Week 1 class 1-2

Most reliable information on web

1. Pharmaceutical company websites
a. Regulated
2. Government websites
a. Health Canada
b. FDA
3. University websites (courses)
4. Scientific journals
a. Each discipline has its unwritten rules
Science vs magic
• Science
– Collect facts
– Draw conclusions based on those facts
– Test your conclusions in several ways
• Magic, superstition
– Draw the conclusions you want
– Find some facts to fit those conclusions
Avoid testing or challenging your
 Human brain’s default mode is “magic”
• We create our own reality
– Draw the conclusions you want
– Find some facts to fit those conclusions
– Avoid testing or challenging your conclusions
– Ignore or explain away contradictory evidence
Concept of science is new
• Developed in last 150 years
1. Collect facts
2. Draw conclusions based on those facts
3. Test your conclusions in several ways
4. Include all evidence
Life expectancy (2009)
- We live in a unique time and place
- current life expectancy higher than at any other time in history

Rank Country Years of Life

1 Macau 84.4

2 Andorra 82.5

3 Japan 82.1

4 Singapore 82.0

5 San Marino 82.0

6 Hong Kong 81.9

7 Australia 81.6

8 Canada 81.2

9 France 81.0

159 World Average 66.6

224 Swaziland 31.9

• Approx. 30 to 35 years for most of recorded history

– Last 6,000 years
• Approx. 30 to 35 years through the stone age
– 500,000 to 6000 years ago
• 82 years in 2009 (Canada)
– Most Improvements over the last 150 years
– Life span is an educated guess – written records and archaeology
 – important to remember that only “important” people make it into historical
records,
– life expectancy is mostly the “ordinary” people
– Most improvements in life span have happened over last 150 years
Life expectancy through history
– Variations smoothed out as records are not precise
– number of 35 years is an estimate made by combining data from various sources
– numbers may vary depending on source used
– range is more appropriate
– CA 81.2 life expectancy
– World average – 66.6 yrs.’
– Increased improvement -> 150 yrs.’
Increase only in last 150 years
- Data for united states
- 150 years ago, life expectancy was same as that of the stone age
- - special time in history to be living now
Life in the “good old days”
1. Harsh
2. Cruel
3. Short
4. Now – improved quality of health, better health state, less parasites
Disease was common and dangerous
Life with worms
1. less parasites - lice ands flees
2. worm- deworm

1 – hookworm
2- tapeworm – can lay 1,000,000 eggs per day,
3 – tapeworm eggs
4- roundworm max size 50 cm lay 200,000 eggs/day
5 pinworms – migrates out of colon and lays eggs in anus - itching

Improved quality of life in Canada

1950s -> infection-> illness->death
2019->body is wearing out->illness
Lower respiratory infection: common but infection not deadly
MVA: Most common now
• 1900
– 44 years
– Main causes of death
– Pneumonia
– Tuberculosis
– Influenza
(this lasted until 1950’s
 • 2004
– 82 years
– Main causes of death
– Heart disease
– Cancer
– Stroke
– Lower respiratory infection
– Traffic accidents
– Diabetes
o Data for Canada
o life expectancy has doubled in last 100 years
o changes also in quality of life
o causes of death have shifted from infectious disease to “wear and tear”
o historically people lived entire lives in an unhealthy state
o constantly sick (parasites)
o this condition still exists in many developing countries
Main reasons for improved health
• Improved sanitation-
Outhouses common in cities
Chamber pot used when cesspits were available
Open vs closed sewers
Populations exposed to dead and dying-people used to die at home being directly in
contact with the corpse
Now – we do not come into contact with corpse must have special training to handle
dead bodies
Separating human waste from humans – not coming into contact with faeces

• Clean drinking water

Nature does not make pure water
Stream water – must be boiled
Guinea worm – dracunculiasis
Microscopic parasite
Adult – lives in humans/ animals
Invades muscles – and lives in it
It magnifies pain – making you want to soak your foot into water – hence leaving site
and reproducing
 Worms exit the body: puncture skin and leaks out into water
Simple water treatment makes the difference: filtration of water
Major improvement is chlorination
1. Kills anything left by filtration
2. Preserves – ensure nothing gets in during transportation

• Refrigeration
Food spoilage was common before refrigeration
Seasonal availability
Modern food storage year round
Creates best possible diet
• Vaccination
Pharmaceuticals improve health
Greatest achievement in medicine
• Immunization (vaccination)
Very successful for viral diseases
Smallpox
– Eliminated in 1977
– Only exists in labs and biological weapons
– Polio eradicated from North America 1991
Currently less that 30 cases world-wide
2 countries
>300,000 cases in 1998
Major eradication barrier is politics

• Antibiotics
Antibiotics for bacterial infections
Penicillin reduced maternal mortality
 Improved health using the scientific method
1. Sanitation
2. Clean drinking water
3. Refrigeration
4. Vaccination
5. Antibiotics
Modern drugs work
1. Each starts with a scientific idea

nited States 49.1 %

pan 14.1 %

ermany 7.7 %

ance 7.1 %

nited Kingdom 4.2 %

anada 3.8 %
aly 3.8 %

l Others 10.3 %

2. Each is optimized using scientific methods

3. Each is tested scientifically

North American drug market (2009)

1. Prescription drugs
a. $ 300 billion
2. Over-the-counter (OTC) drugs
a. $25 billion

World drug markets (2009)

United states – 49.1%
Half the drugs self in the world are according to the USA standards
CA- 38.8%

