Atropa Belladonna
Drugs

Author: Matteo Masoero
Date: 13/02/2013

Description

DESCRIPTION

Atropa Belladonna, is a poisonous plant also called deadly nightshade. It grow up in the mountain area in North Europe, Africa and West Asia. This plant is a perennial herb classified in the Solanaceae family, has an inclusive height among the 70-150 cm, the flowers are green-purple, that bloom during the summer, the berries are black. Despite the pleasant aspect, the whole plant results to be poisonous and provokes, if ingested, thirst, vomit, hallucinations followed by convulsion and death.

Hystory

The Atropa Belladonna takes the name from its lethal effects and the use in the field of the cosmetics. Atropa, in the Greek mythology, it is tied up to the Goya Atropo(Goya) that cut the life's thread. The name Belladonna takes its origin in the Renaissance because Italian' dames used this plant to improve the colour of the skin and to give brigtness to the eyes. The substance atropine is extracted by this plant which was prepared the ointment called witches'whisper. This substance is also very well know in medicine since the time of Ippocrate in 400 B.C. The atropine has a particular charm that has involved in the centuries witches, poets, writers, medical scientists and alchemists. In Middle Ages, these plants are used in the rituals to meet Satana because they have powers both hypnotics that aphodisiacs.
Fascinated by this substance a teacher German, Will Enrich Peuckert, in 1960, found a witchcraft recipe drawn by the book “Magic Naturalis” of Giambattista and, following the instructions,Peuckert prepares an ointment that uses on himself. It falls in catalepsy and in a twenty hours deep sleep during which he was tormented by horrible visions: monsters, infernal landscapes, diabolic beings and satanic creatures.

MODE OF ACTION

Its roots, leaves and fruits contain alkaloids like atropine, scopolamine. Alkaloids usually derive from vegetable, they possess one or more nitrogen (N) atoms and they have strong physiological actions on human and animals, they are strongly basic and very poisonus(Herbal Extracts and Phytochemicals: Plant Secondary Metabolites, 2011). Atropine acts by interfering with the transmission of nerve impulses by acetylcholine,a small organic molecule liberated at the nerve ending as a neurotrasmitter, because it is an antagonist of muscarinic receptors located into the central nervous sistem, smooth muscles, cardiac muscle and exocrine glands. This is a competitive type of antagonism, and the effect can be overcome with high concentration of acetylcholine. Muscarinic receptors has a pocket with a aspartate recidue responsable of the ionic bond with atropine, this site of bond is the same used by acetylcholine (Farmacologia)

All muscarinic receptors are G-protein coupled receptors, there are five subtypes of muscarinic AChRs based on pharmacological activity. M1, M3 and M5 receptors cause the activation of phospholipase C, generating two secondary messengers (IP3 and DAG) eventually leading to an intracellular increase of calcium, while M2 and M4 inhibit adenylate cyclase, thereby decreasing the production of the second messenger cAMP and leading to an inhibition of voltage-gated Ca2+ channels. Atropine binds these receptors and inhibit their activaction by acetylcholine, the systemic effect of this action is the inhibition of the parasympathetic nervous system.

BIOSYNTHESIS

The biosynthesis of Atropine starting from L-Phenyalanine first undergoes a transamination forming Phenypyruvic Acid which is then reduced to Phenyl-lactic Acid. Coenzyme A then couples Phenyl-Lactic Acid with Tropine forming Littorine, which then undergoes a radical rearrangement initiated with a P450 enzime forming Hyoscyamine Aldehyde. A dehydrogenase then reduces the aldehyde to a primary alcohol making Hyoscyamine, which upon racemization forms atropine.

