HL CHEM D: Medicine and Drugs
BY HEIMAN KWOK 12N03S13.7.14
D.1 PHARMACEUTICAL PRODUCTS
Background Information
• The best way to fight disease is by maximizing the effectiveness of the body’s natural defence system, by supplementing our natural healing process
• Prevent Entry > Attack Invaders > Immune System
Effect of Medicine and Drugs on the functioning of the body
• Alter incoming sensory sensations • Alters mood or emotions • Alters physiological states, including
consciousness, activity level or coordination
• The Placebo Effect - used as a control substance; shows the power of suggestion, or the body’s natural healing
NOTE THAT Medicine and Drugs…
• May or may not be from doctors or pharmacies
• May or may not have beneficial medical properties
• From Plants or Fungi in labs or from GMO• Helpful/ Harmful • Legal/ illegal
RECOGNISE Categories of Medicine
• Infection Fighters: Antiseptics, Antibiotics, Antivirals
• Affecting metabolism: hormones and vitamins • Affecting CNS: stimulants, depressants,
analgesics (painkiller), anaesthetics (remove sense of felling)
Methods of Administration
• Oral: taken by mouth – tablets, capsules, pills, liquids, enteric = coating, so its of slow release
• Inhalation: vapour breathed in; rapid, anaesthesia smoking – asthma, nicotine and cocaine
• Parenteral/ Injection 1. intramuscular (to the muscle) – vaccines; 2. intravenous (bloodstream) – local anaesthetics; 3. subcutaneous (underneath the skin) – dental injections
Methods of Administration
• Topical: skin patches and ointments absorbed directly from the skin into the bloodstream – hormone treatments such as nicotine patches and oestrogen
• Rectal: inserted into the rectum – can be destroyed by acids treatment of digestive illnesses, haemorrhoids
• Eye or Ear Drops: liquids delivered directly to the opening – treatment of infections in the eye or ear
Lethal Dose
• Lethal Dose = dose of a substance in mg per kg of body mass that kills 50% of the sample
• The smaller the LD 50, the more toxic the substance
Effective Dose
• Effective Dose = dose of a substance in mg per Kg of body mass that work 50% of the sample
• The smaller the ED 50, the more effective the substance
Therapeutic Window
• ^ = ratio of the lethal dose to the Effective dose
• Therapeutic Effect – the intended physiological effect
• Range of a drug’s concentration in the blood between its therapeutic level and its toxic level so the dosage is safe
• The wider the window, the safer the substance
Stages in Research, Development and testing of new Pharmaceutical Products
1. Research 2. Development – purification, working out how
it works3. Testing – on animals: work out the (effective
dose on 50%), also show side effects 4. Clinical Trials 3 phases - double blinded
randomized placebo test on human patients
CASE STUDY: Thalidomide
• Sleeping aid to combat morning sickness • One isomer of the racemic mixture was
harmful • Caused deformations in the babies of
pregnant women • Caused by not testing on pregnant mice or
having clinical trials on humans
Drug Effect
• Main Effect: desired • Side Effect: unintended physiological effects
• Eg. Morphine for pain relief, however constipation is side effect; or for diarrhea but pain relief as a side effect
• Depends on the purpose sought after
Tolerance
• Over time and regular use, the user needs increasing dosage of a drug to receive the same physiological effect
• The user’s dose gets closer to • For some drugs, tolerance develops to one effect of the
drug and not to other effects (side)• If the drug is not taken for a long time > decrease in
tolerance > overdose • Dependence or Addiction: user becomes dependent on
the drug to feel normal and suffers from withdrawal symptoms if the drugs is not taken; eg. Heroin, alcohol
D.2 ANTACIDS
Excess secretion = Gastric Juice
• Gastric glands in the lining of the stomach produce HCl which keep the pH of the stomach at 1-2
• Acid environment kills bacteria and provides optimum environment for digestive enzymes
• ^ can cause acid indigestion, heart burn/ acid reflux to the esophagus and stomach ulcers
Pepsinogen and Pepsin
• Pepsinogen forms pepsin in an acidic environment
• Pepsin breaks down proteins into amino acids
Antacids
• Weak bases (not SB as they will burn the gullet)• A remedy, drug that helps combat excess acid
by neutralising HCl and toning down the pH
• Aluminium Hydroxide ()• Magnesium Hydroxide ()• Sodium Hydrogencarbonate ()• Calcium Carbonate ()
Antacid Equations
CaCO3 + 2 HCl CaCl2 + H2O + CO2
NaHCO3 + HCl NaCl + H2O + CO2
Al(OH)3 + 3 HCl AlCl3 + 3 H2O
Mg(OH)2 + 2 HCl MgCl2 + 2 H2O
MgO + 2 HCl MgCl2 + H2O
Alginates and anti-foaming agents
• Some contain alginates which produce a neutralising layer 1) produces a neutralising layer on top of acid 2) prevents acid from rising reflux into the esophagus
• Others contain anti-foaming agents (dimethicone/ simethicone) which prevents formation of gases and reduces bloating and flatulence as a result of Carbon Dioxide production
Antacids Side Effects
• Mg compounds cause constipation• Al: laxative or causes diarrhoea • Carbonates: produce Carbon Dioxide causing
bloating and flatulence • Because antacids change the pH of the
stomach, they can alter other chemical reactions including the absorption of other drugs. They should never be taken for an extended period without medical supervision.
