uses in medicine. drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. agonists increase the level of receptor activation; antagonists reduce it. acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. however, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery. nicotinic receptors nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. ach opens a na+ channel upon binding so that na+ flows into the cell. this causes a depolarization, and results in an excitatory post-synaptic potential. thus, ach is excitatory on skeletal muscle; the electrical response is fast and short-lived. curares are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies. muscarinic receptors main article: muscarinic receptor muscarinic receptors form g protein-coupled receptor complexes in the cell membranes of neurons and other cells. atropine is a non-selective competitive antagonist with acetylcholine at muscarinic receptors. cholinesterase inhibitors main article: cholinesterase inhibitors many ach receptor agonists work indirectly by inhibiting the enzyme acetylcholinesterase. the resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions if the dose is high. they are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents (sarin and vx nerve gas) or pesticides (organophosphates and the carbamates). many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. in clinical use, they are administered in low doses to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain). synthesis inhibitors organic mercurial compounds, such as methylmercury, have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase. this inhibition may lead to acetylcholine deficiency, and can have consequences on motor function. release inhibitors botulinum toxin (botox) acts by suppressing the release of acetylcholine, whereas the venom from a black widow spider (alpha-latrotoxin) has the reverse effect. ach inhibition causes paralysis. when bitten by a black widow spider, one experiences the wastage of ach supplies and the muscles begin to contract. if and when the supply is depleted, paralysis occurs. comparative biology and evolution acetylcholine is used by organisms in all domains of life for a variety of purposes. it is believed that choline, a precursor to acetylcholine, was used by single celled organisms billions of years ago for synthesizing cell membrane phospholipids. following the evolution of choline transporters, the abundance of intracellular choline paved the way for choline to become incorporated into other synthetic pathways, including acetylcholine production. acetylcholine is used by bacteria, fungi, and a variety of other animals. many of the uses of acetylcholine rely on its action on ion channels via gpcrs like membrane proteins. the two major types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to be responsive to acetylcholine. this means that rather than having evolved from a common homolog, these receptors evolved from separate receptor families. it is estimated that the nicotinic receptor family dates back longer than 2.5 billion years. likewise, muscarinic receptors are thought to have diverged from other gpcrs at least 0.5 billion years ago. both of these receptor groups have evolved numerous subtypes with unique ligand affinities and signaling mechanisms. the diversity of the receptor types enables acetylcholine to create varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes. ach receptors are related to 5-ht3 (serotonin), gaba, and glycine receptors, both in sequence and structure, strongly suggesting that they have a common evolutionary origin. history in 1867, adolf von baeyer resolved the structures of choline and acetylcholine and synthesized them both, referring to the latter as "acetylneurin" in the study. choline is a precursor for acetylcholine. this is why frederick walker mott and william dobinson halliburton noted in 1899 that choline injections decreased the blood pressure of animals. acetylcholine was first noted to be biologically active in 1906, when reid hunt (1870–1948) and rené de m. taveau found that it decreased blood pressure in exceptionally tiny doses. in 1914, arthur j. ewins was the first to extract acetylcholine from nature. he identified it as the blood pressure decreasing contaminant from some claviceps purpurea ergot extracts, by the request of henry hallett dale. later in 1914, dale outlined the effects of acetylcholine at various types of peripheral synapses and also noted that it lowered the blood pressure of cats via subcutaneous injections even at doses of one nanogram. the concept of neurotransmitters was unknown until 1921, when otto loewi noted that the vagus nerve secreted a substance that inhibited the heart muscle whilst working as a professor in the university of graz. he named it vagusstoff ("vagus substance"), noted it to be a structural analog of choline and suspected it to be acetylcholine. in 1926, loewi and e. navratil deduced that the compound is probably acetylcholine, as vagusstoff and synthetic acetylcholine lost their activity in a similar manner when in contact with tissue lysates that contained acetylcholine-degrading enzymes (now known to be cholinesterases). this conclusion was accepted widely. later studies confirmed the function of acetylcholine as a neurotransmitter. in 1936, h. h. dale and o. loewi shared the nobel prize in physiology or medicine for their studies of acetylcholine and nerve impulses.