Atropine is an alkaloid drug derived from levohyscocyamine, a plant compound found in the family Solanaceae[1]. It's chemical name is 8-methyl-8-azabicycolo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate, and the most common medicinal form of atropine is atrophine sulfate ((C17H23NO3)2·H2SO4·H2O)[2]. It is a competitive antagonist of both acetylcholine receptors and phospholipase 2A and has a variety of effects on both humans and animals.
In humans, atropine is metabolized approximately 50%, hydrolyzed to tropine and toropic acid, and the remaining unchanged drug is excreted in the urine[3].
As a plant compound, Atropine has been used for hundreds of years. Its first recorded use was in the 4th year of B.C.E, where it was used to treat wounds, gout, sleeplessnes, and was even thought to be a love potion[4]. It was also used by Cleopatra and women in the Renaissance era to dilate their pupils to give them a more beautiful appearance[5]. It has since been studied extensively and, although it is inherently poisonous, it is now used for a wide spectrum of medical ailments. It can be given orally, intravenously, rectally, or subcutaneously (in animals).
Function and Basic Mechanism
Atropine is part of the tropane group alkaloid family, which includes other substances such as cocaine. Atropine is a competitive antagonist of muscarinic acetylcholine receptors [6], a group of G-class receptor proteins, blocking the action of acetylcholine and therefore suppressing the actions of the parasympathetic nervous system[7].
Acetylcholine Receptors
The protein structure of an acetycholine receptor can be seen on the right. Although there is not a PDB ID for atropine in complex with the acetylcholine receptor, it is important to understand the structure of the acetylcholine receptor, and subsequently, how atropine and other alkaloids interact with it. One can see that each color in the current model represents a portion of the complex protien, which contains five domains. The regions can then be displayed in gray, while the hydrophillic regions appear purple. This shows a transmembrane alpha-helix region in the center of the molecule, a large hydrophillic complex on the exoplasmic face of the protein, and another hydrophillic region on the cystolic face of the protein. By highlighting the of the acetylcholine receptor, it is also easy to see how the secondary structure is concentrated to specific regions of the molecule. Alpha helicies span the majority of the transmembrane and cystolic regions, and beta sheets (with the exception of only a few alpha helicies) make up the majority of the exoplasmic receptor face. Atropine interacts with the of the exoplasmic face. It interacts so well, it is actually considered to be a "pure antagonist" by some [8].
Atropine first enters the acetylcholine receptor and binds to the at the top of the receptor. They then interact with the, residues which define a hydrophobic region through which a dehydrated ion could pass through. These residues can be seen more clearly through this representation.
The interaction of atropine and phospholipase 2A will be discussed in detail later in this article.
[9]
Inhibition of Acetylcholine Receptors
The image to the left depicts a synapse. A neurotransmitter, such as acetylcholine, goes across the synaptic cleft and binds to its receptor, which can be seen in great detail in the 3D image. Atropine inhibits the effect of acetylcholine by complexing the acetylcholine receptor on the other side of the cleft, subsequently inhibiting the binding of acetylcholine. If atropine does not allow acetylcholine to bind to the acetylcholine receptor, then the effects of acetylcholine are inhibited. This prevents activation of the parasympathetic nervous system and has a wide variety of medical effects.
Medical Uses
Since atropine affects the parasympathetic nervous system, it has a wide variety of effects. It is largely and perhaps most commonly used as an ophthalmic drug, as it paralyzes the accommodation reflex and dilates the pupil[10]. The mechanism for dilation involves blocking the contraction of the circularly pupillary sphincter muscle, which is normally stimulated by acetylcholine release[11].