D.3 ANALGESICS - PAINKILLERS
How is pain perceived?
• Where you are injured; prostaglandins are produced
Ways Analgesics Prevent Pain
• Mild Analgesics eg. Ibuprofen, Paracetamol are considered non-addictive: intercept the transmission of pain at the source; indirectly blocks the enzyme-controlled synthesis of prostaglandins
• Strong Analgesics (opioids/ narcotics) eg. morphine may have dependence: temporarily binds to opioid receptors sites in the brain and CNS – hence you don’t sense the pain but its still there
• Relative value of these two approaches to pain management
Derivatives of Salicylic Acid (eg. Aspirin) in Use
• Mild analgesic for minor aches and pains to relieve headaches, sunburn pain and pain of arthritis
• Anti-pyretic to reduce fever• Anti-inflammatory agent to prevent swelling
from injuries • Anti-platelet to prevent clotting by inhibiting
the production of prostaglandins, prevents heart disease
Aspirin and Paracetamol (non-steroidal analgesics and anti-inflammatory)
• Aspirin • Benzene Ring • Ester • Carboxylic Acid
• Paracetamol • Benzene Ring • Hydroxol • Amide • Carbonyl
Aspirin vs ParacetamolAspirin Paracetamol
Analgesic – painkiller? Yes Yes
Antipyretic – reduces fever Yes Yes
Anti-inflammatory Yes No
Anti-Platelet Yes (No)
Side Effects Stomach wall irritant, blood anti-coagulant, internal bleeding, ulceration
No upset stomach or internal bleeding
Severe Side Effects (over dosage)
Gastrointestinal Bleeding following use of alcohol
Serious kidney, liver and brain damage
Allergies 0.5% get skin rashes, respiratory difficulty, shock
Rare
Child-Use Friendly No; causes Reye’s Syndrome – fatal liver and brain disorder
Yes
Codeine, Morphine and Diamorphine (Heroin)
• P.631 of Brown and Ford
• Potent-ness: Codeine > Morphine > Heroin
Use of Morphine and its derivatives (Opiates)
Advantages Disadvantages Relief of Severe Pain eg. From injury, chronic disease (cancer), surgery Treatment of diarrhoea by its constipating effect Relieve coughing by supressing the brain stem
Relief from emotional and psychological pain
Analgesia, drowsiness, mood changes, mental clouding, anxiety, fear, sedation, nausea, vomiting Tolerance – due to adaption of neurons and Cross Tolerance (tolerance to similar opiates)
P.141 Figure 1509 Green and Damji Physical Dependence – withdrawal symptoms
D.4 DEPRESSANTS
Effect of Depressants
• Figure 15.9 P.633
• Supresses the brain and CNS • Changes the communication between brain cells by
altering the concentration or activity of the chemicals called neurotransmitters
• Cause a DECREASE in brain activity which in turn influences the functioning of the other parts of the body such as the heart and breathing rate
• (NOTE: analgesics are also depressants)
Effect of Use of alcoholSocial Physiological
Sense of occasion Antiseptic
Creates mild excitement Hardens the skin
Allows users to become more talkative, confident and relaxed
Craving or compulsion to drink
Lost in productivity Physical addition – withdrawal symptoms such as nausea, sweating, anxiety, increased blood pressure
Increased crime, accidents rates Tolerance – needing increasing amounts for the same effect
Effect of Abuse of alcoholShort Term Long Term
Loss of self-restraint, memory, concentration and insight are impaired
Dependence – Alcoholism w/ withdrawal symptoms
Loss of balance and judgement Liver disease eg. Cirrhosis, liver cancer
Violent behaviour associated with domestic abuse and family breakdown
Coronary heart disease
Dangerous risk-taking behaviour leading to accidents
High blood pressure
Dehydration caused by increased urine output – leading to hangover and lost of productivity
Fetal alcohol syndrome
At high doses - vomiting, loss of consciousness, coma and death
Permanent brain damage
Detection of ethanol in Breath
Breathalyser • The alcohol in the blood is realised into the air
with the exhaled breath • The alcohol vapour is oxidised by Potassium
Dichromate +6 to +3 which then changes from orange to green
• The extent of colour change is then measured using a photocell and converted into a percentage BAC mass in grams of ethanol per 100 ml of blood
