The active ingredients in drugs and medicines can be isolated from a plants and animals or synthesized artificially. Drugs supposed to assist human body’s natural self-healing capabilities. Placebos are drugs containing no active ingredient, which “fool” the human body into healing. D. 1. 2 Outline the stages involved in the research, development and testing of new pharmaceutical products. The research and development of new medicines is a long and costly process. It usually takes up to 12 years and costs more than $200 million. 1. First the drug must be isolated or synthetized. 2. The drug is tested on animals. LD50 and ED50 are determined.
3. The drug moves to Clinical Trials a. Human Pharmacology – testing on small group of healthy volunteers for safety b. Therapeutic Exploratory – evaluates drug’s efficiency and side effects c. Confirmatory Stage – large-scale testing of drug 4. A local drug regulatory agency approves a medicine and decides whether it will be 5. OTC (over the counter) or on prescription only. LD50 is a lethal dose necessary to kill 50 percent of animal population. ED50 is an effective dose, one creating a noticeable effect in 50% of animal population. The ratio between LD50 and ED50 is called the Therapeutic Index. Therapeutic Index = LD50 / ED50
Therapeutic determines a safety of drug. If the therapeutic index of a drug is 10, a person would have to intake ten times more drug than the effective dose for the effects to be lethal. According to the therapeutic index, the researchers decide whether a dosage must be controlled. If TI is low, the dosage must be closely controlled. During testing, half of the patients receive a real drug and the other half similar-looking placebo. This determined whether the drug has a real effect or the pill only fooled body into healing. NOTE: We must know Thalidomide as an example of what can go wrong during R&D process of a drug.
Thalidomide alleviates morning sickness during pregnancy. The drug’s development revealed severe side effects – babies, whose mothers used the medicine, got born with deformed limbs. D. 1. 3 Describe the different methods of administering drugs. There are five ways of administering a drug: 1. Injection a. Intravenous – veins b. Intramuscular – muscles c. Subcutaneous – under skin 2. Orally – mouth 3. Rectally – anus 4. By inhalation 5. Topically – on the skin (ointments, creams, …) D. 1. 4 Discuss the terms therapeutic window, tolerance and side-effects.
Therapeutic window – the difference between the effective dose and lethal dose; also called therapeutic index Side effects – the undesired effects of drugs Ex: aspirin thins the blood (used as an anti-clotting agent to prevent a hearth attack) Morphium, the pain reliever, causes constipation. Tolerance – a person taking a drug often gets used to the active ingredient, so it takes larger and larger doses to obtain the drug’s desired effect. There is a danger that a body would create a physical addiction to a drug. For instance, an addiction to caffeine: if the addict does not get his/her coffee, he/she gets headaches.
Another issue is that with increasing dose, the user is coming closer and closer to the lethal dose. Risk-to-benefit ratio – determines whether the side effects (risk) of the drug are acceptable in relation to its curing effects; for example, a drug curing baneful disease would be accepted despite high risks D2: Antacids D. 2. 1 State and explain how excess acidity in the stomach can be reduced by the use of different bases. Human stomach contains gastric juices secreted by some cells of the stomach walls. The gastric juices are acidic, with pH between 1. 0 and 3. 0, because they contain hydrochloric acid (HCl).
Excessive acid production causes heartburn and damage of the mucus covering the walls of the stomach. Moreover, excess production of acid creates an ideal environment for the bacteria Helicobacter pylori, causing peptic ulcers. Hearthburn – the situation when gastric juices overflow through esophagus Ulcers – scars on the walls of stomach, indirectly caused by an excessive acidity. Antacids are weak bases, utilized to neutralize the excess acidity in a human stomach. They relieve the pain of ulcers and prevent ulcers and heartburn from happening. Antacids are metal oxides, hydroxides, carbonates or hydrogencarbonates. Antacid Ingredient Name
Chemical Formula Tums Calcium carbonate CaCO3 Gaviscon Aluminum hydroxide Al(OH)3 Milk of Magnesia Magnesium hydroxide/oxide Mg(OH)2, MgO Common ingredients of antacids are alginates and anti-foaming agents. Alginates create a layer of mucus on the walls of stomach and in esophagus, which prevents the heartburn. Anti-foaming agents prevent flatulence (farting) and burping. A common anti-foaming agent isdimethicone. D3 Anelgesics D. 3. 1 Describe and explain the different ways that analgesics prevent pain. Analgesics are drugs that relieve pain. They can be mild or strong. Mild analgesics intercept the pain stimulus at its source.
