NSAIDs Flashcards
name and describe types of nsaids
Aspirin = Unique
Traditional nsaids = Big family, Ibuprofen
Cox 2 inhibitors = Small family, Cox 2 selective = celecoxib
Acetaminophen= Does not act the same way as other nsaids
describe history of aspirin
Plant = chew or swallow
White willow bark = Salix aba, 1828
Leaves of meadowsweet = Spirea ulmaria, 1839
Some pain relief but also SERIOUS side effects
Removed salicin = used to remove pain and fever
describe history of aspirin - 1897
chemist working for drug company
Father had rheumatoid arthritis
Did relieve pain but also GI issues and distress
Chemist made a simple derivative of the molecule here and he put acetyl group on it
=acetylsalicylic acid
Worked - good reilef and less side effects
Name =
A = acetyl
Spir = spirea
In = drug
= ASPIRIN
Felix hofffmann
Sold in 1899
Synthesized at bayer company
Ddint know much about cells
describe what happened in 1971
70 years later = figured out mechanism of action = 1971
ASA blocks prostaglandin synthesis
John vane= English pharmacologist, nobel prize, 1982, aspirin mechanism of action
how do nsaids work
a
how prostaglandins made
Phospholipase frees up arachidonic acid from the cell membrane
= Normal constituent, Arachidonic acid = 20 carbons
Free arachidonic acid acted on by enzymes = cox1 co2 (cyclooxygenases)
= Make prostaglandins
Enzyme sticks cyclic molecule on end of arachidonic acid structure
Why called prostaglandin
Originally isolated from semen
Thought it must be made by prostate gland and only found there but not true
Found all over body
Discovered in human semen, 1930s
describe Features = prostaglandins E2
Unsaturated carboxylic acids
20 carbon skeleton
Cyclohexane ring
Subscript = 2 or 3 indicates double bond
Made by almost all cells
Autocrine and paracrine functions = On cell itself, Cell next door *NOT ENDOCRINE
Rapidly inactivated
what do cyclooxygenases do
make prostaglandins and thromboxanes from arachidonic acid
Subtrate for many different compounds
describe cyclooxygenases
forms ring and adds 2 oxygens
Dimer
Sticks out of endoplasmic reticulum
Arachidonic acid release from membrane
Enters active site
2 active sites on enzyme
Get product = protaglandins
where do nsaids act
G protein coupled receptors
Prostanoids receptors
subgroups = PGD, E, F, I & T
Receptors = DP1, DP2, …, EP1, EP2, … and TP
where do nsaids act- functions
Have different functions
Sometimes opposing functions
Inhibit or activate adenylyl cyclase
Biological effects
Can alter ion channels
Controlling cell motility and other things
what are eicosanoids
(all of the structures formed from 20 carbon initial structure)
describe Diverse effects of eicosanoids
Prostaglandin E receptors =
1-4, When activated = have big effects on cells= Brain,kidney, vascular smooth muscle, platelets
Also synthesis of thromboxanes = involved in handling platelets and blood flow through vasculature
Also prostacyclins have a role in kidney and platelets
describe Prostaglandin synthesis
Fever, renal homeostasis, pain, inflammation, GI cytoprotection (protect stomach lining from gastric acid by increasing mucus secretion)
describe Prostacyclins
pain and inflammation and some kidney and vascular effects
Platelet aggregation
Vasoconstriction
describe eicosanoids - normal vs inflammation
Compounds always have role in normal physiology but increasing synthesis = for pain and inflammation
describe eicosanoids - normal
Semen viability
Intestinal motility
Myometrial tone
Cytoprotection
Bronchial tone
Temperature control
describe eicosanoids - inflammation
Injury and inflammation = synthesis and relative balance has changed
Very important in pathological side of things
Responsible for fever
Asthma
Ulcers = GI problems
Diarrhea
Dysmenorrhea
Inflammation
Bone erosion
Pain
describe cox1
Cox 1= mainly involved in physiological control of things
Constitutive enzyme
Platelet aggregation
Gastric mucosa
Kidney
describe cox2
involved in normal function but mostly induced during injury and inflammation
Inducible enzyme
Pathology = inflammation - Higher level cox2 - Swelling and inflammation and pain and vasodilation
IL 1, TNF induce
Steroids inhibit
what are nsaids valuable in
decreasing pain = analgesic
Inflammation = antiinflammatory
Fever= antipyretic (mild = useful but high fever= bad)
what is pain
Pain → impulse that generates pain goes up into spinal cord = relay and then shoots up through a relay on the thalamus and you are aware of it through connections on cortex
