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Medicines and Drugs
Option D
D.1 PHARMACEUTICAL PRODUCTS
Background In the Body Defenses
Non-specific Defense Mechanisms
Specific Defense
Mechanisms
First Line: barriers to
prevent entry
Second Line: attack
pathogens
Third Line: immune
system
• Skin
• Mucous membranes
• Closures and
secretions of natural
openings
• Phagocytosis
(engulfing invaders)
• Blood clotting
• Inflammatory
response
• Antibody production
and secretion
• Memory cells
• Drug: chemical that affects how the body
works (good/bad)
• Medicine: substance that improves health
– Natural
– Synthetic: other ingredients help with
presentation and administration
– Therapeutic effect
• Effects of Drugs
– Alteration of physiological state
• Consciousness, activity level and coordination
– Alteration of incoming sensory sensations
– Alteration of mood or emotions
Types of Drugs
• Analgesics, stimulants, depressants
– Target: nervous system/brain
• Antacids
– Target: metabolic processes
• Antibacterial/Antivirals
– Supplement body’s ability to fight pathogens
Placebo Effect
• Power of suggestion
• A pharmacologically inert substance (often a sugar
pill) produces a significant reaction because the
patient expects, desires, or was told it would
happen
• Used as a control in clinical trials
• Highlights the body’s natural healing powers
Drug Administration
Method of Administration
Description
Example
Oral
Taken by mouth
Tablets, capsules, pills,
liquids
Inhalation
Vapor breathed in;
smoking
Respiratory conditions
(asthma); abuse
(nicotine/cocaine)
Skin Patches
Absorbed skin  directly
to blood
Hormone treatments
(estrogen, nicotine)
Suppositories
Inserted into rectum
Digestive illnesses,
hemorrhoids
Eye/ear drops
Liquids delivered to
openings
Treatment for infections
Method of Administration
Description
Example
Parenteral (injection)
Intramuscular
Vaccines
Intravenous
Local anesthetics
Subcutaneous
Dental injections
• Therapeutic effect: intended physiological
effect
• Side-effects: unintended physiological effects
– Beneficial: aspirin (heart disease)
– Benign: drowsiness, nausea, constipation
– Adverse: damage to organs, birth defects
– Must be evaluated through course of treatment
• Therapeutic window: range of a drug’s
concentration in the between its therapeutic
and toxic level
– Dosing regime determined
• Amount of drug per dose and frequency of doses
• Tolerance: reduced response to drug
– Need higher doses, risk toxic effects
• Dependence/Addiction
– Dependent of drug to feel normal
– Suffers withdrawal symptoms
Volunteers
• Identification of lead
Blind
compounds
studies
• Synthesis of analogues
Eliminate
• Biological testing
investigator bias
Collection of
adverse drug
reaction data
• Lead compounds: identifying and extracting
compounds  show biological activity
– Plants/bacteria
• Analogues: chemically related compounds
– Combinatorial chemistry
– High-throughput screening
• Thalidomide
– Early 1960’s
– Given to pregnant women to treat morning
sickness
– Later found to cause major birth defects
• One isomer controls morning sickness, the other leads to
birth defects (optical isomers)
D.2 ANTACIDS
Stomach Acid
• Stomach Acid = pH 1 – 2
– Production of HCl by gastric glands
– Kills microorganisms
– Optimum environment for digestive enzymes
• Excess gastric juice:
– Acid Indigestion: discomfort in stomach
– Heartburn: stomach acid rising into esophagus
– Ulcer: lose of stomach tissue/inflammation
Antacids
• Antacids  weak bases to neutralize stomach
acid
– Metal oxides/hydroxides, carbonates, hydrogen
carbonates
– React to produce salt + water
• Do not directly coat ulcers  allow stomach
lining time to heal
• Alignates  barrier preventing reflux
Types
