Medicines and Drugs Option D - PowerPoint Presentation

Slide1

Medicines and Drugs

Option DSlide2

D.1 Pharmaceutical ProductsSlide3

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 cellsSlide4

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 effectSlide5

Effects of Drugs

Alteration of physiological state

Consciousness, activity level and coordination

Alteration of incoming sensory sensations

Alteration of mood or emotionsSlide6

Types of Drugs

Analgesics, stimulants, depressants

Target: nervous system/brain

Antacids

Target: metabolic processes

Antibacterial/Antivirals

Supplement body’s ability to fight pathogensSlide7

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 powersSlide8

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 infectionsSlide9

Method

of Administration

Description

Example

Parenteral

(injection)

Intramuscular

Vaccines

Intravenous

Local anesthetics

Subcutaneous

Dental injectionsSlide10

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 treatmentSlide11

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 dosesSlide12

Tolerance: reduced response to drug

Need higher doses, risk toxic effects

Dependence/Addiction

Dependent of drug to feel normal

Suffers withdrawal symptomsSlide13

Identification of lead compounds

Synthesis of analogues

Biological testing

Blind studies

Collection of adverse drug reaction data

Volunteers

Eliminate investigator bias Slide14

Lead compounds: identifying and extracting compounds

 show biological activity

Plants/bacteria

Analogues: chemically related compounds

Combinatorial chemistry

High-throughput screeningSlide15

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)Slide16

d.2 antacidsSlide17

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/inflammationSlide18

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 refluxSlide19

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 reactionsSlide20

d.3 analgesicsSlide21

Perception of pain

Best defense mechanism

Sensation unpleasant, especially chronic pain

 analgesics (painkillers)Slide22

Pain Receptors – send message to brain

Brain

 PAIN

Prostaglandins – chemicals released by damaged cells (thermal, chemical, mechanical)

Stimulate

Inflammatory response: dilating blood vessels

Swelling

 more pain

FeverSlide23

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 functionSlide24

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 ladderSlide25

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 clottingSlide26

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)

yesSlide27

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 pupilsSlide28

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 diarrheaSlide29

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 regulatedSlide30

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 symptomsSlide31

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 lipid-soluble  easier to cross blood-brain barrierSlide32

Narcotic Effects

Feeling of well-being, contentment

Causes dulling of pain, lessening of fear, tension

Long-term effects: constipation, reduced libido, loss of appetite, reduced nutrition

Quick dependence – withdrawal effects (cold sweats, anxiety)

Increase in tolerance

Social effects: crime, infections (HIV, Hepatitis)

Breaking dependence: slow – may use methadone (reduces drug cravings) - weanSlide33

D.4 depressantsSlide34

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 activitySlide35

Dosage Effect

Description

Low to moderate Dose

Calmness

Relief from anxiety

Very relaxed muscles

H

igh Dose

Slurred speech

Staggering gait

Altered perceptions

Sleep induced

Extremely High Doses

Respiratory depression

Coma/death

Tranquilizer

Sedative

HypotonicSlide36

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 effectSlide37

Ethanol Abuse

Short-term

effects

Long-term effects

Loss of self-restraint;

memory, concentration, insight impaired

Alcoholism

(withdrawal symptoms)

Loss of balance,

judgment

Liver disease (cirrhosis, liver cancer)

Violent behavior

(abuse)

Coronary

heart disease

Dangerous

risk-taking behavior (operating machinery)

High blood pressure

Dehydration (hangover, loss of productivity)

Fetal alcohol

syndrome

Vomiting,

loss of consciousness, coma, death

Permanent brain damageSlide38

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 lungsSlide39

Synergistic Effects

Drug

Ethanol effect

Aspirin

Increased

bleeding of stomach lining – ulcers

Other

depressants (barbiturates, sleeping pills)

Induce heavy

sedation - possible coma

Tobacco

Increase incidence of cancers (intestines

and liver)

Other drugs

Affect

their metabolism by liver – greater, prolonged drug effectsSlide40

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 temperatureBreathalyser – look at extent of color changenot very accurateC

2

H

5

OH

CH

3

COOH

Cr(VI) - orange

Cr(III) - green

REDOXSlide41

Detection of Ethanol

Analysis of breath

Infrared spectroscopy –

intoximeter

Size of dip at C-H correlates to ethanol concentrationsSlide42

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 accurateSlide43

Detection of Ethanol

Analysis of blood and urine

Gas-liquid chromatography

Blood/urine - vaporized

Injected into stream of inert gas

Boiled at different temps

Amt

of vapor detectedSlide44

Other Depressants

Benzodiazepines

Depress activity in brain controls emotion

 tranquilizers

Most common sleeping pill  muscle relaxants

Cause dependence Slide45

Diazepam (Valium)

Nitrazepam

(

Mogadon

)

Diazepine

structure - 7 heterocyclic ring (C, 2N)