Detection of ethanol in Breath 2
Infrared Spectroscopy with an intoximeter (more accurate)• Causes vibrational motions depending on the mass
of the atoms and the length/ strength of the bonds within the molecule
• Compares the intensity of IR radiation through the sample with the intensity through air
• Does not distinguish between ethanol an propanone which is often present in the breadth o a diabetic patient
Detection of ethanol in Blood and Urine
• Gas-liquid Chromatography • Blood or Urine is vapourised and injected into a stream of
an inert gas (mobile phase) over the surface of a non-volatile liquid (stationary phase)
• Components of the vapour including ethanol gas move at different rates depending on their boiling pints and relative solubility in the two phases
• Leaving the column holding the liquid phase after a specific interval of time known as retention time
• Area under the peak is compared the a known standard in the mixture such as propan-1-ol
Synergistic effects of ethanol with other drugs
• With Aspirin – causes increased bleeding of the stomach lining and increased risk of ulcers
• With other depressants such as barbiturates such as sleeping pills – can induce heavy sedation, possibly leading to coma
• With Tobacco – increases the incidence of cancers esp. liver and intestines
• With other drugs – interfere with the metabolism by the liver which may cause greater and prolonged effects of the drug
Commonly used depressants and structures
D.5 STIMULANTS
What are Stimulants?
• Acts on the brain and CNS • Changes the communication between brain
cells by altering the concentration or activity of the chemicals called neurotransmitters
• Cause an INCREASE in brain activity which in turn makes the body more alert
• Prevent excessive drowsiness through the day and so allow greater concentration and though processes to be possible
What are Stimulants?
• Results include increased heart rate, blood pressure, wakefulness, restlessness, agitation and insomnia
• Results are temporary and then followed by fatigue, insomnia and depression
• Sympathomimetic Drug = simulates sympathetic nervous system/ mimics adrenaline
Physiological Effects of Stimulants
• Facilitate breathing by causing relaxation of the air passages – treatment of respiratory infections such as sever bronchitis
• Reduce appetite – treatment for obesity • Cause palpitations or tremors to occur • In excess – cause extreme restlessness,
sleeplessness, fits, delusions and hallucinations
Adrenaline (Epinephrine)
• Released at times of stress ‘flight or fight response’
• Increases heart rate and blood pressure • Increase blood flow to the brain and muscles • Increase air flow to the lungs • Increase mental awareness
• Noradrenaline or norepinephrine are similar
Amphetamine
• Stimulates and enhances the effects of Noradrenaline and Adrenaline
• Increases mental alertness and physical energy • Side Effects: dilation of the pupils of the eyes, decreased
appetite, possible blurred vision and dizziness • Highly addictive and toxic – rapid development of
tolerance and dependence leads to deterioration of body systems
• Serious long term effects: severe depression and reduced resistance to infection
Nicotine ConsumptionShort Term Effect Long Term Effects
Increases concentration – not in ms High blood pressure
Relieves Tension and Boredom Increases stress on the heart: Increases risk of heart disease including angina
Helps counter fatigue Coronary thrombosis
A vasoconstrictor; Increases heart rate and blood pressure
Increases level of fatty acids in the blood – lead to atherosclerosis and stroke
Decreases urine output Over-stimulation of stomach acids which can lead to increased risk of peptic ulcers
Lipid Stable Molecule Able to cross the blood-brain barrier – brings about rapid effects on brain activityIncrease levels of adrenalineIncreased consumption over timeMild but highly addictive stimulant found in tobaccoInitial stimulant response is usually followed by mild depression which encourages frequent use.