EFFECT

(Atropa Belladonna intoxication: a case report, 2012)

Atropa Belladonna is associated with an acute intoxication called anti-cholinergic toxidrome.
The ingestion of 10 berries would be toxic to an adults, an 3 berries for a child. The risk of intoxication is children in important for the possible confusion with other berries. Atropa Belladonna poisoning has central and peripheral nervous system effect, they are dose dependent. Central nervous effect are ataxia, disorientation, short-term memory loss, confusion, hallucinations, psychosis, agitated delirium, seizures, coma, respiratory failure or cardiovascular collapse. The peripheral effect are mydriasis with cycloplegia, dry mucous membranes, hyperreflexia, flushed skin, diminished bowel sounds or ileus, urinary retention, tachycardia, and hypertension or hypotension. This anti-cholinergic toxidrome can be confused with post-traumatic brain damage and acute psychosis. This effect are dose dependent, the therapeutic dose of atropine is 0.5-2mg and this administration causes decrease in heart rate by vagal stimulation, dryness of mouth, inhibition of swearing, mild dylation of pupils. Great doses of 2mg cause all typical effect of anti-cholinergic toxidrome like:
- 5mg: difficult swallowing, headache, dry hot skin, reduced intestinal peristalsis
- 10mg: pulse rapid and weak, mydriasis (iris obliterated), hot dry scarlet skin, ataxia, allucination, coma, delirium.

ABSORPTION, METABOLISM, EXCRETION

After oral administration, the atropine is quickly absorbed by the GI system except the stomach. Absorpition result more rapid after with intramuscular of subcutaneous injection than GI because less drug needed for the same effect. After the absorpiton, up to 50% of atropine is bound to protein. The liver metabolized atropine and the excretion is managed by the kidneys (80-90%) and feces. The Clearance is 5,9 ml/min/kg, and the substance half life is 4,3 h. ( Anticholinergic side-effects of drugs in elderly people,2000)

THERAPEUTICAL USE

Anticholinergic drugs like atropine are used in anesthesia because they reduce the activity of salivatory glands and correct tha vagal-induced bradycardia. The atropine is suitable for the care of a lot of GI problems like abnormal intestinal motility, bile-stone, irritate bowel syndrome. In oculistic, it is used for its ability to induce mydriasis and reduced ocular accomodation because the atropine stops the answers to the cholinergic stimulation of the muscle sphincter of the iris and the ciliary muscle. If the atropine is administered locally, the ocular effect is considerable and the accomodation returns normal after 7-12 days (Farmacologia). In 2006 anticholinergic drugs were used also for the initial treatment of early idiopathic Parkinson’s disease (PD) (Drug therapy in patients with Parkinson’s disease,2012)

Comments
2014-04-11T12:03:52 - Luigi Scavino

Alberto Peano and Damiano Maria Vallero
Academic year 2013-2014
Course of Laboratory Medicine

ATROPINE

Introduction
Atropine is a natural alkaloid originally extracted from Atropa belladonna (Figure 1) and then found in others plants of the family Solanaceae. It is a drug with a wide range of effects in humans including anesthesia, anti-arhythmia, bronchodilatation, mydriasis and parasympathicolysis. Brand names of atropine include Atropair, Atropen, Atropine sulfate, Atropinol and Atropisol (University of Alberta database - DrugBank , Wikipedia)

Figure 1: Atropa belladonna

History
The term “alkaloid” derives from the Arabic al-qali, the plant from which soda was first obtained. Alkaloids are nitrogenous compounds that constitute the pharmacologically active principles of several flowering plants. The use of alkaloid-containing plant extracts as potions, medicines, and poisons date back to the start of civilization. Famous examples include Socrates’ death in 399 B.C. by ingestion of hemlock (scientific name Conium maculatum). Medieval european women utilized extracts of deadly nightshade (the common name of Atropa belladonna) for the same purpose, hence the name “belladonna” (Alkaloid biosynthesis - The basis for metabolic engineering of medicinal plants, 1995)

