Atropine

Absorption

Intravenous atropine follows a non-linear pharmacokinetic model at doses between 0.5 and 4 mg. After intramuscular administration, atropine is rapidly absorbed. In adults given 1.67 mg of atropine intramuscularly, the Cmax was 9.6 ng/mL and the Tmax went from 3 to 60 minutes. In healthy subjects given 30 μL of atropine ophthalmic solution, the Cmax and Tmax were 288 pg/mL and 28 minutes, respectively. Atropine is well absorbed in the gastrointestinal tract and rapidly delivered to systemic circulation. When administered intramuscularly, atropine has a bioavailability of 50%. The AUC0-INF and Cmax of atropine are higher in females than males (15%).

Toxicity

High doses of atropine may cause palpitation, dilated pupils, difficulty swallowing, hot dry skin, thirst, dizziness, restlessness, tremor, fatigue and ataxia. Toxic doses of atropine lead to restlessness and excitement, hallucinations, delirium and coma. In cases of severe intoxication, atropine can cause a circulatory collapse, leading to a decline in blood pressure and respiratory failure that may ensue in death following paralysis and coma.
In case of atropine overdose, supportive treatment should be administered. Provide artificial respiration with oxygen if respiration is depressed, and follow cooling methods to reduce atropine-induced fever, especially in pediatric patients. In case of urinary retention, catheterization may be required. Atropine is mainly eliminated through the kidney; therefore, urinary output must be maintained and increased if possible. In case of atropine-induced photophobia, the room should be darkened. A short-acting barbiturate or diazepam may be given as needed to control marked excitement and convulsions; however, large doses should be avoided since central depressant action may coincide with the depression that occurs late in atropine poisoning. Central stimulants are not recommended. The acute oral toxicity (LD50) of atropine in mice is 75 mg/kg.

Description

Atropine is considered to be the most effective antidote for both OP and CB intoxication. By effectively competing with acetylcholine for the same cellular receptors, it prevents overstimulation of the autonomous parasympathetic system. Most importantly, it helps prevent asphixia, the main cause of death. In human subjects, it is customary to constantly infuse atropine in order to maintain optimal concentration throughout recovery from the “cholinergic crisis.” In wildlife rehabilitation, this is impractical and subjects need to be repeatedly injected with atropine.

Description

Scopolamine?(1)?and its biochemical precursor hyoscyamine?(2)?are deadly-nightshade alkaloids that are also found other plants of the Solanaceae family such as mandrake, jimsonweed, and tomato. Hyoscyamine is the enantiomer of the well-known nightshade alkaloid atropine.
Both alkaloids are extremely poisonous and have hallucinogenic effects. (Mandrake is sometimes called “insane root”.) They are anticholinergics, and, when used in small doses, they have medical uses such as treating gastrointestinal disorders. Plant extracts containing them have been used medicinally and ritually since biblical times or earlier.
Scopolamine is used criminally to poison people, not only to murder them but also to make them vulnerable to robbery or rape. Despite its adverse effects, it also has been tried as a “truth drug”.

Description

Atropine is a naturally occurring tropane alkaloid extracted from plants of the family Solanaceae including deadly nightshade (A. belladonna). It is a non-selective, competitive antagonist of the muscarinic acetylcholine receptor types M₁, M₂, M₃, M₄, and M₅ (pKBs range from 8.9-9.8). Atropine increases firing of the sinoatrial node and conduction through the atrioventricular node of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions. It is classified as an anticholinergic (parasympatholytic) drug and commonly used to dilate the pupils, increase heart rate, reduce salivation and other secretions, and as an antidote against organophosphate poisoning.

Chemical properties

White or almost white, crystalline powder or colourless crystals.

Chemical properties

Atropine, also known as daturine, C17H23NO3, white, crystalline substance, optically inactive, but usually contains levorotatory hyoscyamine. Compound is soluble in alcohol, ether, chloroform, and glycerol; slightly soluble in water.

Physical properties

Appearance: atropine appears as colourless, odourless crystals or a white crystalline powder. Solubility: very soluble in water and soluble in ethanol. Melting point: melting point of atropine isn’t higher than 189?°C (melting time decomposition) (Chinese Pharmacopoeia), 114–118?°C (United States Pharmacopeia) and 115– 119?°C (British Pharmacopoeia). The chemical structure of atropine is made up of amino alcohol esters. It is easy for atropine to be hydrolysed into tropine and despun tropic acid under alkaline condition. Atropine is stable in faintly acid and neutral aqueous solution, most stable at pH 3.5–4.0.

