Medicinal Chemistry

Injections

- Advantage - can be put directly where needed rather than spread all over the body - Reduces: -- the dose -- the chance molecular structure will be altered by body before it arrives at the right place - Disadvantage - usually requires medically trained staff - Intravenous - into bloodstream -- bypassing acidic digestive system -- quickens arrival -- but drawback of spreading out the dose - Subcutaneous - directed into body fat - perfect for molecules that are -- low water soluble -- soluble in fat - Intramuscular - straight into muscle tissue

Nuclear medical waste

- Another class of medical waste comes from the field of nuclear medicine. - Nuclear medicines involve the use of radioactive substances to diagnose and to treat certain diseases, such as cancer. - Radioactive isotopes that are ingested or injected into a patient can enhance medical imaging techniques to better diagnose broken bones, the presence of tumours, the risk for heart attack or the functioning of specific organs. - Nuclear waste can be produced from unused samples of radioisotopes used and also from any materials or equipment that have come in contact with the radioisotopes. - All objects that have come in contact, or have come in close proximity, with these isotopes must be collected and disposed of carefully. - These objects could include syringes, disposable gloves, bedding and other absorbent materials, cotton swabs and vials.

Tolerence

- Another factor to consider is the tolerance of the drug. - When some drugs are taken for an extended period of time, the effective action of the drug on the body can decrease with each exposure. - This can be due to decreased absorption of the drug with prolonged usage, which can occur if the nasal or digestive tract becomes irritated, making injection possibly a better option. - This sometimes also requires a dose to be increased over time in order to have the same desired effect on the body.

Proton pump inhibitors

- Another option for decreasing acid in the stomach is to restrict the release of the acid. - The hydrogen ions (H+) are produced in the parietal cells and released through a proton pump, while the chloride ions (Cl-) are released from a separate pump, into the stomach. - The release of hydrogen ions into the stomach goes against the concentration gradient, so the proton pump is required to actively transport H+ from low to high concentration, the opposite of diffusion (when substances naturally move from high to low concentration). = Proton pump inhibitors (PPIs), such as omeprazole or esomeprazole, work by irreversibly binding to the proton pump with a covalent bond, preventing it from pumping hydrogen ions into the stomach. - As a result, PPIs are much more effective than H2 receptor antagonists at relieving the symptoms of excess stomach acid.

Antibiotic waste from animals

- Another source of antibiotic waste is from animals. - Routinely, animals that are raised for food or food products are injected with antibiotics to prevent and control the infections that result from modern-day farming practices, which tend to crowd many animals into small spaces. - Healthy animals, like cows, pigs and chickens, are often treated with antibiotics as a prevention, even if there is no evidence of active infection on the farm. - The excreted animal waste would contain antibiotic-resistant bacteria and unmetabolised antibiotics, which then flow into the wastewater system. - Animal manure applied to fields for growing crops then puts these harmful bacteria and antibiotics into the fruits and vegetables grown with contaminated soil. - A lot of medicinal waste, including antibiotics, is incinerated on site at hospitals or pharmaceutical companies, but dangerous compounds, such as dioxins, can be generated in this process. - The harmful byproducts of incineration must then be filtered and collected as solid waste, which must then be disposed of carefully to ensure that these substances do not end up in the environment.

Antacids

- Antacids can be made from a variety of compounds, but must contain a base in order to neutralise the excess hydrochloric acid produced by the stomach. - The base must not be a very strong base, as it could cause damage to the mouth and oesophagus on the journey to the stomach. - Many brands of antacids contain calcium carbonate, a white powdery solid that is easily pressed into a tablet, and other compounds, such as flavourings, colours and binding agents. - When chewed and swallowed, the calcium carbonate reacts with hydrochloric acid in a typical neutralisation reaction: -- CaCO3 (s) + 2HCl (aq) → CaCl2 (aq) + CO2 (g) + H2O (l) - The products of calcium chloride, carbon dioxide and water, are neutral, so they will not further aggravate the stomach. - The calcium carbonate does not neutralise all of the stomach acid, but just some, in order to leave sufficient acid for digestion. - Other additives are included in the antacid tablet, including flavouring, colour and antifoaming agents to decrease bloating from the carbon dioxide gas that is produced during neutralisation. - Different brands of antacids use different bases, but the concept is still the same. - Here are some examples of other antacids. - Image xx

Fighting infection with antiviral medicines

- Antiviral medicines are a new class of drugs that fight viral infections, but do not use the same pathway of action as vaccines. - Antiviral medicines work to fight the virus after infection occurs, whereas vaccines must be given before an infection occurs. - Since antiviral medicines are given after a positively diagnosed infection, they are useful in decreasing the severity and duration of the illness, but are not effective in preventing the illness from occurring in the first place, like vaccines. - Antiviral medicines are given for a variety of reasons. - Some people with compromised immune systems, such as the elderly or those with cancer or HIV, might not be able to fight a viral infection on their own. - Antiviral medicines can decrease the severity and shorten the duration of the illness, preventing further complications. - For example, influenza in an otherwise healthy adult may take up to one week for recovery, but in a person with a compromised immune system, illness can last for weeks or can make the person more susceptible to other infections while their system is so weak. - Another reason antivirals are used would be for 'accidental' exposure to a virus. Healthcare workers occasionally are exposed to blood-borne viruses, like HIV or hepatitis, by an accidental prick with a needle that has been used on an infected patient. - When this occurs, antiviral medicines can be quite effective in reducing the transmission of the virus if taken immediately after exposure. - There are a few different ways that antiviral medicines work.

Vaccines for influenza

- As introduced earlier, the vaccine for influenza is provided annually and considered to be the most effective method of combating the virus. - The reason for this is that there are more than 300 known variations of the virus and the virus keeps mutating and changing all the time, so one vaccine cannot provide protection against all known and future variations of the virus. - When an influenza vaccine is made, doctors and scientists work together to predict the three most likely variations that pose the greatest risk of infection. - Some years, the predictions are good and those who receive a vaccination are protected, but other years, the predictions are wrong and even those vaccinated become infected with a different variation of the virus. - Viruses can mutate, or change, as they replicate. This generally occurs by mistake since the virus reproduces quickly, but it can make a new strain of virus that is not recognised by the immune system or by antiviral medicines, ensuring greater survival for the virus. There are two methods of mutation. - One is antigenic drift, where small mistakes are made in the reproduction process, resulting in changes to the proteins on the outside of the virus, making a new strain. - When this occurs, the immune system does not recognise the virus any more and it can infect host cells, even if immunity to a different strain of the virus had already been established. - The other method of mutation is antigenic shift, where two or more different strains of the virus infect the same cell, producing a new hybrid strain. - The hybrid strain now contains a combination of different proteins on the outside of the virus, which the immune system is not able to recognise and fight

Factors influencing the bioavailability of aspirin

- Aspirin can be chemically modified to a salt to increase its solubility in aqueous solutions. - By dissolving the acetylsalicylic acid in sodium hydroxide, the hydrogen on the carboxyl functional group is replaced by a sodium ion, as shown in the reaction below, to make sodium acetylsalicylate, sometimes called soluble aspirin. - Image xx - The sodium acetylsalicylate product is more soluble in water than the aspirin molecule, as ions have a stronger attractive force to the dipoles in water molecules than the intermolecular forces of the carboxyl functional group. - Having a product with greater aqueous solubility means that orally ingested sodium acetylsalicylate will reach the stomach more quickly. - The bioavailability of soluble aspirin, however, is almost the same as the insoluble form because the ionic salt reacts with stomach acid to produce (insoluble) aspirin. - One method of increasing the bioavailability of aspirin is to administer the drug intravenously.

The synthesis of aspirin

- Aspirin is an example of how a naturally-occurring compound has myriad benefits. - From the first extraction from willow bark, scientists have improved upon the process of synthesising pure forms of aspirin. - Today, aspirin is prepared from salicylic acid and acetic anhydride to produce aspirin (acetylsalicylic acid) and acetic acid (also known as ethanoic acid) - In the reaction the acetic anhydride molecule is cleaved, with one part of the molecule replacing the hydrogen atom of the -OH group on the salicylic acid and the other part of the molecule accepting the hydrogen atom to form acetic acid. - This reaction, as with other esterification reactions, requires an acid catalyst and heat to drive the reaction forward. - The aspirin product is white crystals that can be collected by filtration (gravimetric or vacuum filtration) when the mixture cools in an ice bath following the reaction. - If its not left in the dry, the equillibrium goes back as water is added and aspirin is inefective

Bacteria vs Virus

- Bacteria require a constant supply of oxygen, nutrients and water to perform cellular functions, so some bacteria cannot live long outside of a host organism on surfaces of objects and are easily killed with cleaning products containing ethanol or bleach. - Viruses do not perform cellular functions, so they do not have the same requirements as bacteria for water, nutrients or oxygen. - Therefore, some viruses are more robust and can live on surfaces outside of a host organism for much longer than bacteria and are not easily killed with cleaning products.