The biological consequences of smoking
LUNGS• Destroyed Cilia • Cough• Mucus collected in lungs • Infected mucus• Infections – Bronchitis• Lung Cancer (caused by carcinogens in tar),
Emphysema (reduces surface area of alveoli, inefficient gases exchange)
The biological consequences of smoking
CIRCULATORY SYSTEM • High blood pressure (caused by nicotine) – • Increased risk for heart attacks• Increased risk for stokes• Blood becomes sticky (increased clotting)• Red blood cells can’t carry oxygen due to carbon
monoxide boning with them hemoglobin• Coronary heart disease
Effect of Caffeine
Short Term Effect Long Term Effects
Enhancement of metal energy, alertness and ability to concentrate
Can cause anxiety, irritability and
Acts as a diuretic, increasing volume of urine can cause dehydration
Dependence: side effects or withdrawal include headaches and nauseaRestlessness
Trembling/ shaking
Increased Heart Rate
Sleeplessness, insomnia
D.6 ANTIBACTERIALS
Historical Development of Penicillins
• https://www.youtube.com/watch?v=7qeZLLhx5kU• Accidently discovered by Alexander Fleming as there was
a clear region around where no bacterial colonies were growing around the mould
• Isolated by Howard Florey and Ernst Chain which incidentally saved many lives in WW2 as treatment from bacterial infections – found industrial methods to create; did more drug testing (prove it was safe to use of humans)
• Structure determined by Dorothy Hodgkin as Penicillin G• Produced by microorganisms to combat microorganisms
How Penicillins work
• Figure 1519 P.423
• Deactivating the proteins that a bacteria needs to form a cell wall (transpeptidase)– prevents formation of cell wall
• Increase uptake of water by bacteria • Bacteria ruptures due to osmotic pressure
Effect of changing the Side Chain
• Changing the side chain will slightly change the ranger of bacteria it is effective against and how it is tolerated by the patients
• Semi-synthetic penicillin eg. Ampicillin• Reducing occurrence of penicillin resistant
bacteria as the modified penicillins are able to withstand the action of an enzyme
How the structure of penicillin is modified to create new antibiotics
• Keeping the B-lactum the same and changing the side chains by adding organic substances and reactants
Board-spectrum vs Narrow-spectrum
• Board-spectrum Eg. Chest infections, skin infections
• Narrow-spectrum eg. Bladder infections
• TB requires a cocktail of different antibacterial – as many bacteria are extremely resistant to penicillin so a mixture is used
• Over prescribing is an issue
Importance of patient compliance and effect of penicillin over prescription
• Problem with the use of penicillin is bacterial resistance
• Resistance bacteria produce an enzyme, penicillinase which can open penicillin’s beta-lactam ring and render it inactive
• Eg. TB requires several drugs to combat to prevent the rise of a super bug TB
Bacteria Mutation and Antibiotic Resistance
• Bacteria can create a resistance to antibiotics • If antibiotics do not kill all the bacteria (ie.