Almost instantaneous
what happens when injured - gen
Sensitive nerve endings all over body
Free nerve endings respond to injury
If injury = immediate release of blood and constituents in injured tissue
what happens when injured - specifics
Releases various prostaglandins
More cells come in from blood and cope with injury
Immediate release prostaglandins
And other things = bradykinin
= stimulate free nerve endings
If prolonged = stimulate nerve endings and impulse goes here =
Synapse in spinal cord
Inflammation to any injury - not mild
Activate macrophages and mast cells
Release all kinds of mediators =
Histamine, prostaglandin, E2, bradykinin, interleukins = Act on receptors
Instantaneous
Nocioceptors = prostaglandins sensitive to other mediators
More serious injury = platelets and thrombosis
what happens when injured - specifics spinal cord
some activity in spinal cord
If noxious problem persists = changes take place in spinal cord
Nsaids can act here
classical signs inflammation
4 classical signs =
Heat
redness = Vasodilation
Swelling = Leakage of vessels
pain
Also may be loss of function
Ex = break bone
describe nsaids for chronic issues
Usually occurs acutely but if have arthritis = happens in multiple joints
Nsaids useful for relieving pain with an acute injury in one place but ALSO relieving pain from chronic issues
describe changes caused by inflammation - gen
reaction of living tissues to injury
Additional cells and mediators from circulation
Pull in mast cells, macrophages, neutrophils
Peripheral nociceptor
Prostaglandin E2 very important here in periphery
Receptors on nerve ending
End result = impulse that travels into spinal cord and goes up into it
describe changes caused by inflammation - longer time
If long problem or significant inflammation = get changes in the spinal cord and further synthesis of prostaglandin E
= increased receptors for prostaglandins on postsynaptic side and on neighbouring internours and on primary afferent fibres
Complicated
Usually action in tissue but also spinal cord to dampen sensation of pain
describe uses of nsaids and acetaminophen - therapeutic overview
Relief of mild to moderate somatic pain including headache, toothache, myalgia (muscle pain), arthralgia (joint pain)
Relief in inflammatory disorders including rheumatoid arthritis (autoimmune problem), osteoarthritis (pretty common, in people who use particular joints more), gout (except acetaminophen)
Reduce fever
Prophylaxis (prevention) of myocardial infarction and stroke (aspirin only)= Major use of aspirin worldwide
describe uses of nsaids and acetaminophen - therapeutic overview generally
Cardiovascular diseases= Atherosclerosis, cerebrovascular diseases, heart failure, cardiomyopathy, stroke
Chronic inflammatory diseases = IBD, COPD, RA, psoriasis, chronic pancreatitis, CIDP, CICTD
Bone muscular and skeletal diseases = Osteoporosis, osteoarthritis, DDD, muscular dystrophy
Decrease incidence of some types of cancer = Lung cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer, lymphoma
what is Most common use besides preventing heart attack
or joint pain
Rheumatoid arthritis and osteoarthritis
Osteoarthritis =
Tends to be focused on certain joints
Can impair walking
Hip replacements can be done
Milder problems solved by taking nsaids
describe nsaids for animals
Also used in horses
For horse races
Dogs
Hip arthritis in dogs
Relieve pain and inflammation
Has to be tested tho
For species
TOXIC TO CATS
describe nsaids treating fever - what is fever
Temperature regulating center in the hypothalamus
Can be altered by exogenous pyrogens = bacteria and viruses, can cause infection and release pyrogens
what are pyrogens
elevates body temperature and act in hypothalamus
what can also release endogenous pyrogens - fever
Also macrophages, monocytes and t cells can release endogenous pyrogens
Move into hypothalamus and trigger increase in temp
what raises set point - fever
Increase in production of prostaglandin E2 and raises set point
Impulses sent to periphery = person starts to vasoconstrict and sweating = lose less heat
With The shivering and muscle contraction = generate more heat
= Increase body temp
describe how nsaids help control fever
Hypothalamic set point = have prostaglandin E2 increases in terms of synthesis
Drugs interfere and control fever
describe Side effects of common nsaids - upper GI