Modern pharmaceutical industry is young

• Started in 1856
• Uses scientific methods
– Chemistry
– Biology
– Molecular biology
– Epidemiology
• Works hard to remove bias
• Regulated by government- heavily
Most ancient medications were useless
• Made-up” cures
– People believe in magic
• Feel better just by getting treatment
• Only a very small number of treatments actually worked
– A few of these are still used today
• Many treatments actually harmful
Most ancient drugs from plants?
Plants -produce poisons –> uses that as a defense mechanism
Animals -no poisons –> defend its self
Drugs are poison
Right amount matters – right dosage
Small amount  beneficial
High dose harmful
Insulin low poison
Not the substance but the amount that makes the difference – toxic vs non-toxic
• Drugs
– Produce desired (beneficial) biological effect
• Poisons
– Produce undesired (harmful) biological effect
– Poison
– Drug
– pharmakon
Sola dosis facit veneum
• Poison – kill
• Potion – cure
• Only the dose makes the poison
Dosages
• Normally we assume
– low doses produce beneficial effects (drug)
– high doses produce harmful effects (poison)
• Sometimes
– low doses produce harmful effects (poison)
– higher doses produce beneficial effects (drug)
Only the dose makes the poison
Dose makes the poison
• Ask “how much”?
• Works for lots of things
– Drugs
– Pollution
– Finances
– Everyday issues
How were drugs discovered before 1900?
• Observation (rare)
– People observed the effect of the drug
– Strong poisons
• Philosophy (very common)
– Based on belief
– Cure arrived at by reasoning – make it up
– Healing often connected with superstition, magic, religion
Drugs from observation
• Strong poisons (common)
– Easily identified
 – Low dose makes it into a drug
• Opium, digitalis, nicotine, cocaine
• Weak poisons (uncommon)
– Large quantity for effect
• Caffeine, salicin
Papyrus Ebers
• Egyptian medical document 1500 BC
• Scroll about 20 meters long
• Thousands of medical treatments
– Most useless
– A few are still used today
Identification of opium for pain
• Opium (extracted from poppy seeds)
– Narcotic painkiller
– Sedative
• Toxic in high doses
• Drug in low doses
Opium is basis of modern painkillers
• Analgesics
– Reduce pain
• Codeine
• Oxycodone
• Fentanyl
• Methadone
• Demerol
Identification of cocaine as a stimulant
• Observation
– extracted from coca leaves
• Topical painkiller
• Stimulant
Modern anesthetics designed from cocaine
• Anesthetics
– Reduces sensation
• Novocain
• Procaine
• Lidocaine
• Benzocaine
Problems with observation
• Human brain searches for patterns
– Even when they are not there
• Ancients did not use experiments or statistics
– Anecdotal evidence (stories)
– Drug and effect may be coincidence
– Perceptions subject to placebo effects
 – People lie
• Once “evidence” is available, hard to contradict
– Many harmful remedies retained because of this
– Parent’s cold remedies
Human brain searches for patterns
Apophenia
• Seeing patterns or connections in random or meaningless data
– Even when they are not there
Pareidolia
• Perceiving sounds or images as something else
Anecdotal evidence is misleading
Anecdotal evidence relies on chance
• Medication and cure may not be connected
– May eat a plant at same time you were getting better anyway
• Poison and harm may not be connected
Only experimental evidence is reliable
• Make a measurement
• Measure properly
• Measure accurately
Must rely on statistical significance
• Collect data from large number of experiments
Problems with traditional remedies
• Poor control over dose
– Plants produce variable amounts of active ingredient
Preparation changes chemical composition
No standardization
• No instructions
– Information passed verbally
– Imprecise
– Poor reproducibility
Difficult to correct information
• False information often spreads faster than true information
• Once someone accepts an idea, they are unwilling to change
Tomatoes once thought to be poisonous
In North America bugs not knowingly eaten
Philosophy to identify cures
• Cure arrived at by reasoning (make it up)
• Search for “proof” afterward
• Healing often connected with superstition, magic, religion
Hippocrates develops doctrine of humors
• Universe is made of 4 elements
– Earth
– Air
– Fire
 – Water
Hippocrates develops doctrine of humors
• Body is made of 4 humors
– Blood
– Phlegm
– Yellow bile
– Black bile
• Universe is made of 4 elements
– Earth
– Air
– Fire
– Water
Doctrine of humors
• 4 humors are normally in balance
• Too much or not enough of a humor causes disease
• Cure by re-balancing the humors
– Diagnose using the properties of the humors
• Fever associated with hot and dry
– Cure using cold and wet
Too much thinking
• Properties of 4 elements
– Earth - dry
– Air - cold
– Fire - hot
– Water - wet
• Properties of 4 humors
– Blood - cold
– Phlegm - wet
– Yellow bile – hot
– Black bile - dry
Bloodletting and the doctrine of humors
• Re-balance blood humor
Creative methods to remove blood
Bloodletting often killed the patient
Rebalance with emetics and purges
Doctrine of humors was stupid
• Based on incorrect idea
– The Universe is not made of 4 elements
– Humans are not made of 4 humors
• Treatments developed using it were harmful and painful
– Bloodletting
– Purges
– Fasting
– Special foods
D
doctrine of Signatures
Jakob Bohme, shoemaker and philosopher (1575-1624)
– God left clues to tell us how to use
things
– Disease and cure were linked
– This approach is/was used by almost
all cultures
Walnuts look like brains
• Eating walnuts is good for brain health
Boneset stems grow “through” the leaves
“Sharks don’t get cancer”
• Sharks have cartilage whereas we have bones
– Shark cartilage used as cancer treatment
Breath Mints have chlorophyll
Parsley and fresh breath
• Fresh breath – Parsley
• Parsley – Green
• Green – Chlorophyll
• Chlorophyll – Fresh breath
Mandrake roots look like people
• Mandrake roots used for many medicinal and magical purposes
– Primary use was a cure for demonic possession
Screaming mandrake root
• Believed that the plant would scream when harvested
Mandrake harvest using a dog
• Protect against the screaming
– Ensure the magic is preserved
Rhino horn is a phallic symbol
• Powdered rhino horn used in Chinese medicine as an aphrodisiac

Mercury is a heavy liquid

• People drink mercury as a purgative
Doctrine of signatures is crap
• Most remedies developed this way were harmful
• At best were harmless
– Denied the patient proper treatment
• Lack of rationality or evidence
– Based on appearance or location
– Required imagination to see connections
Life expectancy through history
- Variations smoothed out as records are not precise
- number of 35 years is an estimate made by combining data from various sources
- numbers may vary depending on source used
 - range is more appropriate
- Some problems require surgery
Amputation without anesthetic
Amputation had to be done quickly
Amputation learned by trial and error

Sir Humphry Davy discovers nitrous oxide

Nitrous oxide as a propellant
William T.G. Morton and ether 1846
William T.G. Morton 1846
Less than 30 % survived surgical treatment
Joseph Lister uses phenol as antiseptic
1867
Carbolic acid sprayer
Carbolic acid spray during surgery
Toxic effects of phenol on doctors
Washing and glove use was safer

Antisepsis brought to Canada by Thomas Roddick 1877

Listerine becomes household product
Listerine for dandruff
Listerine no longer contains phenol

William Perkin first synthetic dye - 1856

Dye companies became pharmaceutical companies
The first artificial drug – 1897

Artificial drugs were better and cheaper

Most modern drugs are artificial
• Designed for optimal activity, safety
 • Provide convenience
• Manufactured in large quantities
– Lower cost?
Most pharmaceuticals are made from oil
– Genetically engineered drugs
– Safest source of human protein
Rules are important
• Regulation of drugs
• Regulation of medical devices and procedures
Before 1907 there were no rules
• ANYBODY could make and sell drugs
– No proof that anything worked
– No safety testing
– No testing of any kind
• Most drugs were “made-up”
– Put some leaves in a bottle with water or alcohol
– Start selling it
Rise of patent medicine late 1800’s
• Included the word “Patented” on the label
– Public thinks patented = quality
• You could sell ANYTHING
Mrs. Winslow sooths with opium
Kickapoo Indian Oil cures all with alcohol
Alcohol was the most common “active ingredient”
– Alcohol
– Opium
– Cocaine
– “feel good
Great Radium Spring water
It’s Radioactive
William J.A. Bailey makes Radithor
Twisted science – from cancer to morons
Eben M. Byers was a believer
Medicine from Death’s Laboratory
Board of Food and Drug Inspection
• Formed in 1907
– First government regulations for medicines
– Labeling only
– No regulation of therapeutic claims
– No safety testing
Patent medicine = Fake medicine
Massengill company and drug safety
Sold sulfanilamide (antibiotic) as a powder
Massengill sells sulfanilamide elixir
Message to the AMA
• “please wire collect by Western Union suggestion for an antidote”

Labeling forced drug off the market

– Legal definition of elixir is a substance dissolved in ethanol

Government inspectors track down drug

• Recovered 234 of 240 gallons that were sold
• 107 dead
• 260 permanently disabled
Food and Drug Administration (FDA) created
Problems still occur
Thalidomide
• Developed as a sedative – 1957
– Very few side effects
• By 1962, thalidomide recognized as a teratogen
– Phocomelia
– Attenuated limbs
Teratogen causes birth defects
• From Greek word “teratos” for “monster”
• Thalidomide was tested in rats
– Rats do not often give birth to deformed pups
– In humans, problems with
a fetus result in
miscarriage, stillbirth or
birth defects
Modern safety standards
– Safety testing done in at least 2 species
– At least one must be a primate
– Must show that the drug is bioavailable
• Gets into body
– Must use relevant doses
Industry regulation is important
– Ensures safe products
– Ensures products work
– Ensures good manufacturing quality
– Regulation increases costs
Modern drugs work
– Each starts with a scientific idea
– Each is optimized using scientific methods
– Each is tested scientifically
– Manufacturing is standardized
– Drug industry is tightly regulated
o Must provide scientific proof
WEEK 2: class 3
PAIN MEDICATION

