Medicines and Drugs Option D

D.1 PHARMACEUTICAL PRODUCTS

Background In the Body Defenses

Non-specific Defense Mechanisms

• • • First Line: barriers to prevent entry Skin Mucous membranes Closures and secretions of natural openings • • • Second Line: attack pathogens Phagocytosis (engulfing invaders) Blood clotting Inflammatory response

Specific Defense Mechanisms

• • Third Line: immune system 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

Oral Inhalation Skin Patches Suppositories Eye/ear drops

Description

Taken by mouth Vapor breathed in; smoking Absorbed skin  to blood directly Inserted into rectum Liquids delivered to openings

Example

Tablets, capsules, pills, liquids Respiratory conditions (asthma); abuse (nicotine/cocaine) Hormone treatments (estrogen, nicotine) Digestive illnesses, hemorrhoids Treatment for infections

Method of Administration

Parenteral (injection)

Description

Intramuscular Intravenous Subcutaneous

Example

Vaccines Local anesthetics 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

• • • Identification of lead compounds Synthesis of analogues Biological testing Volunteers Blind studies Eliminate 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  acid weak bases to neutralize stomach – Metal oxides/hydroxides, carbonates, hydrogen carbonates – React to produce salt + water Do not directly coat ulcers  lining time to heal allow stomach 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 Swelling  Inflammatory response: dilating blood vessels 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  function do not interfere with brain

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

Analgesic (painkiller) Antipyretic (fever reducer) Reduces Inflammation Side-effects Severe side-effects (over-dosage) Synergistic effect with alcohol Allergic reactions Use for Children Yes Yes Yes Stomach wall irritant, blood anti-coagulation Reye’s syndrome in children Increased risk of stomach bleeding Relatively common No (baby aspirin)

Paracetamol (acetaminophine)

Yes Yes No Does not irritate stomach wall Serious kidney, liver, brain damage Toxic side-effect can by increased Rare 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  regulated dependence, must be

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  properties similar Morphine  Heroin – Esterification reaction: both OH groups converted to ethanoate (ester) groups • Reaction with ethanoic acid (CH3COOH) – Loss of OH group  soluble  less polar  becomes lipid easier to cross blood-brain barrier

Narcotic Effects

Feeling of well-being, contentment Increase in tolerance Causes dulling of pain, lessening of fear, tension 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

Loss of self-restraint; memory, concentration, insight impaired Loss of balance, judgment Violent behavior (abuse) Dangerous risk-taking behavior (operating machinery) Dehydration (hangover, loss of productivity) Vomiting, loss of consciousness, coma, death

Long-term effects

Alcoholism (withdrawal symptoms) Liver disease (cirrhosis, liver cancer) Coronary heart disease High blood pressure Fetal alcohol syndrome Permanent brain damage

ingestion

Metabolism of Ethanol

OH group – polar Readily soluble in aqueous solutions Small molecule – dissolve in lipids 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 – – C 2 H 5 OH(aq) ↔ C 2 H 5 OH(g) – in lungs Kc fixed values at particular temperature Breathalyser – look at extent of color change • not very accurate REDOX C 2 H 5 OH Cr(VI) orange CH 3 COOH 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 Boiled at different temps Amt of vapor detected Blood/urine vaporized

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  awareness – Prevent drowsiness state of mental 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  mechanism coping – Increase heart rate/ blood pressure – Increase blood flow – Increase air flow – Increase mental awareness

Adrenaline Secondary amine Noradrenaline – – neurotransmitter Sympathetic nervous system 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  injection needs direct 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  ones left to reproduce only – 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

Components: – Protein – Nucleic acid (RNA/DNA) No cellular structure Require host cell for replication • •

Bacteria

More complex cellular structures Ability to survive and reproduce independently of host

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(NH 3 ) 2 Cl 2 ), 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  hybridization despite sp 2 and sp 3 – Ring seeks angles of 120 ° and 109.5

° – Weakens bonds  biological activity breaks easily  key to

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

2 OH groups – polar Less potent

Heroine

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, high throughput 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  compound desired activity, lead 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 drug receptor 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 Acid Sodium salt of aspirin is more soluble 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  reaction site (steric hindrance) blocking one • 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