or responses of overdosage may occur. These increase in severity and extent with larger doses of the drug (excitement, hallucinations, delirium, and coma with a dose of 10 mg or more). However, in the presence of organophosphate poisoning, higher doses of atropine may be tolerated.
Pralidoxime Chloride
Symptoms of pralidoxime chloride overdose have been observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to effects of the poison.
