Mechanism of Action:
Atropine. Atropine competitively blocks the effects of acetylcholine, including excess acetylcholine due to organophosphorous poisoning, at muscarinic cholinergic receptors on smooth muscle, cardiac muscle, and secretory gland cells and in peripheral autonomic ganglia and the central nervous system.
Pralidoxime. Pralidoxime reactivates acetylcholinesterase which has been inactivated by phosphorylation due to an organophosphorous nerve agent or insecticide. However, pralidoxime does not reactivate acetylcholinesterase inactivated by all organophosphorous nerve agents (e.g., soman). Reactivated acetylcholinesterase hydrolyzes excess acetylcholine resulting from organophosphorous poisoning to help restore impaired cholinergic neural function. Reactivation is clinically mportant because only a small proportion of active acetylcholinesterase is needed to maintain vital functions. Pralidoxime cannot reactivate phosphorylated acetylcholinesterases that have undergone a further chemical reaction known as "aging".
Atropine reduces secretions in the mouth and respiratory passages, relieves airway constriction, and may reduce centrally-mediated respiratory paralysis. In severe organophosphorous poisoning, a fully atropinized patient may develop or continue to have respiratory failure and may require artificial respiration and suctioning of airway secretions. Atropine may cause thickening of secretions.
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. Atropine increases heart rate and reduces atrioventricular conduction time. Adequate atropine doses can prevent or abolish bradycardia or asystole produced by organophosphorous nerve agents.
Atropine may decrease the degree of partial heart block which can occur after organophosphorous poisoning. In some patients with complete heart block, atropine may accelerate the idioventricular rate; in others, the rate is stabilized. In some patients with conduction defects, atropine may cause paradoxical atrioventricular (A-V) block and nodal rhythm.
Atropine will not act on the neuromuscular junction and has no effect on muscle paralysis or weakness, fasciculations or tremors: pralidoxime is intended to treat these symptoms.
Systemic doses of atropine 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. Atropine can dilate cutaneous blood vessels, particularly the "blush" area (atropine flush), and may inhibit sweating, thereby causing hyperthermia, particularly in a warm environment or with exercise.
Pralidoxime chloride has its most critical effect in relieving respiratory muscle paralysis. 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 has a minor role in relieving muscarinic signs and symptoms, such as salivation or bronchospasm.
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. Single dose DuoDote pharmacokinetic and pharmacodynamic data for atropine are shown in Figure 1. The intramuscular injection site was the antero-lateral thigh.
Mean atropine plasma concentrations shown in Figure 1 indicate a plateau beginning at about 5 minutes postdose and extending through 60 minutes postdose.
Figure 1. Mean atropine plasma concentrations after a single DuoDote intramuscular injection which delivers 2.1 mg of atropine and 600 mg pralidoxime chloride, n=24 healthy subjects [men (n=12), women (n=12)].
The Cmax, Tmax and T½ of atropine given intramuscularly by DuoDote delivery system was 13 ± 3 ng/mL, 31 ± 30 minutes, and 2.4 ± 0.3 hours, respectively. The protein binding of atropine is 14 -22% in plasma. DuoDote AUC0-inf and Cmax, values for atropine are 15% higher in females than males. The half-life of atropine is approximately 20 minutes shorter in females than males.
In healthy volunteers, approximately 50-60% of intravenous atropine is excreted in the urine as unchanged drug with approximately 17-28% renally eliminated in the first 100 minutes. Noratropine, atropine N-oxide, tropic acid, and tropine are the reported metabolites in the urine. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver. Half-life of intravenous atropine is 3.0 ± 0.9 hours in adults and 10.0 ± 7.3 hours in geriatric patients (65-75 years of age).
Atropine pharmacokinetics have not been evaluated in patients with renal or hepatic impairment. Since atropine is approximately equally metabolized and renally excreted, atropine elimination in patients with mild to moderate renal impairment might not differ substantially from that of healthy subjects. Patients with severe renal or hepatic impairment may eliminate atropine more slowly and might require smaller, and/or less frequent, doses after initial atropinization.
Pralidoxime chloride is rapidly absorbed after intramuscular injection. DuoDote single dose pharmacokinetic data for pralidoxime chloride 600 mg are provided in Figure 2. These data are derived from the bioavailability study described above for atropine pharmacokinetics.
Figure 2. Mean pralidoxime plasma concentrations after a single DuoDote intramuscular injection which delivers 2.1 mg of atropine and 600 mg pralidoxime chloride, n=24 healthy subjects.
The Cmax, Tmax and T½ of pralidoxime following 600 mg pralidoxime given intramuscularly by DuoDote delivery system was 7 ± 3 mcg/mL, 28 ± 15 minutes, and 2 ± 1 hour, respectively. In the same study, a single DuoDote injection produced a mean Cmax, for pralidoxime about 36% higher in females than males. Tmax is 23 minutes in females and 32 minutes in males. Pralidoxime half-life in males and females are 153 and 107 minutes, respectively.
In healthy volunteers, approximately 72-94% of intravenous pralidoxime is excreted unchanged in the urine, about 57-70% in the first 30 minutes, partly as metabolite. Pralidoxime is subject to active renal secretion. Elimination of pralidoxime can be reduced by the concurrent administration of organic bases, such as thiamine, but not organic acids, and can be altered by urine pH. Pralidoxime distributes into tissues and is not appreciably bound to serum protein.
Pralidoxime pharmacokinetics have not been evaluated in patients with renal or hepatic impairment. Since pralidoxime is primarily excreted in the urine, a decrease in renal function will result in increased blood levels of the drug. Thus, dose reduction should be considered for patients with renal insufficiency.