Biochemistry
Atropine is a racemic mixture of equal parts of D- and L-hyoscyamine (Figure 2). Hyoscyamine (IUPAC name: (1R,3S,5S)-8-methyl-8azabicyclo [3.2.1] octan-3-yl 3-hydroxy-2-phenylpropanoate) is a compound with molecular weight of 289 Da and chemical formula C 17 H 23 NO 3

Figure 2: structural formula of D- and L-hyoscyamine

Hereafter the biosynthesis pathway:
I. L-phenylalanine is transaminated to phenylpyruvic acid and then reduced to phenyl-lactic acid (Figure 3)
II. putrescine-N-methyltransferase catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to an amino group of putrescine, which is the first committed step in the biosynthesis of nicotine and tropane alkaloids. This enzyme is expressed in tobacco plant such as in Atropa belladonna because first steps of nicotine biosynthesis, obtained from tobacco plant, are the same of atropine biosynthesis. N-methyl-putrescine is then converted to tropinone, whose keto group is in turn converted by the tropinone reductase-I to the alpha-hydroxyl of tropine (Figure 4)
III. phenyl-lactic acid binds to coenzyme A and reacts with tropine to form littorine, that go through a radical transposition to make hyoscyamine aldehyde. At last, a dehydrogenase reduces the aldehyde to alcool forming hyoscyamine (Figure 3)
IV. is also possible to obtain atropine through a chemical synthesis. This process, first discovered by Richard Willstater, is based on the reaction of tropine with tropic acid while in the presence of hydrochloric acid (Figure 4) (Synthesis of essential drugs, 1st edition (R. Vardanyan, V. Hruby), PubChem database, Alkaloid biosynthesis - The basis for metabolic engineering of medicinal plants, 1995)

Figure 3: biosynthesis of atropine

Figure 4: biosynthesis of tropine and chemical synthesis of atropine

Pharmacokinetic
Atropine is rapidly and well absorbed after oral or intramuscular administration. Atropine disappears rapidly from the blood and is distributed throughout the various body tissues and fluids. It can readily cross the blood-brain (about 95% of intestinal absorbed quota) and the placental barrier. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver (atropine is a substrate of cytochrome P450 3A4). At last, from 13 to 50% of the drug is excreted unchanged in the urine (University of Alberta database - DrugBank)

Pharmacodynamic
Muscarinic acetylcholine receptors (M1-5) mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Atropine is a competitive muscarinic receptor antagonist (Figure 5) that determine a wide range of anti-cholinergic effects:
- mild vagal stimulation
- transient cardiac slowing (mechanism unknown) followed by tachycardia as a result of vagal blockade at the sinoatrial node
- decrease of bronchial secretions
- relaxation of bronchial smooth muscle
- reduction of tone and motility of the gastrointestinal tract and urinary bladder
- depression of salivary and sweat secretion
- mydriasis
- restlessness, excitement, irritability and hallucinations (University of Nebraska database - Autonomic and cardiovascular pharmacology)

Figure 5: mechanism of action of atropine

Therapeutic uses
Thanks to its anticholinergic effects atropine is recommended in a lot of pathological states and clinical situations, relating to a wide range of medical specialties:
- analgesic spasmolytic in the treatment of gastro-intestinal spasms and biliary or hepatic colic
- antispasmodic in asthma
- cough medicine (in association with codeine and dyphylline)
- treatment of tremor and rigidity in Parkinson's disease
- mydriatic and cycloplegic (to perform ophthalmoscopy)
- preanesthetic (to inhibit salivation and respiratory secretions and to prevent the risk of vagal inhibition of the heart)
- during ophthalmic surgery (to reduce the incidence of the oculocardiac reflex)
- treatment of bradycardia and cardiac arrest in intensive care medicine
- antidote to nerve agent poisoning (this is the reason why soldiers at risk are equipped with atropine loaded in autoinjectors) (Miller's Anesthesia, 7th edition (R. D. Miller), University of Nebraska database - Autonomic and cardiovascular pharmacology)