• Magnesium: fast acting, laxative
• Aluminum: long release time, constipation,
linked to Alzheimer’s (not proven)
• Sodium/Calcium: carbon dioxide product 
bloating
– Anti-foaming agents (dimethicone)
• Can affect pH which changes normal reactions
D.3 ANALGESICS
• Perception of pain
– Best defense mechanism
Sensation unpleasant, especially chronic pain 
analgesics (painkillers)
Prostaglandins – chemicals released by damaged cells
(thermal, chemical, mechanical)
Stimulate
Fever
Inflammatory response:
dilating blood vessels
Swelling  more pain
Pain Receptors – send message
to brain
Brain  PAIN
Analgesics
• Block pain at different sites
• Mild Analgesics:
– Aspirin, non-steroidal anti-inflammatory drugs
(NSAIDs) – ibuprofen
– Prevent stimulation of pain at nerve endings
• Inhibit release of prostaglandins as site of injury
– Non-narcotics  do not interfere with brain
function
Analgesics
• Strong Analgesics:
– Opioids (morphine)
– Blocks transmission of pain signals
between brain cells
– Alters perception of pain
– Narcotics: change behavior, mood,
cause drowsiness
– Most effective, but create dependence
• WHO three step analgesic ladder
Mild Analgesics
• Aspirin
– Original use - Salicylic Acid (willow trees)
• Which caused vomiting
– Added an ester
• More palatable, less irritating
• First and most widely used
– Blocks synthesis of prostaglandins  reduces
inflammation, fever, pain, reduces blood clotting
Aspirin
Paracetamol
(acetaminophine)
Analgesic (painkiller)
Yes
Yes
Antipyretic (fever
reducer)
Yes
Yes
Reduces Inflammation
Yes
No
Side-effects
Stomach wall irritant,
blood anti-coagulation
Does not irritate
stomach wall
Severe side-effects
(over-dosage)
Reye’s syndrome in
children
Serious kidney, liver,
brain damage
Synergistic effect with
alcohol
Increased risk of
stomach bleeding
Toxic side-effect can by
increased
Allergic reactions
Relatively common
Rare
Use for Children
No (baby aspirin)
yes
Strong Analgesics
• Derivatives of opium (extract from poppy seeds)
– Codeine
– Morphine
– Diamorphine (heroin)
• Act on central nervous system – block perception
of pain
• Side Effects
– Constipation, suppressing cough reflex, constriction of
pupils
Codeine
Functional Groups:
Benzene ring
Ether (2)
Alkene
Alcohol (1)
Tertiary amine
Source: raw opium (0.5%)
Therapeutic Uses:
Second stage of pain management (in
addition to aspirin/acetaminophen)
Cough medications
Short term treatment of diarrhea
Morphine
Functional Groups:
Benzene ring
Ether
Alkene
Alcohol (2)
Tertiary amine
Source: raw opium (10%)
Therapeutic Uses:
Management of severe pain (advanced
cancer)
Habit forming  dependence, must be
regulated
Diamorphine (Heroin)
Functional Groups:
Benzene ring
Ether
Alkene
Ester-ethanoate (2)
Tertiary amine
Source: semi-synthetic drug
– reaction of morphine
Therapeutic Uses:
Used medically in few countries for pain relief
Most rapidly acting, most abused narcotic
Initial euphoric effects  dependence  increase in tolerance
Withdrawal symptoms
Similarities
• All have same basic structure  similar
properties
• Morphine  Heroin
– Esterification reaction: both OH groups converted
to ethanoate (ester) groups
• Reaction with ethanoic acid (CH3COOH)
– Loss of OH group  less polar  becomes lipidsoluble  easier to cross blood-brain barrier
Narcotic Effects
Feeling of well-being,
contentment
Causes dulling of pain,
lessening of fear, tension
Increase in tolerance
Quick dependence –
withdrawal effects (cold
sweats, anxiety)
Long-term effects:
constipation, reduced libido,
loss of appetite, reduced
nutrition
Social effects: crime,
infections (HIV,
Hepatitis)
Breaking dependence: slow – may
use methadone (reduces drug
cravings) - wean
D.4 DEPRESSANTS
Depressants
Drugs that act on brain/spinal cord (CNS)