Leave one mutated bacteria living)• One, strong bacteria can rapidly reproduce
asexually, increasing bacterial populations • All bacteria are now resistance to antibiotics • Hence, the infection is difficult to control
Beneficial Mutation
Increased resistance because of misuse
• Over-prescription by doctors
• Patient compliance: patients not completing a full course of penicillin or antibiotics
• Antibacterials used in animal feedstock even when the animals do not have a disease – antibacterials end up in the food chain
D.7 ANTIVIRALS
Bacteria vs Virus Bacteria Virus
Cell Wall Protein Coat
Single stand of DNA (check!); more complex DNA
One type of nucleic acid (DNA or RNA) simpler DNA
Nucleus No nucleus or cytoplasm
Self-repreducing Reproduce and replicate (multiply) only in living organisms
MRS GREN H Do not feed, excrete or grow
Bacteria
• Microscopic unicellular organisms• NO have a nucleus but has a circular
chromosome of DNA (plasmids)• Have a cell wall, cell membrane, cytoplasm • Some Bacteria carry out photosynthesis but
most feed off living or dead organisms• Examples: Lactobacillus (rod-shaped: produces
yoghurt from milk), Pneumococcus (spherical pathogen – causes pneumonia)
Viruses FIGURE 15.12 P.646
• Microscopic unicellular organisms (smaller than bacteria)
• Parasitic – lives off other organisms and can infect every type of them
• Wide variety of shapes and size, have no cellular structure but has a protein coat: contains only one type of nucleic acid, DNA or RNA
• Can reproduce only inside living cells • A pathogenic example is HIV which causes AIDS and
immune system disorder
Reasons why it is hard to tackle viruses
• High Speed in reproduction and multiply • Rapid Mutation – less susceptible to drugs• Fast Spreading to all parts of the body before symptoms
arise • Bacteria are more complex and can be killed or their
actions reduced by simple chemical agents but viruses cannot be killed (only stopped by reproducing) and must be targeted on a genetic level
• Hence flu vaccines are developed each year according to the most abundant strain of virus around
How viruses replicate itself
• Using house cell’s metabolism
Ways in which antibiotics work
• Beta-lactum ring bonds with transpeptidase to prevent bacteria from making normal cell walls
• Interferes with the chemical activities essential to bacteria’s life function
General information about antivirals
• Manufactured to be virus specific – not broad• Not that many antivirals available • Don’t destroy the virus but INHIBITS its
development • Harmless to host
Ways in which antiviral drugs work
• Finding chemical ways to block enzyme activity within the host cell, stopping the virus and preventing replication in host cells – hence ‘dying out’; Changes the cell membrane which prevents virus from entering cell
• Altering the cell’s ribosomes (genetic material) so the virus cannot use them to multiply
• Traps the virus inside the cell after its reproduction
Difficulties associated with solving the AIDS problem
1. The Virus destroys T-helper cells (certain type of cell membrane of the white blood cells), the very cells in the immune system that should be defending the body against the virus
2. The virus tends to mutate very rapidly even within a patient. It is thought that there is more variation in HIV in a single patient than in influenza virus worldwide in a year. These variation means that the virus ‘escapes’ the immune response because the patient has to make a response to the new virus
Difficulties associated with solving the AIDS problem
3. The virus often lies dormant within host cells so the immune system has nothing to respond to 4. HIV has a similar metabolism to that of the human cell making effective treatment with antiviral drugs and vaccine development difficult 5. Control and treatment of HIV is controlled by the high price of antiretroviral agents (very $$$)6. ^ socio-economic reasons by high risk Countries 7. Cultural issues such as discrimination and stigma
D.8 DRUG ACTION
Importance of Geometrical Isomerism CISPlatin
• In chemotherapeutic drugs, sometimes only one of cis and trans of a drug can ‘work’ by correctly disrupting the function of DNA in the cancer cells preventing cell division
• Transplatin has NH3 too far apart to work• Eg. Platinum complex such as cisplatin and its
derivative carboplatin only the cis isomer has the groups in the correct orientation to bind to the two adjacent guanine
Importance of Chirality, optical isomerism
• Two enantiomers act differently in the presence of a chiral environment (turn differently in plane polarised light)
• When biologically synthesised within cells (in vivo), only one enantiomer is produced
• When produced by synthetic processes outside the body (in vitro), they yield a mixture of enantiomers, racemate
• Then we must analyse the physiological effects of each isomer to determine whether it should be marketed as a racemate or single enantiomer
Importance of Chirality: Thalidomide
• Thalidomide which was prescribed and marketed for morning sickness in women was available as a racemate
• However, one enantiomer caused serious deformities in the fetus and only the other had the intended therapeutic effect of inducing sleep and calmness
Importance of Beta-lactam ring action of Penicillin
• The beta-lactam ring is strained at 90 degrees bonds and is hence very reactive, it binds and deactivates the transpeptidase enzyme which is key for the construction of the cell wall of the bacterium.
