chemical paper(exact three pages)(Your grade on the third essay will depend, to large measure, on the improvement demonstrated relative to the first two essays.)

LECTURE 9. From Alcohol and Aspirin to Hallucinogens and Opioids La Nuit Etoilée  (The Starry Night) is an oil on canvas by Dutch post-impressionist painter Vincent van Gogh (1853-1890). Painted in June 1889, it describes the view from the east-facing window of his asylum room at Saint-Rémy-de-Provence, just before sunrise, with the addition of an ideal village. He spent a long period in 1889-90 in a clinic because of his mental instability, before committing suicide. You do not have to be a chemist to wonder about the source of the swirls, spirals and other strange effects. Van Gogh's instability and suicide have been blamed on the liqueur-like drink absinthe, a fashionable French beverage in the half century up to the first world war.

Absinthe, is a green liquid with an anise smell, made by distilling a mixture of alcohol, herbs (notably wormwood) and water. In the late 19th century, it became a national drink in France. Fashionable among the artistic community, it became cheap enough to be the spirit “beverage of choice” among the poor.  Writers such as Baudelaire, Edgar Allan Poe and Verlaine relied upon it, and a whole range of artists (Degas, Gauguin, Manet, Picasso, Toulouse-Lautrec, and Van Gogh) are associated with it, often for including it in their paintings. Known as la fée verte (the green fairy), absinthe gave rise to l'heure verte, the time (5 pm) when drinkers in all walks of life went to a café for their absinthe, what we would now call a “Happy Hour”. 

L'Absinthe

Artist	Edgar Degas
Year	1875–76

We begin by considering alcoholic beverages and their effect on the brain. How does alcohol affect the brain? Alcohol has a profound effect on the complex structures of the brain. It blocks chemical signals between brain cells (neurons), leading to the common intermediate symptoms of intoxication, including impulsive behavior, slurred speech, poor memory, and slowed reflexes.

If heavy drinking continues over extended periods of time, the brain adopts to the blocked signals by responding more dramatically to certain brain chemicals, the neurotransmitters. After alcohol leaves the system, the brain continues over-activating the neurotransmitters, causing painful and potentially dangerous withdrawal symptoms that can damage brain cells. This damage is made more acute by “binge drinking” and sudden withdrawal. Alcohols damage to the brain can take several forms. The first is neurotoxicity, which occurs when neurons over react to neurotransmitters for too long. Too much exposure to a neurotransmitter can cause neurons to eventually “burn out.” Since neurons make up the pathways between different parts of the brain, when they begin “burning out,” it can cause noticeable slowing in the response of these pathways. People with alcohol dependence often experience “brain shrinkage,” which is reduced volume of both gray matter (cell bodies) and white matter (cell pathways) over time. There are some subtle differences in how brain damage occurs in men and women, but regardless of gender, loss of brain matter increases with age and amount of alcohol consumed. What are the observable effects of this damage? Since alcohol affects a large portion of the brain, many different kinds of cognitive impairment can occur as a result of heavy drinking, including problems with verbal fluency and verbal learning, processing speed, working memory, attention, problem solving, spatial processing and impulsivity. Parts of the brain relating to memory and “higher functions” ( for example, problem solving and impulse control) are more susceptible to damage than other parts of the brain, so problems in these areas tend to be worse than others. Adolescents are especially at risk for long-lasting or permanent damage and performance deficits, since their most-impacted areas of the brain are still in development. Without treatment, cognitive impairment grows worse, eventually developing into a lasting syndrome known as alcohol related dementia. This syndrome represents about 10% of all dementia cases (additionally, alcohol is estimated to contribute to roughly 29% of all other dementia cases). Cognitive deficits are made worse by malnutrition, especially a deficiency of vitamin B (a common deficiency in alcohol-dependent individuals). Malnutrition and heavy alcohol consumption can cause serious impairments in memory and language over time and can potentially result in permanent cognitive disorder called Wernicke-Korsakoff syndrome, which causes amnesia and can lead to coma if left untreated. In Lecture 5, we commented on the different physiological effects induced by methanol and ethanol. methanol

and ethanol Methanol is a highly toxic alcohol with a smell and taste similar to ethanol. Small amounts (around 50 - 100 ml ) cause permanent blindness and severe neurological dysfunction leading to death. More than half of methanol-related morbidity and mortality is classified as accidental and therefore preventable. In addition, it can be suicidal by ingestion of a variety of commercial paint thinners, gasoline anti-freeze, windshield products, organic solvents, shellac varnish, washer fluid, photocopying fluids, perfumes, and in some eau de cologne. Occasionally, it is due to the fraudulent adulteration of wine or other alcoholic beverages. Its ingestion causes high anion gap metabolic acidosis from the production of formic and lactic acids and central nervous system disturbances ranging from inebriation and drowsiness to obtundation (A condition in which the senses have been dulled by trauma, mistreatment, or psychological stress.), seizure and coma. Aspirin The active ingredient in aspirin is acetylsalicylic acid, C9 H8 O4 . This organic acid was found  in leaves from the willow tree,  and has been used for its health effects for at least 2,400 years. Medicines made from willow and other salicylate-rich plants appear in clay tablets from ancient Sumer as well as the Ebers papyrus from ancient Egypt. Hippocrates (around 400 BC) referred to the use of salicylic tea to reduce fevers. Aspirin has been manufactured since 1899 by the German company Bayer. There are many generic varieties of aspirin. A generic drug manufacturer must prove that their product contains the same active ingredient(s) as the brand name product. Aspirin can be used to fight a host of health problems: cerebral thromboses (with less than one tablet a day); general pain or fever (two to six tablets a day); and diseases such as rheumatic fever, gout, and rheumatoid arthritis. The drug is also beneficial in helping to ward off heart attacks. In addition, biologists use aspirin to interfere with white blood cell action, and molecular biologists use the drug to activate genes.