Changes communication between brain cells
Alter concentration or activity of neurotransmitters
Cause depression (decrease) in brain activity
Dosage Effect
Low to moderate Dose
Calmness
Relief from anxiety
Very relaxed muscles
High Dose
Slurred speech
Staggering gait
Altered perceptions
Sleep induced
Extremely High Doses
Respiratory depression
Coma/death
Description
Tranquilizer
Sedative
Hypotonic
Ethanol
• Alcohol in beer, wine, hard liquor
• Most widely used psychoactive drug
Uses of Ethanol
Antiseptic properties – clean wounds
Hardening effect – prevent formation of blisters
Diets – adds sense of occasion to meals, rituals,
festivities
Low Doses
Create mild excitement
Beneficial effect on circulation – anti-clotting effect
Ethanol Abuse
Short-term effects
Long-term effects
Loss of self-restraint; memory, Alcoholism (withdrawal
concentration, insight impaired symptoms)
Loss of balance, judgment
Liver disease (cirrhosis, liver
cancer)
Violent behavior (abuse)
Dangerous risk-taking behavior
(operating machinery)
Dehydration (hangover, loss of
productivity)
Vomiting, loss of
consciousness, coma, death
Coronary heart disease
High blood pressure
Fetal alcohol syndrome
Permanent brain damage
Metabolism of Ethanol
OH group – polar
Readily soluble in aqueous solutions
Small molecule – dissolve in lipids
ingestion
Pass from gut to blood
90% breakdown occurs in liver, remaining by
kidney and lungs
Synergistic Effects
Drug
Aspirin
Other depressants
(barbiturates, sleeping
pills)
Tobacco
Other drugs
Ethanol effect
Increased bleeding of stomach lining –
ulcers
Induce heavy sedation - possible coma
Increase incidence of cancers
(intestines and liver)
Affect their metabolism by liver –
greater, prolonged drug effects
Detection of Ethanol
• Analysis of breath
– Volatile compound – at body temperature
C2H5OH(aq) ↔ C2H5OH(g) – in lungs
– Kc fixed values at particular temperature
– Breathalyser – look at extent of color change
• not very accurate
C2H5OH
Cr(VI) orange
REDOX
CH3COOH
Cr(III) green
Detection of Ethanol
• Analysis of breath
– Infrared spectroscopy – intoximeter
• Size of dip at C-H correlates to ethanol concentrations
Detection of Ethanol
• Analysis of breath
– Fuel cell
• Ethanol is oxidized to ethanoic acid then to water and
carbon dioxide
• Converts energy released from oxidation to detectable
voltage  ethanol concentration
• Very accurate
Detection of Ethanol
• Analysis of blood and urine
– Gas-liquid chromatography
Injected into stream of
inert gas
Blood/urine vaporized
Boiled at
different temps
Amt of vapor
detected
Other Depressants
• Benzodiazepines
– Depress activity in brain controls emotion 
tranquilizers
– Most common sleeping pill  muscle relaxants
– Cause dependence
Diazepam (Valium)
Nitrazepam (Mogadon)
Benzene Rings
Diazepine structure - 7
heterocyclic ring (C, 2N)
Largely non-polar –
high lipid solubility
cross brain-blood barrier
• Fluoxetine hydrochloride (Prozac) –
– anti-depressant
– Increases serotonin levels
– Treats depression, eating/panic disorders
D.5 STIMULANTS
Stimulants
• Increase brain activity  state of mental
awareness
– Prevent drowsiness
• Facilitate breathing
– Treatment of respiratory infections
• Reduce appetite
– Treatment of obesity
• Cause palpitations/tremors
• Cause extreme restlessness, sleeplessness, fits,
delusions, hallucinations
Amphetamines
• Mimic adrenaline
– Hormone released during stress  coping
mechanism
– Increase heart rate/ blood pressure
– Increase blood flow
– Increase air flow
– Increase mental awareness
Adrenaline
Noradrenaline
– neurotransmitter
– Sympathetic nervous
system
Secondary amine
Primary amine
Amphetamines – stimulant drug
Phenyl: substituted
benzene ring
Ethyl: 2C chain
Amine: NH
attached to C
Amphetamines