Side effects and toxicity
The anticholinergic effects of atropine can produce tachycardia, pupil dilation, dry mouth, urinary retention, inhibition of sweating (anhidrosis), blurred vision, constipation and depression. However, most of these side effects are only manifested with repeated or excessive dosing. In instance of overdose, therapy includes removal of the drug from stomach, artificial respiration and, if body temperature is high, administration of physostigmine (which counteracts both central and peripheral blockade of cholinergic nerves) (Cardiovascular pharmacology concepts, PubMed Health database, United States National Library of Medicine - Toxnet)

Examples of clinical cases
During the work we have found several papers relating to interesting clinical cases, some of which hereafter summarized:
* a 20-year-old man was diagnosed with a carotid tumor and underwent surgery. When the operation was initiated, the patient developed sudden cardiac arrest. Chest compression was immediately initiated, and atropine 0.5 mg was administered. Subsequently circulation was restored and the surgery was successfully performed (Case report of cardiac arrest during carotid body tumor resection, 2014)
* a 44-year-old female was scheduled for a varicosectomy. Two hours after the administration of the spinal anesthesia, the heart rate dropped to 42-45 beats/min, and 0.5 mg of atropine was injected intravenously. Shortly after ventricular tachycardia occurred, making necessary the transfer to the intensive care unit. In consequence, further considerations should be taken in regards to the benefits found from the use of atropine in bradycardia not accompanied by hypotension (Atropine injection followed by coronary artery spasm with ventricular tachycardia during spinal anesthesia, 2013)
* a 20-day-old male infant developed generalized tonic–clonic seizures after the administration of a homeopathic medicine containing Atropa belladonna for infantile colic. His clinical signs and symptoms disappeared after a dose of benzodiazepine, instilling the suspect of central anticholinergic intoxication (Seizures caused by ingestion of Atropa belladonna in a homeopathic medicine in a previously well infant: case report and review of the literature, 2013)
* a 11-years-old girl, under Rifampicin and Isoniazid for lymph node tuberculosis, was given Atropa belladona by an herbalist. She developed an anti-cholinergic toxidrome, a condition characterized by mydriasis, blurred vision, photophobia, dry mouth, tachycardia, decreased bowel sounds, difficulty in swallowing and speaking, hyperthermia, hypertension, seizures, loss of consciousness and coma. The patient was monitored in a critical care unit for vital findings and received a symptomatic treatment based on oxygenotherapy, antiemetic, stomach protection and hydroelectrolytic supply. The anti tuberculosis treatments was stopped because of its hepatic side effect. The evolution was marked by neurological improvement and disappearance of delirium (Atropa Belladonna intoxication: a case report, 2012, Belladonna alkaloid intoxication: the 10-year experience of a large tertiary care pediatric hospital, 2013)
* a 38-year-old primiparous woman was administered epidural analgesia. The patient showed progressive changes in mental status, respiratory depression, bradycardia, and hypotension; accidental subdural injection was inferred as the cause of these complications. Since the fetus showed severe bradycardia (70 beats/min), despite being in the normal range (100-150 beats/min) before this event, 0.5 mg of atropine were injected. At 5 min after intrauterine fetal resuscitation, the fetal heart rate was 100 beats/min (Intrauterine fetal bradycardia after accidental administration of the anesthetic agent in the subdural space during epidural labor analgesia, 2013)
* the body of a 51-year-old man was found in the boot of his car, which had been left in a public car park in France. The autopsy failed to determine the cause of death, and samples were collected and submitted for toxicological analysis; routine toxicological analyses were performed on the peripheral blood and urine, and in light of these first results atropine was specifically quantified in all the biologic samples, showing the presence of the drug in all the victim’s samples. The postmortem concentrations measured in the victim are consistent with a massive overdose of atropine, proving that this is a case of murder by atropine poisoning (Atropine eye drops: an unusual homicidal poisoning, 2014.)

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