Peter Test 1

- Extreme temperatures

- Injury

- Chemical irritation

Pain triggers

the physiological process of detecting/transmitting noxious stimuli to the CNS

Nociception

- Transduction

- Conduction

- Transmission

- Modulation

- Perception

Nociception Steps

ascending pathways

transmission

descending pain pathway (attenuates pain through endogenous opioids)

modulation

<30 days

Acute pain

Months to years

chronic pain

0-2

mild pain

4-6

moderate pain

8-10

severe pain

Soft tissues and musculoskeletal structures

somatic

Internal organs

visceral

feels like it's coming from a nearby somatic structure

Referred pain is visceral, but

- nociceptive

- neuropathic

- nociplastic

Non-cancer pain

Tissue damage

Nociceptive

CNS/PNS damage

Neuropathic

- central sensitization

- CNS becomes hypersensitive and amplifies pain signals

- example is fibromyalgia

Nociplastic

- Nerve and bone pain

- Inflammation and chemotherapy (treatment-related)

cancer pain

Abnormally increased pain

Hyperalgesia

Pain from stimulus that doesn't usually cause pain

Allodynia

Inability to feel pain

Analgesia

Reduce prostaglandin synthesis by inhibiting COX enzymes

NSAIDS MOA

maintains GI epithelium

COX 1

is overexpressed in inflammatory diseases

COX 2

-anti-inflammatory

- analgesic

- antipyretic

NSAIDS effects

- Inhibit chemotaxis (directed movement of cells in response to a chemical gradient)

- Decrease IL-1

- Produce Reactive Oxygen Species

anti-inflammatory

Reverse peripheral sensitization

analgesic

Suppress PGE2 production

antipyretic

- Irreversible COX inhibitor

- Antiplatelet effects last 7-10 days

Asprin

- Reduces platelet aggregation

- primary use

Low dose aspirin (<325 mg)

Antipyretic and analgesic effects

Intermediate dose aspirin (325-2,400 mg)

Anti-inflammatory effects

High dose aspirin (2,400-4,000 mg)

Reye's syndrome when used for viral infections and fever

Asprin has an increased risk of _____ in children

GI bleeding (except for aspirin)

NSAIDS BBW

An increased risk for nephrotoxicity and AKI

NSAIDS AE

- celecoxib

- increased risk for CV events (MI, stroke, HF)

- decreased risk for GI events

COX-2 selective NSAIDS

- diclofenac

- meloxicam

- increased affinity for COX-2 but still retain activity for COX-1

- caution in patients with increased CV risk

partially selective NSAIDS

- ibuprofen

- naproxen

- aspirin

- decreased risk for CV events

- aspirin is cardio protective at low doses

- increased risk for GI events

nonselective NSAIDS

Take aspirin 1 hour before or 8 hours after

Ibuprofen special considerations

- One of the safest NSAIDs

- Has a long t1/2

Naproxen special considerations

- Has many dosage forms

- Oral

- Topical

- Ophthalmic

- Patch

- Injection

- Has increased risk of bleeding and CV events after an MI

Diclofenac special considerations

- Strong GI effects

- Pancreatitis

- Headache

- Effective for acute inflammation

indomethacin special considerations

Also inhibits LOX enzymes

- ketoprofen special considerations

Affects TNF-alpha and nitric oxide synthase (NOS)

flurbiprofen special considerations

- very High GI bleeding risk

- very Potent

- PO

- IV

- IM

ketorolac special considerations

- Dosed QD, but high doses are needed

- Has a low risk of GI damage

nabumetone special consideration

Useful in gout (since it is uricosuric)

oxaprozin special consideration

- Inhibits neutrophil migration and lymphocyte function, and decreases ROS formation at high doses

- Has a high risk of peptic ulcers and bleeding

piroxicam special consideration

- Useful in RA and OA

- Has a high risk of MI and thrombosis

meloxicam special consideration

- Renal toxicity

- Rashes

- HTN

- Thrombotic events

celecoxib special consideration

- Inhibits COX-3

- Has minimal effects on COX-1 or COX-2

acetaminophen MOA

- Analgesic and antipyretic effects

- No anti-inflammatory effects

acetaminophen has

4g/day

acetaminophen max dose

Severe hepatotoxicity

acetaminophen AE

N-acetylcysteine

________ is the antidote for acetaminophen overdoses

antipyretic

anilides have _____ effects

- Methemoglobinemia

- Jaundice

anailides toxicities

iron in hemoglobin is oxidized to a ferric state, which prevents it from carrying oxygen effectively

Methemoglobinemia

- Carboxylic acid is necessary, and must be adjacent to a hydroxyl group

- Presence of di-fluoro groups increase lipophilicity and acidity

salicylates

Optimal separation of carboxylic acid from the aromatic ring is one methylene unit