• Sympathomimetic drugs
– Small doses: increase mental awareness and
physical energy
– Side Effects:
• Pupil dilation, decreased appetite, blurred vision,
dizziness
– Rapid development: tolerance and dependence
– Long term effects:
• Severe depression, reduced infection resistance
Amphetamines
• Designer drugs
– Modifications to chemical structure
– Methamphetamine
• ‘speed’ ‘crystal meth’
• Ecstasy
Nicotine
• Most widespread, abused stimulants
• Intake:
– Inhalation, chewing
• Lipid-soluble molecule
• Actions in brain:
– Increases adrenaline levels
– alter other neurotransmitters in brain
Nicotine Consumption
Short-Term Effects
Increases concentration
Relieves tension/boredom
Helps counter fatigue
Increases heart rate/blood
pressure
Decreases urine output
Long-term Effects
High blood pressure
Increases risk of heart disease
(angina)
Coronary thrombosis
Increases fatty acid levels in
blood  atherosclerosis, stroke
Over-stimulation of stomach
acids  ulcers
Nicotine
• Habit-forming (dependence/tolerance)
• Withdrawal symptoms:
– nausea, weight gain, drowsiness, inability to
concentrate, depression, nicotine cravings
• Social factors - peer pressure
• Cigarettes: chemical cocktails
– Chronic lung diseases, adverse fetal affects,
cancers
Caffeine
• Most widely used stimulant, unregulated
• Action on brain:
– Reduce physical fatigue
– Restore mental alertness
• Respiratory Stimulant
– Increasing rate of energy release in cells
• Intensifies, prolongs adrenaline effects
Caffeine Consumption
Small Amounts
Enhancement of mental
energy, alertness, ability to
concentrate
Acts as a diuretic: increasing
urine volume, cause
dehydration
Large Amounts
Cause anxiety, irritability,
insomnia
Dependence: withdrawal
effects – headaches, nausea
Helps bodies absorb some analgesics (often in
formulation)
Tertiary Amines
Heterocyclic rings (containing C and N)
D.5 ANTIBACTERIALS
• 1891 – treatment of malaria using methylene
blue (dyes)
• Late 1800’s – Paul Ehrlich ‘magic bullet’
– Arsenical drug – treated syphilis patients
• 1933 – sulfonamide drugs
– Cure septicemia
– Reduced childbirth deaths
Antibiotics
1928 – Alexander Fleming (Scottish)
Worked on bacterial cultures
Mold (Penicillium notatum) created clear zone - killing bacteria
Concluded: mold produced something that inhibited bacterial
growth  birth of antibiotics
1940s – Howard Florey (Australian), Ernst Chain (German) - England
Successfully isolated penicillin as the antibacterial agent
produced by the mold
Human trials conducted in 1941 – due to high need from WWII
1941 – production moved to US to avoid bombing
Large scale production – deep fermentation tanks – corn steep liquor
1945 – Dorothy Hodgkin (British)
Using X-ray crystallography – determined structure of Penicillin G
Core structure: beta-lactam (4 member ring with 1 N and 3 Cs)
Responsible for antibacterial properties
Irreversible enzyme inhibitor – prevents development of cross-links
in cell wall  weakens cell wall  cell dies in reproductive phase
Effective against wide
range of bacteria
Infections: ear, nose,
throat, mouth, wounds
1945 – Dorothy Hodgkin (British)
Using X-ray crystallography – determined structure of Penicillin G
Disadvantage: penicillin G broken down by stomach acid  needs direct
injection
Different forms developed – modifying side chain
Enable drug to retain its properties when ingested via pill
Antibiotic Resistance
• Resistant Bacteria produce enzyme (penicillinase)
– Opens beta-lactam ring – rendering inactive
• Created by
– Overprescribed
• Normally small numbers of bacteria have appropriate
genetic mutationrepeated exposure to antibiotic  only
ones left to reproduce
– Antibiotics in animal feeds
• Increases amount of antibiotics in human food chain -- .