Prescription drugs
• $300 billion per year (U.S.)
• Requires doctor’s prescription
Over the counter – OTC
• $25 Billion per year (U.S.)
• No prescription required
• Some are “behind the counter”

Top OTC meds (North America 2016)

• Cough and cold. 8.2

• Pain reliever. 4.1
• Antacid. 2.7
• Toothpaste. 1.5
• Laxative 1.3
• $8.2 billion
• $4.1 billion
• $2.7 billion
• $1.5 billion
• $1.3 billion
Important considerations when buying
1. Safety: Dose makes the drug
Dose
Size of person
Side effect –all drugs have side effects
• ALL drugs have side effects
• Effect – what is it?
– Info is easy to find
– Label or box
– Google
• Incidence – how common is it?
– Info is difficult to find
• Need both to evaluate risk
• side effect – what can happen to you – on the printed bottle –piece of paper
• How does it occur – rare vs common – how often does this occur

2. Indications
What to use for?
 Many people take the wrong drug
Many people take drugs unnecessarily
Which one you should use
Common with cold – purchasing wrong medication
3. Counter-indications
When you should NOT use
• Conditions
• Drug combinations
• Foods
• “Natural” remedies
Pregnant
If you are already taking medication – heart condition

Pain relievers most common OTC drug

• $4.1 billion per year (North America)
• 50 billion tablets (North America)
• 16,000 tonnes/year
• 500 dump trucks
Aspirin – one of World’s most popular drugs
1. Alcohol
2. Caffeine
3. Aspirin
4. Nicotine?
Salix
• Genus (family)
– Willow
– Poplar
– Beech
– Wintergreen
• Salicylates –
• weak poisons
Sumerians used willow leaves for pain 2,200 BC
Egyptians used willow for inflammation
Knowledge of herbs lost in dark ages- Church controlled the drugs – the knowledge of willow
disappeared and was not used

Reverend Edward Stone 1702 – 1768

• Rector in Church of England
• Described treatment for ague in 1763
• Argue – fever
Willow bark has a bitter taste
• Similar to quinine
• Quinine – malaria
• Willow bark - fever
Doctrine of signatures
• Association between disease and cure
– People who live near swamps get malaria
– People with malaria have fever
– Treat malaria with quinine
– Quinine is bitter
– Willow bark is bitter
– Willows grow in swamps
• Willow bark will cure fever!!!
Willow bark for fever
• Dried bark
• Ground to a powder
• Given for fever
• Expensive
• Limited supply
• Variable effectiveness
• Had to live in the area where it would be available
• Reasonable in common
• Variable -various result in variable effectiveness on the drugs

Active ingredient in willow is salicin

• Isolated in 1829
• Salicin compound – produces the effect of willow

Chemical structures
• Represent the shape and function of molecules
• Match shapes to match function
• The molecules actually look like the drawings
• A little Salicin from a lot of bark-
• Bark -30g and salicin – 1.5 kg

Salicin converted to salicylic acid in 1838

• Better drug than salicin (lower dosages)
• Occurs in meadowsweet flowers (very small amounts)
1. Analgesic- pain
2. Antipyretic – fever
3. Anti inflammatory – swelling
• salicylic acid- better drug and in low amount
• Work better
• Body turns salicin to salicylic acid
Salicylic acid manufacture from coal tar
Advantage: manufacture in a different way
1. Second option is better Synthetic - cold tar to salicylic acid
cold tar->Salicylic acid ->Kolbe-Schmitt reaction
Coal tar was a waste product in 1800’s
Cold tar- cold gas – fuel - by product is cold tar that was a byproduct that was dumped

Synthetic vs “Natural”
• Natural
58 billion tablets require 2 million tonnes of bark
Natural: plant or animals extract from natural source – pulling the compound from it
• Synthetic
58 billion tablets require 62,000 tonnes of oil
Synthetic: is better than natural -advantage
1. Available in much larger quantities
2. Cost a lot less than natural
3. Don’t have to cut plants and trees
4. Oil is used to manufacture medication

Dye companies specialized in coal tar chemistry

• Natural – expensive …Rich …limited
• Synthetic – not expensive and available to everyone
• Cold tar – started out with dye
• Salicylic acid made and sold by dye companies

Salicylic acid was a drug with problems- Stomach irritation - disadvantage

1. Analgesic
2. Antipyretic
3. ant inflammatory
4. Bitter taste
5. Stomach irritation
Felix Hoffmann 1868 – 1946
• Father had arthritis
– Took salicylic acid
for pain
– Suffered from
stomach problems
– Chemically modifying- the drug
Process of drug optimization

• Taste less bitter

• No stomach irritation
• Not effective for pain
 O O

OH OH

OH O
CH3
Not right – he was guessing
August 10, 1897
O O

OH OH

OH O

O
Salicylic acid Acetasalicylic acid
1. Acetasalicylic acid – reduce pain and fever , inflammation
2. Side effects a lot less
3. World first drug - aspirin
4. Aspirin initially sold as a powder
5. Natural- Coffee – caffeine
6. Synthetic – coal tar -Acetasalicylic acid
Aspirin tablets became more popular
1. Bayer tablet – made them into powder
2. Realized the tablet
3. No bad taste and effective control of the dosage
Aspirin and A.S.A.
• Acetasalicylic acid (A.S.A.)
O

OH

O Aspirin -brand name

O

OH

O A.S.A.- generic name

 • Generic – scientific name
A lot better use than brand name
• Brand -easy to remember and not scary -mostly used

A.S.A.
A.S.A. effective for muscle pain
A.S.A. not effective for visceral pain
• Internal organs – visceral
• ASA – would help with pain outside the body-muscle

• Benefits
– Pain
– Fever
– Inflammation
– Reduce heart attack risk
• Side effects
– Tinnitus
– Stomach irritation
– Blood clotting
Prostaglandins are local hormones
• Produced and “used” in same cell
• Exist for short time
• ASA- involved with Prostaglandins- that carry information from one place to another
• They are hormone
• They are short term – don’t last long and are used quickly (as quick as they are made)

Prostaglandin biosynthesis
CO2H
CO2H cyclooxygenase
O

O
arachadonic acid
OH
Prostaglandin

pain
fever
inflammation
• Cyclooxygenase- aspirin blocks it
• Arachdonic – Prostaglandins-pain relieve
 • Cycolooxygenase – enzyme

• Myocardial infarction • Aspirin • Placebo

• Fatal • 10 • 26

• Non-fatal • 129 • 213

• Enzymes are machines

• Drugs block machine action
• Aspirin blocks the cyclooxygenase machine
A.S.A. for pain, inflammation and fever
• Aspirin and heart disease
• One Aspirin tablet every 2 days for 5 years***
• One Aspirin tablet every 2 days for 5 years
Prostaglandins and blood clotting
CO2H

CO2H cyclooxygenase O

O
arachadonic acid
OH
Prostaglandin

CO2 H
OH

Blood clotting
HO O
OH

Thromboxanes

Aspirin to prevent heart attack

• Prescription – down sides associated with HA without having a Hx
 • Cuts down risk by half

A.S.A. and cancer?

Homemade explosives
Anders Breivik
Start with aspirin – to make picric acid – explosive
• Asprin as the raw material for the booms/ explosives
• A.S.A. to make explosives

Side effects of A.S.A.