stomach
Dyspepsia = gastric discomfort
Erosions = Of musical lining, Can cause bleeding
Anemia - GI bleeding = Not normal number of circulating blood cells
Ulcers - bleeds/perforations
describe Side effects of common nsaids - renal
Renal dysfunction
Renal failure - acute/chronic
Blood pressure
Heart failure - If significance problems
describe Side effects of common nsaids - Anti platelet effects
= contributes to blood loss
If too much = bad
describe chronically taking nsaids
More issues if chronic use or high doses
Ex = rheumatoid arthritis
Taking high dose
Lining of stomach = secrete HCL, lining of music, protecting stomach
Nsaids can = Interfere with production of prostaglandins and mucus and bicarbonate
= Decreases protective features, Protection from HCL
Nsaids get access to these exposed ells
Does not affect everyone
Biological variability
Can get ulcers
describe aspirin generally
Tea from willow leaf
1800s = salicin
Felix hoffmann
Aspirin = generic name
Easy to manufacture and cheap
Most commonly used drug in the world
Close to 3 billion worth of aspirin sold every year
describe aspirin history
400 BC: Greece, Hippocrates gives willow leaf tea to relieve pain
1828: In Italy, active ingredient is extracted from willow and named salicin
1897: In Germany, Bayer’s Felix Hoffmann develops and patents a process for synthesizing aspirin. 6 First clinical trials begin because back then, people just swallowed the drug.
1899: Aspirin was launched for the first time
1930s: Bayer’s patent runs out; aspirin generic
what are aspirin features
Analgesic, anti inflammatory, antipyretic, antithrombotic
Used in other parts of the world for pain and inflammation and fever
In canada = mainly for preventing heart disease
describe aspirin - cox1
homodimer
Attached to cell membrane
Arachidonic acid comes in and then acted on by enzyme
Aspirin acetylates enzyme = leaves acetyl group
Inactivates cyclooxygenase = permanent inhibition
Sine acetyl group stays there and doesn’t come off
Inactivated enzyme
Have to synthesize more of enzyme
Irreversible effect
Salicylic acid bound = serine acetylated
can aspirin bind cox1 and 2
Aspirin = small molecule so can block both cox1 and cox2
Variety of effects
Anti pain anti inflammatory
Vascular effect = block thromboxane and prostacyclin
describe aspirin and thromboxane A2 - gen
Thromboxane A2 made in platelets = causes vasoconstriction, thrombosis
can block with aspirin
Platelets have No nuclei
Blockade for life of platelet = 8-12 days
Decreases risk of blood clot in coronary or cerebral artery
describe aspirin and thromboxane A2 - doses
Little doses of aspirin
Decreases potential of platelets to clump and cause thrombus
Decrease chance of thrombus forming in vasculature
Will not block all since low dose
describe aspirin and thromboxane A2 - platelets
Platelet activated
Thromboxane A2
Platelets clump and thrombus forms
Activates glycoprotein receptor
Aspirin interferes with thromboxane a2 = agonist ADP, thrombin, epinephrine, etc
Useful in preventing strokes and heart attack = small doses
describe another action of aspirin - discovered by chance
Also discovered by chance = long term aspirin use lowers colon cancer risk
Led to discovery that inflammation is a part of carcinogenesis
describe kinetics of aspirin
Low dose = first order kinetics
Switch to zero order at high dose = longer to get rid of it
describe aspirin pharmacokinetics - metabolism and excretion
Aspirin converted back to salicylic acid and a significant amount is just excreted in urine , Other parts of it = type 2 reaction converted something we can easily excreted from kidney = add glucuronide
Salicylic acid can be reabsorbed from kidney
If urine changed to alkaline conditions = resorption is less and it will remain in lumen
More excreted
Alkaline urine more excreted
what is salicylism
aspirin toxicity = if chronic use, or kids swallow
salicylism side effects
Headache, tinnitus, dizziness, hearing impairment, dim vision = Cns effects, Tinnitus = if hear ringing in ears = must cut down since getting to toxic dose
Condusion, drowsiness
Sweating and hyperventilation
Nausea, vomiting
Marked acid base disturbance = issue
Hyperexia
Dehydration
Cardiovascular and respiratory collapse, coma convulsions and death
If overdose
can be fatal
Easy ways to monitor concentration in blood
can you give aspirin to kids
Do not give aspirin to kids
REYE’s syndrome