More exposure
Antibiotic Resistance
• Responses
– Develop different penicillin forms (modified side
chains) – withstand affects of penicillinase
– Controlling and restricting use of antibiotics
• Legislation
– Education and encouragement of patients to
complete full antibiotic course (patient
compliance)
D.7 ANTIVIRALS
Viruses
Bacteria
• Components:
• More complex cellular
structures
• Ability to survive and
reproduce
independently of host
– Protein
– Nucleic acid (RNA/DNA)
• No cellular structure
• Require host cell for
replication
Attacking Viruses
• Problems:
– Viruses live within cells – cannot be targeted
– No metabolism – no antibiotics
– Rapid multiplication
– Rapid mutations – changes susceptibility to drugs
Antivirals
• Vaccinations
– Prepares antibodies – less likely to
get sick
• Altering host cells DNA
• Block enzyme activity within host
cell
• Antiviral Drug – amantadine
– Changes cell membrane – prevent
viral entry
Prevents viral
reproduction
AIDS
• Cause: HIV (human immunodeficiency virus)
• Attacks host immune system
• Enters CD4 T cells (specific white blood cell) with RNA and
reverse transcriptase
– RNA  viral DNA
• vDNA incorporates into host DNA  replicates with host
• Released upon cell death
Difficulties of AIDS
• Destroys T-helper cells
– Communicate between macrophages
(phagocytes) and B cells (produce antibodies)
• Rapid mutation, even within current host
– More variation in one host than all types of
Influenza
• Lies dormant
Antiretroviral Drugs
• Act a different stages in HIV life cycle
– Inhibit reverse transcriptase
• AZT (zidovudine)
– Delays progression of disease, does not eradicate
– Prevents mother-child transmission
– Block binding on host cell
– Inhibit assembly of new viral particles
• Cost: side-effects
• Benefit: prolong length and quality of life
D.8 DRUG ACTION
Stereoisomerism
Differ in 3D arrangement of atoms
Stereoisomerism
Different spatial arrangements of atoms in
molecules
Geometric isomerism
Cis-trans isomerism
Exists where there is restricted
rotation around atoms
Optical isomerism
Chirality exists where there is
an asymmetric carbon atom
Geometric Isomerism
• Anticancer Drugs
– Disrupting DNA function in cancer cells 
prevents cell division
• Double strand – connected via H-Bonds
• Carries (-) charge at cell pH
• Found in nucleus
Geometric Isomerism
• Anticancer drugs
– Platinum complex: cisplatin (Pt(NH3)2Cl2),
carboplatin
• Testicular/ovarian tumor treatment
• Square planar geometry – minimizes repulsive
interactions between electrons in d orbital
Exchanges
1 or 2
negative
Cl with
water
ligand
Reactive
(+)
charged
species
Replace water and Cl
ligands with bonds to
Guanine base
DNA repair processes inhibited
Only cis isomer works – proper orientation for reactions
Optical Isomerism
• Chiral Drugs
– Enantiomers – forms mirror image
• C bonded to 4 different groups
Compounds – identical chemical properties
React differently in presence of chiral binding in body –
only 1 enantiomer is biologically active
Creates difference in
physiological properties
Chirality
• Biological synthesis  produces 1
enantiomeric compound
• Synthetic processes  mixture of
enantiomers (racemate)
– Must analyze physiological effects of each isomer
– Marketed as racemate or single enantiomer
Thalidomide Tragedy
Sold as racemic mixture – not complete research
• Thalidomide
– Two forms interconvert under physiological
conditions
– Further use:
• (S) form prevents formation of new blood vessels
– Suppressing tumor growth?
– Treatment of HIV/AIDS or leprosy?