Originator

Atromed,Promed Exports,India

History

Mandragora (mandrake) was described for treatment of wounds, gout and sleeplessness and as a love potion in the fourth century BC by Theophrastus. Atropine extracted from the Egyptian henbane was used by Cleopatra in the last century BC to dilate her pupils in the hope that she would appear more alluring. In the Renaissance, women used the juice of the berries of Atropa belladonna to enlarge the pupils of their eyes for cosmetic reasons. It isn’t until the first century AD that Dioscorides found that wine containing mandrake can be used as an anaesthetic treatment for pain or sleeplessness in surgery or cautery. The combination of extracts containing tropane alkaloids and opium was used to treat diseases, which was popular in the Roman and Islamic Empires and Europe. The combination was replaced by the use of ether, chloroform and other modern anaesthetics about 100?years ago. The mydriatic effects of atropine were studied by the German chemist Friedlieb Ferdinand Runge (1795–1867). In 1831, the German pharmacist Heinrich F.? G. Mein (1799–1864) succeeded in separating pure atropine from plants. The substance was first synthesized by German chemist Richard Willst?tter in 1901. In 1889, Richard Willst?tter first confirmed the chemical structure of atropine. Atropine was first synthesized by A.?Ladenburg. Homatropine, a kind of tropic alkaline ester, is used in the diagnosis and treatment in ophthalmology, and it has a shorter acting time than atropine. Quaternary ammonium compounds of atropine obtained by alkylation of nitrogen atoms have anticonvulsant function, which does not affect the central nervous system, due to their polarity. In 1970, atropine sulphate was synthesized in Hangzhou, the location of the first pharmaceutical factory in China, which increased the yield, reduced the cost and met the requirements of clinics.

The Uses of Atropine

Atropine is used in medicine and is an antidote for cholinesteraseinhibiting compounds, such as organophosphorus insecticides and certain nerve gases. Atropine is commonly offered as the sulfate. Atropine is used in connection with the treatment of disturbances of cardiac rhythm and conductance, notably in the therapy of sinus bradycardia and sick sinus syndrome. Atropine is also used in some cases of heart block. In particularly high doses, atropine may induce ventricular tachycardia in an ischemic myocardium. Atropine is frequently one of several components in brand name prescription drugs.

The Uses of Atropine

anticholinergic, mydriatic

The Uses of Atropine

Scopolamine is found in the leaves of Daturametel L., D. meteloides L., and D. fastuosavar. alba (Cordell 1978). It is used as asedative, a preanesthetic agent, and in thetreatment of motion sickness (Merck 1989).

Background

Atropine is an alkaloid originally synthesized from Atropa belladonna. It is a racemic mixture of d-and l-hyoscyamine, of which only l-hyoscyamine is pharmacologically active. Atropine is generally available as a sulfate salt and can be administered by intravenous, subcutaneous, intramuscular, intraosseous, endotracheal and ophthalmic methods. Oral atropine is only available in combination products. Atropine is a competitive, reversible antagonist of muscarinic receptors that blocks the effects of acetylcholine and other choline esters. It has a variety of therapeutic applications, including pupil dilation and the treatment of anticholinergic poisoning and symptomatic bradycardia in the absence of reversible causes. Atropine is a relatively inexpensive drug and is included in the World Health Organization List of Essential Medicines.

Indications

The intravenous, intramuscular, subcutaneous, intraosseous and endotracheal use of atropine is indicated for the temporary blockade of severe or life-threatening muscarinic effects. The intramuscular use of atropine in the form of a pen injector is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides in adult and pediatric patients. The ophthalmic use of atropine is indicated for mydriasis, cycloplegia, and penalization of the healthy eye in the treatment of amblyopia.
In combination with difenoxin or diphenoxylate (tablets for oral use), atropine is indicated as adjunctive therapy in the management of acute nonspecific diarrhea.

What are the applications of Application

Atropine is a competitive antagonist of mAChR M (muscarinic acetylcholine receptors)

Definition

An alkaloid that is the 3(s)-endo isomer of atropine.

Definition

atropine: A poisonous crystalline alkaloid,C₁₇H₂₃NO₃; m.p. 118–119°C. Itcan be extracted from deadly nightshadeand other solanaceous plantsand is used in medicine to treat colic,to reduce secretions, and to dilatethe pupil of the eye.

Production Methods

Atropine is prepared by extraction from Datura stramonium, or synthesized. The compound is toxic and allergenic.

