MSK test 2

Analgesics definition

Decrease the awareness to pain while raising the pain threshold

Anti-inflammatory definition

Drugs that are designed to inhibit or reduce inflammatory in animals and man

Antipyretics definition

decrease the temperature in a feverish individual, but not in a normal temperature individual

What is the inflammatory process

Initiated by stimulus including physical trauma, radiation, chemicals, heat, infection, and hypersensitivity

• Causes the release of chemical mediators

Chemical mediators definition

compounds released by one cell type that attach to the receptor of a second cell type to affect the response by that second cell

histamine role in inflammation

Increase vascular permeability, increase blood flow to injured area

Prostaglandins and leukotrienes role in inflammation

pain response, vascular permeability, and chemotaxis

Phagocytes role in inflammation

Neutrophils and macrophages remove debris

Serotonin role in inflammation

Increase capillary blood flow and vascular permeability

Chemical mediators properties

have a short half life and are called local hormones

Arachidonic acid properties

unsaturated fatty acid that is the substrate for the production of compounds that help the inflammatory response

Another word for Arachidonic acid

Eicosanoids

Role of arachidonic acid in the body

Contributes to swelling, redness, and pain (inflammation symptoms)

Phospholipase A role in body

Catalyzes the intracellular release of arachidonic acid from the phospholipids

what are the two pathways to produce arachidonic acid metabolites

Cox pathway and Lipoxygenase pathway

What are the four main metabolites of arachidonic acid

-prostaglandins

-prostacyclin

-thromboxanes

-leukotrienes

When is the cox pathway induced to make more metabolites

tissue damage

Prostaglandins structure

20-carbon cyclopentano-fatty acid derivatives

When would the highest level of prostaglandins be observed

infection or injury

What are the traditional approaches to arthritic disorders

-Nsaids

-Glucocorticords

-disease-modifying antirheumatic drugs

NSAIDS MOA

decrease PG production by inhibiting one or both pathways (COX-1 or COX-2)

Salicylates history

-5th century B.C Hippocrates recommended chewing willow bark ti patients suffering from fever and pain

-1838 salicylic acid was obtained from salicin

-1860 kolbe synthesized salicylic acid from sodium phenoxide and CO2

ASA MOA that is different to other NSAIDs

Covalently modifies COX by acetylating SER530 0f COX-1 and SER516 of COX-2

• more potent for COX-1

What is the structural activity relationship of ASA

Phenolic and carboxylic acid must be ortho

Major SE of ASA

Symptoms of Peptic ulcers (from damage to the mucus layer and inhibition of the COX-1), Nausea and vomiting, and disturbances of the GI tract

what drug is the prototype of all salicylic acid derivatives

Aspirin

Salsalate benefits

as effective as ASA but fewer side effects. Does not cause GI bleeding and able to use in ASA sensitivity patients

Salicylamide benefits

• Not acidic

Lack of gastric irritation and able to be used in ASA sensitive people

Has analgesic and antipyretic activity, though small anti-inflammatory activity

Diflunisal benefits

Longer acting, slower onset medication. More potent than ASA

expensive

Indomethacin usage

short term treatment of acute gouty arthritis, spondylitis, and osteoarthritis

Indomethacin potentecy

one of the most potent NSAIDs in use (10x that of ASA)

Indomethacin main SEs

Mainly on GI tract, Headache/dizziness and tinnitus

Indomethacin NSAID class

Arylacetic Acids

Sulindac NSAID class

Non-nitrogenous analog (PRODRUG)

Sulindac SEs

commonly associated with indomethacin

Sulindac usage

long term use in the treatment of RA, gouty arthritis, osteoarthritis and spondylitis

Ibuprofen and ibufenac NSAID drug class

Racemic arylacetic acid derivatives

Ibuprofen and ibufenac potency

More potent than ASA but less potent than Indomethacin

Ibuprofen and ibufenac usage

RA and osteoarthritis

Fenoprofen calcium potency

less potent than indomethacin, Ibuprofen and ibufenac, ketoprofen, and naproxen

Fenoprofen calcium cation

when used with concurrently with hydrantoins, sulfonamides, and sulfonylureas

Displaces medication from binding site

When is Naproxen not recommended

Pregnant or lactating women or children under 16

Tolmetin anti-flammatory activity

phenylbutazone < tolmetin < indomethacin

Suprofen usage

marketed as 1% eye drop for prevention of surgically induced miosis during cataract extraction

Ketoprofen MOA

inhibitis COX as well as leukotrienes and leukocyte migration into inflamted joint