• This leads to a halting of bacterial cell wall construction leading to death as the bacteria takes up too much water and due to osomic pressure, bursts
Increased potency of Diamorphine (Heroin) compared to morphine
• Two polar hydroxyl groups are replaced by two less polar ester groups
• Ester groups make heroin molecule more fat-soluble = hence more rapidly absorbed into the CNS and the brain (crosses the blood-brain barrier easier)
• Increasing potency and addictiveness
D.9 DRUG DESIGN
Compound Library
• Electronic database – theoretical drug synthesis• Contains molecules which have been isolated or
synthesized and tested by pharmaceutical companies for possible pharmaceutical properties
• Information on compounds – name, structure, 3D image, properties, biological activity
• Pharm companies use such libraries to identify ‘lead’ compound for a particular ‘target’ molecules such as an enzyme, DNA or a receptor
Combinatorial Chemistry
• Involves simultaneous automated chemical synthesis • A large number of different but structurally related
compounds (all possible compounds) from a small number of reactant molecules which are reacted with a variety of reactants
• Uses “mix and split” technique and resin beads (provides surface for the attachment and subsequent reaction of successive reactant molecules – when synthesis reaction is complete – produce is cleaved from bead and released in sol.)
• Screen each product for its biological activity resulting in a “combinatorial library”
Combinatorial Chemistry• synthesis of large numbers of compounds using a variety of
starting materials;automated process reacts a small number of compounds with avariety of reagents;(to produce) a large number of products;mix-and-split technique;small amounts of compounds are attached to resin/beads;library of many different but related compounds;compounds are tested for biological activity/effectiveness aspossible drugs;parallel synthesis can produce smaller, more focused libraries; 3 max
• (ii) purification of the product is relatively easy / product can beisolated by washing and filtration;
Parallel Chemistry/ Synthesis
• Synthesis of smaller but selected group of compounds with a different compound in each reaction vessels
• No need to be mixed and separated as multiple experiments run in parallel
• Usually liquid or gas reactions
Difference
• Combinatorial: massive library generated in the end of the many combinations of molecules; produces a mixture of compounds in same vessel
• Parallel: much smaller group of compounds produced; produces a single product in each reaction vessel
Solid-Phase Chemistry
• Used in combinatorial and parallel synthesis• Solid resin bead – then product cleaved off
• Advantages: easy to rinse off as it is attached to a solid bead
Mix and Split
• Different reactants are mixed and then split into separate portions ie each portion has all reactants
• Each portion with go on to do a different reactant
• Separate portion are then mixed
Use of Computers
• Using combinatorial libraries • 3D modelling software can be used to show
interaction between medicine and active site on target molecules/ receptor without actually making the medicine
• This allows the design of molecules with the perfect fit and then attempt to chemically produce them
Use of Computers
• Evaluation of biological and pharmaceutical effects of new drugs, if the structure of a new molecules is known
• Test effectiveness of binding • Find the polarity of the molecule • How quickly the body absorbs the drug
Modified Polarity to increase its aqueous solubility
• Which facilitates its distribution around the body
• Non-polar molecules with either acidic (carboxylic acid) or basic (amine) groups the polarity can be changed by converting them into ionic salts
Chiral auxiliaries to form the desired enantiomer
• Produce and synthesis ONLY the desired enantiomer – NOT producing racemic mixture then separating
• Chiral auxiliary gets attached to the starting product – as it is chiral itself it only allows one optical isomer to be synthesised – as it is asymmetrical
• The chiral auxiliary is removed and recycled
MIND ALTERING DRUGS – SEE SECTION D PDF
LSD, mescaline, psilocybin, THC
• Mind Altering drugs/ hallaucingogens produce a qualitative change in thought, perception or mood
• Cause vivid illusions and fantasies • THC: at low doses get exited, at high doses it
produces change in perception, visual hallucinations, no tolerance develops but leads to moderate psychological dependence
