Pain (MC) - Block 2 Flashcards
What type of compounds of PPB?
- Lipophilic
- Acidic
What are the indications for non-narcotic?
- Mild to moderate pain without altering consciousness
- Dull aches
- Ceiling effect
- No tolerace/physial dependence
What is the difference between Cox 1 and 2?
What is an analdesic?
Relief of pain, minor aches
What is anti-inflammatory?
Reduction of inflammation associated with arthritic syndromes
What is antipyretic?
Reduction of elevated body temp
Acetaminophen
MOA, BBW, Metabolism, Elimination, Dosing
MOA: analgesic, antipyretic (NOT anti-inflammatory)
BBW: hepatotoxicity
Metabolism: Both CYP2E1 and CYP3A4 are induced by ingestion of alcohol
Elimination: Gluthione and renal
Dosing: 4 g/day
What is the antidote for tylenol?
N-acetylcysteine
Why is APAP not considered an NSAID?
- Not anti-inflammatory
- Weak acid
- Doesn’t have antiplatelet or gastric ulcerogenic activity
How are NSAIDs excreted?
Renal
How are NSAIDs distributed?
All in synovial fluid after repeated dosing
Describe the toxicity of NSAIDs?
Nephro (interference with autoreg of renal blood flow) and hepatotoxic
NSAIDs
MOA, Interaction
MOA: inhibti PG synthesis via inhibition of COX1/2
Interactions: highly acidic so it interferes with drug that PPB, inhibits metabolism PG
What is the function of PGE2?
Enhanes local inflammation -> localized edema and hyperalgesia
Ihibition of prostanoid synthesis causes:
- Anagesia
- Antipyretics
- Anti-inflam
- Anti-thrombotic
- Closure of ductus arteriosis (X in pregnancy)
- GI tox
Why do NSAIDs cause gastric damage?
How does aspirin differ from other NSAIDs?
Covalently modifies COX enzymes (irreversible)
Aspirin
MOA, PK
MOA: 10-100 more potent against COX1 than COX2
PK: Absorption is sensitive to pH of stomach, raising gastric pH slows absorption, more ionized
ADR of aspririn?
Mostly GI
Hypersensitivity rare but fatal (skin rahses, watersecretions, uricaria, rhinitis, edema, bronchoconstriction, anaphylaxis)
Indicatiosn for aspirin?
Ana;gesia, antipyretic, anti-inflammatory, uricosuric, CV effects
How does aspirin bind to receptor?
Ser initiates nucleophilic attack on acetoxy on aspirin -> salicylate anion leaves and acetoxy group irreversibily covalently bind to ser
What is the warning when using salicylates in children?
Development of Reyes: sudden vomiting, violent HA, and unusual behavior
* Warning against their use in children under 16 with influenza, chicken pox, or flu-like illness
What is the SAR of arylalkanoic acids?
a-carbon = unsubstituted = arylacetic acid
* aryl group = phenyl -> “fenac”
a-carbon has a methyl = arylpropionic acid (chiral – racemic mixture because rapid epimerization but S enantiomer = active)
* aryl group = phenyl -> “profen”
Second aromatic ring good for activity (noncoplanar increased lipophilicity or blocked CYP metabolism)
Stable para substituents -> longer DOA
What are the types of arylacetic acids?
- Indomethacin (Indocin, Tivorbex)
- Sulindac
- Diclofenac (Cambia, Voltaren, Zipsor, Zorvolex)
- Nabumetone (Relafen)
Indomethacin
MOA, ADR
MOA: very potent antipyretic and analgesic
* Cis-like is required for anti-inflammatory
* Uriosuric (for gout)
ADR: GI plus CNS (headache/dizziness/vertigo), ears (tinnitus)
* Aggravate depression, epilepsy, Parkinsonism
How does sunlindac differ from other NSAIDs?
Prodrug with longer DOA because active metabolite have half-life 2x of parent
Sunlindac
ADR
ADR: Less Gi effect due to prodrug form
* GI/CNS ADR milder and less common do to less PG activity
What makes diclofenac potent?
Three potential MOA:
1. Inhibition of COX system -> decreased prostaglandins and thromboxanes
2. Inhibition of lipoxygenase pathway -> decreased leukotrienes
3. Inhibition of arachidonic acid release and stimulation of its reuptake
Thought that chlorines push the ring out of plane of other ring -> important for COX binding
Diclofenac
MOA, ADR
MOA: Very potent anti-inflammatory, analgesic and antipyretic
ADR extensively metabolizd by CYP2C9 -> risk of hepatotoxicity
What is a structure that can cause hepatotoxicity?
Diclofenac
- Open para to the amine -> hydroxyl insertion in para position
- Amines para to an OH
What makes Nabumetone special?