Ketoprofen usage

Long term treatment of RA and osteoarthritis

Nabumetone NSAID drug class

Non-acidic prodrug

Nabumetone Prodrug benefits

decreased GI side effects

Oxaprozin structure

a propionic acid derivative without alpha-methyl group

Flurbiprofen formulation

1st topical formulation used for ophthalmic use that inhibits intraoperative miosis induced by prostaglandins

Ketorolac structure

cyclized heteroarylpropionic acid derivative with alpha-methyl group being fused to the pyrrole ring

Ketorolac usage

short term pain management relieving moderate to severe pain usually after surgery

Diclofenac usage

One of the most widely used drugs around the world

RA, osteoarthrosis, and spondylitis

Diclofenac MOA

Inhibits lipoxygenase pathway, resulting in decreased production of leukotriene

Inhibits Arachidonic acid release and stimulation of its uptake = less arachidonic acid

Etodolac MOA

racemic mixture but only the S-isomer has anti-inflammatory properties

Highly selective for COX-2

Etodolac usage

RA

When would it be best to use a Arylacetic acid agent (Indomethacin, Sulindac, Tolmetin, Diclofenac, ketorolac, and Etodolac)

Patient who can not tolerate ASA

It has fewer side effects than usual anti-inflammatory doses of ASA

If one agent is not effective able to just switch to different arylacetic acid agent

What drug are in the N-arylantranilic acid group

Mefenamic Acid

diclofenac is also considered one

N-Arylanthranilic Acid structure

consider structural analogs of the arylacetic acid derivative

Mefenamic Acid usage

Relief of mild or moderate pain

arthritis, osteoarthritis and primary dysmenorrhea

Mefenamic Acid SEs

diarrhea, GI ulceration and bleeding, headache, nausea, drowsiness

Mefenamic Acid safety profile

cannot be used safely for over 7 days

What medications are in the Oxicam NSAIDs

Piroxicam and meloxicam

Meloxicam COX selectivity

Cox-2 selective

Oxicams usage

RA, osteoarthritis and primary dysmenorrhea as an analgesic

What NSAID is the most selective that is widely used in the market

Celecoxib

Why is COX-1 beneficial for increased GI protection

maintaining normal processes in the GI tract by stimulating HCO3- secretion and mucus, and producing an overall reduction in acid secretion

What is the primary side effect of COX-2 inhibitors to look out for

increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke

what are the Aniline & p-Aminophenol derivatives

drugs that possess analgesic and antipyretic and there is NO anti-inflammatory activities

Antidote for APAP and MOA

NAC

N acetylcysteine substitutes for the depleted glutathione by enhancing hepatic glutathione stores & by enhancing disposition by nontoxic sulfate conjugation

Where is most of the analgesic effect of opioids take place in the body for the CNS

Dorsal horn of the spinal cord

In the process of nociceptive pain where does opioid take there effect in the process

Transmission and modulation

What is the one SE of opioids that the body does not build up a tolerance to

Constipation

What are the side effects that go away with tolerance of opioids

Nausea and vomiting

sedation

slowed/stopped breathing

What opioid is superior to another for severe pain

None

Morphine MOA

Agonist at mu and kappa opioid receptor

Morphine metabolism

UGT2B7

When do you have to start dose adjusting

Morphine

50 CrCl

when do you have to stop morphine

30 CrCl

Toxic metabolite of Morphine

M3G

What opioid would you prefer in liver disease patients

Morphine, hydromorphone, and oxymorphone

M3G accumulation causes in the body

Myoclonus, seizures, and death

Morphine and histamine interaction on the body

Itching and hypotension

Active metabolite of codeine

Morphine

What is the main metabolism CYP pathway for codeine

CYP2D6

Why would you choose morphine in a patient

Cheap, less PG and PK DDI, and many different formulations

Why would you not choose morphine for a patient

Opioid allergy (true or pseusoallergy), Pruritus, and hypotension

Severe renal impairment

Chronicity of pain (leading to risk of chronic opioid AEs)

Methadone MOA

Agonist at the mu opioid receptor, antagonist at the NMDA receptor, weakly inhibits serotonin & norepinephrine reuptake

Methadone metabolism

CYP2B6 and CYP3A4 main and many other more

Methadone dose reduction threshold

10 CrCl

Methadone main interaction in body

QT prolongation

Methadone Half life

4-14 days to reach SS

Avg half life of 22 days

What is the max dose for opioid naive patients for methadone

2.5 mg Q8H

Tramadol metabolism

Prodrug into active by CYP2D6

Tramadol dose adjustment threshold

30 CrCl

Toxic metabolite of tramadol

M1

M1 toxicity MOA in the body from tramadol

strong Mu agonist and can cause CNS depression if accumulated

SSHH risk for tramadol

Serotonin syndrome, ↑ seizure risk, ↑ hypoglycemia, ↑ risk for hyponatremia