Barker Pharmacology of Non-opiate Drugs Flashcards
What are the different chemical structures classified as NSAIDs?
-Salicylates
-Arylpropionic acid
-Arylacetic acids
-Enolic acids
What are the salicylate NSAIDs?
Aspirin
What are the arylpropionic acid NSAIDs?
-Ibuprofen
-Naproxen
What are the arylacetic acid NSAIDs?
-Indomethacin
-Diclofenac
-Ketorolac
-Etodolac
What are the enolic acid NSAIDs?
-Piroxicam
-Meloxicam
Therapeutic applications of NSAIDs
-Analgesic
-Anti-inflammatory
-Antipyretic
-Prophylactic to reduce risk of myocardial infarction - aspirin
Examples of when NSAIDs will be used for analgesic purposes
-Chronic postsurgical pain
-Myalgias and arthralgias/sprains and strains
-Inflammatory pain
-Dysmenorrhea (specific PGE effect)
Examples of when NSAIDs will be used for anti-inflammatory purposes
-Bursitis and tendonitis
-Osteoarthritis
-Rheumatoid arthritis
-Gout and hyperuricemia
-Rib fracture
What is the inflammatory response to injury?
Rubor (redness), tumor (swelling), calor (heat), dolor (pain)
Three phases of the inflammatory response
-Acute - vasodilation leading to increase permeability
-Subacute - infiltration of neutrophils causing more inflammation
-Chronic - proliferation
What inflammatory mediators are recruited in an inflammatory response
Eicosanoids
What are the eicosanoids in an inflammatory response?
-Arachidonic acid metabolites
-Prostaglandins (redness, heat, pain)
-Thromboxanes
-Leukotrienes (swelling)
-Cytokines (pain)
Aspirin mechanism of action
-Irreversibly inhibits cyclooxygenase1/2 by acetylation of COX
-Modifies cyclooxygenase 2 activity -> produce lipoxins
-Duration of effect corresponds to time required for new protein synthesis
Mechanism of action of NSAIDs besides aspirin
-Competitive (reversible) inhibitors of cyclooxygenase 1/2
-Some arylacetic acids also inhibit leukotriene synthesis, contributing to anti-inflammatory effect (indomethacin and diclofenac)
Aspirin contraindication
Risk in treating children with fever or viral origin due to the development Reye’s syndrome
Aspirin clinical pearls
-Historically one of the most common and effective agents for analgesia, antipyresis, and anti-inflammatory use
-Frequently used as prophylactic for anti-coagulation
-No tolerance development to analgesic effects
How is aspirin absorbed?
-Rapidly absorbed
-Passive diffusion of unionized acid at gastric pH
-Delayed by presence of food
How is aspirin distributed in the body?
-Distributed throughout most tissues and fluids
-Competes with many drugs for protein binding sites
How is aspirin metabolized and excreted?
-Aspirin half-life 15 min - hydrolysis at multiple sites
-Salicylate half-life 6-20hrs - dose dependent conjugation (saturated)
-Active secretion and passive reabsorption in renal tubule
-Increased excretion with increased urinary pH
Mild effects of salicylism/aspirin poisoning
-Vertigo
-Tinnitus
-Hearing impairment
CNS effects (moderate -> severe) of salicylism/aspirin poisoning
-Nausea, vomiting, sweating, fever
-Stimulation followed by depression
-Delirium, psychosis -> stupor -> coma
-Respiratory alkalosis caused by hyperventilation (moderate for adults)
-Metabolic acidosis caused by lowering of blood pH (high dose or kids)
Treatment of salicylism/aspirin poisoning
-Increase urinary excretion using dextrose or sodium bicarbonate
-Trap in urine pKa of salicylate 3.0 -> ionized in urine -> can not go back
-Treat by correcting metabolic imbalance (usually potassium level)
Ibuprofen and naproxen clinical pearls
-All are potent reversible cyclooxygenase inhibitors
-Half-lives: ibuprofen 2 hr, naproxen 14 hr (otherwise drugs quite similar)
-Better tolerated than aspirin
-Inter-patient variation in response and adverse effects
Therapeutic use of diclofenac
-Excellent alternative to ibuprofen and naproxen
-Increased risk of peptic ulcer and renal dysfunction with prolonged use
-Arthrotec (diclofenac/misoprostol) for chronic use. Misoprostol=PGE1 analog
Therapeutic use of indomethacin
-One of the most potent reversible inhibitors of PG biosynthesis
-High incidence and severity of side effects long-term
-Acute gouty arthritis, ankylosing spondylitis
Therapeutic use of sulindac
-Less toxic derivative of indomethacin
-Still significant side effects
-Rheumatoid arthritis and ankylosing spondylitis
Pharmacology of enolic acids
-Used to treat arthritis
-Great joint penetration
-One of the least GI side effects
-At low doses meloxicam is cox-2 selective
-Long T1/2
-Meloxicam = 20 hours
-Piroxicam = 57 hours
Adverse renal effects of NSAIDs
-Inhibition of renal PGE2 synthesis can lead to increased sodium reabsorption, causing peripheral edema
-Higher risk with longer half-life NSAIDs
-Higher risk with long-term use
Adverse effects of NSAIDs
-Decreased renal function
-Transient inhibition of platelet aggregation (increased risk of GI bleeding)
-Inhibition of uterine motility
-GI distress/ilceration
What is another therapeutic use of NSAIDs related to one of the adverse effects?