How aspirin works as an anticoagulant

- Blood is made up of many components - mainly plasma (which has water as a solvent), but also red and white blood cells, antibodies and other substances. - Blood is slightly viscous due to the presence of dissolved fats, proteins and other components. - Since blood is travelling within a contained system of vessels pumped by the heart, any blockage or leak could have devastating effects. - When a blood vessel is damaged, such as when cutting your finger, small fragments of broken blood cells, called platelets, coagulate, or clump together, to stop the leak of blood out of the circulatory system. - This is commonly known as blood clotting. - Over time, the walls of the vessel can repair itself and the body returns to normal blood flow and pressure. - For people with low levels of platelets, such as those with the condition of haemophilia, the blood does not clot well and this can lead to a severe loss of blood or even death. - If the blood vessels become blocked with fat and cholesterol, such as after a lifetime of an unhealthy diet, the blockage results in parts of the body not receiving the nutrients that the blood carries. - Platelets also contribute to the blockage by perceiving the blockage as damage. - If the blockage occurs in the artery leading to the heart, the heart begins to pump harder to draw more blood toward itself and the heart muscle becomes damaged. - This is called a myocardial infarction, or commonly a heart attack. - If the blockage occurs in the artery leading to the brain, blood and the oxygen it carries do not reach the brain, causing damage. - This is called a stroke. - Aspirin works by slowing down the clumping of platelets, so instead of coagulating, they anti-coagulate. - People experiencing symptoms of a heart attack or stroke are sometimes recommended to chew two aspirin tablets while on their way to hospital to reduce the severity of the attack. - Aspirin can also be taken as a prophylactic, or preventative measure, to slow or prevent the formation of a blockage in the first place. - Generally a low dose of aspirin is used for this purpose, and is often recommended to middle-aged or elderly people with a family history of stroke or heart disease, or even for pregnant women, as pregnancy can increase the risk of blood clots.

General structure of Codeine

- Codeine has one hydroxyl functional group substituted with an O bonded to a methyl alkyl functional group, which forms an ether and therefore slightly decreasing the polarity and water solubility, compared to morphine. - As a result codeine can pass into the brain better, resulting in a bioavailability of about 90% when taken orally. - However, codeine is less effective at binding to receptors in the brain and therefore has 1/10 the strength of morphine, so it is only suitable for mild to moderate pain.

Aspirin Commercially

- Commercially, aspirin production is a little different to the small-scale process in a classroom laboratory. - The drug company Bayer held the patent on the synthesis of aspirin from 1899 until the 1930s, when the drug patent ran out and it could be made by other companies, making it a generic drug. - Drug companies must take great care to ensure that they are producing a high yield of a very pure sample. If the reaction yield is low, due to the reaction not going to completion, loss of product in the collection method or impure reagents, then the company will lose money, so this is economically unfavourable. - Likewise, if the yield is low, the purity of the product will also be low, and it could be dangerous for the company to distribute a product that contains impurities or does not contain the dose it claims to have on the product label.

Use of penicillin

- Communicable diseases are generally spread via two routes - bacteria and viruses. - Bacteria are single-celled organisms that divide by binary fission within the organism that they have infected. - Some bacteria are harmful, such as the salmonella that causes food poisoning, while others are harmless or even beneficial, such as the bacteria that live in your small intestine and produce vitamin K in exchange for a place to live and nutrients. - Bacterial infections can be treated with antibiotics, such as penicillin, that stop the growth and reproduction of bacteria. - Viruses are small capsules of DNA (deoxyribonucleic acid, which is genetic material) that require a host organism in order to replicate. - Viruses are much smaller than bacteria and do not contain the organelles necessary to divide on their own. Viral infections are difficult to treat and there are many such infections that have no cure, such as HIV (human immunodeficiency virus). - The only course of treatment for a virus is prevention with an immunisation. In other cases, the body's immune system will eventually fight off the virus, as with a cold or influenza.

General structure of Diamorphine

- Diamorphine has the two hydroxyl functional groups substituted with O bonded to an acetyl side chains, which forms 2 ester groups and greatly reduces the polarity and solubility in water compared to morphine and codeine. - The bioavailability of diamorphine is less than 35% when taken orally. - As a result, diamorphine is generally not taken orally, but is injected intravenously. - With the decrease in polarity, diamorphine can pass into the brain much more easily than both morphine or codeine. - It also binds to the receptors in the brain more effectively than both morphine and codeine, making diamorphine have 4-5 times the strength of morphine. - It is rarely used medically and only for severe pain due to its highly addictive nature. - Diamorphine is used recreationally, but is regarded as an illegal drug in many countries.

Core structure of penicillin

- Different strains of fungi produce different penicillin molecules. - The core structure of the penicillin molecule is shown below, with different options for side chains. The key feature of any penicillin molecule is the beta-lactam ring. - The beta-lactam ring is important for the action of penicillin in preventing the growth of bacteria. - Different side chains for the R-group give rise to different penicillin structures and functions. - Penicillin G, also known as benzyl penicillin, is a very potent antibiotic that has been used successfully to treat syphilis, meningitis and other bacterial infections. - Notice that the benzene ring is nonpolar and as a result, penicillin G must be injected to have an effect, as it is not water-soluble enough to be absorbed by oral ingestion. - Penicillin V, by contrast, contains an oxygen before the benzene ring. - This provides slightly more solubility in water and therefore penicillin V is prescribed as an oral antibiotic to treat minor infections like tonsillitis. - Some penicillins are chemically modified by altering the side chain in order to give the antibiotic enhanced medicinal effects or to improve the bioavailability. - Penicillin G is not stable in the acidic environment of the stomach, so it cannot be taken orally and must be injected to have better bioavailability. - Penicillin V is stable in acid, so it can be prescribed orally. - Ampicillin is produced by chemically modifying the R group to include an amino group. - The presence of this amino group allows ampicillin to better penetrate the cell walls of bacteria and thus has greater action on stopping the growth of bacteria for respiratory infections. - The amino group also allows for greater solubility in water, so ampicillin is often prescribed orally, rather than intravenously.

Synergistic effects of aspirin and alcohol

- Drug labels warn that drinking alcoholic beverages (those that contain ethanol) while taking aspirin can cause an increased risk of stomach bleeding. - Aspirin and alcohol have a synergistic effect; that is, each drug has a higher medicinal effect when taken in combination than they would when taken separately. - People taking aspirin are advised to not consume alcohol to avoid the increased risk of stomach bleeding or other toxic effects.

H2 receptor antagonists

- Drugs can act to either increase or decrease a process in the body by interacting with targeted receptors. - An agonist is a substance that binds to a receptor and fully activates it, while an antagonist binds to a receptor and blocks it or prevents the action of other agonists. - An example of an agonist are opiates, such as morphine, that bind to opiate receptors to activate them in their action of pain relief. - An example of an antagonist is aspirin, which binds to cyclooxygenase receptors to prevent their action in the pain response to trauma. - One method to decrease acid release into the stomach is with an H2 receptor antagonist drug. - One example of an H2 receptor antagonist is ranitidine. - This drug interferes with the histamine receptor and blocks its action (the 'H' in H2 antagonist stands for histamine). - The result is that acid will not be produced by the cells where ranitidine interferes with the histamine receptor, since all three receptors are required to be activated in order to produce acid. - Like many drugs, ranitidine must first be processed by the liver before the drug can have the desired medicinal effect. - The active metabolite is the form of the drug after it has been processed by the body. - Ranitidine, therefore does not have as immediate an effect on stomach acid as antacids do because there is a time delay for the liver to metabolise the drug before it is active.

Topically

- Drugs may also be applied topically so that the effects is limited mainly to that side of the disorder such as the surface of the skin - Such drugs include: -- cream -- ointment -- spray

Animal Testing Phase

- During the animal testing phase, scientists administer different quantities of the drug to determine the dose required to have the desired medical effect. - The minimum dose required to have an effect on 50% of the population is known as the effective dose, known as ED50 (Effective Dose for 50% of the population). - Scientists must also determine the lethal dose, which is the dose of the drug that is enough to kill half of the population, known as LD50 (Lethal Dose for 50% of the population).