Modes of operation: (1) interfere with the production if prostaglandins, chemicals that cause pain; (2) reduce fever; (3) reduce swelling. Strong analgesics (narcotics) relieve pain by temporarily bonding to the pain receptors in in the brain. They prevent the transmission of pain impulses into the brain. D. 3. 2 Describe the use of derivatives of salicylic acid as mild analgesics and compare the advantages and disadvantages of using aspirin and paracetamol (acetaminophen). Salicylic acid was an analgesic obtained from the bark of willow trees. However, salicylic acid had severe side effects.
Therefore, researchers modified the structure of salicylic acid, creating derivatives. Derivative molecules mean they have different active groups attached to them. Derivatives of salicylic are used as mild analgesics. They control the release of prostaglandins and thus reduce pain. Two examples of derivatives of salicylic acid are aspirin and paracetamol. Both medicines are painkillers and reduce fever (antipyretic). However, only aspirin reduces inflammation. Aspirin Paracetamol Advantages Disadvantages Advantages Disadvantages ? Prevents blood clotting, so prevents heart attacks ? Reduces inflammation
? Irritates stomach walls, so may induce peptic ulcers and stomach bleeding ? Allergic reactions ? Reye’s syndrome in children, a potentially fatal liver and brain disorder ? Safe in the correct dose ? Safe for children ? Blood disorders ? Kidney damage ? Overdose – liver damage, brain damage and death D. 3. 3 Compare the structures of morphine, codeine and diamorphine (heroin, a semi-synthetic opiate). Morphine, codeine and diamorphine (heroin) are powerful strong analgesics, which block the perception of pain in the brain. Morphine Codeine Diamorphine (heroin) Benzene ring Ether Alkene Alcohol (x2) Tertiary amine Benzene ring Ether (x2)
Alkene Alcohol Tertiary amine Benzene ring Ether Alkene Ethanoate (x2) Tertiary amine Morphine and codeine are obtained from the opium (found in the puppy plants). Low concentrations of heroin can be found in opium; however, this drug is usually prepared synthetically. Morphine + ethanoic acid > heroin + water The reaction between morphine and ethanoic acid is a condensation reaction. The acid reacts with alcohol groups in morphine (also referred to as hydroxy or –OH groups). The product of the reaction is water and heroin. D. 3. 4 Discuss the advantages and disadvantages of using morphine and its derivatives as strong analgesics.
Morphine Codeine Diamorphine (heroin) Adv. Dis. Adv. Dis. Adv. Dis. ? Management of severe pain such as advanced cancer ? Treatment of diarrhea ? Major side effect – constipation ? Can lead to dependence ? Second stage pain treatment with paracetamol and aspirin ? Cough treatment ? Fewer side effects than morphine and heroine ? May not completely treat the pain ? Relief of very severe pain ? Euphoric effects ? Strong addiction with rapidly increasing tolerance ? Dependence leads to withdrawal symptoms ? Death ? Productivity cost due to money spend on drugs D4 Depressants D. 4. 1 Describe the effect of depressants.
Depressants are drugs that depress (calm and relax) the central nervous system by interfering with the transmission of nerve impulses in the neurons. Effect by dose: Low doses – increase feeling of calm, drowsiness, increased spontaneity, slower mental activity Moderate doses – soothing, reduction of anxiety, altered perception High doses – slurred speech, faltering movement, altered perception, sleep Extremely high doses – low breathing and heart rates, sleep, coma, death Effect by type: Tranquilizers (alcohol, valium) reduce nervous tension without inducing sleep in moderate doses.
Sedatives (barbiturates) sooth distress without inducing sleep in moderate doses. Hypnotics (chloral hydrate) induce sleep. NOTE: Depressants are often described as anti-depressants because they relieve depression. D. 4. 2 Discuss the social and physiological effects of the use and abuse of ethanol. Short-term: ? Loss of self-restraint ? Impairment of memory and concentration ? Loss of balance ? ‘hangover’ – dehydration and headache due to increased urine output ? Vomiting, loss of consciousness, coma and death ? Violent behavior at home – domestic abuse ? Driving under influence – car accidents Long-term:
? Dependence – alcoholism ? Liver disease – cirrhosis or cancer ? Fetal alcohol syndrome ? Coronary heart disease ? Permanent brain damage ? Deterioration of relationships, and a general decrease in performance in daily activities D. 4. 3 Describe and explain the techniques used for the detection of ethanol in the breath, the blood and urine. Breath analyzer contains acidified potassium dichromate(VI) crystals, which turn from orange to green as they are reduced by ethanol in breath. Works because ethanol passes from stomach to the blood and to the lungs, where blood-air equilibrium is established.
