Lecture 73 - Pharmacology of Non-Opiate Drugs Flashcards
CLINICALLY USED NON-OPIOIDS FOR (CHRONIC) PAIN
- NSAIDs
TYPES OF NSAIDS CLASSIFIED BY CHEMICAL STRUCTURES
Salicylates: Aspirin
Arylpropionic acids: Ibuprofen, naproxen
Arylacetic acids: Indomethacin, diclofenac; Ketorolac, Etodolac
Enolic acids: Piroxicam (Feldene); Meloxicam (Mobic)
THERAPEUTIC APPLICATIONS OF NSAIDS
Analgesic: Chronic postsurgical pain - Potentially inhibit bone healing (post-orthopedic); Myalgias and arthralgias/sprains & strains; Inflammatory pain; Dysmenorrhea (specific PGE effect)
Anti-inflammatory: Bursitis and tendonitis; Osteoarthritis; Rheumatoid arthritis - Ankylosing spondylitis; Gout and hyperuricemia; Rib fractures
Antipyretic (fever)
Prophylactic to reduce risk of myocardial infarction – antiplatelet effect, Aspirin
AN INFLAMMATORY RESPONSE TO INJURY IS PAINFUL
“Rubor, tumor, calor, dolor”: Redness, swelling, heat, pain
Three phases: Acute - Vasodilation => increased
permeability; Subacute - Infiltration; Chronic - Proliferation
RECRUITMENT OF EICOSANOIDS CONTRIBUTE TO INFLAMMATORY PAIN
Mediators recruit inflammatory cells: Eicosanoids - Arachidonic acid metabolites; Prostaglandins (redness, heat, pain); Thromboxanes; Leukotrienes (swelling); Cytokines (pain)
NSAIDS are _____ inhibitors
COX inhibitors in the Arachadonic acid pathway
ASPIRIN, UNLIKE OTHER NSAIDS IRREVERSIBLY INHIBITS COX ENZYMES
Aspirin: Irreversibly inhibits cyclooxygenase1/2 by acetylation of COX (Ser529); Modifies cyclooxygenase 2 activity -> produce lipoxins; Duration of effect corresponds to time required for new protein synthesis
Other NSAIDs
Competitive (reversible) inhibitors of cyclooxygenase 1/2
Some arylacetic acids also inhibit leukotriene synthesis, contributing to anti-inflammatory effect - Indomethacin (Indocin), Diclofenac (Voltaren)
THERAPEUTIC USE OF ASPIRIN AS PAINKILLER
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
Risk in treating children with fever of viral origin: Reye’s syndrome
PHARMACOKINETIC PROPERTIES OF ASPIRIN/SALICYLATES - absorption
Rapidly absorbed
Passive diffusion of unionized acid at gastric pH
Delayed by presence of food
PHARMACOKINETIC PROPERTIES OF ASPIRIN/SALICYLATES - distribution
Throughout most tissues & fluids
Competes with many drugs for protein binding sites
PHARMACOKINETIC PROPERTIES OF ASPIRIN/SALICYLATES - metabolism and excretion
Aspirin half-life 15 min - hydrolysis at
multiple sites
salicylate half-life 6-20 hr – Dose
dependent conjugation (saturated)
Active secretion & passive reabsorption in renal tubule
Increased excretion with increased urinary pH (i.v. bicarb)
CLINICAL FEATURES OF SALICYLISM/ASPIRIN POISONING
Mild effects: Vertigo, tinnitus, hearing impairment
CNS effects (moderate –> severe): Nausea, vomiting, sweating, fever; Stimulation followed by depression; Delirium, psychosis –> stupor –> coma; Respiratory alkalosis (moderate, adults) - Caused by hyperventilation; Metabolic acidosis (high dose or kids) - Lowering of blood pH
SALICYLISM/ASPIRIN POISONING treatment
acute medical emergency
Reduce salicylate load: ↑ Urinary excretion (dextrose, sodium bicarbonate); Trap in urine pKa of salicylate is 3.0 -> ionized in urine -> can’t go back
Treat by correcting metabolic imbalance
ARYLPROPIONIC ACIDS ARE VERY COMMONLY PRESCRIBED NSAIDS
Ibuprofen (Advil), Naproxen (Aleve): 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 ARYLACETIC ACID DERIVATIVES - diclofenac
Voltaren, available as gel
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 (to protect gut lining and decrease risk of peptic ulcer)
THERAPEUTIC USE OF ARYLACETIC ACID DERIVATIVES - indomethacin
One of most potent reversible inhibitors of PG biosynthesis
High incidence & severity of side effects long-term
Acute gouty arthritis, ankylosing spondylitis
THERAPEUTIC USE OF ARYLACETIC ACID DERIVATIVES - sulindac
Less toxic derivative of indomethacin
Still significant side effects
Rheumatoid arthritis & ankylosing spondylitis
PHARMACOLOGY OF ENOLIC ACIDS NSAIDS
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 EFFECTS OF NSAIDS
Renal function: 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
Transient inhibition of platelet aggregation
§Increased risk of bleeding (GI bleeds)