1. Death
– More than 60 tablets at once
2. Ringing in the ears
• Tinnitus-Ringing in the ears
o More than 10 tablets
o Warning of salicylism (aspirin poisoning)
• Reversible
• Valuable warning about poisoning your self
• Over dose??
3. Stomach irritation – excess HCl
• FATAL 10- 20 thousand a year
• Excess hydrochloric acid – aid for digestion
 • Mucus protects the stomach- Stomach secretes mucous to prevent HCL … from
damaging it
Prostaglandins help to protect the stomach
• Decrease acid production
• Increase mucus production
• Prostaglandin- lower the amount of acid and increase the mucous
• Help with stomach
• Disadvantage – block enzymes at muscle and stomach (doesn’t have the ability to select
only muscle)
• More HCL and less mucous
• Aspirin blocks Cyclooxygenase
CO2H

arachadonic acid

cyclooxygenase

CO2H

O
OH
Prostaglandin

Aspirin causes acid damage in the stomach

• Increase acid production
• Decrease mucus production
• Long term aspirin use causes stomach damage
Tablets can cause stomach irritation
• Tablet gets trapped in the lining of the stomach
• Local layer where acid gets out of the lining causing - irritation
Bufferin
• Contains an antacid
– MgSO4 (gypsum)
• Pills dissolve quickly
Plastic coating on A.S.A. tablets
• People with arthritis – use plastic coasting
• If they get trapped it doesn’t leak out into the lining of the stomach
Avoid irritation of the stomach
• Drink h20 to help with the pills
• Water inflated stomach – creating a smooth surface – pill don’t get stuck!

Reye syndrome and influenza

 • Reye syndrome - 1970
• Affected Children
• Function of the brain was affected – link with aspirin and this syndrome
• No more children’s aspirin – in north America
• Children’s aspirin no longer available
• No causative link between ASA and Rye syndrome
• Children’s Aspirin removed as a precaution
Cause vs association
• An association between two things does not mean that one thing influenced (caused)
the other
• Association- public takes it as a link
• Not tested before we get them – down side
• We don’t know for sure about reye syndrome If there’s a link or not – it was never
tested scientifically
Cause
• Requires a body of evidence
– Association between two things
– Control experiments
• Eliminate other possibilities
– Experiments with animals
– Biochemical explanation of the effect
– Deliberately change one factor to look for changes in the other
• Media – association
• A is associated with B
• But not sure if they are
Regular and extra strength
• Difference is dose sage
Tablets and caplets and gelcaps
• Little difference in the speed
• Same amount of time to be effective despite being advertised
Some forms add caffeine for headaches
• A.S.A. 325 mg
• Caffeine 32 mg
Name brand vs generic
 • Quality often costs more
Expectations
• People associate name brands and quality
True for physical devices – brand to brand – material and manufacture
Drugs – chemical substances (same doses and consistant doses
Generic drugs are the same quality as name brands
• Same chemical substance
• Same dosage
• Equivalent bioavailability
– Same amount of drug enters the body
• Brands - paying for the physical
• Drug- chemical substances – don’t differ … Same chemical substances … brand don’t
matter
What matters is Bioavailability – how much drug gets in

• Not all of the pill gets into the body

• Drug into body(blood stream) vs drug administered
• Brand name – try to say they have a better bioavailability

A.S.A. Summary

Benefit Side effect

Pain yes Reduced blood clotting yes

 Fever yes Stomach irritation yes
Long term use e.g aspirin
Inflammation yes Rye syndrome maybe

Prevent heart attack yes

Price per 100 tablets

Bayer aspirin $ 9.49
Less standard

Bayer aspirin (extra strength) $ 9.99

People buy more
Bufferin $12.49

Bayer coated aspirin $15.82

Avoids stomach irritation

Anacin $11.49

Bayer Aspirin Low Dose $17.99

Cost double – 1/4 that is in a standard Bayer aspirin X8
Small – but identical
Why expensive? taken by prescription – assume to be willing
or able to pay for this
Avoid – cut the same bayer into 4
Ingredient is the exact same low dose
Generic A.S.A. $2.50

Generic A.S.A. $7.99

A. Cahn and P. Hepp 1886 -

• Experimenting to find a vermifuge

• Noticed fever reduction in person who was given acetanilide
H
N

Antikamnia (antifebrin)
• Made from coal tar
• 10% coal tar is this stuff
• Pain reliever
Carl Duisberg
• Chemist at Bayer
• Needed to dispose of 50 tons of aminophenol
H
N

NH2 H
N

HO O
HO
Identified – they are identical by attaching the two
Discovered phenacetin

Phenacetin
Not in NA- in Australia
• APC tablet
– Aspirin
– Phenacetin
– Caffeine
• Reduce pain
Both drugs converted to acetaminophen in body - 1947
 Antikamnia
 Acetaminophen
 Phenacetin

Acetaminophen pain relief

Acetaminophen raises pain threshold  Less able to fell pain

OH
O OH
O O
N
OH H N
H

Arachidonic acid AM404

 Acetaminophen for muscle pain

 Acetaminophen for visceral pain
 Acetaminophen is an antipyretic Ability to reduce fever
 Both muscle and visceral
 Un like ASA
 Does not inhibit prostaglandin synthesis- No effect on inflammatory
material  response to the body pain

Arthritis use - variable effectiveness

1. Osteoarthritis
2. Rheumatoid arthritis
Inflammation or swelling of the joints
Use pain reliever for the source as well would be better
Stomach irritation
• A.S.A.
– Strong irritation (chronic)
• Acetaminophen
– Weak irritation (?)
– Still listed as a side effect
Death
• More than 60 tablets
• #1 suicide drug in England
Acetaminophen liver toxicity

Glucuronyl transferase
acetaminophen removal from body

Cytochrome P450

toxic metabolite Liver Damage

1st  safe: glucuronyl transferases  enzyme

Never take for hangover
• Alcohol stimulates liver function
• Alcohol Less pill  risk over dose
• Or many pills  over dose
Acetaminophen poisoning is very common
Acetaminophen in many prescription meds
Acetaminophen in many OTC meds
• No risk of Rye syndrome No association for acetaminophen
Children’s Tylenol in small bottles
 Small bottle – package
 Couple of doses
 Safety feature
 Taste good –may be appealing to child  may cause over dose

Tylenol regular Acetaminophen 325 mg

- 50 % more product
- In extra strength
Tylenol extra strengthAcetaminophen 500 mg
Tylenol arthritis or muscle & body Acetaminophen 650 mg
Difference –
- name – arthritis vs muscle and body
- Price – arthritis more expensive
Tylenol migraine
• Acetaminophen 500 mg
• Caffeine 65 mg
• Amount – small amount of caffeine
• Half a cup of coffee
Tylenol and cyanide - 1982
Cyanide - poisoning
Capsules used to poison people
Tylenol was recalled by J & J
- Johnson and Johnson
- Withdraw – from the entire world
- Stopped production
Tylenol caplets replace capsules
- Replaced capsule caplet
- Need spealized – machinery
Safety seal added to all OTC meds
Safety seal must be intact
Developed after  cyanide
Acetaminophen Summary
Benefit Side effect

Pain yes Reduced blood clotting no

Fever yes Stomach irritation no

Inflammation no Rye syndrome no

Prevent heart attack no Liver toxicity yes

Price for 100 tablets

Tylenol $10.49

Tylenol extra strength $9.00

More product
Bought more
Tylenol migraine $13.88

Tylenol muscle and body – same $18.74

Tylenol arthritis- high price –same $22.98

Tylenol PM $17.98

Children’s Tylenol $32.99

Expensive
 Generic acetaminophen (brand X) $3.20
Costco – more tables
Cheaper
Generic acetaminophen (brand Y) $7.99