Fuel cell may also contain acidified chromium(VI) crystals. In this device, the ethanol is oxidized using an oxidizing agent, which generates electricity. The potential difference, generated by the redox reaction, is proportional to the alcohol contained in the blood. Infrared absorption intoximeters use infrared spectroscopy to determine the alcohol content. The C-H bond in ethanol absorbs particular infra-red wavelength and the apparatus measures how much at this wavelength is absorbed. Depending on how much light the sample absorbs, the amount of ethanol in breath can be determined.
May not work with diabetics, who breathe out a lot of ketones, which shows a false positive. Gas-Liquid Chromatography (blood and urine) Can only be done in a laboratory. Gives very accurate results. Blood or urine is vaporized and injected into a stream of an inert gas over the surface of a non-volatile liquid. Due to their different solubilities and boiling points the molecules in the blood or urine travel as different speeds along the liquid. The time taken to move along the liquid is called the retention time. D. 4. 4 Describe the synergistic effects of ethanol with other drugs.
Ethanol may increase the effect of a drug: alcohol increases the risk of stomach bleeding with aspirin and boosts the potency of sedatives. Also, ethanol increases toxic effects of paracetamol. Alternatively, ethanol may reduce/negate effects of some drugs. D. 4. 5 Identify other commonly used depressants and describe their structure. Other commonly used depressants include Valium, Mogadon and Prozac. They can be all found in the data booklet. Valium and Mogadon have a similar structure, but Valium contains Cl on its benzene ring, while Mogadon contains NO 2 on its benzene ring. Uses: Valium – treats anxiety and tension.
Mogadon – sleeping pill, contains seizures and infant spasms Prozac – improves mood by making serotonin more available D5 Stimulants D. 5. 1 List the physiological effects of stimulants Stimulants are drugs which increase a person’s state of mental alertness. All stimulants tend to increase concentration, but other psychological effects vary according to the given stimulant. Stimulants decrease appetite. Generally speaking, the physiological effects of stimulants are: 1) Increased blood pressure and heart rate 2) Constriction of arteries 3) Dilation of pupils 4) Sweating 5) Reduced appetite D. 5.
2 Compare amphetamines and epinephrine (adrenaline). Amphetamines mimic the effects of adrenaline (epinephrine), the “flight or fight” hormone. Amphetamine is a sympathomimetic drug: it mimics the stimulation of the sympathetic system, a structure responsible for subconscious reflexes, by adrenaline. Structural similarities: Both adrenaline and amphetamine have (1) a benzine ring and (2) an amine. Strutural differences: In adrenaline the amine is primary, while in amphetamine it is secondary. Also, adrenaline contains three alcohol groups, while amphetamine does not. Both amphetamine and adrenaline speed up the heart rate and blood pressure.
Thus, they work to avoid sleeping (narcolepsy=uncontollable desire to sleep). In the short term, amphetaines increase mental energy, reduce apetite and induce a sense of euphoria. In the long-term, amphetamines can lead to severe addicition and depression. D. 5. 3 Discuss the short and long term effects of nicotine consumption. Nicotine is a sympathomimic drug, contained in tobacco leaves. Short-term effects: 1) Increased heart rate and blood pressure 2) Reduction in urine outpute 3) Increased mental alertness and physical energy 4) Constricts blood vessels which puts stress on the heart Long-term effects:
1) Risk of heart disease and coronary thrombosis due to the strain it puts on the heart 2) Risk of peptic ulcers due to excess production of gastric juices 3) Tolerance and addiction 4) Cost to society and family – smokers spend large amount of money on cigarettes D. 5. 4 Describe the effects f caffeine and compare its structure with that of nicotine. Effects of caffeine include, (a) In small amounts 1) Frequent unrination 2) Increased concentration and alertness 3) Increased breathing rate (b) In large amounts 1) Anxiety 2) Irritability 3) Sleeplessness (insomnia).