Leftover solvents

- During the synthesis and production of medicine, pharmaceutical companies generate a lot of waste. - In a given reaction to synthesise medicines, the solvent accounts for 80-90% of the initial mass (with the reactants only accounting for the other 10-20%), so the leftover solvents, with any impurities, account for the majority of waste generated by pharmaceutical production. - Water is a common solvent for chemical reactions involving ionic or polar reagents, but in the synthesis of pharmaceuticals, many compounds involved are not polar, so nonpolar solvents must be used. - Nonpolar solvents require different disposal methods from polar solvents like waste water. - Some examples of solvents used include liquid hydrocarbons, such as hexane or heptane, benzene derivatives, such as methylbenzene (commonly known as toluene), alcohols, such as methanol, ethanol or propan-2-ol, or ethers, such as tetrahydrofuran. Some of these solvents have a larger environmental impact than others, so proper disposal is important. - Examples of solvents xx

How the body fights viral infections

- For mild viral infections, time is all that is required to fight off the infection because the body has an immune response, a series of processes designed to fight infection. - When a virus attacks a healthy host cell, proteins called antigens on the outside of the cell change. - Other cells, called T-cells, recognise that the infected cell is abnormal by the presence of these antigens and the T-cells attack the abnormal cell. - In order to stop the viral infection, the T-cells must kill the abnormal host cells before the viruses are formed and released. - The body quickly makes more T-cells to stop the continued growth of the virus, which can take a few days. In time, all of the T-cells will have killed all of the host cells and the virus does not have a chance to reproduce. - The body has a 'memory' for some previous infections and will quickly act to destroy the virus if infected again. - While the T-cells are actively seeking and killing infected host cells, other cells called B cells work to recognise the antigens present on the surface of the host cells. - The B cells quickly make antibodies that bind to the antigens. - When the virus is present, the antibodies surround the virus and macrophages, a type of white blood cell, swallow and destroy the cluster of antibodies and virus. - Some antibodies are made continually, so a second exposure to a virus does not result in a successful infection because the antibodies quickly surround the virus and it is destroyed. - Reinfection with the same exact virus does not occur because the body now has lifelong immunity to that virus. - Varicella, commonly known as the chicken pox virus, is an example of a viral infection that generally only happens once per lifetime. - Other viruses, like the common cold or influenza, have different strains of the same virus, so you can be reinfected with a variation of the same virus over and over again. - Images xx

What is 'green' chemistry?

- Green, or sustainable, chemistry aims to reduce waste and energy to produce safer compounds and to limit the use and production of dangerous or harmful compounds in the process. - The principles of green chemistry vary from country to country, but the basic concepts are still the same. Table 1 provides some examples of green chemistry principles. - Examples xx

Transmission of HIV

- HIV can only be transmitted by certain bodily fluids, such as blood, breast milk, vaginal fluids or semen, where the virus is in higher concentration. - It can be spread during sexual contact with an infected person, by sharing unsterilised needles or other surgical equipment, by receiving a blood transfusion with infected blood products or from mother to baby during pregnancy or breastfeeding. - It cannot be transmitted by casual contact, such as shaking hands or sharing a glass of water, or through saliva or nasal secretions. - The viral load in these secretions is too low and the virus does not survive well outside of an infected person.

HIV - Retrovirus

- HIV is classified as a retrovirus, a special type of virus that contains slightly different genetic material than a traditional virus (it contains a single strand of RNA compared to a double strand of DNA in a traditional virus). - Antivirals used to treat retroviruses are called antiretroviral medicines, and these are a new hope in the management and prevention of HIV. - The replication of the virus includes an additional step of converting RNA to DNA, so this makes the virus more prone to mutation (mistakes in the genetic code). - Mutations can result in a virus that is constantly changing so much that the medicines designed to combat it are ineffective

Human Drug Trials

- In human drug trials, the lethal dose is not something scientists seek to determine, but rather the toxic dose is measured as the upper limit of the therapeutic window. - The lethal dose could be extrapolated for the weight of a human, using the dose and weight of the animal used. - This is the dose where a serious toxic effect is observed for 50% of the population, the TD50. The method for measuring toxicity may vary depending on the type of drug, but could include blindness, birth defects or another serious medical condition, such as causing cancer. - The toxic dose would be lower than the lethal dose. - Image xx

Penicillin production

- In order to produce the quantities of penicillins that are required for a large population, growing fungi in a Petri dish is not sufficient. - Populations of fungi are fermented in large, stainless steel tanks under controlled conditions in a sterile environment. - Penicillin is produced when the fungi are under stress, not under regular growth conditions. In order to produce a stressful environment, scientists provide penicillin with lactose sugar, rather than glucose sugar that the fungus prefers as a food source. - The temperature, pH and other nutrients added to the batch also ensure that the fungi are under stress. 1. Penecillium mold naturally produces the antibiotic penecillin 2. Scientists learnt to grow mold in deep fermentation by adding a kind of sugar and other ingredients. This process increased the growth of penecillium 3. Then, scientists seperated the penecillin product from the mold 4. Finally, penecillin is purified for use as an antibiotic medicine

Uses of aspirin

- In order to test the purity of a sample, several methods can be used. - A simple melting point determination is something you might do in your classroom laboratory. - Aspirin has a melting point of 136°C and a pure sample will melt very close to this temperature; the sample will also melt over a narrow range of temperatures, known as the melting point range. - An impure sample will have a melting point lower than the theoretical temperature, as impurities disrupt the crystalline structure, weakening the attractive forces between particles. - The lower the purity, the greater temperature difference from the theoretical melting point, and the broader the melting point range. - Commercially, purity can also be tested using infrared spectroscopy. Infrared spectroscopy (IR) identifies specific types of bonds in a molecule. - For aspirin, the types of bonds expected in a pure sample are strong absorption around 1700 cm-1 for the C=O bond in carboxylic acids, and broad absorption around 2800 cm-1 for the O-H bond in carboxylic acids. - Using IR is helpful to determine if the sample tested contains the type of bonds (and thus specific functional groups) expected in aspirin, or it might identify the bonds present in the impurities.

Testing purity of apirirn

- In order to test the purity of a sample, several methods can be used. - A simple melting point determination is something you might do in your classroom laboratory. - Aspirin has a melting point of 136°C and a pure sample will melt very close to this temperature; the sample will also melt over a narrow range of temperatures, known as the melting point range. - An impure sample will have a melting point lower than the theoretical temperature, as impurities disrupt the crystalline structure, weakening the attractive forces between particles. - The lower the purity, the greater temperature difference from the theoretical melting point, and the broader the melting point range. - Commercially, purity can also be tested using infrared spectroscopy. Infrared spectroscopy (IR) identifies specific types of bonds in a molecule. - For aspirin, the types of bonds expected in a pure sample are strong absorption around 1700 cm-1 for the C=O bond in carboxylic acids, and broad absorption around 2800 cm-1 for the O-H bond in carboxylic acids. - Using IR is helpful to determine if the sample tested contains the type of bonds (and thus specific functional groups) expected in aspirin, or it might identify the bonds present in the impurities.

The 'flu'

- Influenza is a common virus that affects nearly everyone at least once in their lives. Influenza affects approximately 5-10% of adults each year and 20-30% of children worldwide, resulting in 250,000 to 500,000 deaths per year (World Health Organisation). - Individuals who are otherwise healthy are able to battle the flu and return to normal health, but the elderly or those with compromised immune systems are most at risk of influenza-related complications or death. - Common influenza prevention includes regular hand washing and minimising contact with infected individuals, but also annual vaccines are available. - When a case of influenza is particularly severe, antiviral medicines can be given to shorten the duration and reduce the risk severity. - Symptoms: headache, runny or stuffy nose, coughing, vomiting

Addiction

- Many medicines also have the potential for addiction. - Addiction can occur when the body quickly adapts to the presence of the medication and experiences negative effects in its absence. - This can lead to physical or emotional discomfort and 'cravings' for the drug. - How and why drug addiction occurs is still unclear. - Some medicines, especially those used for pain, can quickly become habit-forming, especially when taken by a method that has a quick absorption, such as with injection or inhalation. - A slower, time-released method, such as with oral ingestion or a skin patch, can help to keep the levels of medicine in the body lower and more consistent, and avoid dependency.

Methods of administration

- Medicines need to be absorbed into the blood stream so that they can reach the site where their effect - Speed of absorption into the blood affected by route taken by medicine - 4 Main methods are: -- oral -- inhalation -- through the anus -- by injection

General structure of morphine

- Morphine contains two hydroxyl functional groups, which add polarity and water solubility to the structure. - Morphine is prescribed orally in a tablet or liquid or by intramuscular or intravenous injection. - The bioavailability of morphine taken orally is approximately 30%.