Indications

This product was recorded in the Pharmacopoeia of the People’s Republic of China (2015), the British Pharmacopoeia (2017), the United States Pharmacopeia (40), the Japanese Pharmacopoeia (17th ed.), the Indian Pharmacopoeia (2010), the European Pharmacopoeia (9.0th ed.), the International Pharmacopoeia (5th ed.) and the Korean Pharmacopoeia (10th ed.). Atropine sulphate is commonly used in clinics. Dosage forms are injection, tablet and eye ointment; atropine sulphate was mainly used to treat toxic shock and organic phosphorus pesticide poisoning, to relieve visceral colic, as preanaesthetic medication and to reduce bronchial mucus secretion. The indications of atropine sulphate eye gel are iridocyclitis, fundus examination and mydriasis.

Manufacturing Process

Atropin was obtained from belladonna roots and by racemisation of Lhyoscyamine with dilute alkali or by heating in chloroform solution. The alkaloid was crystallised from alcohol on addition of water, or from chloroform on addition of light petroleum, or from acetone in long prisms, m.p. 118°C, sublimed unchanged when heated rapidly. It is soluble in alcohol or chloroform, less soluble in ether or hot water, sparingly so in cold water (in 450 L at 25°C) and almost insoluble in light petroleum. Atropine is optically inactive.

brand name

Atrophate [Veterinary] (Schering-Plough Animal Health); Atropisol (Ciba Vision, US Ophthalmics); Isopto Atropine (Alcon).

Therapeutic Function

Anticholinergic

World Health Organization (WHO)

Atropine, an alkaloid with anticholinergic activity extracted from Atropa belladonna, has been widely used in medicines for centuries for its antispasmodic and mydriatic properties. It is also used for premedication prior to anaesthesia. Preparations containing atropine remain available and the substance is included in the WHO Model List of Essential Drugs.

General Description

Atropine is the tropine ester of racemictropic acid and is optically inactive. It possibly occurs naturallyin various Solanaceae, although some claim, with justification,that whatever atropine is isolated from naturalsources results from racemization of (-)-hyoscyamine duringthe isolation process. Conventional methods of alkaloidisolation are used to obtain a crude mixture of atropine andhyoscyamine from the plant material. This crude mixture isracemized to atropine by refluxing in chloroform or by treatmentwith cold dilute alkali. Because the racemizationprocess makes atropine, an official limit is set on thehyoscyamine content by restricting atropine to a maximumlevorotation under specified conditions.
Atropine occurs in the form of optically inactive, white,odorless crystals possessing a bitter taste. It is not very solublein water (1:460, 1:90 at 80°C) but is more soluble inalcohol (1:2, 1:1.2 at 60°C). It is soluble in glycerin (1:27),in chloroform (1:1), and in ether (1:25). Saturated aqueoussolutions are alkaline in reaction (pH 9.5). The free baseis useful when nonaqueous solutions are to be made, such asin oily vehicles and ointment bases. Atropine has a plasmahalf-life of about 2 to 3 hours. It is metabolized in the liverto several products, including tropic acid and tropine.

Hazard

Extremely toxic, poison, paralyzes the parasympathetic nervous system by blocking the action of acetylcholine at nerve endings.

Health Hazard

The toxic effects are similar to atropine. Thesymptoms at toxic doses are dilation of the pupils, palpitation, blurred vision, irritation,confusion, distorted perceptions, hallucinations,and delirium. However, the mydriaticeffect is stronger than that of many othertropane alkaloids. Scopolamine is about threeand five times more active than hyocyamineand atropine, respectively, in causing dilationof the pupils. Its stimulating effect on thecentral nervous system, however, is weakerthan that of cocaine but greater than thatof atropine. The oral LD50 value in mice iswithin the range of 1200 mg/kg.
The histidine reversion–Ames test formutagenicity gave inconclusive results.

Pharmacokinetics

Atropine is an antimuscarinic agent that antagonizes the effects of acetylcholine. In small doses, atropine slows heart rate, and tachycardia develops due to paralysis of vagal control. Compared to scopolamine, atropine has a more potent and prolonged effect on the heart, intestine and bronchial muscle, but a weaker effect on the iris, ciliary body and certain secretory glands. Atropine leads to increased respiratory rate and depth of respiration, possibly due to the drug-induced bronchiolar dilatation rather than its mild effect on vagal excitation.
At an adequate dose, atropine abolishes different types of reflex vagal cardiac slowing or asystole. Atropine can be used to prevent or abolish bradycardia or asystole induced by the injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. When vagal activity is an etiologic factor, atropine may also lessen the degree of partial heart block. In clinical doses, atropine 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. The use of topical atropine in the eye induces mydriasis by inhibiting the contraction of the circular pupillary sphincter muscle normally stimulated by acetylcholine. This results in the contraction of the countering radial pupillary dilator muscle and pupil dilation.
The use of atropine may precipitate acute glaucoma and convert partial organic pyloric stenosis into complete obstruction. Atropine may also lead to complete urinary retention in patients with prostatic hypertrophy and cause the thickening of bronchial secretions and formation of viscid plugs in patients with chronic lung disease.