• Single enantiomers  becoming increasingly
common on drug market (50%)
Beta-lactam ring
Beta-Lactam Ring
• Highly unusual
– 90° bond angles formed  despite sp2 and sp3
hybridization
– Ring seeks angles of 120° and 109.5°
– Weakens bonds breaks easily  key to
biological activity
Beta-lactam ring reacts
with transpeptidase
(enzyme used to
synthesize bacterial cell
wall)
Prevents polypeptide
cross-links formation
Weakening cell wall
Cell dies and bursts
Bacterial Resistance
• Enzyme – beta-lactamase
– Destroys antibacterial prosperities by breaking
beta-lactam ring
• Create derivatives
– Methicillin/oxacillin
• Beta-lactam rings with modified side chains
• Prevent pencillinase binding
Solubility and Uptake
• Polar molecules are water soluble
– Dissolved in blood (aqueous solution)
– Transported throughout body (except brain)
• Non-polar molecules
– Cross hydrophobic blood-brain barrier
Solubility and Uptake
Morphine
Heroine
2 OH groups – polar
Less potent
2 ethanoate groups – less polar
More potent:
Faster action
Higher concentration
More active x2
• Heroin undergoes metabolic changes in brain
– Esterases – hydrolyzes ester links
– Pro-drug: metabolic products (morphine) bring
effects
• Morphine derivative: 6-acetylmorphine
– Only 1 ester link  more potent than heroin
• Does not undergo hydrolysis
– Produced as metabolite from heroin
D.9 DRUG DESIGN
• Compound Libraries
– Identifying lead compounds for target molecule
• Rational drug design: targeted synthesis and testing of
molecules
– Based on knowledge in molecular biology
– Information stored for future purposes
• Biologically relevant information through chemical
screening
– Need for efficiency in drug designing
• Combinatorial synthesis, parallel synthesis, highthroughput screening
Combinatorial synthesis
• Synthesizing groups of compounds
simultaneously (combinatorial libraries)
– 10,000 – 500,000 compounds
• Many small scale synthesis reactions
– Variety of starting materials and reagents
– Screen products  desired activity, lead
compound
• Mimics natural process of random mutation
and natural selection
• Solid Phase– peptide combinations
– Mix and Split
•
•
•
•
Components linked to solid support (resin bead)
Mixed, split into equal portions
Each portion reacted with different building blocks
Mix, split, repeat
– Information put into libraries
• Solution Phase
– Non-peptide drug molecules
– Synthesize smaller molecules
Parallel Synthesis
• Produces single product (unlike mixture created
in combinatorial synthesis)
– More focused and less diverse library
• Teabag procedure
– Porous bags of resin suspended in reagents
• Synthesize highly reactive intermediate via simple step series
• React these with different reagents
• Research in structure activity relationships, drug
optimization
High-throughput screening
• Helps create large compound libraries
– Robotics and micro-scale chemistry
– 100,000 compounds/day testing capacity
• Large # of compounds against large # of
targets
– Easily identifiable reactions
Computer-aided Design (CAD)
• Creation of virtual drug trials
• Molecular-modelling software analyzes drugreceptor site interaction
• Purpose: design drugs for best fit at receptor
site
– Due to increased knowledge of biomolecular
target
– Using x-ray crystallography/NMR
• Pharmacophore
– Part of drug used for binding
• Research common features of compounds
that target a receptor
– Predict receptor site 3D structure
– Design drug
• Goal:
– Database created for quick searches
– Reduce number of candidate molecules to be
synthesized and tested
Bioavailability
• Percent of drug to bloodstream
– 20-40%
• Polar drugs or ionic groups increase solubility
of drug
– More efficient distribution
Aspirin is not very
soluble
Sodium salt of aspirin
is more soluble
Acid
Conjugate base – more
readily broken down in
body
NH  base
Weak base
Chloride salt
Conjugate acid
Production of Single Enantiomer
• Asymmetric synthesis (enantioselective)
– Chiral auxiliary
• Chiral molecule binds to reactant  blocking one
reaction site (steric hindrance)
• Forces reaction in one direction
– Used with Taxol
• 11 chiral carbon centers
• Use titanium and rhodium chiral catalysts
D.10 MIND-ALTERING DRUGS
Hallucinogens
• No basis in reality  appear realistic
• Disrupt normal serotonin activity
– Responsible for coordinating, processing hearing
and sight
– Changes nervous connections
• See table handout
Cannabis Drugs
• Common form: Hashish
– Resinous material
– Not a narcotic – does have sedative/hypnotic
properties
• Alters perception, thought, feeling
• Effects in Body
–
–
–
–
Depresses CNS
Causes mental relaxation, euphoria
Loss of inhibition
Alteration of time/space perception
• Side-effects
– Palpitations, loss of concentration, light-headedness,
weakness, sense of floating
• Over-dose
– Respiratory depression, collapse due to synergistic
effects
• Withdrawal symptoms
– Insomnia, anxiety, restlessness
Legalizing
• For illegal status
– Cause dependence, diminish sense of responsibility,
medical costs due to long-term use, gateway drug
• Counter-arguments
– No proven link it is gateway drug, no more damaging
than tobacco/alcohol, if legal – protect users from
gangs
• Medically
– Treat nausea, vomiting (chronic pain), glaucome,
asthma, convulsive disorders