Outside of ophthalmic use, Atropine is also used in the treatment of heart conditions such as bradychardia (low heart rate), asystole, and subsequently, cardiac arrest. Because atropine blocks acetylcholine, and therefore the parasympathetic nervous system, the vagus nerve cannot slow the heart and it remains at a constant rate[12]. In addition, salivary, sweat, and mucus glands are inhibited by atropine, which is useful in treating asthma, or when keeping the airways of a surgical patient clear under anesthesia. Recently, it is thought to be a useful drug in patients with schizophrenia and patients suffering from neural trauma, because it reduces inflammation in the neural tissues by binding to phospholipase 2A. This will be discussed in more detail in the next section
Atropine is also a good antidote for poisoning by organophosphates and nerve gases, prime agents in bioterrorism[13], because Atropine blocks acetylcholine at muscscarininc receptors. Atropine, however, has side effects that include nausea, dizziness, blurred visions, tachycardia, and hallucinations, and due to these side effects it has recently become more popular as a recreational drug.
[14]
Uses in Veterinary Medicine
Like human medicine, atropine is widely used in veterinary medicine in a variety of different medical situations. Although it is widely used in ophthalmic situations, it is even more commonly used as a preanesthetic in surgical patients to increase the heart rate and decrease mucous secretions, allowing the airway to remain clear during surgery. It is most often given subcutaneously, but can also be given as a pill. It is sometimes given in concjunction with morphine to decrease salivation that is often a side effect of morphine [15].
Considerations when taking Atropine
First and foremost, Atropine is a toxin. Although it is now used extensively in medicine and is considered safe in the correct dosages, it is important to know the risks associated with this medication. Side effects often include dizziness, drowsiness, dry mouth, decreased sweating, dilated pupils, blurred visions, and even hallucinations [16]. Persons with allergies to alkaloids, or persons with glaucoma or asthma, and should be given only when necessary in patients with high blood pressure, liver disease, enlarged prostate, congestive heart failure, or downs syndrome[17].
The proper dose of atropine is approximately 0.1 mg/ml in adults and 0.05 mg/ml in children when taken orally or given intravenously [18]. Atropine can be given orally, intravenously, rectally, or topically, and in veterinary medicine, it can be given intramuscularly or subcutaneously.
Interaction of Atropine with Phospholipase A2
(1th6).
Phospholipase 2A in complex with cell membrane
In addition to its ability to form complexes with acetylcholine receptors, atropine can also complex with phospholipase A2. Phospholipase A2 is a category of heat-stable enzymes which are involved in cell signaling processes, such as the inflammatory response. [19]. Phospholipase 2A is an upstream regulator of inflammatory processes, and more specifically, it recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond, releasing lysophospholipids [20].
This protein is found in mammals, reptile venom, and bacteria. In humans, the overproduction of phospholipase A2 leads to neurologic disorders such as schizophrenia and possibly autism [21]. An inhibitor of Phospholipase A2, such as Atropine, could be used to treat disorders associated with neural trauma, since Phospholipase A2 increases inflammation which could be potentially complicate neural trauma cases [22].
The image to the above shows the membrane-bound phospholipase A2 in blue [23].
Atropine in the Active Site of Phospholipase A2
Atropine is an inhibitor of phospholipase 2A, and can be seen in complex with this enzyme on the left. The can be seen more clearly in gray using the ball-and stick representation of the drug and protein. It can also be seen in green in this , where protein appears in brown, ligands appear in green, and solvents appear in blue. Finally, the
portions of the protein can be highlighted from blue to red in a rainbow, and the active site with atropine can be seen in the middle of the protein.
Atropine interacts with phospholipase 2A at residues asp29 and tyr49 on the protein. The
of atropine interacting with phospholipase 2A can be seen on the right. The amino acid residues in the active site are labeled. As seen in the acetylcholine receptor, the regions of the phospholipase 2A enzyme are found in the active site, which is where the atropine binds and inhibits the enzyme. The hydrophobic regions, represented in gray, can be seen surrounding atropine, which is positioned in the active site and capped by red oxygen atoms.
Removing the labels, atropine can be seen making contact with the atoms emphasized by the space filling model, interacting with the of phospholipase 2A through white as-tricks.