So rare, only occurs in some people
Hard to study
Other nsaids can be given to children instead of this one
describe traditional nsaids
Many drugs
Blocks cox1 and 2
Depends on drug
describe traditional nsaids- ibuprofen
Iso-butyl-propanoic-phenolic acid
C12H18O2
MANY different names
Should not take aspirin before ibuprofen
why can we not take aspirin with ibuprofen
Ex = low dose aspirin for cardiovascular effects then if need something for pain = do not take ibuprofen
Since aspirin permanently acetylated enzyme
When take ibuprofen - before or after = they block each other
If take ibuprofen first = aspirin cannot access
Other way around too
Describe Pharmacokinetics nsaids
Liver deals with it
P450
conjugation = now water soluble and can be excreted by kidney
Inactivated then made water soluble - kidney gets rid of tem
Describe cox2 inhibitors
COX2 inhibitors
Some nsaids designed specifically for this
Cox2 - mainly activated during tissue injury and inflammation
Maybe if can block= give fewer side effects
Thromboxanes platelets, And prostaglandins = endothelial cell
Describe cox2 inhibitors compared to low dose aspirin
Low dose aspirin = less platelet aggregation and inhibit coagulation and cause vasodilation = More blood flow and less clotting
If cox2 inhibitor= Still have cox1 so bigger chance of platelet aggregation = risk
Cox 1 vs 2 inhibitors
Some developed specific for cox2 BUT Problems tho
Non selective cox inhibitors = effect both
Selective cox 2= only effect on Pain fever and inflammation
But also has some functions in body generally = Renal electrolyte homeostasis and renal blood flow maintenance
Knock out this role = bad if inhibit
Channel wider in cox2 in enzyme
describe Celecoxib
selective cox2 inhibitor
Vs aspirin
Aspirin can get into both
Celecoxib = designed so can get into the bigger one but not the smaller one- wont block cox1
describe Ex = rofecoxib vs naproxen
1 year long study
Adverse cardiovascular effects increases a bit with using only cox2 inhibitor
Small difference
Rofecoxib taken off market after this experiment
Taken off by company that made it
Beneficial effects must be greater than potential side effects
describe acetaminophen
Name by chemical structure =
Para acetylaminophenol = Acetaminophen
Para acetylaminophenol = Tylenol, Trade name
Sales gone up beyond aspirin and ibuprofen- Aspirin no longer given to kids
Combined with many things
Many different names
what does acetaminophen do
Analgesic, antipyretic, NOT anti inflammatory
Brings down fever
Helps with pain
why is acetaminophen not anti inflammatory
Specific cyclooxygenase?
Do not KNOW
Acetaminophen only acts in some tissues = endothelial cells, not platelets or inflammatory cells
describe Pharmacokinetics acetaminophen
t1/2 = 2-3 hours - Not long
1500mg/dose
Can be converted to toxic metabolite that damages liver
describe Pharmacokinetics acetaminophen - metabolites
Hepatotoxic metabolites
If have overdose = serious liver damage
Can be metabolized many ways = Glucuronide conjugate, sulfate conjugate, cysteine conjugate
Can also be converted to toxic metabolite by p450s
Injures liver
Can kill you
Gradually
describe acetaminophen poisoning
High fatal poisoning cases
Sometimes kids get into it
Sometimes people take it on purpose
Stages of poisoning
describe stages of acetaminophen poisoning
The effects don’t show up immediately:
0-24 hours: anorexia, nausea, vomiting => if treated on the first day, the rest can be avoided
24-72 hours: abdominal pain, right upper region, elevated serum enzymes indicating liver injury.
72-96 hours: vomiting and symptoms of liver failure, sometimes renal failure, and pancreatitis.
> 5 days: the resolution of hepatotoxicity or progression to multiple organ failure – sometimes fatal => if ignored for over 5 days, can cause many organ failures and thus death.
describe how to help acetaminophen poising
Metabolite - Can be conjugated with glutathione = now harmless
With poisoning = exceeded capacity of glutathione
Antidote = glutathione precursor
N acetylcysteine
describe label of acetaminophen - interaction with alcohol
Ethanol acetaminophen interaction
Chronic ethanol - at risk of acetaminophen hepatotoxicity
ETOH induced p450 enzymes (1AA2, 2E1, 3A4) that convert acetaminophen into toxic metabolites that cause liver injury
ETOH depletes glutathione stores, slowing removal of metabolites
Increased possibility of liver injury