Ibuprofen
• Developed 1961
• Originally by prescription only
• OTC use approved 1984
• Pain relief lasts longer
Inhibits cyclooxygenase
• Blocks the active site
Sticks into the pocket and cyclooxygenase occupies space where the enzyme would be– block
the enzyme

Ibuprofen summary 8 hours longer lasting

• Advil Ibuprofen 200 mg
• Motrin and Advil are the same stuff
• Advil and Motrin same thing ..
• The amount is the difference

enefit Side effect

ain yes Reduced blood clotting yes

ever yes Stomach irritation yes

flammation yes Rye syndrome no

event heart attack no Liver toxicity no

 Read the back of the box NOT the front
- Back is more reliable than the front
- Difference: wording migraine !! maybe shape or the price
Advil $23.60

Extra strength Advil $24.29

Advil Migraine $32.40

Motrin $12.49

Extra Strength Motrin $14.69

Super Strength Motrin $24.98

Children’s Motrin $45.79

Generic Ibuprofen Brand X $4.59

Generic Ibuprofen Brand Y $17.68

Price for 100 tablets

Naproxen
• Aleve
• Very good for
inflammation
• Generic now available
• Relatively expensive
• Newer
• 12- 17 hrs
• Expensive
 Top pain relievers (North America)
• Acetaminophen 43 %
• A.S.A. 28 %
• Ibuprofen 26 %
Naproxen 3%

Benefits and side effects

Effect A.S.A. Acetaminophen Ibuprofen Naproxen

Pain yes yes yes yes

Fever yes yes yes yes

Inflammation yes no yes yes

Prevent heart yes no no no

attack

Reduced blood yes no yes yes

clotting

Stomach yes no yes yes

irritation

Rye syndrome maybe no no no

Liver toxicity no yes no no

 COX-1 and COX-2 CYCLOOXYGENASE
CO2H
CO2H cyclooxygenase
O

O
arachadonic acid
OH
Prostaglandin

pain
fever
inflammation
Effect of COX-1 inhibition
Stomach: blocking this enzyme
2 effects – longer period of time
Ulcers – internal bleeding
1. HCl production increases
2. Mucus production decreases
• Platelets
– Clotting is inhibited
• Long term COX-1 inhibition
– Ulcers in stomach can bleed severely
• Harmful effects!
Effect of COX-2 inhibition
– Reduces pain
– Reduces inflammation
– Reduces fever
• Beneficial effects!

Inhibit both COX-1 and COX-2

• COX-2 is beneficial
– Reduce pain
– Reduce inflammation
COX-1 is harmful
– Stomach irritation
– Blood clotting inhibited
 – Bleeding ulcers in chronic users
– Long time use

Selective COX-2 inhibitor for arthritis

 VIOXX Clinical Trials
• Approximately 60 studies were done
– More than 5000 patients
– No serious side effects
– No difference in cardiovascular disease vs placebo
• Drug approved in 1999
– Sales averaged $ 2.5 billion/year

VIGOR - VIOXX GI Outcomes Research

VIGOR was done for marketing

• Illustrate reduced risk of ulcer

– 18 month study
– Used naproxen as a placebo
• Used VIOXX at twice the normal dose
• naproxen was given at the normal amount
– Study showed 54 % reduction in serious GI side
effects with VIOXX
– Cox-2 inhibitor
• 56 out of 4047 for VIOXX
• 121 out of 4029 for naproxen
Full VIGOR data released to FDA
• Increase risk of heart attack
– 0.4 % for VIOXX (45 out of 4047 patients)
– 0.1 % for naproxen (19 out of 4029 patients)
– No difference in mortality
• Paper in NEJM reported no adverse effects
– Only data from first 10 months was included
After 18 months – heart attack increases x4 higher
1st 10 months – no problems
Published in journals rather than FDA

FDA Analysis of 1.4 million patients

• Estimated that VIOXX caused 88,000 – 139,000 heart
attacks during 1999-2004
• In 2004, Merck voluntarily removed drug from market
– Cut 7000 jobs
– >10,000 lawsuits
 removed product due to the lawsuits

2005 Advisory Panel Conclusions

- Benefits outweigh risks
- Current arthritis treatment
o FDA estimates 10,000 to 20,000 deaths/year from
gastrointestinal bleeding
o VIOXX as an arthritis treatment
o FDA estimates 18,000 – 28,000 heart attacks/year
o Risk of heart attack similar to ibuprofen
o Improved labeling and MD education
o Knowing the risk – educates doctors and patient is
aware  steps to avoid heart attacks in place.
- Merck refused to re-introduce the drug
o Risks outweigh benefits
>10,000 lawsuits
*** Benefits out ways the risk
Did not put it back in the market
Extra from week 2 :
Antikamnia (Antifebrin) made by Chemist in bayer (Carl Duisberg)
Made from Coal Tar,
Needed to dispose 50 tons of Aminophenol,
Phenacetin
APC tablet was made up of aspirin and Phenacetin and Caffeine,
Acetaminophen (Tylenol) Extra strength?
For muscle pain and visceral pain
How does it work? To the body and what's its function
It prevents fevers as well but does nhibit the prostaglandin synthesis.
Side effect can lead to death, more than 60 tablets can lead to suicide.
Another can be Liver toxicity,
Liver protect poison (Chemical processor) If exposed to some external nature can
cause the enzyme to react to the liver and in which chemically can lead to liver damage instead
of using Glucuronyl transferase. It’s cuz the system actually activates by itself which creates the
enzyme that exposes the drug to poison.
Alcohol can activate the drug into poison.
Children Tylenol is ensured to not be able to any kind of serious damage, the most is the limit to
the body to not create poison.
Arthritis and muscle body Tylenol are the same.
Acetaminophen brings use to reduce pain and fever, but the side effect is poison.
Extra strength to be the same as regular and migraine has extra caffeine and more
expensive
Ibuprofen
Works same as aspirin and blocks cyclooxygenase
Works on pain and fever and inflammation and side effect can be reduced blood clotting
and stomach irritations
Motrin and Advil are the same, but the difference is the number of drugs used.
Naproxen
Very good for inflammation, and more expensive.
Cox 1 and cox 2?
Cyclooxygenase
Stomach blocks the enzyme and increases HCI and decrease mucus which would be poisoning
and also clotting is inhibited.
What are they and what is the difference?
,
Vioxx risks heart attack and others risk death
Vioxx was exposed because of 10-month paper in the American journal of medicine and
not the 18 months so they got attacked by lawsuits. And in which was brought back because
they later labelled it correctly since it only hits heart attacks not death.
A.S.A Is for physical pain the muscle and it helps reduce pain, fever, and inflammation by
nullifying the cyclooxygenase enzyme. Reduce blood clotting but gives stomach irritation if taken
too much.
Acetaminophen (Tylenol) for both muscle and organ pain, it’s for pain and fever and it’s better
because the side effects are less, then the A.S.A because it does not give Rye syndrome. Since it’s
not good against inflammation, we tend to use Naproxen since it contains everything, but
relatively expensive. Never take it with alcohol because it makes them poisonous and if taken in
a long time it creates liver toxicity.
Ibuprofen helps with pain and fever and inflammation and it also reduces blood clotting and
gives us stomach irritation, if taken too much.
Cox 1 and Cox 2
Cyclooxygenase and Prostaglandin, so if we take a drug, we nullify Cycloo and in which
will affect us in the long run with ulcers and stomach problems, but it helps us with outside pain
Vioxx helps us with taking in COX 2 and later in the long run it will hurt us in the heart. For
to take in cox 1 there are certain medications for it.
  Nearly half of body’s mass
 Can transform chemical energy (ATP) into directed mechanical energy, which is
capable of exerting force
 Terminologies: Myo, mys prefixes for muscle
 Sacro- flesh
 Example: sarcoplasm: muscle cell cytoplasm
Three types of muscle tissue
 Skeletal muscle tissue (elongated cells)
Cover skeletal muscles organs attach and cover skeleton
StraitedVoluntary muscle conscious control
Overall body mobility
Contract rapidly but rest after a short period
 Cardiac muscle tissue
Only in the heart, constitute the bulk of the heart wall
Straited and Involuntary stimulated by the nervous system
 Smooth muscle tissue (elongated cells)
Found on the walls of hollow visceral organs
Stomach, urinary bladder and respiratory passages
Role  forces fluids and other substance’s through internal body channels
Form valves to regulate the passage of substances through internal body
opening
Dilates and centrists the pupil of your eyes
Forms erector pili muscles attached to hair follicles
No striationsvisceral and involuntary
Only skeletal and smooth muscle cells are elongated and referred to as muscle fibers