General structure of opiates

- Morphine is the active medicinal ingredient in the latex extracted from the opium seed pod. - The morphine extracted can be used directly or be processed to make two other drugs, codeine and diamorphine, the latter commonly known as heroin. - All three drugs work as analgesics, but the minor differences in their chemical structures result in a change of potency and bioavailability. - Opiates must travel to the brain, where they interfere with nerve impulses. - Since blood is polar, there must be sufficient polar functional groups to keep the drug soluble. - The brain, however, is surrounded by a layer of lipids, or fats, which are highly nonpolar. - In order for the drug to pass from the blood and into the brain, there must also be sufficient nonpolar functional groups.

Antiretroviral treatment (ART)

- Most patients on antiretroviral treatment (ART) take a 'cocktail', or mixture of different antiretroviral drugs to target the different stages of the retrovirus life cycle. - This helps to ensure that the virus life cycle can be more effectively stopped. - Taking ART can be very effective at reducing the patient's viral load, the concentration of virus in a blood sample, to undetectable levels in the blood, ensuring a longer, healthier life and reducing the risk of transmission to other people. - Antiretroviral drugs can also be effective at stopping the transmission of HIV if exposed. - If ART drugs are taken immediately after exposure, such as after a prick from an infected needle, between sexual partners or from mother to unborn baby, the rate of transmission is greatly reduced. - Image xx

Non-polar Solvents

- Nonpolar solvents are not so easy to dispose of and many cause harmful effects to the environment. - Benzene and its derivatives are often carcinogenic (cancer-causing) to humans and animals and can inhibit photosynthesis in plants. - Hexane is a neurotoxin that can cause numbness and weakness in the arms and legs and stunted growth in plants. - Ethers, like tetrahydrofuran, can cause dizziness, leading to unconsciousness, in humans and animals and can lead to severe dehydration in plants. - Improper disposal of these compounds poses a great risk to the plants, animals and people that might come in contact with them.

Gamma Radiation

- Nuclear medicine generates waste that can still emit gamma radiation, which causes damage at the cellular level, specifically damage to DNA. - These changes result in cell damage, uncontrolled cell growth, or cell death. - There are sources of naturally occurring isotopes that release gamma radiation that you come in contact with regularly, but at such low levels that the degree of cell damage is undetectable or the cell is able to repair the damage. - The risks of serious health effects from gamma radiation depend on the level of the dose that is absorbed by the body in a given time period. - Exposure to significant gamma radiation results in radiation sickness, which can occur from drinking contaminated water, eating fruits or vegetables grown in contaminated water or even just by being in close proximity to a source of radioactive isotopes. - Low-dose exposure to gamma radiation can result in skin rashes, nausea, diarrhoea and vomiting. High-dose exposure can result in cancer, decreased fertility or death. - The treatment for radiation sickness is with antibiotics, blood transfusions and even stem cell transplants

Radioactive waste disposal

- Nuclear waste is classified into two categories - high-level waste (HLW) and low-level waste (LLW), depending on the level of radiation that is emitted. - HLW contains a greater radioactive content and is typically produced from spent uranium fuel from nuclear reactors and other liquid waste that comes in contact with the fuel. - LLW contains less radioactive content and typically includes protective clothing, tools and cleaning materials used at nuclear power generating stations and also the nuclear medical waste generated from hospitals, which includes patient linens, used syringes and empty vials. - HLW generates a lot of heat during the radioactive decay process and is typically stored in large pools of water, called wet storage, until the level of radiation is low enough that it can be safely transported and stored in steel cylinders, dry storage. - LLW is safe enough that it can be transported to a central storage facility and stored in dry storage. The steel cylinders in dry storage can be buried and encased in concrete or additional steel to limit the amount of radiation emitted. - The steel cylinders must be resistant to corrosion, to avoid leaks, and are also welded shut. - When nuclear waste is not stored properly, the risk of exposure to people, animals, plants and the environment can be high. - The rate of radioactive decay for isotopes can be minutes, hours, days or years, so appropriate measures to keep the waste away from people, including the workers that are employed to handle the waste, must be done carefully. - The transportation of nuclear waste by transport truck or railway from one location to another is also risky in the event that there is a spill, traffic accident or derailment.

Interfering with the release of the newly-formed viruses

- Once the assembled viruses are ready to be released, the host cell must activate certain proteins to allow the viruses out. - Drugs can be used to block the action of these 'release molecules'. The newly made viruses are then trapped inside the host cell and are not able to be released to infect other healthy cells. - Image xx

Oseltamivir

- One example of a successful green chemistry practise is in the synthesis of the antiviral drug oseltamivir, known by the trade name Tamiflu. - The precursor for the synthesis of the drug is found naturally in certain plants, such as the sweetgum plant, certain pine needles and also from the Illicium verum plant, commonly known as Chinese star anise. - The precursor, shikimic acid, is present in concentrations of 3-7% in the star anise seeds. - When the demand for oseltamivir increased beyond the ability to produce it, scientists had to find another way of obtaining shikimic acid that did not put the population of the star anise plant at risk.

Blocking the virus from entering the cell

- One method is to block the binding of the virus to the host cell. - Viruses identify appropriate host cells by binding and docking to specific receptors on the cell membrane. - Drugs can be used that either mimic the virus to bind to the cell receptors or that mimic the cell receptors to bind to the virus. - Designing effective molecules to interfere with the virus-receptor binding action is a challenge. - Another method is to block the entry of the genetic material from the virus into the host cell. - Once the virus docks to the receptor, it must inject its genetic material into the host cell, which requires some help from the host cell to allow foreign material to enter. - Cell membranes are selectively permeable to allow needed nutrients into the cell and to maintain a barrier for the protection of the cell against damaging material. - Drugs that interfere with the ability of the viral genetic material to enter the host cell are effective at preventing the virus from reproducing.

Inhilation

- Only if drug is absorbed by lungs - eg: asthma - Unusual way of administering

Methadone treatment

- Opiates can produce a euphoric sensation at high doses, which results in illegal use and addiction. - Methadone is an opiate derivative that can bind to the opiate receptors but does not produce the euphoric effects of morphine. - Methadone is an effective treatment option to help with tolerance, addiction and withdrawal symptoms. - Image xx

Opiates and pain

- Opiates work by interfering with the neurotransmitters and receptors in the transmission of the pain signal across. - Your body produces substances called endorphins that work as natural pain relievers. - Endorphins are produced when we are in pain, but also during stress and extreme physical exercise. - The word "endorphin" comes from the two words 'endogenous morphine', which means naturally occurring morphine. - Endorphins bind to endorphin receptors (also called opioid or opiate receptors) in brain cells to intercept the pain signal. - Opiates also bind to the same endorphin receptors, since they share a similar chemical structure. - As the endorphin receptors cannot tell the difference between a natural endorphin and an opiate, the pain signal is interrupted centrally for the body. - Endorphins and opiates often cause a feeling of euphoria, not just from the relief of pain, but also because of chemical changes that occur in the brain when opiates are present. - For example, dopamine is a neurotransmitter that is produced when the endorphin receptor binds to a natural endorphin or to an opiate. - The release of dopamine causes feelings of pleasure, which adds to the addictive nature of opiates. - Image xx

Morphine derivatives - codeine

- Opium latex does naturally contain about 3% codeine, but most codeine is made synthetically from morphine through a chemical reaction. - Codeine is sometimes referred to as methylmorphine since one hydroxyl functional group is replaced with a methyl alkyl group via a methylation reaction. - This makes an ether linkage. - This reaction is actually reversed in the liver when the body is breaking down the codeine for elimination. - Image xx

How stomach acid is produced

- Rather than neutralising excess stomach acid, like antacids, some medicines work to stop the production of excess acid in the first place. - There are two main factors to stomach acid production - synthesis of the acid and the release of the acid into the stomach. - Drugs can work on either factor to reduce the amount of acid that makes it way to the stomach. - In the stomach, acid is produced in specialised cells, called parietal cells, which then release the acid when required. - The acid is made and released on demand, otherwise the acid could cause damage to the stomach lining. - The stimulus to release acid can be triggered by eating food, stress or a increase in the pH of the stomach contents. - There are three receptors in the parietal cells that must all be activated to produce and release stomach acid. - They are called the histamine receptor, gastrin receptor and acetylcholine receptors. - Interfering with the action of any of these receptors will stop acid production and release.