Delaying preterm labor
Clinical pearls associate with NSAID GI distress side effect
-Risk increases with age
-Though less than salicylate NSAIDs
-Risk increases with long-term use
-20-50% depending on dose and duration
-Treat with misoprostol -> PGE1 analog (induces labor)
Therapeutic use of acetaminophen
-Highly effective as an analgesic and antipyretic
-Limited anti-inflammatory activity
Advantages of acetaminophen compared with NSAIDs
-No GI toxicity
-No effect on platelet aggregation
-No correlation with Reyes syndrome
-Liver disease patients <2 gr/day is ok
Disadvantages of acetaminophen compared with NSAIDs
-Little clinically useful anti-inflammatory activity
-Acute overdose may lead to fatal hepatic necrosis
-Mechanism of action is still unclear
Adverse effects of acetaminophen
-Renal toxicity, papillary necrosis (vasoconstriction by inhibition of PGE2) (more toxicity aspirin, NSAIDs)
-Dose-dependent potentially fatal hepatic necrosis
-Patients unaware that it is in multiple products
What is the dose limit of acetaminophen before hepatic necrosis?
4 g/day
What increases risk of hepatic necrosis in people who take acetaminophen?
High alcohol consumption (also nephrotoxic)
Mechanism of action in alcohol induced acetaminophen toxicity
-Alcohol increases CYP450
-Increase in CYP450 activity leads to an increase in toxic acetaminophen metabolites
How do you treat acetaminophen hepatotoxicity?
N-acetylcysteine
Why were most selective COX-2 inhibitors withdrawn?
hgih chance of blood clots, strokes and heart-attacks
Which selective COX-2 inhibitor is still available?
Celecoxib
What side effects do selective COX-2 inhibitors not have?
Ulcers and GI bleeds
Black box label for celecoxib
Serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal
NSAID contraindications
-Chronic kidney disease
-Peptic ulcer disease
-History of GI bleed
-Cardiovascular risk in patients with coronary heart disease
-All NSAIDs, when used in high doses, can interfere with bone healing
-Can cause asthma exacerbations (less likely in COX-2 specific NSAIDs)
Which NSAID has the highest cardiovascular risk?
Diclofenac
Which NSAID has the lowest cardiovascular risk?
Naproxen
What are the sodium channel blockers
-Lidocaine
-Bupivacaine
-Benzocaine
When is lidocaine used?
Local analgesia, itch, burn
Lidocaine onset
15 minute onset and lasts 30-120 min
Bupivacaine duration of action
Longer lasting (3.5hr), epidural anesthesia
Bupivacaine use
Epidural anesthesia
Benzocaine use
-OTC use
-Oral ulcers
-Ear pain
What differentiates benzocaine from the other sodium channel blockers?
It has an ester group which means it has a higher risk for allergies
What is the most important sodium channel for pain?
NaV1.7
Which anticonvulsants can also be used for treatment of pain?
-Lamotrigine
-Carbamazepine
-Oxcarbazepine
Which tricyclic antidepressants can be used for the treatment of pain?
-Amitriptyline
-Nortiptyline
SNRI mechanism of action
-Increase norepinephrine levels
-Can act on alpha2A-adrenergic receptors in spinal cord
-Provides analgesia
Which SNRIs have sodium channel functionality?
-Duloxetine
-Venlafaxine
What is duloxetine used for?
-Diabetic pain
-Fibromyalgia
-Peripheral neuropathy
What is venlafaxine used for?
-Off label diabetic neuropathic pain
-Non-selective opioid effects
Side effect of venlafaxine
Cardiac toxicity -> cardiac Nav channels
What are the SNRIs lacking sodium channel functionality
-Milnacipran
-Tapentadol
What is milnacipran used to treat?
Fibromyalgia
What is tapentadol used to treat?
Diabetic neuropathic pain
Tapentadol mechanism of action
NRI and MOR agonist
What alpha2a adrenergic agonists are used to treat pain?
Clonidine
Major function of calcium channel blockers as possible analgesics
Heart rate and blood pressure
Which calcium channel blockers are used as analgesics?
-Gabapentin
-Pregabalin
-Ziconotide
-Levetiracetam
What receptors do gabapentin and pregabalin target?
-Alpha2
-Delta
-Cav1, 2 selective
Gabapentin and pregabalin clinical pearls
-Not metabolized, not protein bound
-No drug-drug interactions
T1/2=4-8hrs
Ziconotide clinical pearls
-Snail toxin
-I.t. pump (expensive)
-Use in opioid tolerant patients
Levtiracetam clinical pearls
-Well tolerated
-May cause mood symptoms