Pharmacology

Atropine is a blocker of typical M-choline receptor. In addition to terminating the gastrointestinal smooth muscle spasm, inhibiting glands, dilating pupils, increasing intraocular tension, adjusting vision through paralysis, accelerating heart rate and dilating bronchi, large doses of atropine dilate blood vessels, terminating the spasmodic contraction and improving minicirculation. Atropine can excite or inhibit the central nervous system in a dose-dependent manner. Atropine exerts longer and stronger effect on heart, intestine and bronchial smooth muscle than other belladonna alkaloids. Atropine also relaxes the pupillary sphincter and the ciliary muscle and dilates the pupils by blocking M-choline receptor in ocular tissue. Blockers of M-choline receptor included atropine, scopolamine, anisodamine and anisodine. Belladonnas not only block M-choline receptor in internal organ cells but also in the central nervous system. Compared with atropine, scopolamine has an oxygen bridge, which increases central nervous system function. The oxygen bridge of scopolamine is partially broken and then becomes anisodamine, which is difficult to pass through the blood-brain barrier, and symptoms caused by atropine in the central nervous system were less than that caused by atropine. Peak concentration of plasma can be reached at 15–20?min after intramuscular injection of atropine and at 1–2?h after oral administration and can last for 4–6?h. Most of the atropine can be absorbed by the gastrointestinal tract and other mucous membranes, and a little of the atropine can be absorbed by the eyes and skin. The t1/2 is 3.7–4.3?h. Binding rate of plasma protein is 14–22%. Volume of distribution is 1.7?L/kg after oral administration. Atropine can rapidly distribute to different organ systems and pass the blood-brain barrier and the placenta. After absorption by the eye’s conjunctiva, 30% of the products are excreted unchanged via the kidneys; the others become metabolites by hydrolysis and glucuronidation or glucosidation. After 1% gel eye drop, enlarged pupil function lasts for 7–10?days, and regulatory paralysis lasts for 7–12?days.

Clinical Use

The best known of the muscarinic blocking drugs are the belladonna alkaloids, atropine (Atropine) and scopolamine (Scopolamine).They are tertiary amines that contain an ester linkage. Atropine is a racemic mixture of DL-hyoscyamine, of which only the levorotatory isomer is pharmacologically active.Atropine and scopolamine are parent compounds for several semisynthetic derivatives, and some synthetic compounds with little structural similarity to the belladonna alkaloids are also in use.All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group.

Safety Profile

Poison by ingestion, subcutaneous, intravenous, and intraperitoneal routes. Human systemic effects by ingestion and intramuscular routes: visual field changes, mydriasis @updlary dtlation), and muscle weakness. An experimental teratogen. Other experimental reproductive effects. An alkaloid. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Atropine, the D,L-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester of |á-hydroxymethyl phenylacetic acid (14.1.4), can be synthesized by a standard scheme of synthesizing of tropane alkaloids. Condensation of maleyl aldehyde with methylamine and acetonedicarboxylic acid gives tropenone (14.1.1), which is the main starting material for the synthesis of both atropine and scopolamine. The carbonyl group of tropenone is reduced, thus forming tropenol (14.1.2), after which the double bond between C6 and C7 of the tropane ring is hydrogenated, giving tropine (14.1.3). Esterification of the tropenol gives the desired atropine (14.1.4) [1¨C6].

Environmental Fate

Atropine competitively antagonizes acetylcholine at the neuroreceptor site. Atropine prevents acetylcholine from exhibiting its usual action but does not decrease acetylcholine production. Cardiac muscle, smooth muscle, and the central nervous system are most affected by the antagonism of acetylcholine.

Metabolism

Atropine is mainly metabolized by enzymatic hydrolysis in the liver. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. The metabolism of atropine is inhibited by organophosphate pesticides.

Purification Methods

Atropine crystallises from acetone or hot water, and sublimes at ~ 100o/high vacuum. [Beilstein 21/1 V 235.]

Toxicity evaluation

Free atropine is only slightly soluble in cold water. It melts at 115°C but decomposes upon boiling.
Environmental monitoring of atropine is not routinely performed by regulatory bodies. Hazardous short-term degradation products are not likely to occur. Accidental environmental exposure may occur through unintentional ingestion of toxic plants of the Solanaceae family, such as the deadly nightshade.