4) Addiction and withdrawal symptoms such as nausea Caffeine Nicotine Pentagon ring Hexagon ring Tertiary amine (1) Alkene Secondary amide (2) Pentagon ring Hexagon ring Tertiary amine (1) Alkene D. 6 Antibacterials D. 6. 1 Outline the historical development of penicillin. Discovery of penicillin is usually attributed to the Scot Alexander Fleming. Fleming left an open dish with Staphylococcus aureus, in his laboratory and when he returned from a holiday, a mold grew inside the petri dish. This mold inhibited the growth of bacteria. Fleming publishes his results in 1929, but he did not pursue the discovery.
Penicillin was pursued by Howard Florey and Ernst Chain, who isolated and purified penicillin. They also showed the penicillin was harmless on mice and as the first used the drug on humans. The two men received a Nobel Prize for Chemistry. In the US, companies started mass production of penicillin. First, by growing the fungi in large tanks and then by synthetizing the drug. D. 6. 2 Explain how penicillins work and discuss the effect of modifying the side chain. Penicillin is bactericidal, which means it kills bacteria. 1) Penicillin interferes with the enzymes that bacteria need to form normal cell walls.
2) Attempting cell division, bacteria swell and osmotic pressure puts stress on their cell wall 3) The cell walls burst and bacteria disintegrate All penicillins have common structure, including the beta-lactam ring. The beta-lactam ring is a square arrangement of carbon and nitrogen atoms with other atoms attached. The R- is a functional group attached to the penicillin. Different functional groups provide penicillin different properties. Some bacteria developed resistance against penicillin and produce the enzyme penicillinase, which breaks break down the beta-lactam ring.
Attaching different functional groups can make penicillins more resistant to penicillinase. Also, some penicillins, such as Penicillin G, had to be injected as they got broken down by the stomach acid – nowadays, the functional groups were modified, so that penicillin can be taken orally. D. 6. 3 Discuss and explain the importance of patient compliance and the effects of penicillin over prescription. 1) Due to the use of antibiotics to cure minor ailments, some bacteria became resistant to certain kinds of penicillins. 2) Harmless and helpful bacteria in the digestive system can be wiped out.
3) Bacteria mutate, which results in “superbugs” resistant to antibiotics. This requires costly development of new antibiotics. Patient compliance is important to avoid mutation of bacteria, but also to ensure no allergic reaction will occur (many people are allergic to penicillin). Farmers often add antibiotics into feedstock to prevent illnesses and to bolster the growth of animals. This may result in a mutation of harmless bacteria. Humans consume the meat, taking in the antibiotics as well as the resistant bacteria in. D. 7 Antivirals D. 7. 1 State how viruses differ from bacteria.
Relevant points: 1) viruses are 20x smaller than bacteria; 2) unlike bacteria viruses are not cellular – bacteria have cell wall and nucleus 3) viruses do not have cytoplasm, while bacteria do 4) viruses do not feed, excrete and grow, while bacteria does 5) viruses use cell material of the invaded cell to reproduce themselves, while bacteria use cell division Viruses inject their RNA or DNA into their host cell’s cytoplasm and use the cell to replicate. The new cell either releases the virus or releases other infected cell. This change in cell structure cause symptoms of viral infection. D. 7.
2 Describe the different ways in which antiviral drugs work. 1) Prevent viruses from leaving the host cell. 2) Block the reverse transcriptase enzyme activity to avoid a conversion of the virus into a form that can enter the host cell. 3) Alter the host cell’s genetic material, so that viruses cannot use it to multiply. 4) Block the enzyme activity within the host cell, so viruses cannot multiply. D. 7. 3 Discuss the difficulties associated with solving the AIDS problem The antiviral agents are very expensive, which makes treatment of HIV difficult in developing countries. People cannot afford the drugs.
There are sociocultural issues fostering the spread of HIV, too: Sociocultural issue Why is this a valid issue? Condom use Cultural resistance and high cost Cultural factors Misinformation, ignorance and wishful thinking Illegal activities Drug use and prostitution D. 8 Drug action D. 8. 1 Describe the importance of geometrical isomerism in drug action. Stereoisomers are compounds with the same molecular and structural formula, but a different arrangement of atoms in space. Geometric isomers are a type of stereoisomers. In general, geometric isomers occur in species with a bond with restricted rotation.