Aryl acetic acids

- Optimal separation of carboxylic acid from the aromatic ring is one methylene unit

- Alpha-substitution with a branched alkyl group is detrimental

- Highest level of anti-inflammatory activity occurs with the S-(+) isomer

Aryl propanoic acids

Display different pharmacophores

Oxicams

CYP2C9 metabolism by oxidation of pyridine

Piroxicam

CYP2C9 metabolism by thiazole methyl group

Meloxicam

Carboxylic acid group is replaced with sulfonamide

Selective COX-2 inhibitors

- Most opioids act on the mu-opioid receptors

- Directly inhibit neurons to lead to the activation of descending inhibitory neurons (inhibit an inhibitory, or GABAergic, neuron)

Opioid MOA

- Close presynaptic voltage-gated Ca2+ channels (VGCCs).

- Open postsynaptic K+ channels

opioids cellular effects

- Analgesia

- Addiction (“reward pathway”)

- Euphoria

- Dysphoria

- Sedation

- Opioid-induced hyperalgesia

- Respiratory depression (Cause of overdose/death)

- Cough suppression

- N/V

- Temperature fluctuations

- Neuroendocrine effects

- Miosis (pupil constriction)

opioids CNS effects

- miosis

- constipation

Patients will not develop tolerance to

- Constipation

- Urinary retention

- Immune system modulation

- Vasodilation

- Pruritus

- Bronchoconstriction

opioids peripheral effects

- Addiction, abuse, and misuse that can lead to OD and death

- Respiratory depression (that can be fatal)

- Increased risk of death when combined with other CNS depressants (benzodiazepines, alcohol, etc)

- Accidental ingestion in children can be fatal

- Crushing, dissolving, or chewing long-acting products can deliver a fatal dose

- Life-threatening neonatal withdrawal with prolonged use during pregnancy

opioids BBW

- Oral doses need to be much higher than IV doses due to the first pass effect

- Renally excreted

opioids PK

CYP3A4

fentanyl is metabolized by

CYP2D6

Codeine (a prodrug), oxycodone, and hydrocodone are metabolized by

Involves reduced clinical efficacy after using (higher doses are needed to achieve the same effects)

opioid tolerance

- Receptor down-regulation

- Anti-opiate chemicals

- Can be avoided with "opioid rotation"

opioid tolerance occurs due to

- psychological

- physical

opioids dependance can be

Desire/compulsion to take the drug despite harm

Psychological

Withdrawal symptoms occur with cessation of drug exposure

Physical

- Codeine

- loperamide

- Diphenoxylate/atropine

- methadone

- buprenorphine

- fentanyl

- meperidine

opioid agonist drugs

- analgesia

- Cough

- Diarrhea

- opioid use disorder

- anesthesia adjuvant

- post-anesthetic shivering

opioid agonists treat/cause

codeine

cough

- loperamide

- Diphenoxylate/atropine

diarrhea

- Methadone

- Buprenorphine

opioid use disorder

fentanyl

anesthesia adjuvant

Meperidine

Post-anesthetic shivering

- Naloxone

- Naltrexone

- Methylnaltrexone

- Naloxegol

- Naldemedine

opioid antagonist drugs

- opioid overdose

- OUD

- opioid-induced constiptaion (OIC)

opioid antagonists treat/cause

Naloxone

opioid overdose

Naltrexone

OUD

- Methylnaltrexone

- Naloxegol

- Naldemedine

opioid-induced constipation (OIC)

Oxymorphone

Hydromorphone

Levorphanol

Morphine

Oxycodone

Hydrocodone

Dihydrocodeine

Codeine

- old heads love mouthing off (go) home dirty clown

order of potency (most to least)

- morphine

- hydromorphone

- oxymorphone

- methadone

- fentanyl

- sufentanil

- alfentanil

- remifentanil

- meperidine

- levorphanol

strong agonists

- codeine

- oxycodone

- dihydrocodeine

- hydrocodone

- diphenoxylate

- loperamide

mild/moderate agonists

- buprenorphine

- butorphanol

- nalbuphine

- pentazocine

mixed receptor actions

- tramadol

- tapentadol

other CNS analgesics

- Naturally occurring

- Benzene ring

- Piperidine ring (N17)

- Phenol (C3)

- Secondary alcohol (C6)

- Alkene (C7-C8)

morphine

- Tertiary basic amine (N17)

- Central carbon (C13) with no hydrogens

- Phenyl ring attached to the central carbon (C13)

- Two carbons between the central carbon (C13)

in morphine there must be

agonist/antagonist activity

N17 substituent determines

activity

Phenol at C3 affects