The wide range of effects that aspirin can produce made it difficult to pinpoint how it actually works, and it wasn't until the 1970s that biologists hypothesized that aspirin and related drugs (such as ibuprofen) work by inhibiting the synthesis of certain hormones that cause pain and inflammation. [Hormones are regulatory substances produced in an organism and transported in tissue fluids such as blood or sap to stimulate specific cells or tissues into action.] Since then, scientists have made further progress in understanding how aspirin works. They now know, for instance, that aspirin and its relatives actually prevent the growth of cells that cause inflammation.

As a further example of how a change in a single functional group (See Lecture 5) can change the chemical, physical and physiological properties of a molecule, note that both aspirin and oil of wintergreen are synthesized from the same precursor, salicilic acid. See structure and reactions below.

Autonomic nervous system  drugs

The autonomic nervous system controls the involuntary processes of the glands, large internal organs, cardiac muscle, and blood vessels. It is divided functionally and anatomically into the sympathetic and the parasympathetic systems, which are associated with the fight-or-flight response or with rest and energy conservation, respectively.

Organization of the autonomic nervous system.Encyclopædia Britannica, Inc.

Modern pharmacological understanding of the autonomic nervous system emerged from several key insights made in the early 20th century. The first of these came in 1914, when British physiologist Sir Henry Dale suggested that acetylcholine was the neurotransmitter at the synapse between preganglionic and postganglionic sympathetic neurons and also at the ends of postganglionic, parasympathetic nerves. Preganglionic neurons originate in the central nervous system, whereas postganglionic neurons lie outside the central nervous system. Dale showed that acetylcholine could produce many of the same effects as direct stimulation of parasympathetic nerves. Firm evidence that acetylcholine was in fact the neurotransmitter emerged in 1921, when German physiologist Otto Loewi  discovered that stimulation of the autonomic nerves to the heart of a frog caused the release of a substance, later identified to be acetylcholine, which slowed the beat of a second heart perfused with fluid from the first. Similar direct evidence of the release of a sympathetic neurotransmitter, later shown to be  norepinephrine (noradrenaline), was obtained by American physiologist Walter Cannon in 1921.

Norepinephrine

Both acetylcholine and norepinephrine act on more than one type of receptor. Dale found that two foreign substances,  nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine. The structure of muscarine is given below, that of nicotin later in this Lecture. Muscarine

Nicotine stimulates skeletal muscle and sympathetic ganglia cells. Muscarine stimulates receptor sites located only at the junction between postganglionic parasympathetic neurons and the target organ. Muscarine slows the heart, increases the secretion of body fluids, and prepares the body for digestion. Dale therefore classified the many actions of acetylcholine into nicotinic effects and muscarinic effects. Drugs that influence the activity of acetylcholine, including atropine, scopolamine, and tubocuraine, are known as cholinergic drugs (see later text). A similar analysis of the sympathetic effects of norepinephrine, epinephrine, and related drugs was carried out by American pharmacologist Raymond Ahlquist, who suggested that these agents acted on two principal receptors. A receptor that is activated by the neurotransmitter released by an adrenergic neuron is said to be an  adrenoceptor . Ahlquist called the two kinds of adrenoceptor alpha (α) and beta (β). This theory was confirmed when Sir James Black developed a new type of drug that was selective for the

β-adrenoceptor. Adrenoline is a hormone secreted by the adrenal glands, especially in conditions of stress, increasing rates of blood circulation, breathing, and carbohydrate metabolism and preparing muscles for exertion.

α-adrenoceptors and β-adrenoceptors are divided into subclasses: α1 ,α2 and β1, β2, β3. These receptor subtypes were recognized by their responses to specific agonists and antagonists, which provided important leads for the development of new drugs. For example, salbutamol was discovered as a specific β2-adrenoceptor agonist. It is used to treat asthma and is a great improvement over its predecessor, isoproterenol. Because the activity of isoproterenol is not specific, it acts on β1-adrenoceptors as well as β2-adrenoceptors, resulting in cardiac effects that are sometimes dangerous. Salbutamol and other agents that act on adrenoceptors, including albuterol,  ephedrine, and imipramine, are known as adrenergic drugs.  