Characteristic of muscle tissues EEESTC

1. Excitability (responsiveness): ability to receive and respond to stimuli by
changing its membrane potential chemical stimulus usually NT released by a
nerve cell
2. stimulus usually a chemical (NT, hormone, pH)
3. response = AP along sarcolemma + muscle contraction
4. Contractility: ability to shorten forcibly when adequately stimulated
 5. Extensibility: ability to be stretched or extended muscles shortened when
contracted
6. Elasticity: ability to recoil or resume resting length after being stretched

Muscle Functions
Four important functions
1. Produce movementlocomotion and manipulation
2. Maintain posture and body positionagainst gravity
3. Stabilize joints
4. Generate heat – shivering maintains a role in normal body temp
Additional functions
Protects organs, forms valves, controls pupil size

 Skeletal muscle has a rich blood supply because contracting muscle fibers use
huge amounts of energy and require almost continuous delivery of oxygen and
nutrients via the arteries.

 Muscle cells also give off large amounts of metabolic wastes that must be
removed through veins if contraction is to remain efficient.

 Capillaries, the smallest of the body’s blood vessels, take a long and winding
path through muscle, and have numerous cross-links, features that accommodate
changes in muscle length. They straighten when the muscle stretches and contort
when the muscle contracts

 In an intact muscle, there are several different connective tissue sheaths.

Together these sheaths support each cell and reinforce and hold together the
muscle, preventing the bulging muscles from bursting during exceptionally
strong contractions.

Epimysium outside & overcoat

dense, fibrous connective tissue that surrounds the whole muscle
Perimysium
fibrous connective tissue surrounding fascicles (groups of muscle fibers)
muscle fibers grouped into fasciclesperimysium surrounds fascicles
Endomysium within the muscle
fine layer of areolar connective tissue that surrounds each muscle fiber (cell)
Deep fascia:
still coarser layer of dense connective tissue that binds muscles into
functional groups
e.g. hamstrings are separated from quadriceps by deep fascia
 when muscle fibers contract, they pull on these sheaths, which transmit the
pulling force to the bone to be moved. The sheaths contribute somewhat to the
natural elasticity of muscle tissue, and also provide routes for the entry and exit
of the blood vessels and nerve fibers that serve the muscle.
 When a muscle contracts, the movable bone, the muscle’s insertion, moves
toward the immovable or less movable bone, the muscle’s origin. In the muscles
of the limbs, the origin typically lies proximal to the insertion.
Muscle Fiber Microanatomy
long, cylindrical cell with many oval nuclei (cell membrane is the sarcolemma)
huge cells (diameters of 10-100 μm & lengths in cm)
sarcoplasm contains lots of
[Link]granules of stored glycogen for glucose for the cell during muscle activity
for ATP 2. Myoglobin red pigment that contains 02 for transportation
[Link]

3 specialized structures
1. Myofibrils lots
2. Sarcoplasmic reticulum
3. T tubules
Myofibrils
each muscle fiber (cell) consists of parallel myofibrils
• ~80% of cell volume (100s to 1000s per cell)
• myofilaments (actin, myosin, etc.) arranged in a pattern, forming end-to-
end sarcomeres
• densely packed
• bunch or sarcomeres- myofilaments(even smaller) make up myofibrils
muscle (organ)fascicle muscle fibermyofibrilssarcomere
myofilaments/filament

Striations
Stripes formed from repeating series of dark and light bands along length of each
myofibril
H zone: lighter region in middle of dark A band
M line: line of protein (myomesin) that bisects H zone vertically
I bands: lighter regions
Z disc (line): coin-shaped sheet of proteins on midline of light I band

Sarcomeres
• area between two Z-lines (that zeeee shiiit )
• Smallest contractile unit (functional unit) of muscle fiber and skeletal muscle
• Band I AI
•
• sarcomeres give this muscle type the name “striated muscle
Myofilaments
 smallest of the structures
– Orderly arrangement of actin and myosin myofilaments within sarcomere
– Actin: thin filaments
 Extend across I band and partway in A band
 Anchored to Z discs
 the proteins actin and myosin play a role in motility and shape
change in virtually every cell in the body. This property reaches its
highest development in the contractile muscle fibers. There are two
types of contractile myofilaments in a sarcomere:
– Myosin: thick filaments
 Extend length of A band
 Connected at M line
Actin  drives contraction
Dark  filaments overlap
Light area  single
Molecular composition of myofilaments
Thick filaments: myosin = two heavy + four light polypeptide chains
o Heavy chains intertwine to form myosin tail
o Light chains form myosin globular head
o During contraction, heads link thick and thin filaments together, forming cross
bridges
o Myosins are offset from each other, resulting in staggered array of heads at
different points along thick filament
o Actin-bidning site  ATP binding site
Other myofibril proteins:
• Elastic filament: composed of protein titin
• Dystrophin: Links thin filaments to proteins of sarcolemma
• Mutated dystrophin  muscle dystrophy disorder lack contraction
• Nebulin, myomesin, C proteins: alignment

Thick filament
 muscle contraction depends on the myosin- and actin-containing myofilaments.
As noted earlier, thick filaments are composed primarily of the protein myosin.

 muscle contraction depends on the myosin- and actin-containing myofilaments.

As noted earlier, thick filaments are composed primarily of the protein myosin.

 Each myosin molecule consists of six polypeptide chains: two heavy (high-
molecular-weight) chains and four light chains.

 The heavy chains twist together to form myosin’s rodlike tail, and each heavy
chain ends in a globular head that is attached to the tail via a flexible hinge

 During contraction, they link the thick and thin filaments together, forming cross
bridges, and swivel around their point of attachment, acting as motors to
generate force. Myosin itself splits ATP (acts as an ATPase) and uses the released
energy to drive movement.

Thin filament
 Composed chiefly of the protein actin
 Actin has kidney-shaped polypeptide subunits, called globular actin or G actin.
 Each G actin has a myosin-binding site (or active site) to which the myosin heads
attach during contraction.
 G actin subunits polymerize into long actin filaments called filamentous, or F,
actin.
 Two intertwined actin filaments, resembling a twisted double strand of pearls,
form the backbone of each thin filament
Tropomyosin a rod-shaped protein, spiral about the actin core and help stiffen and
stabilize it.

Successive tropomyosin molecules are arranged end to end along the actin filaments,
In a relaxed muscle fiber, they block myosin-binding sites on actin so that myosin heads
on the thick filaments cannot bind to the thin filaments.