Shikimic acid

- Shikimic acid has now been successfully produced using bacteria in the process of biosynthesis. - Escherichia coli can produce large quantities of shikimic acid in a multi-step process, which has decreased the demand for the star anise plant. - E. coli need a source of carbohydrates (sugar) and a controlled temperature condition that is close to room temperature, so the reaction conditions are cost- and energy-effective. - This is an example of a green chemistry solution to synthetically produce larger quantities of a naturally-occurring compound using bacteria to minimise the energy consumption and waste production while minimising the use of solvents.

Polar Solvents

- Solvents that are less harmful to the environment include polar solvents, like water and alcohols. - The disposal of polar solvents generally involves filtration or distillation to remove harmful impurities, such as unused reactants or catalysts required during the reaction. - Water can then be disposed of just like any water sample into the local waste water for further treatment. - Alcohols can be diluted with water to very low concentrations and disposed of as waste water or they can be incinerated with a combustion reaction. -- Methanol combustion: 2 CH3OH (l) + 3 O2 (g) → 2 CO2 (g) + 4 H2O (g) -- Ethanol combustion: CH3CH2OH (l) + 3 O2 (g) → 2 CO2 (g) + 3 H2O (g)

Antibiotic resistance

- Some bacterial infections do not respond to a course of antibiotics. - This is because some bacteria are capable of producing enzymes that destroy penicillin. - These enzymes are known as penicillinase or beta-lactamase. - Penicillinase works to break the beta-lactam ring in the penicillin molecule, thus rendering it ineffective in binding to transpeptidase (also known as the penicillin binding protein). - Different R-groups on the beta-lactam ring make penicillin more resistant to the action of penicillinase. - For example, having a larger, bulkier R-group seems to make penicillin more resistant to penicillinase, so naturally-occurring penicillins can be chemically modified to make penicillin more effective at stopping the growth of bacteria. - Bacteria that produce penicillinase in large quantities are known to be penicillin-resistant. These strains of bacteria are very difficult to treat and require potent antibiotics at a high dose. - It is believed that the overprescription of antibiotics has led to greater antibiotic resistance in recent years, as bacteria have adapted to produce larger quantities of penicillinase as a survival mechanism. - Another factor influencing antibiotic resistance is the course of the prescription. - If a person does not complete their entire prescribed dose, the weaker bacteria (those that produce lower quantities of penicillinase) would have been effectively killed, but the stronger ones (the ones producing more penicillinase) would still remain. - These cells would then survive to reproduce, thus making an entire population of cells that are resistant to the effects of penicillin.

Stoichiometry for Stomach Acid

- Stoichiometry can be used to calculate the amount (in mol) of acid that can be neutralised by the base, using the mass and molar mass of the base or using the volume and concentration of the liquid antacid. - For example, if an antacid tablet contains 80.0 mg of aluminium hydroxide, the amount (in mol) of the base can be determined as follows: - n(Al(OH)3) = m/M = 0.0800/78.01 = 0.00103mol - Note that in this calculation, the mass in milligrams (mg) was converted to grams (g) by dividing by 1000. - The answer was then rounded to 3 significant figures. - Using the molar ratio from the balanced chemical equation allows us to calculate the amount (in mol) of acid that can be neutralised by this amount of base. -- Al(OH)3 (s) + 3HCl (aq) → AlCl3 (aq) + 3H2O (l) - From the balanced equation, we can see that the molar ratio of Al(OH)3 to HCl is 1:3. - Therefore, 0.00103 mol of Al(OH)3 will react with three times as much HCl: n(HCl) = 3 × 0.00103 = 0.00309 mol - This tells us that one antacid tablet containing 80.0 mg of Al(OH)3 can neutralise 0.00309 mol of hydrochloric acid. - Note that the answer could also be given as 0.00308 mol without rounding up at each step.

Use of opiates

- Table - Morphine is used for moderate to severe pain, such as following surgery, during childbirth or after breaking a bone. - Morphine can also be used effectively for sedation in minor surgical procedures, such as during wisdom tooth surgery. - Strong analgesics are required in many circumstances. - Codeine, the mildest opiate, is prescribed for minor pain, such as a headache, but is also used as a cough suppressant. - Codeine is metabolised slowly by the liver back into morphine, making it useful as a long lasting analgesic for low levels of pain. - Some people, however, are able to metabolise codeine very quickly, converting it to morphine at a dangerous speed, so codeine cannot be prescribed for all people. - The use of diamorphine as a treatment for severe pain is controversial, due to its highly addictive nature. - Since it is a stronger analgesic than morphine, it can be administered at lower doses. - It is effective in alleviating severe chronic pain, such as for patients in end-of-life stages (palliative care) suffering from terminal illnesses. - It is also used for pain relief following childbirth by caesarian section and even in children suffering from severe post-operative pain.

Oral

- Tablet, capsule or syrup - Has to survive rigours of digestive system - Stomach acid can deactivate some drugs - Advantage: Easiest way for patient to take drug

How does HIV work

- The HIV virus attacks a type of T-cells that contain a CD4 antigen (sometimes called CD4 cells) to reproduce and make more viruses. - CD4 cells, like all T-cells, are part of the body's immune response, so the problem with an HIV infection is that over time, the CD4 cells that are involved in producing more viruses are killed when the CD4 cell bursts open, releasing the newly-made viruses. - Depleting the body's immune system response weakens it, leaving the body susceptible to any form of infection. - In time, when nearly all the CD4 cells are gone, the patient would be diagnosed with AIDS and even a common cold virus could result in death.

How the structure of penicillin allows for action

- The beta-lactam ring is the core structure of all penicillin molecules. - When bacteria divide by binary fission to make two identical cells, new cell walls are required in order for the two cells to separate and to have structure and protection. - Cell walls are made with layers of peptidoglycan, a polymer made of sugars and amino acids, also known as murein, that is sandwiched between two lipid layers. Without a functioning cell wall, a bacterium would not have the rigid structure required to function and would instead rupture, causing the death of the cell. - When the layers of peptidoglycan are made for the cell wall, they are cross-linked, which means there are covalent bonds holding the layers together (this is common in polymers). - This cross-linking provides additional structure and rigidity for the cell wall. - Cross-linking occurs by the action of certain enzymes, known as transpeptidase, also known as the penicillin binding protein (PBP). - The beta-lactam ring effectively binds to transpeptidase (the penicillin binding protein) and thus interferes with the action of the enzyme, therefore not allowing the cell wall to be cross-linked. - A cell wall that is missing the necessary cross-linking will eventually have too much water entering the cell via osmosis, causing the cell to burst. - Since animal cells do not have a cell wall or transpeptidase, penicillins cannot bind, so they have no effect on animal cells.

The chemical structure of ranitidine

- The chemical structure of ranitidine has ionic charges, allowing it to dissolve very well in water, making it able to be well absorbed by oral ingestion (40-80% bioavailability), so it is generally swallowed as a tablet or as granules dissolved in water. - Ranitidine has a low incidence of side effects: generally headaches are reported, and very few serious side effects have been noted. - The drug is effective for about 4-6 hours after ingestion, so it is generally taken twice a day. - There are different doses available, depending on the severity of the symptoms.

Antibiotic waste

- The disposal of expired or unused antibiotics poses a large threat to the environment, since these drugs are very commonly prescribed. - People are advised to complete an entire course of antibiotics when prescribed, but often people will stop taking the medicine when they feel better, resulting in unused medicine that must be disposed of properly. - Pharmaceutical companies are also required to make drugs with an expiration date, after which the integrity and effectiveness of the drug cannot be guaranteed. - The expired drugs would still have some medicinal effect, so they must also be disposed of properly to avoid releasing antibiotics into the environment. - When antibiotics are flushed down a toilet or thrown in the garbage, they can enter the water supply or leach into the soil. - The risk is that the drugs will kill the bacteria that they come in contact with in nature. - The bacteria often perform helpful functions in the ecosystem. - Bacteria populations in nature can help to keep other, more harmful populations of bacteria, algae or fungi in control, so the presence of antibiotics in bodies of water or soil can kill the 'good' bacteria and allow for the growth of 'bad' bacteria or harmful overgrowths of algae or fungi.

Dosage

- The dosage of a drug partially determines the method of administration. - The dosage refers to the amount of the drug that the person would be required to take, which may be measured in units of grams or millilitres, for example. - The dosage of the drug also includes the frequency of administration required to maintain the level needed to have a medicinal effect in the body, based on the concentration in the bloodstream. - Some medicines may only require a single dose, while others may need to be taken multiple times per day. - Medicines with very low doses could be better administered by oral ingestion of a prepared syrup that is diluted with a solvent (such as water or ethanol) and other ingredients, like flavouring, rather than by injection with a very small volume of a concentrated preparation. - Ingesting a larger volume of a diluted syrup would help to ensure that the entire dose has been administered.