Nonacidic prodrug
Nabumatone
ADR
Minimal GI ADR since nonacidic and ineffective PG inhibitor
Examples of arylpropionic acids
- Ibuprofen (Motrin)
- Ketoprofen
- Suprofen
- Ketorolac
- Oxaprozin
Ibuprofen
MOA, PK, DOsing
MOA: Analgesic but not anti-inflammatory
PK: size and lipophilicity mimic an aromatic ring
Dosing: ≤1600 mg/day
How does ketoprofen differ from ibuprofen?
Inhibits synthesis of leukotrienes and leukocyte migration in addition to inhibiting prostaglandin biosynthesis
What is the problem with suprofen?
Used as an analgesic -> reports of severe flank pain and transient renal failure
ONly 1% ophthalmic solution
What drug is very toxic 5x that of other NSAIDs and can only be used for 5 days?
Ketorolac
What makes ketorolac special?
Good analgesic activity comparable to opioids
Oxaprozin
PK, ADR
PK: Prolonged DOA
ADR: rash and mild photosensitivity
SAR of oxicams
Aryl or heteroaryl ring = optimal
Plus ring -> noncoplanar
(and must be primary carboxyamide – enhances acidity)
Desinged to be noncarboxylic acid to be well tolerated and potent
How is oxicam acidic despite noncarboxylic features?
Hydroxyls are stabilized by resonance
What is the difference between the types of Oxicams?
Piroxicam: more COX1 selective
Meloxicam (Mobic): More COX2 selective
What is the difference between COX 1 and 2 pockets?
COX 1: Isoleucine
COX 2: Valine (larger binding site)
- Harder for larger, relatively rigid side-chain substituents to enter COX-1
How does COX2 inhibitors differ from nonselective?
Decreased GI ADR, but increased risk of CV effects
* For patients with low cardiovascular risk but increased GI toxicity risk
Types of COX2 inhibitors?
- Celecoxib (Celebrex)
Celecoxib
PK, Binding
PK: metabolized by CYP2C9 and inhibits CYP2D6
Binding: Ionic bond and Val binds to ring
What is the site of action for skeletal muscle relaxants?
Most DO NOT act at neuromuscular junction (except dantrolene)
Main effect: to depress CNS -> relax motor neurons
* More brain or CNS relaxants than muscle relaxants
What is the indication for skeletal muscle relaxants?
Muscle spasms from strains, sprains, and musculoskeletal trauma or disease
What are the types of muscle tone modulators?
- Methocarbomol (Robaxin)
- Metaxalone (Skelaxin)
- Carisoprodol (Soma)
- Cyclobenzaprine (Flexeril)
- Orphenadrine
- Chlorzoxazone
What are the indications for muscle tone modulatpors?
Acute muscle spasm (2-3 week max course)
What are the ADRs for muscle tone modulators?
- Sedation, mood changes
- Drug and alcohol interaction
- HIgh risk for abuse
Orphenadrine
MOA, Indication
MOA: anticholinergic, ethanolamine antihistamine
Indication: Pain of all etiologies
Types of anti-spasmodics? Site of action?
- Dantrolene
- Baclofen
- Tizanidine
- Benzodiazepines
CNS and spinal cord
Tizanidine
MOA, PK, ADR
MOA: Analog of clonidine – presynaptic inhibition of motor neurons at α2 adrenergic receptors
PK: heavily metabolized
* Hepatic injury/death due to liver failure have been reported
ADR: Drowsiness, hypotension, dry mouth, hepatotoxicity, rebound hypertension
Baclofen
MOA, ADR
MOA: GABAB receptor agonist
1. Closure of presynaptic calcium channels
2. Increased postsynaptic K+ conductance
3. Inhibition of dendritic calcium influx channels
ADR: Excessive weakness, rebound spasticity
Benzodiazepines
MOA, ADR
MOA: Acts at GABAa
* Positively modulates opening of Cl- channels -> neuron hyperpolarizes
ADR: Sedation, abuse
What are direct-acting muscle relaxant?
Dantrolene
Riluzole
Dantrolene
MOA, ADR, BBW
MOA: acts at sarcoplasmic reticulum in skeletal muscle
* Binds to ryanodine receptor (calcium channel protein) to close channel -> inhibits release of calcium
* Acts directly on contractile mechanism of skeletal muscle to decrease force of contraction – w/o effects on neural pathways, neuromuscular junction or excitable properties of muscle fiber membranes
* Minimal effects on cardiac and smooth muscle (different ryanodine channel)
ADR: Non-specific on skeletal muscle -> AE = generalized muscle weakness
* Sedation
BBW: hepatotoxicity
Riluzole
MOA, Indication
MOA: Blocks tetrodotoxin (TTX) sensitive sodium channels associated with damaged neurons
Indication: Amyotrophic lateral sclerosis (ALS)