Troponinthe other major protein in thin filaments, is a globular protein with three
polypeptide subunits

 One subunit attaches troponin to actin.

 Another subunit binds tropomyosin and helps position it on actin.
 The third subunit binds calcium ions.

Elastic filament we referred to earlier is composed of the giant protein titin

 Titin extends from the Z disc to the thick filament, and then runs within the thick
filament (forming its core) to attach to the M line.
 It holds the thick filaments in place, maintaining the organization of the A band,
and helps the muscle cell spring back into shape after stretching.
 Titin does not resist stretching in the ordinary range of extension, but it stiffens
as it uncoils, helping the muscle resist excessive stretching, which might pull the
sarcomeres apart.
 dystrophin, which links the thin filaments to the integral proteins of the
sarcolemma (which in turn are anchored to the extracellular matrix).

Sarcoplasmic reticulum: SKELETAL MUSCLE FIBER—> 2 sets of intracellular tubules

that help regulate muscle contraction [Link] 2. T tubules

 SR network of smooth ER tubules surrounding each myofibril / Most run

longitudinally

– Terminal cisterns form(storage) perpendicular cross channels at the A–I

band junction
– SR: Stores and releases Ca2+
T tubules

Tube formed by protrusion of sarcolemma deep into cell interior

at A-I junction sarcolemma penetrates cytoplasm to form hollow, elongated tubes; T-

tubule = transverse tubule (lumen continuous with ECS)

Triad: group of 3 structures (2 terminal cisternae + 1 T-tubule (middle)

Sliding Filament Model of Contraction

during contraction, thin filaments slide past thick filaments, causing actin and myosin
to overlap more

Neither thick nor thin filaments change length, just overlap more

NS stimulation  myosin head binds to actin forming cross bridge

Z discs are pulled toward M line / Z discs become closer

I bands shorten / H zones disappear

A bands move closer to each other

Shortens

Relaxed  slight over lap

Contacted come together heads of the myosin pulls muscle together motor neuron

The Neuromuscular Junction

Stimulus for muscle contraction comes from the NS (motor neurons)

• Axon branches end on muscle fiber, forming neuromuscular junction (NMJ) or

motor end plate
• NMJ = axon terminals, synaptic cleft, and junctional folds
• Like neurons, muscle cells are excitable
• AP crosses from neuron to muscle cell via the neurotransmitter acetylcholine
(ACh)
Events at the Neuromuscular Junction
Four steps must occur for skeletal muscle to contract:
Events at neuromuscular junction / Muscle fiber excitation / Excitation-contraction
coupling / Cross bridge cycling
1. AP arrives at axon terminal
2. Voltage-gated Ca2+ channels open, Ca2+ enters motor neuron
3. Ca2+ entry causes release of ACh NT into synaptic cleft
4. ACh diffuses across to ACh receptors (Na+ chemical gates) on sarcolemma
5. ACh binding to receptors, opens gates, allowing Na+ to enter resulting in end
plate potential
6. Only when it reaches threshold
7. Acetylcholinesterase degrades ACh
 [Link] of an AP across the
Sarcolemma
1. End plate potential
ACh binds to ACh receptors on
sarcolemma  opening of
chemically gated ion channels
Na+ diffuses into muscle fiber 
inside becomes less negative
(more positive)
Results in local depolarization
called end plate potential (EPP)

[Link]: generation and

propagation of an action potential (AP)
If EPP reaches threshold, voltage-gated Na+
channels open
Influx of Na+ triggers AP that is
unstoppable  muscle fiber contraction
AP spreads across sarcolemma from one
voltage-gated Na+ channel to next one in
adjacent areas, causing that area to
depolarize
 [Link]: restoration of
resting conditions
Na+ voltage-gated channels close,
and voltage-gated K+ channels
open
K+ efflux out of cell rapidly brings
cell back to initial resting
membrane voltage
Refractory period: muscle fiber
cannot be stimulated for a
specific amount of time, until
repolarization is complete

events that transmit AP along sarcolemma

(excitation) are coupled to sliding of myofilaments
(contraction)
AP is propagated along sarcolemma, down into T
2+
tubules  Ca release from SR

When [Ca2+]LOW: myosin binding sites on actin blocked by

tropomyosin

Ca2+ influx: binds to troponin >> shape change & brief

detachment from actin >> moves tropomyosin away from
myosin binding sites >> sites are exposed

Ca2+ release leads to contraction

AP is brief and ends before contraction is seen

 1. Cross bridge formation: in response
to changes in [Ca2+]; high-energy
myosin head attaches to actin thin
filament active site
2. Working (power) stroke: myosin
head pivots and pulls thin filament
toward M line
3. Cross bridge detachment: ATP
attaches to myosin head, causing
cross bridge to detach
4. Cocking of myosin head: energy from
hydrolysis of ATP “cocks” myosin
head into high-energy state
This energy will be used for power stroke in next
cross bridge cycle

Four steps of the cross-bridge cycle

Motor unit
Each muscle is served by at least one motor nerve
Motor nerve contains axons of up to hundreds of motor neurons
Axons branch into terminals, each of which forms NMJ with single muscle fiber

Motor unit is the nerve-muscle functional unit

motor neuron and all muscle fibers (four to several hundred) it supplies
Smaller the fiber number, the greater the fine control
Type of movement need  number of muscles stimulated
Smaller muscles smaller motor neurons
Bicept – bigger  1 motor neuron stimulating hundreds of muscles
Size  determines action

The Muscle Twitch

Muscle twitch: simplest contraction resulting from a muscle fiber’s response to a single
AP from motor neuron
• Muscle fiber contracts quickly, then relaxes
• Some are rapid & brief/ others slow & sustained
Three phases of muscle twitch
 • Latent period: events of excitation-contraction coupling (No muscle
tension seen)
• Period of contraction: cross bridge formation: Tension increases
• Period of relaxation: Ca2+ reentry into SR: Tension declines to zero
Muscle contracts faster than it relaxes
Differences in strength & duration of twitches due to variations in metabolic properties
& enzymes between muscles
e.g.: eye muscles contraction are rapid and brief, whereas larger, fleshy muscles (calf
muscles) contract more slowly and hold it longer

Graded Muscle Responses

• vary strength of contraction for different demands
– Required for proper control of skeletal movement
• Responses are graded by:
– Changing frequency of stimulation
– Changing strength of stimulation
• Twitch: basic muscle contraction
• Wave (temporal) summation- two stimuli received by a muscle in rapid
succession

Muscle Responses to Changes in Stimulus Frequency

 Fused (complete) tetanus
If stimuli frequency further increase, muscle tension
reaches maximum
contractions “fuse” into one smooth sustained
contraction plateau
Prolonged muscle contractions lead to muscle fatigue

Unfused (incomplete) tetanus

If stimuli frequency increases, muscle tension reaches
near maximum
Produces smooth, continuous contractions that add up
(summation)

Recruitment (or multiple motor unit summation):

stimulus is sent to more muscle fibers, leading to more
precise control
Types of stimulus involved in recruitment:
Subthreshold stimulus: weak stimulus, no contractions
seen
Threshold stimulus: stimulus is strong enough to cause
first observable contraction
Maximal stimulus: strongest stimulus that increases
maximum contractile force
All motor units have been recruited

Increase in stimuli no effect in contractions

Max out all the motor units

Muscle Responses to Changes in Stimulus Strength

Recruitment works on size principle
Muscle tone: Constant, slightly contracted state of all muscles