Drug activity

- The drug must interact with specific sites in the body where it has an effect: the "target site". - Some drugs have an effect on specific types of cells, such as with chemotherapy drugs and cancer cells. The target cells are identified by three-dimensional receptors into which the drug fits like a key in a lock. - If the drug passes by cells that do not contain the receptor, it will not bind to the cell and have a medicinal effect. - Other drugs work to increase or decrease the action of enzymes in the body. - For example, penicillin, a common antibiotic, works to inhibit the enzyme needed for bacteria to form their cell wall. - As a result, the bacteria cells burst without the structure of their rigid cell wall.

HIV virus

- The human immunodeficiency virus, or HIV, attacks the cells that make up the body's immune system. - If left untreated, HIV develops into acquired immune deficiency syndrome, or AIDS. - In the past, an HIV diagnosis was certainly a death sentence, but today HIV-positive individuals can live long and relatively healthy lives with the right combination of medicines, the most powerful drugs being antivirals. - Symptoms Image xx

Magnitude of the therapeutic index

- The magnitude of the therapeutic index is an indication of the "safety" for the dosage of the drug. For drugs with a smaller TI value (close to 1), the dosage of the drug must be carefully administered because the minimum effective dose and the toxic or lethal doses are very similar. - This is especially true for drugs or administration methods with a high bioavailability, since a large portion of the dosage is reaching the active site. - Doctors would have to prescribe the drug very carefully and patients would have to also be mindful not to exceed the dosage of the drug. - For drugs with a high TI value, the drug would be viewed as being more safe and also doctors would have more flexibility in prescribing a range of different doses, as required by the patient. - This is also the case for drugs or administrations with a low bioavailability, since a small portion of the dosage reaches the active site. - Many of the drugs available without a prescription would have a high TI value and also sometimes give the consumer options for the dose (i.e. take 1-2 tablets every 4 hours as needed).

Antibiotic Resistence

- The other risk for antibiotics in the environment is that they contribute to antibiotic resistance. - Overexposure to antibiotics causes bacteria to adapt by increasing the production of compounds, like penicillinase, that destroy the beta-lactam ring, rendering the antibiotic useless. - These bacteria then reproduce, making further generations of antibiotic-resistant strains that become difficult to control. This can lead to the formation of a superbug, a strain of bacteria that is resistant to many antibiotics.

The development of new synthetic drugs

- The pathway to making a drug available can take many years and cost a lot of money. Scientists - biologists, chemists and physicists - work together collaboratively (Aims 9 and 10) to research, develop and test new drugs to be more effective with lower risks and side effects. - The maximum yield of the product is the goal, to minimise costs and maximise profits for the drug company. - You may have performed an experiment in class where you measure the percentage yield of your product. - One of the challenges faced in drug synthesis is to extract a large yield of a high purity sample. - The most modern method of drug discovery involves the use of combinatorial chemistry. - Combinatorial chemistry is a laboratory method that involves using robotics to synthesise thousands of different compounds at a time, usually peptides or small molecules. - The compounds can then be tested for effectiveness, and then kept for further testing or modification, or discarded. - With this highly automated process, large volumes of molecules can be synthesised and tested in a short period of time, but it is more of a trial-and-error approach, resulting in a large amount of molecules made that have no activity. - Although it is difficult for scientists to mimic natural processes, combinatorial chemistry is proving to be making new advancements in drug discovery. - Part of the drug development process is to conduct a 'double blind test' where a placebo is offered to one group of patients, while the other group receives the drug. - A placebo is a pill, lotion or injection that does not contain the active ingredient that the drug has, and is used to see if the drug does have a measurable effect compared to not using the drug. - Many times, people taking the placebo report to have improvements in their health, even though they are not taking the actual drug. - This "placebo effect" has been noted in numerous studies. - Image xx

Polarity of Drug

- The physical properties of the drug, such as the polarity, may also affect the bioavailability. - Since the drug must eventually reach the blood, which is polar as it has a water solvent, the drug must have some polarity, since "like dissolves like". - For the drug to enter the cell, it must also have some nonpolarity to pass through the cell membrane. Therefore, drugs must have both polar and nonpolar properties. - The types of functional groups on the drug will determine its overall polarity. - Polar functional groups include hydroxyl, carboxyl or amino groups. - Nonpolar functional groups include alkyl side chains and phenyl rings. - The structure of acetylsalicylic acid, a common pain reliever known as aspirin, is shown below. - You can identify both polar (carboxyl) and nonpolar (phenyl) functional groups, making this medicine suitable for oral ingestion and absorption into the body. - If the drug is administered orally (usually with a sip of water), then a polar drug will generally dissolve within the polar environment of the contents of the stomach. - If the drug is not very polar, it might bind to food particles instead, preventing it from being absorbed. - This is why drugs are sometimes required to be taken either with food or on an empty stomach to ensure better absorption (and thus greater bioavailability).

How viruses reproduce

- The reason why viruses are so hard to stop is because of their small size and method of action. Viruses are extremely small, nearly 1000 times smaller than a human body cell. - They are made up of a protein capsule containing genetic material (deoxyribonucleic acid, known as DNA, or sometimes ribonucleic acid, known as RNA), but no other organelles, as we typically see with other living things made up of cells. - As a result, viruses do not have their own ability to undergo typical processes required of life, such as growth and reproduction. - Rather, they require a host cell to reproduce and make more viruses. Viruses identify and attach themselves to a specific host cell and inject their DNA (or RNA). The host cell is then taken over by the virus to use the host cell's resources to make more viruses. - The host cell bursts, releasing the newly made viruses and dying itself. - Image xx

Side-effects

- The side-effects of a medicine must also be considered. - Some drugs cause other unintentional physiological effects to occur in the body that are not desired, and these are known as side-effects. - For example, some medications may cause drowsiness, nausea, constipation or headaches. - The administration of the drug could be altered to minimise these effects, or sometimes another medicine must also be prescribed to manage the side effects. - For example, intravenous injection allows the medicine to be delivered to the active site much more quickly than other forms of administration; but for medicines with unpleasant side-effects, intravenous injection could result in a severe onset of the side-effects. - Another method with a slower delivery to the active site, such as oral ingestion, might be preferred to manage the side-effects of the drug.

Body absorbing drug

- The speed and ability of the body to absorb and use the medicine, known as metabolism, plays a large role in determining the method of administration. - Injection of the drug directly into the bloodstream has a much faster metabolism than oral injection, for example. - Some drugs are best employed with a quick absorption of the entire dose, such as with an insulin injection when treating diabetes, while others are more effective when absorbed slowly over time, such as the hormones used in birth control skin patches.

The buffering action of the stomach

- The stomach produces acid in response to food ingestion, but the quantity of acid produced and released is regulated to avoid issues with too much or too little acid production. - The stomach generally contains a volume of 20-100 cm3 of fluid, with a total production of about 1.5 dm3 of stomach acid produced daily. - The stomach uses a buffer system to regulate the acidity of the stomach to keep the pH between 1 and 3 at any given time. - Buffers are solutions that resist changes in pH when small amounts of strong acid or strong base are added. - If acidic or basic foods are consumed or small amounts of stomach acid are produced or used up during digestion, the pH of the stomach contents can be 'buffered' and maintained within an optimal range of pH 1 to 3. - The pH of a buffer solution can be calculated using the Henderson-Hasselbalch equation. - pH = pKa + log([A−]/[HA]) - The stomach uses hydrogen carbonate ions (HCO3-) in equilibrium with carbonic acid (H2CO3). - The hydrogen carbonate ions are the conjugate base of the weak carbonic acid. -- H2CO3 (aq) + H2O (l) ⇌ HCO3- (aq) + H3O+ (aq) - If the pH decreases due to the release of too much acid or if acidic foods are consumed, the equilibrium will shift to the left, using up the excess acid. - If the pH increases due to acid being used up during digestion or if basic foods are consumed, then the equilibrium will shift to the right to replenish the acid. - The pKa is an expression of the strength of the weak acid, in this case H2CO3. - The larger the value, the weaker the acid. - Carbonic acid has a pKa of 6.35. [A-] is the concentration of the conjugate base, HCO3- and [HA] is the concentration of the acid, H2CO3. - Example xx - The use of antacids increases the pH of the stomach contents momentarily, which in turn can then lead to further increased acid secretion. - Chronic or excessive use of antacids is not recommended for long-term issues of excess stomach acid because it can worsen the problem. - Antacids are effective for occasional or mild stomach acid issues, but for people experiencing severe or long-term discomfort, medicines that control the production of stomach acid are more appropriate