“Inhibition of uterine motility” - Therapeutic use for delaying preterm labor
Gastrointestinal distress/ulceration: Risk increases with age (> 65 yr), Though less than salicylate NSAIDS, Risk increases with long-term use, 20-50% depending on dose and duration - Treat with misoprostol (Cytotec)=> PGE1
Stomach ulcer analog (induce labor)
THERAPEUTIC USE OF ACETAMINOPHEN (TYLENOL, PARACETAMOL, APAP)
Highly effective as an analgesic and antipyretic: Headaches, fever; Added to opioids - Percocet (oxycodone), vicodin (hydrocodone)
Limited anti-inflammatory activity: Not considered a NSAID
Advantages compared with NSAIDs: No GI toxicity; No effect on platelet aggregation; No correlation with Reye’s syndrome; Liver disease patients <2 gr/day is okay
Disadvantages 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; >than aspirin, NSAIDs
Dose-dependent potentially fatal hepatic necrosis: Dose limit 4 g/day; Increased risk with high alcohol consumption - Hepatotoxic, nephrotoxic, Alcohol => increase CYP450, Increase in toxic acetaminophen metabolites (NAPQI), Treat with n-acetylcysteine to detoxify NAPQI
Patients unaware that it’s in multiple products: E.g. Lortab, Percocet, >100,000 poison control calls, 75 deaths
SIDE EFFECT PROFILE OF NON-SELECTIVE COX INHIBITORS DROVE DEVELOPMENT OF COX-2 SELECTIVE INHIBITORS
Non-selective COX-1/2 inhibitors: Aspirin, Acetaminophen, non-salycilate NSAIDs –> Stomach ulcers, GI Bleeds
Selective COX-2 inhibitors: Rofecoxib (Vioxx)
Reduce ulcers and GI bleeds
Withdrawn due to high chance of blood
cloths, strokes and heart-attacks.
“black box label” for Celecoxib (Celebrex) - Used for arthritis
NSAIDS CONTRAINDICATIONS
ALL NSAIDs should be avoided in patients with chronic kidney disease, peptic ulcer disease, history of GI bleed
ALL NSAIDs carry a cardiovascular risk in patients with coronary heart disease in the short term, but this risk is the highest for diclofenac and lowest for Naproxen
ALL NSAIDs, when used in high doses, can interfere with bone healing: (but orthopedics still uses it, and uses aspirin for Deep Vein Thrombosis prophylaxis post-operatively)
NSAIDs can cause asthma exacerbations: COX-2 specific NSAIDs are less likely to do this
Blocking pain transmission
TRPs, NaV, CaV2.2, CaV3.2
LOCAL ANESTHETICS ARE SODIUM CHANNEL BLOCKERS
Lidocaine: Local analgesia (dentistry), itch, burn; 15 min onset, last 30-120 min
Bupivacaine: Longer lasting (3.5hr) , epidural anesthesia
Benzocaine: OTC use, oral ulcers, ear pain; Esters have higher allergy risk
OVERVIEW OF SODIUM CHANNELS AS ANALGESIC TARGET
Natural toxins
NaV1.7: Severe neuropathic pain - Gain of function mutation; Congenital insensitivity to pain - Loss of function mutation; Expressed in peripheral neurons - High in nociceptive neurons, Low in cardiac muscles or CNS; Small molecule development
SOME PSYCHIATRIC DRUGS ARE ALSO SODIUM CHANNEL BLOCKERS
Anticonvulsant:
Lamotrigine (Lamictal) - Off label peripheral neuropathy, migraine
Carbamazepine (Tegretol) - Trigeminal neuralgia
Oxcarbazepine (Trileptal) - Fewer side effects
Tricyclic antidepressants:
Amitriptyline (Elavil) - Post-herpetic neuralgia, polyneuropathy, fibromyalgia, visceral pain
Nortriptyline (Pamelor)
SODIUM CHANNEL BLOCKERS WITH SNRI FUNCTIONALITY
SNRIs increase norepinephrine levels: Can act on alpha2A-adrenergic receptors in spinal cord, Provide analgesia
Duloxetine (Cymbalta): Diabetic pain, fybromyalgia, peripheral neuropathy
Venlafaxine (Effexor): Off label diabetic neuropathic pain, Non-selective opioids effects
- Naloxone reversible analgesia, Cardiac toxicity -> cardiac Nav channels
SNRI’s lacking sodium channel functionality
Milnacipran (Savella): Fibromyalgia
Tapentadol (Nucynta): NRI and MOR agonist, diabetic neuropathic pain
α2a adrenergic agonists
Clonidine
OVERVIEW OF CALCIUM CHANNEL BLOCKERS AS POSSIBLE ANALGESICS
Major function = heart rate, blood pressure: Diabetic neuralgia; Fibromyalgia, neuropathic pain
Gabapentin (Neurontin), Pregabalin (Lyrica): α2δ – Cav1, 2 selective; Not metabolized, not protein bound; No drug-drug interactions; T1/2=4-8hr
Ziconotide (Prialt): Snail toxin (peptide); I.t. pump ($$$); Use in opioid intolerant px
Levetiracetam (Keppra): Well tolerated, May cause mood symptoms