 Motor units with smallest muscle fibers are

recruited first
 Motor units with larger and larger fibers are
recruited as stimulus intensity increases
 Largest motor units are activated only for most
powerful contractions
 Motor units in muscle usually contract
asynchronously
 Some fibers contract while others rest
 Helps prevent fatigue

Whole Muscle Contraction

• Same principles apply to contraction of both single fibers and whole muscles
• Contraction produces muscle tension
• Contraction may/may not shorten muscle
Isotonic and Isometric Contractions
Isotonic contractions
• the muscle changes in length and moves the load
• The two types of isotonic contractions are concentric and eccentric
• Concentric contractions – the muscle shortens and does work
• Eccentric contractions – the muscle contracts as it lengthens
• Actin filaments shorten and cause movement

Isometric Contractions
Tension increases to the muscle’s capacity, but the muscle neither shortens nor
lengthens
Load is greater than the tension the muscle is able to develop
cross bridges generate force, but actin filaments do not shorten
Force and duration of contraction  stimuli frequencies and intensities

Energy for Contraction and ATP

ATP
• supplies the energy needed for the muscle fiber contract
• Available stores of ATP depleted in 4–6 seconds
• ATP is the only source of energy for contractile activities; therefore
it must be regenerated quickly
• ATP is regenerated quickly by three mechanisms:
• Direct phosphorylation of ADP by creatine phosphate (CP)
• Anaerobic pathway: glycolysis and lactic acid formation
• Aerobic pathway
Pathways for Regenerating ATP During Muscle Activity
Pathways for Regenerating ATP During Muscle Activity
• Aerobic endurance
• Length of time muscle contracts using aerobic pathways
• Light-to-moderate activity, which can continue for hours
• Anaerobic threshold
• Point at which muscle metabolism converts to anaerobic pathway

Muscle Fatigue
Fatigue is the physiological inability to contract despite continued stimulation
Possible causes include:
• Ionic imbalances can cause fatigue
• Levels of K+, Na+ and Ca2+ can change disrupting membrane
potential of muscle cell
• Increased inorganic phosphage (Pi) from CP and ATP breakdown
may interfere with calcium release from SR or hamper power
• Decreased ATP and increased magnesium
• As ATP levels drop, magnesium levels increase and this can
interfere with voltage sensitive T tubule proteins
• Decreased glycogen
Lack of ATP is rarely a reason for fatigue, except in severely stressed muscles

Excess Postexercise Oxygen Consumption

For a muscle to return to its pre-exercise state:
• Oxygen reserves are replenished
• Lactic acid is reconverted to pyruvic acid
• Glycogen stores are replaced
• ATP and creatine phosphate reserves are resynthesized
All replenishing steps require extra oxygen, so this is referred to as excess postexercise
oxygen consumption (EPOC)
• Formerly referred to as “oxygen debt”

Factors that Increase force of Muscle Contraction

1. Number of muscle fibers stimulated
2. Relative size of fibers: hypertrophy of cells increases strength
 3. Frequency of stimulation:  frequency allows time for more effective
transfer of tension to noncontractile components
4. Length-tension relationsip:
5. If sarcomere is less than 80% resting length, filaments overlap too much,
and force decreases
6. If sarcomere is greater than 120% of resting length, filaments do not
overlap enough so force decreases

Velocity and Duration of Contraction

How fast a muscle contracts and how long it can stay contracted is influenced by:
1. Muscle fiber type
2. Load
3. Recruitment
Muscle fiber type
Classified according to two characteristics
1. Speed of contraction – slow or fast fibers according to:
• Speed at which myosin ATPases split ATP
• Pattern of electrical activity of motor neurons
2. Metabolic pathways used for ATP synthesis
• Oxidative fibers: use aerobic pathways
• Glycolytic fibers: use anaerobic glycolysis

Based on these two criteria, skeletal muscle fibers can be classified into three types:
1. Slow oxidative fibers: low-intensity, endurance activities eg
maintaining posture
2. Fast oxidative fibers : medium-intensity activities eg sprinting or
walking
3. Fast glycolytic fibers: short-term intense or powerful movements
eg: hitting a baseball
• (see Table 9.2)
Most muscles contain mixture of fiber types, resulting in a range of contractile speed
and fatigue resistance
 • All fibers in one motor unit are the same type
• Genetics dictate individual’s percentage of each

Velocity and Duration of Contraction

Load and recruitment
• Load: muscles contract fastest when no load is added
• The greater the load, the shorter the duration of contraction
• The greater the load, the slower the contraction
• Recruitment: the more motor units contracting, the faster and more
prolonged the contraction

Adaptation to Exercise
Aerobic (Endurance) Exercise
• such as jogging, swimming, biking leads to increased:
• Muscle capillaries
• Number of mitochondria
• Myoglobin synthesis
• Results in greater endurance, strength, and resistance to fatigue
• May convert fast glycolytic fibers into fast oxidative fibers
Resistance exercise

• typically anaerobic, such as weight lifting or isometric exercises,

leads to
• Muscle hypertrophy
• Due primarily to increase in fiber size
• Increased mitochondria, myofilaments, glycogen stores, and
connective tissue
• Increased muscle strength and size

Smooth Muscle
Found in walls of most hollow organs:
Most smooth muscle organized into sheets of tightly packed fibers

Arrangement of Fibers & Microscopic Structure

• small, spindle-shaped cells; one centrally-located nucleus
• diameter 2-10 um; length 100-500 um
• cells separated by fine CT; sheets of closely opposed fibers; usually at least 2
sheets with opposite orientations
• alternating contractions of opposing layers provide mixing, peristalsis, expelling
 • varicosities instead of NMJs; bulbous swellings of autonomic ns - release NT
into wide synaptic cleft near smooth muscle cells - diffuse junctions

Differences between Smooth and Skeletal Muscle Fibers

- Fusiform, mononucleated
- Length: 100-400 m
- Absence of streaks and sarcomeres
- Presence of myosin and actin
- Dense body: anchor points for actin filaments  correspond to the Z lines of the
striated muscles
SR less developed than in skeletal muscle; no T tubules; but SR touches sarcolemma &
smooth muscle cells have large SA/volume ratio
• interdigitating thick & thin filaments:
• tropomyosin but no troponin (calmodulin instead)
Contraction of Smooth Muscle
• electrical coupling via gap junctions slow, synchronized contractions
• some smooth muscle cells are pacemaker cells
Mechanism:
1. actin & myosin interact by sliding filament mechanism
2. final trigger is rise in intracellular Ca++
sliding process is energized by ATP

Differences between Smooth and Skeletal Muscle Fibers

Speed of contraction
- In skeletal muscles: very fast muscle twitch (20 to 200 milliseconds)
- In smooth muscles: very slow muscle twitch (200 msec to> 1 sec).
Nervous and hormonal control
- In skeletal muscles: ACh is always the neurotransmitter, which is always
excitatory.
 - In smooth muscles:
1. ACh is not the only neurotransmitter, and its effect may be
excitatory or inhibitory, depending on the type of receptors present
on the smooth muscle fibers.
2. Several other neurotransmitters can also trigger or inhibit smooth
muscle contraction. Noradrenaline: excitatory (causes contraction)
for the majority of blood vessels but inhibits (causes relaxation) in
the respiratory tract

Organs attached to bones Only in heart; bulk In walls of

& skin of heart walls hollow organs,
Elongated cells = muscle
Striated / e.g., stomach,
fibers urinary
Involuntary
Striated (striped) / bladder, and
Voluntary Pacemaker sets airways
rate of
Contract rapidly; tire
easily; powerful contraction; Non-striated /
nervous system Involuntary
Require nervous system
stimulation can increase or Can contract
decrease HR without
nervous
system