Omeprazole

- The structure of omeprazole has many polar functional groups, ensuring high bioavailability when taken orally. - Omeprazole, like ranitidine, must be metabolised by the liver before the active metabolite can have an effect on acid secretion. - Omeprazole can sometimes take up to 24 hours to have an effect, due to the slow metabolism. - The active metabolite, however, binds covalently to the proton pump, resulting in a longer-lasting effect compared to ranitidine; sometimes 1-3 days for a single dose. - This makes PPIs provide much longer and more permanent relief compared to antacids or H2 receptor antagonists. - Omeprazole would generally be prescribed for chronic stomach acid problems, not for occasional issues. - When excess stomach acid is regularly released, it can cause damage to the stomach lining, leading to ulcers. - Side-effects to omeprazole are rare and generally mild, but can include fever, stomach pain, nausea and headaches. - Omeprazole is on the World Health Organisation's List of Essential Medicines for its effective relief of stomach acid discomfort. - Image xx

Safer drug synthesis

- The synthesis of some drugs can require the use of precursors that are extracted from plants in nature. - This process sometimes requires the use of leaves, bark, fruit or seeds from the plant, which can be regenerated by the plant, but other times might require the use of the entire plant. - When the entire plant must be harvested, it can be difficult for the crop to meet the demand for the substances required in drug production, so alternatives are required to ensure that the demand is met and that the population of the plant is not at risk.

Equations for Therapeutic Index

- The therapeutic window of a drug is often represented by a ratio, known as the therapeutic index (TI). The TI is calculated using the LD50 and ED50, as shown in the formula below: -- therapeutic index=LD50/ED50 (for animal studies) -- therapeutic index=TD50/ED50 (for human studies)

Limited treatment for influenza

- The use of antivirals for the treatment of influenza is limited. - Healthy individuals can fight the flu, generally in 3-7 days with no additional health risks, so antivirals are usually not required. - Small children, the elderly or those with compromised immune systems (cancer or HIV/AIDS patients) are most at risk for a longer battle with the flu or for the risk of a secondary infection, such as pneumonia. In these cases, antivirals would be recommended. - There are some side-effects, such as nausea or headaches, but these would be considered to be minor in comparison to the severity of the influenza infection itself. - Antivirals must be taken within 48 hours of the first appearance of symptoms or the viral infection would have progressed beyond the capacity of the drug to combat the virus, making the drug ineffective. - Antivirals have also been used as a prophylactic (to prevent contracting influenza) in individuals that have come in close contact with an infected person. - For example, if a family member acquires influenza and there are also small children, pregnant women or elderly family members in the same household that are at certain risk of exposure to the virus, oseltamivir has been shown to be 92% effective at stopping the transmission of the virus, compared to a placebo. - Regular use of antivirals as a prophylactic for influenza is not recommended, as receiving an influenza vaccine is more effective at preventing the flu.

Interfering with the replication of the virus

- The virus uses the host cell's machinery to reproduce, so some antiviral medicines can interfere with this process, producing incomplete viruses. - Some drugs introduce inactive genetic building blocks into infected host cells. - When used to make new viruses, inactivated genetic building blocks then produce viruses which are ineffective. - Other medicines interfere with the host's ability to generate the protein capsule for the virus, so that the newly made viruses do not have the structure and protection of that outer capsule.

Drug development - How are drugs obtained

- There are many natural home remedies for a variety of health problems. - For example, mint leaves can alleviate a stomach upset, cloves can help with a toothache and vinegar can treat sunburn. - Sometimes, however, home remedies are not enough and synthetic drugs must be developed to cure an illness or alleviate the discomfort of symptoms. - Medicines are made in a variety of ways. Some medicines are extracted from natural sources, like plants or animals. - For example, quinine was extracted from the bark of the cinchona tree as a muscle relaxant by the indigenous Quechua population in South America and later used very effectively as a treatment for malaria in Europe beginning in the 1600s, saving countless lives throughout history. - Malaria is an infectious disease carried by mosquitoes and causes flu-like symptoms, but can lead to respiratory distress, renal (kidney) failure and even death. - Currently, over 200 million cases of malaria occur every year, and it is estimated to be the cause of 600,000 deaths in 2010 (World Health Organization). Quinine is not typically prescribed any more as there are other medicines that are more effective, including a variety of anti-malarial drugs that prevent a person from contracting malaria in the first place.

Comparison of opiates

- There are three types of endorphin receptors in the brain. - All three receptors respond with analgesia (pain relief), but each one also produces other side-effects, ranging from hallucinations and anxiety to respiratory depression, nausea and constipation. - These side-effects are the result of chemical changes that occur in the body in response to the binding of the opiate or endorphin to the endorphin receptor. - Image xx - Since morphine, codeine and diamorphine have similar structures, they are all capable of binding to endorphin receptors. - Morphine is capable of binding very well to one type of receptor and also has been shown to interfere with the action of other two types, producing an analgesic effect. - Codeine must first be metabolised in the liver back into morphine. - This conversion is quite slow and other products are also made, which have no medicinal effect. - Codeine, although less polar and more capable of passing into the brain than morphine, is only about 1/10 the strength of morphine. - This is because morphine has a much greater affinity for the endorphin receptors in the brain compared to codeine. - Diamorphine contains more nonpolar functional groups than morphine or codeine, so it is faster at crossing into the lipid layer that surrounds the brain. - Diamorphine can only bind to one receptor, so the effect of diamorphine is immediate, but does not last long.

Improving Purity of Aspirin

- To improve the purity of the product, the aspirin crystals are subjected to a recrystallisation process. Recrystallisation of aspirin (and many other organic solids) generally involves taking the dried white crystals that were obtained and dissolving them in warm 95% ethanol in a flask. - When the crystals have all been dissolved, an equal volume of water is added and the contents cooled on ice until the aspirin crystals recrystallise (and return to white). - The sample is then filtered again, and recrystallisation can be repeated many times to ensure improved purity of the sample. - This process works by removing impurities by dissolving them in ethanol, which has polar and nonpolar properties. - The impurities will dissolve and be rinsed away with the ethanol/water mixture, leaving behind the pure aspirin crystals, which have a melting point of 136°C, meaning it will become a solid when cooled to room temperature. - Image xx

Antiviral medicines - flu

- Two antiviral medicines have been used effectively for the treatment of severe influenza cases. - One drug is called oseltamivir, known by the trade name Tamiflu, and the other is zanamivir, known as Relenza. - Note that there are some similarities in the structures of the two antivirals. - Attached to the ring structures of both molecules are the following functional groups: a carboxamide group, an amino group and an ether group. - Both rings also contain a carbon-carbon double bond. - Zanamivir has a carboxyl group and multiple hydroxyl groups which make it more soluble in polar solvents than oseltamivir. - These antiviral medicines work by blocking the exit of the newly-made viruses from the host cell. - In order for the virus to leave the host cell, an enzyme on the virus, called neuraminidase, cuts through the host's cell membrane. - When this occurs, the newly-made viruses go on to attack other cells and the host cell is left with a hole in the membrane, which generally means death for the cell. - Oseltamivir and zanamivir are referred to as neuraminidase inhibitors, since they both work to inactivate neuraminidase, so the virus is not able to leave or detach itself from the host cell. - Image xx

Solvent waste solutions

- Typical solvent waste disposal methods include incineration by combustion reaction. - The energy produced by these exothermic reactions can be a source of energy, but the carbon dioxide produced is also harmful to the environment, since carbon dioxide is a greenhouse gas. - The carbon dioxide produced can be treated or recaptured to limit its release into the atmosphere. - Many companies have changed their production to run in smaller batches using less solvent and also switching to solvents that are more environmentally friendly. - Dangerous benzene derivatives can be replaced with other nonpolar solvents that can be disposed of more safely. - Chlorinated hydrocarbons (such as chlorofluorocarbons, or CFCs) pose a dangerous risk to the stratosphere due to the production of free radicals that can destroy ozone molecules, so these compounds have been banned or controlled in many countries and alternative compounds used when available. - Some of the solvent waste can be recycled and used again, using fraction distillation equipment. - Fraction distillation works by heating up the leftover solvent mixtures and separating the components (fractions) by boiling points. - The pure fractions of the mixture are then collected, and solvents can be recycled and any other fractions can be discarded. - Recovering solvents does have an initial cost to the company in the purchase of the equipment, but they save money later on since the companies do not have to purchase as much solvent in the future. - Some solvents, such as benzene and its derivatives, can be incinerated in a combustion reaction or, when diluted with water, can be decomposed by bacteria, in a process known as biodegradation. - This process produces the same products as with incineration, but with a lower energy cost since heat is not required to burn the solvent. - Biodegradation is also considered to be a more green process, since carbon dioxide gas is being released at a much slower rate than incineration.