However, in some geometric isomers, when there are different atoms bonded to the same molecule, like in cisplatin, the phenomenon may occur. The trans- and the cis- form of a drug can exhibit different properties. One geometric isomer may have the desired pharmacological effect, while the other may be less effective or have adverse side effects. Example: Cisplatin is a drug used to treat testicular and ovarian cancer. The medicine exhibits geometric isomerism. However, only the cis- form of the drug is effective—the trans- form has no effects whatsoever.
Only cisplatin can react with two guanine molecules in the DNA. Remember that cisplatin is square planar! Cisplatin Transplatin D. 8. 2 Discuss the importance of chirality in drug action. Optical isomers are stereoisomers chiral, or asymmetric, around one of the atoms. Body is a very precise machine, so the chemicals inside often exist as one of the enantiomers. Only one enantiomer of drugs exhibiting optical isomerism sometimes has the desired pharmacologic effect. The other enantiomer may have weaker effect or severe adverse side effects.
The pharmaceutical companies are likely to manufacture only the desired enantiomer because producing the ineffective enantiomer is financially inefficient, or to avoid the adverse effects of the harmful enantiomer. The atom around which a molecule is chiral has four different atoms attached to it! Do not confuse optical isomerism with geo-isomerism! Example: Thalidomide – one enantiomer alleviates symptoms of the pregnancy morning sickness, the other enantiomer causes deformities in the limbs of fetus Ibuprofen – one enantiomer is effective, while the other is not Naproxen – one enantiomer is a pain reliever, the other one is a liver toxin.
Other examples include amphetamine and taxol. We use asterisk (*) to denote the chiral atom. D. 8. 3 Explain the importance of the beta-lactam ring action of penicillin. The beta-lactam ring has an unusual square structure, where each bond is 90?. Due to its irregularity, the beta lactam ring is very reactive. The ring opens and covalently bonds to the enzyme transpeptidase, responsible for the forming of bacterial cell walls. If bacterium is unable to build its cell wall, it bursts, disintegrates and dies. D. 8. 4 Explain the increased potency of diamorphine (heroin) compared to morphine.
Diamorphine (heroin) and morphine have the same functional groups, except for two. While morphine contains two alcohol groups, diamorphine is synthetically modified, so that the two alcohol groups are replaced by esters. Due to the difference in functional groups, diamorphine is much less polar than morphine. As a result of this, heroin can pass the blood-brain barrier much quicker in a much larger concentration. The lower polarity of heroin facilitates the drug’s transportation in the non-polar environment of the central nervous system (CNS)—remember, likes dissolve likes!
Because heroin requires a secondary reaction in brain, which hydrolyzes the ester links, another derivative of morphine, 6-monoacetylmorphine, is even more effective than heroin. 6-monoacetylmorphine has one alcohol and one ester group. D9 Drug Design D. 9. 1 Discuss the use of a compound library in drug design. Compound library is a collection of a very large number of related compounds produced by combinatorial synthesis techniques. Each chemical in the library has associated information about its biological activity, such as the effect on enzymes and ability to bind to certain receptor sites.
Researchers can use this information to find a compound, which fits well the properties of the researched disease (e. g. polarity, stereoisomerism). The process of creating compound libraries is lengthy and expensive, so firms must pay royalties to access the libraries. As opposed to synthesizing and individually evaluating different compounds for biological properties, this approach allows money and time to be saved. D. 9. 2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs. Combinatorial chemistry uses a large number of starting reactants to create a variety of different compounds.
These compounds are then tested for biological activity, such as the effect on enzymes and the ability to bond to receptor sites. This information is then stored in combinatorial libraries. Combinatorial chemistry is very repetitive and lengthy, so it uses a lot of computer mechanics. Combinatorial synthesis utilizes solid phase chemistry. Solid phase chemistry is the following process: 1) Very small resin beads are made—these provide a surface for the attachment and reaction of other molecules. 2) Different molecules are attached to the solid beads.
This is called the “mix and split” method. 3) The products are cleaved from the beads by filtration and washing the beads. Solid phase chemistry can be fully automated and use robotics, which saves time and money. Combinatorial chemistry also uses the mix and split method. The advantages of the combinatorial chemistry are: 1) Mass testing and screening for biological activity 2) High efficiency Parallel synthesis carries out the chemistry to create a single product. Parallel chemistry can produce much smaller and more focused libraries.