Central nervous system  drugs Several major groups of drugs, notably anethetics and psychiatric drugs, affect the central nervous system. These agents often are administered in order to produce changes in physical sensation, behavior, or mental state. General anesthetics induce a temporary loss of consciousness, enabling surgeons to operate on a patient without the patient’s feeling pain. Local anesthetics induce a loss of sensation in just one area of the body by blocking conduction in nerves at and near the injection site. Drugs that influence the operation of neurotransmitter systems in the brain can profoundly influence and alter the behavior of patients with mental disorders.   Psychiatric drugs that affect mood and behavior may be classified as antidepressants, antianxiety agents, antipsychotics or antimanics.

What is a hallucinogen? A hallucinogen is a psychoactive agent that often causes hallucinations, perceptual anomalies, and other substantial subjective changes in thought, emotion, and consciousness that are not typically experienced to such degrees with other categories of drugs.  Research suggests that classic hallucinogens work at least partially by temporarily disrupting communication between brain chemical systems throughout the brain and spinal cord. Some hallucinogens interfere with the action of the brain chemical serotonin, which regulates mood and sensory perception.

Serotonin What are some common hallucinogens? Caffine Caffeine is a central nervous system  (CNS) stimulant. It is the world's most widely consumed psychoactive drug.  Unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. There are several known mechanisms to explain the effects of caffeine. The most prominent is that it reversibly blocks the action of  adenosine on its receptors and consequently prevents the onset of drowsiness induced by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system. Nicotine

Nicotine is a stimulant (alkaloid) that is naturally produced in the nightshade family of plants. It is highly addictive. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors, except at two nicotinic receptor subunits where it acts as a receptor antagonist.

Marijuana (Cannabis)

Marijuana is a psychoactive drug from the Cannabis plant used primarily for medical or recreational purposes. The main psychoactive component of cannabis is tetrahydrocannabinol, which is one of the 483 known compounds in the plant, including at least 65 other cannabinoids. Cocaine

Cocaine, also known as coke, is a strong stimulant. Mental effects may include loss of contact with reality, an intense feeling of happiness or agitation.  Physical symptoms may include a fast heart rate, sweating and large pupils. High doses can result in very high blood pressure or body temperature.  Effects begin within seconds to minutes of use and last between five and ninety minutes. Cocaine has a small number of accepted medical uses such a numbing and decreasing bleeding during nasal surgery.

Cocaine is addictive due to its effect on the reward pathway in the brain. Colombia, Peru and Bolivia are the most important cocaine-producing countries.

What is an opioid?

Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief,  including anesthesia.  Other medical uses include suppression of  diarrhea, replacement therapy for opioid use disorder, reversing  opioid overdose, suppressing cough, as well as for executions in the US. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used non-medically for their euphoric effects or to prevent withdrawal.

Side effects of opioids may include: itchiness, sedation, respiratory depression, constipation, and euphoria. Long-term use can cause tolerance, meaning that increased doses are required to achieve the same effect, and physical dependence, meaning that abruptly discontinuing the drug leads to unpleasant withdrawal symptoms. The euphoria attracts recreational use and frequent, escalating recreational use of opioids typically results in addiction. An overdose or concurrent use with other depressant drugs like benzodiazepine commonly results in death from respiratory depression.

Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract.  These receptors mediate both the psychoactive and the somatic effects of opioids. Opioid drugs include partial agonists, like the anti-diarrhea drug loperamide and atagonists like naloxegol  for opioid-induced constipation, which do not cross the blood-brain barrier but can displace other opioids from binding to those receptors. What are some examples of opioids?

Morphine Morphine is found naturally in a number of plants and animals, including humans. It acts directly on the central nervous system (CNS) to decrease the feeling of pain. It can be taken for both acute pain and chronic pain. It is frequently used for pain from myocardial infarction and during labor. After injection, maximum effect is reached after about 20 minutes when given intravenously and after 60 minutes when given by mouth, while duration of effect is 3–7 hours.

Potentially serious side effects include decreased respiratory effort and low blood pressure. Morphine is addictive and prone to abuse.

Heroin

Heroin is a highly addictive drug processed from morphine, a naturally occurring substance extracted from the seed pod of certain varieties of poppy plants. Common side effects include decreased breathing, dry mouth, drowsiness, impaired mental function, constipation, and addiction. Side effects of use by injection can include abscesses, infected heart valves and pneumonia. Opium (or “poppy tears”, scientific name: Lachryma papaveris) is dried latex obtained from the seed capsules of the opium poppy  Papaver somniferum .

 

Opium poppy seed pod exuding latex from a cu

Approximately 12 percent of opium is made up of morphine, which is processed chemically to produce heroin and other synthetic opioids for medicinal use and for illegal drug trade.  The latex also contains the closely related opiates codeine, and non-analfesic alkaloids such as papaverine and noscapine. The super sleuth, Sherlock Holmes (Robert Downey Jr. in the movies), occasionally used addictive drugs, especially in the absence of stimulating cases. He sometimes used morphine and other times cocaine. Both drugs were legal in 19th-century England. His sidekick, Dr. John Watson (Jude Law), strongly disapproved of his friend's cocaine habit, describing it as the detective's only vice, and was concerned about its effect on Holmes's mental health and intellect. Carfentanil

Loperamide

Naloxegol