Largely non-polar – high lipid solubility

cross brain-blood barrier

Benzene RingsSlide46

Fluoxetine hydrochloride (Prozac) –

anti-depressant

Increases serotonin levels

Treats depression, eating/panic disordersSlide47

D.5 stimulantsSlide48

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, hallucinationsSlide49

Amphetamines

Mimic adrenaline

Hormone released during stress

 coping mechanism

Increase heart rate/ blood pressure

Increase blood flow

Increase air flow

Increase mental awarenessSlide50

Adrenaline

Noradrenaline

neurotransmitter

Sympathetic nervous system

Amphetamines – stimulant drug

Secondary amine

Primary amineSlide51

Phenyl: substituted benzene ring

Ethyl: 2C chain

Amine: NH attached to CSlide52

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 resistanceSlide53

Amphetamines

Designer drugs

Modifications to chemical structure

Methamphetamine

‘speed’ ‘crystal meth’

Ecstasy Slide54

Nicotine

Most widespread, abused stimulants

Intake:

Inhalation, chewing

Lipid-soluble molecule

Actions in brain:

Increases adrenaline levels

alter other neurotransmitters in brainSlide55

Nicotine Consumption

Short-Term

Effects

Long-term Effects

Increases concentration

High blood

pressure

Relieves

tension/boredom

Increases risk of heart disease (angina)

Helps counter

fatigue

Coronary thrombosis

Increases heart rate/blood

pressure

Increases

fatty acid levels in blood

 atherosclerosis, stroke

Decreases urine

output

Over-stimulation of stomach

acids

 ulcersSlide56

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, cancersSlide57

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 effectsSlide58

Caffeine Consumption

Small

Amounts

Large Amounts

Enhancement of mental energy, alertness, ability to concentrate

Cause anxiety, irritability, insomnia

Acts as a diuretic: increasing

urine volume, cause dehydration

Dependence: withdrawal effects – headaches, nausea

Helps bodies absorb some analgesics (often in formulation)Slide59

Heterocyclic rings (containing C and N)

Tertiary AminesSlide60

d.5 AntibacterialsSlide61

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 deathsSlide62

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 liquorSlide63

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, woundsSlide64

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 pillSlide65

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 exposureSlide66

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)Slide67

d.7 antiviralsSlide68

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 hostSlide69

Attacking Viruses

Problems:

Viruses live within cells – cannot be targeted

No metabolism – no antibiotics

Rapid multiplication

Rapid mutations – changes susceptibility to drugsSlide70

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 reproductionSlide71

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 deathSlide72

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 dormantSlide73

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 lifeSlide74

d.8 Drug ActionSlide75

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

O

ptical isomerism

Chirality exists where there is an asymmetric carbon atomSlide76

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 nucleusSlide77

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 orbitalSlide78

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 reactionsSlide79

Optical Isomerism

Chiral Drugs

Enantiomers – forms mirror image

C bonded to 4 different groupsSlide80

Compounds – identical chemical properties

React differently in presence of chiral binding in body – only 1 enantiomer is biologically active

Creates difference in physiological propertiesSlide81

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 enantiomerSlide82

Thalidomide Tragedy

Sold as racemic mixture – not complete researchSlide83

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%)Slide84

Beta-lactam ringSlide85

Beta-Lactam Ring

Highly unusual

90

°

bond angles formed

 despite sp

2

and sp

3

hybridization

Ring seeks angles of 120

°

and 109.5

°

Weakens bonds breaks easily  key to biological activitySlide86

Beta-lactam ring reacts with

transpeptidase

(enzyme used to synthesize bacterial cell wall)

Prevents polypeptide cross-links formation

Weakening cell wall

Cell dies and burstsSlide87

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

bindingSlide88

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 barrierSlide89

Solubility and Uptake

Morphine

Heroine

2 OH groups

– polar

2

ethanoate

groups – less polar

Less potent

More potent:

Faster action

Higher

concentration

More active x2Slide90

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 heroinSlide91

d.9 Drug designSlide92

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 screeningSlide93

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 selectionSlide94

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 moleculesSlide95

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 optimizationSlide96

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 reactionsSlide97

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/NMRSlide98

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 testedSlide99

Bioavailability

Percent of drug to bloodstream

20-40%

Polar drugs or ionic groups increase solubility of drug

More efficient distributionSlide100

Aspirin is not very soluble

Sodium salt of aspirin is more soluble

Acid

Conjugate base – more readily broken down in bodySlide101

NH

 base

Chloride salt

Weak base

Conjugate acidSlide102

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 catalystsSlide103

d.10 mind-altering drugsSlide104

Hallucinogens

No basis in reality

 appear realistic

Disrupt normal serotonin activity

Responsible for coordinating, processing hearing and sight

Changes nervous connections

See table handoutSlide105

Cannabis Drugs

Common form: Hashish

Resinous material

Not a narcotic – does have sedative/hypnotic properties

Alters perception, thought, feelingSlide106

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, restlessnessSlide107

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