D. 9. 3 Describe how computers are used in drug design. Three-dimensional molecules can be created in silico, by computer software. An active ingredient can be made so that the chemical structure of the drug matches the shape of the compound, which the drug is supposed to affect. For example, an alteration in this compound may stop the spread of disease—this is the case of the beta-lactam ring in penicillin. Computer models can also assess the biological and other effects of compounds without the need to synthesize the chemicals in reality. D. 9.
4 Discuss how the polarity of a molecule can be modified to increase its aqueous solubility and how this facilitates its distribution around the body. The polarity of molecules can be increased to make them more water soluble. Because ions are the most water soluble, manufacturers try to make drugs ionic. Many drugs that contain amine group are reacted with hydrochloric acid and are administered as hydrochloride salt. Many drugs that contain carboxylic acid group are reacted with a base (e. g. NaOH) and are administered as their sodium or calcium salt.
Soluble aspirin – makes anion with NaOH; loses H+, so Na+ is attracted to the negative site where H+ was lost Prozac (fluoxetine hydrochloride) – makes cation with HCl; H+ from HCl bonds to nitrogen in Prozac Most drugs are distributed around the body through blood—they dissolve in the blood plasma. Blood plasma is mostly water, a polar solvent. Making a molecule more polar, i. e. transforming it into its ionic form makes the chemical more soluble. This facilitates the distribution of the drug around the human body, i. e. increases the drug’s bioavailability. D. 9.
5 Describe the use of chiral auxiliaries to form the desired enantiomer. A chiral auxiliary is a compound, much like a catalyst, which is used to convert non-chiral molecule into just the desired enantiomer. This is important because sometimes only one enantiomer has the desired pharmacological effect. The working of chiral auxiliaries is described below: 1) Chiral auxiliary attaches to a non-chiral reactant. 2) This creates the stereochemical conditions necessary to force the reaction to follow a certain path. 3) In this path, only one enantiomer is formed. 4) Chiral auxiliary is taken off the product and recycled.
5) The enantiomer is ready and chiral auxiliary can be used again. Chiral auxiliaries are used to synthesize Taxol (paclitaxel), an anti-cancer drug, which is normally found in the bark of a Pacific yew tree. Without chiral auxiliaries, enormous quantities of trees would have to be cut down to meet the demand for Taxol. D. 10. 1 Describe the effects of lysergic acid diethylamide (LSD), mescaline, psilocybin and tetrahydrocannabinol. Drug Effects Lysergic acid diethylamide ? Flashbacks ? Changes in visual and sound perception – hallucinations; good or bad trips ?
Desire to laugh ? Hypertension, dilated pupils, change in body temperature & hearth rate ? Psychological dependence Mescaline ? Subjective hallucinations ? Anxiety, static tremors, psychic disturbances ? Abdominal pain – muscle ache Psilocybin ? Subjective hallucinations milder than with mescaline ? Change in mood – pleasant or apprehensive ? Inappropriate laughter, dizziness ? Muscle weakness is common Tetrahydrocannabinol ? Appetite stimulation ? Lethargy, sluggishness ? Anxiety and irritability ? Psychological dependence.
D. 10. 1 Discuss the structural similarities and differences between LSD, mescaline and psilocybin. Should compare all three to the indole ring. Drug Functional Groups Lysergic acid diethylamide ? Benzene ring ? Alkene (2) ? Secondary amine ? Tertiary amine ? Tertiary amide Mescaline ? Benzene ring ? Primary amine ? Ether (3) Psilocybin ? Benzene ring ? Secondary amine ?
Tertiary amine ion ? Phosphate All three drugs contain benzene ring, LSD and psolocybin also contain cyclopentene ring (?) with secondary amine, so they have the indole part. Mescaline misses the secondary amine.
D. 10. 3 Discuss the arguments for and against the legalization of cannabis. Arguments for: Arguments against: ? Relieves symptoms of Parkinson’s disease ? Stepping stone drug – can lead to the use of harder drugs ? Source of additional tax revenue ? Increased risk of lung cancer ? No more or less harming than tobacco or alcohol. ? Risk of driving or manipulation with machinery under influence, which increases the chance of an injury.