Side effects and addiction

- Unlike aspirin, which acts at the local site of trauma, morphine affects the body's central pain response in the brain, so there are more side effects. - Common side effects that are mild include feeling dizzy, drowsiness, constipation and weight loss. - More serious side effects include blurred vision, chest pains and difficulty breathing. - Symptoms of an overdose can include constricted pupils, fever, muscle pain or spasms and severe sleepiness. - For people taking opiates for an extended period of time, their bodies build a tolerance to the drug. - The tolerance is due to the opiate receptors undergoing changes to become less sensitive to the opiates. - For people taking opiates for extended periods of time, higher doses of the drug are required to have the same medicinal effect. - Doctors must be careful when prescribing opiates for patients long term because of desensitisation. - Since patients require higher and higher doses of opiates to maintain the same medicinal effect, opiates can become habit forming, or addictive, with extended use. - When patients have become accustomed to the medication they can experience physiological addiction and withdrawal to the medication if removed suddenly. - Doctors will generally wean a patient off an opiate by gradually decreasing the dose to avoid withdrawal. - Symptoms of withdrawal include sweating, vomiting, muscle aches and psychological distress.

Morphine derivatives - Diamorphine (heroin)

- Unlike morphine and codeine, diamorphine is not naturally found in the opium latex and it is only made synthetically by reacting morphine with ethanoic acid in an esterification reaction. - The hydroxyl functional groups on the morphine molecule each react by a condensation reaction with the carboxylic functional group on the ethanoic acid. - The result is an ester linkage and the elimination of water. - Image xx

Rectal

- Use of suppositories - Cultural biases here-companies need to consider before marketing drug - British are very resistant to suppositories despite their effeciency - The Germans on the other hand, use them all the time

Vaccines for HIV

- Vaccines for HIV have been under development for many years, but there are currently no vaccines that have been shown to offer enough protection from HIV. - The difficulty in developing an effective HIV vaccine is due to many factors. - It would be unwise to use a heat-killed virus, as some vaccines use, because of the risk that not all of the viruses were killed and the vaccine could actually cause HIV infection. - Many vaccine studies start with animal studies, but HIV does not affect animals the same way as humans, so the clinical trial process is challenging. - Finding human test subjects is difficult because it would be unethical to knowingly infect a person with HIV to test the effectiveness of the vaccine. - Clinical trials in humans would have to involve individuals who are at a high risk of contracting HIV anyway, such as intravenous drug users, workers in the sex trade or the sexual partners of HIV-positive individuals. - Another issue is that HIV is a retrovirus and there are currently no vaccines that have been developed for any retroviruses. - Since a retrovirus contains RNA, which is then converted to DNA and incorporated into the host cell's own genetic material, the HIV viral DNA can remain dormant (inactive) in the host cell for years before it begins to produce viruses and the person shows symptoms of the illness. - Since the virus can remain inactive, the presentation of illness may be delayed and therefore the efficacy of the vaccine may be difficult to measure.

Selective virus

- Viruses are selective in the type of cell they can infect. - They recognise the specific cell type by special proteins, called antigens, on the surface of the cell. - The virus requires interaction with specific antigens on the surface of the cell in order to infect the cell and use it as a host for reproduction. - For example, the rhinovirus, which is responsible for the common cold, can only infect a type of cell in the airway. - Therefore, to 'catch a cold', the virus must be inhaled. - A cold virus present on food that is eaten will not result in a successful infection because it cannot interact with the cells of the digestive tract. - Conversely, bacteria are single-celled organisms that grow and reproduce. - They contain organelles that perform a variety of cell functions and they do not require a host cell to perform those functions. - When a bacterium infects a host organism, like a person or an animal, the bacterium rapidly divides by binary fission, using the host organism's nutrients, but does not attack the cells directly, like viruses do. - Image xx - life cycle of bacterium

The therapeutic index

- When a drug is developed, the dosage must be determined. - There is an effective window where the dosage of the drug is most active. - If the dose is below this window, the concentration of the drug in the body will be too low and thus not have a measurable effect, but if the dosage is too high, it could be dangerous and cause serious side effects or even death. - The dosage of the drug must be within this therapeutic window. - Many factors, such as age, gender and body mass, determine the effectiveness of a drug's action on the body, so only trial and error during clinical trials can determine the effective dosage of a drug. - Since drugs are often produced in standard dosages, these factors must be averaged over the general population, so clinical trials focus on the drug having an effect on 50% of the population of the drug trial.

Bioavailability

- When a drug is taken, the entire dose does not always make it to the target site. - Bioavailability is the fraction of the administered dosage that reaches the target site. - There are several reasons why a portion of the drug does not make it to where it is needed in the body. - Some of these reasons include the administration of the drug, polarity and functional groups. - When a medication is administered intravenously - that is, by injection into a blood vessel - the bioavailability is 100%. - For several reasons, however, many drugs are not administered using this method, so all other methods of administration have bioavailability less than 100%. - When a medicine is ingested orally, the acidity of the stomach or small intestine may destroy some of the drug, the drug may not be completely absorbed or it might even be absorbed by the bacteria in the small intestine.

Production of drugs on large scale

- When a substance that has been identified from a plant or animal has been proven to have effective medicinal properties, it then has to be made on a large scale in order to meet the needs of our population. - Scientists may use animals or bacteria to produce some substances, as with synthetic insulin to treat diabetes. - In 1921, Canadian scientists Frederick Banting and Charles Best first successfully used insulin extracted from the pancreas of cattle to treat children suffering from diabetes. - Today, insulin is synthesised using bacteria or yeast to meet the public demand. - Banting and Best had first tested their methods using dogs, as shown in the video below. - Pharmaceutical companies are always developing new synthetic drugs to work more effectively with fewer side effects than naturally sourced medicines. - Synthetic drugs are made in a laboratory, using chemical reactions to produce and isolate the active medicinal agent. - For example, aspirin is a common pain reliever that was first extracted from the bark of willow trees, but is now made commercially by reacting acetic anhydride with salicylic acid. - The product, acetylsalicylic acid, is then isolated from the other product acetic acid and purified from any other contaminants.

Creating immunity with vaccines

- When a vaccine is administered containing a heat-killed or live attenuated virus (a virus which has had some of its genetic material removed), the same immune response occurs, but the inactivated virus is not able to cause an infection. - The B cells work to produce antigens, so immunity is present if the virus were to enter the body. - Some vaccines are only required once to create enough lifelong immunity, while others must have a 'booster' dose to ensure that the body continues to make antibodies. - The tetanus vaccine must be given approximately every 10 years, while the smallpox vaccine only requires a single dose for lifelong immunity.

How pain is perceived

- When the body experiences a trauma, a chemical pathway occurs with the end result being the production of prostaglandins. - Prostaglandins can increase the body's temperature, causing a fever, and are also part of producing the sensation of pain. - The sensation of pain is caused by the direct action of prostaglandins on the nerve endings locally at the site of the trauma or by acting on the perception of pain in the central nervous system in the brain. - Some analgesics, such as aspirin, work to interfere with prostaglandin production and treat pain (and the associated trauma) locally. - Other analgesics, like opiates, work to interfere with the sensation of pain in the brain (and do not address the trauma). - When the central nervous system receives a pain stimulus from the nerve endings at the site of a trauma, the pain signal is transmitted through the nerve cells, called neurons, to the spinal cord and then the brain. - Neurons can communicate to one another using chemicals called neurotransmitters, to transmit the signal faster and across small gaps between neurons, called synapses, where they interact with receptors on the neuron on the other side of the synapse. - Specific parts of the brain are then stimulated to give the sensation of pain.

How aspirin works for pain relief or fever

- When we experience physical trauma, the cells in our body respond with a series of steps that ends with the production of chemical substances called prostaglandins. - These prostaglandins result in the sensation of pain, swelling and sometimes fever. - Aspirin works by stopping the enzyme that produces prostaglandins, which is called cyclooxygenase (known as COX). - Aspirin does not have a specific target site, but rather acts to inhibit the production of prostaglandins throughout the body, so any and all pain, swelling or fever will be treated.

Comparison of oseltamivir and zanamivir.

Image xx