Lecture 73 - Pharmacology of Non-Opiate Drugs

Question 1

CLINICALLY USED NON-OPIOIDS FOR (CHRONIC) PAIN

Answer 1

1. NSAIDs

Question 2

TYPES OF NSAIDS CLASSIFIED BY CHEMICAL STRUCTURES

Answer 2

Salicylates: Aspirin
Arylpropionic acids: Ibuprofen, naproxen
Arylacetic acids: Indomethacin, diclofenac; Ketorolac, Etodolac
Enolic acids: Piroxicam (Feldene); Meloxicam (Mobic)

Question 3

THERAPEUTIC APPLICATIONS OF NSAIDS

Answer 3

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

Question 4

AN INFLAMMATORY RESPONSE TO INJURY IS PAINFUL

Answer 4

“Rubor, tumor, calor, dolor”: Redness, swelling, heat, pain
Three phases: Acute - Vasodilation => increased
permeability; Subacute - Infiltration; Chronic - Proliferation

Question 5

RECRUITMENT OF EICOSANOIDS CONTRIBUTE TO INFLAMMATORY PAIN

Answer 5

Mediators recruit inflammatory cells: Eicosanoids - Arachidonic acid metabolites; Prostaglandins (redness, heat, pain); Thromboxanes; Leukotrienes (swelling); Cytokines (pain)

Question 6

NSAIDS are _____ inhibitors

Answer 6

COX inhibitors in the Arachadonic acid pathway

Question 7

ASPIRIN, UNLIKE OTHER NSAIDS IRREVERSIBLY INHIBITS COX ENZYMES

Answer 7

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

Question 8

Other NSAIDs

Answer 8

Competitive (reversible) inhibitors of cyclooxygenase 1/2
Some arylacetic acids also inhibit leukotriene synthesis, contributing to anti-inflammatory effect - Indomethacin (Indocin), Diclofenac (Voltaren)

Question 9

THERAPEUTIC USE OF ASPIRIN AS PAINKILLER

Answer 9

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

Question 10

PHARMACOKINETIC PROPERTIES OF ASPIRIN/SALICYLATES - absorption

Answer 10

Rapidly absorbed
Passive diffusion of unionized acid at gastric pH
Delayed by presence of food

Question 11

PHARMACOKINETIC PROPERTIES OF ASPIRIN/SALICYLATES - distribution

Answer 11

Throughout most tissues & fluids
Competes with many drugs for protein binding sites

Question 12

PHARMACOKINETIC PROPERTIES OF ASPIRIN/SALICYLATES - metabolism and excretion

Answer 12

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)

Question 13

CLINICAL FEATURES OF SALICYLISM/ASPIRIN POISONING

Answer 13

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

Question 14

SALICYLISM/ASPIRIN POISONING treatment

Answer 14

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

Question 15

ARYLPROPIONIC ACIDS ARE VERY COMMONLY PRESCRIBED NSAIDS

Answer 15

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

Question 16

THERAPEUTIC USE OF ARYLACETIC ACID DERIVATIVES - diclofenac

Answer 16

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)

Question 17

THERAPEUTIC USE OF ARYLACETIC ACID DERIVATIVES - indomethacin

Answer 17

One of most potent reversible inhibitors of PG biosynthesis
High incidence & severity of side effects long-term
Acute gouty arthritis, ankylosing spondylitis

Question 18

THERAPEUTIC USE OF ARYLACETIC ACID DERIVATIVES - sulindac

Answer 18

Less toxic derivative of indomethacin
Still significant side effects
Rheumatoid arthritis & ankylosing spondylitis

Question 19

PHARMACOLOGY OF ENOLIC ACIDS NSAIDS

Answer 19

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

Question 20

ADVERSE EFFECTS OF NSAIDS

Answer 20

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)

Question 21

THERAPEUTIC USE OF ACETAMINOPHEN (TYLENOL, PARACETAMOL, APAP)

Answer 21

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

Question 22

ADVERSE EFFECTS OF ACETAMINOPHEN

Answer 22

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

Question 23

SIDE EFFECT PROFILE OF NON-SELECTIVE COX INHIBITORS DROVE DEVELOPMENT OF COX-2 SELECTIVE INHIBITORS

Answer 23

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

Question 24

NSAIDS CONTRAINDICATIONS

Answer 24

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

Question 25

Blocking pain transmission

Answer 25

TRPs, NaV, CaV2.2, CaV3.2

Question 26

LOCAL ANESTHETICS ARE SODIUM CHANNEL BLOCKERS

Answer 26

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

Question 27

OVERVIEW OF SODIUM CHANNELS AS ANALGESIC TARGET

Answer 27

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

Question 28

SOME PSYCHIATRIC DRUGS ARE ALSO SODIUM CHANNEL BLOCKERS

Answer 28

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)

Question 29

SODIUM CHANNEL BLOCKERS WITH SNRI FUNCTIONALITY

Answer 29

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

Question 30

OVERVIEW OF CALCIUM CHANNEL BLOCKERS AS POSSIBLE ANALGESICS

Answer 30

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