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Therapeutics P2 Winter Semester > PHRM845-FINAL EXAM > Flashcards

PHRM845-FINAL EXAM Flashcards

Pharmacology of Non-opiate drugs

1
Q

Opioids are not the ___

A

Panacea: “cure all” and not right for all pain

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2
Q

What non-opioid is used for chronic pain?

A

NSAIDs

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3
Q

Salicylates

A

Aspirin

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4
Q

Arylpropionic acids

A

Ibuprofen
Naproxen

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5
Q

Arylacetic acids

A

Indomethacin
Diclofenac
Ketorolac
Etodolac

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6
Q

Enolic acids

A

Piroxicam
Meloxicam (has COX-2 activity)

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7
Q

Therapeutic applications of NSAIDS

A

-Analgesic
-Anti-inflammatory
-Antipyretic (fever)
-Prophylactic to reduce MI risk–antiplatelet effect with ASA

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8
Q

Analgesic effect from NSAIDs is useful in…

A

-Chronic post-surgical pain
~Potentially inhibit bone healing (post-orthopedic)
-Myalgias and arthralgias/sprains and strains
-Inflammatory pain
-Dysmenorrhea (specific PGE effect)

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9
Q

Anti-inflammatory effect from NSAIDs is useful in…

A

-Bursitis/tendonitis
-OA
-RA (ankylosing spondylitis)
-Gout (prevents uric acid buildup) and hyperuricemia
-Rib fractures

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10
Q

An inflammatory response to injury is ___

A

painful

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11
Q

Inflammatory response: rubor, tumor, calor, dolor

A

Redness, swelling, heat, pain

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12
Q

Three phases of inflammatory response and what happens in each phase

A

Acute: vasodilation–>increased permeability & fluid leakage causing swelling
Subacute: infiltration of neutrophils–>inflammation–>pain
**Other chemical mediators are released when His is released
Chronic: Proliferation

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13
Q

Mediators recruit inflammatory cells which may contribute to pain. What are these inflammatory cells? What is their function?

A

Eicosanoids
-Arachidonic acid metabolites that become prostaglandins (heat, redness, pain)
-Thromboxanes (potent vasoconstrictor and stimulus for platelet aggregation)
-Leukotrienes (swelling)
-Cytokines (pain)

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14
Q

NSAIDs are ___ inhibitors in the ___ pathway

A

COX
Arachidonic acid

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15
Q

Aspirin

A

-Irreversible COX 1/2 inhibitor by acetylation
-Modifies COX-2 activity–>produces lipoxins (“turns off” its ability to generate prostaglandins, but “switches on” its capacity to produced novel protective lipid mediators)
-Duration of effect corresponds to time required for new protein synthesis b/c once acetylated, it is inactivated

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16
Q

Other NSAIDs MOA

A

-Competitive (reversible) inhibitor of COX 1/2
-Some arylacetic acids also inhibit leukotriene synthesis leading to anti-inflammatory effect
-Indomethacin
-Diclofenac

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17
Q

Therapeutic use of ASA as a painkiller

A

-One of the most effective for analgesia, antipyresis, and anti-inflammatory
-Frequently used as prophylactic for anticoag
-No tolerance development to analgesic effects
-Risk in tx children with fever of viral origin (Reye’s syndrome)

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18
Q

Absorption of ASA/salicylates

A

-Rapidly absorbed
-Delayed by presence of food

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19
Q

Distribution of ASA

A

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

20
Q

Metabolism and excretion of ASA/salicylates

A

-ASA half-life is 15 min (hydrolysis at multiple sites)
-Salicylate half life is 6-20 hours (dose-dependent conjugation–saturation)
-Active secretion & passive reabsorption in renal tubule
-Increased excretion with increased urinary pH (IV bicarb)

21
Q

Mild effects of salicylism/ASA poisoning

A

Vertigo
Tinnitus
Hearing impairment

22
Q

CNS effects (mod/severe) of salicylism/ASA poisoning

A

-N/V/sweating/fever
-Stimulation followed by depression
-Delirium/psychosis–>stupor–>coma
-Respiratory alkalosis (mod, adults)–>caused by -hyperventilation
-Metabolic acidosis (high dose or kids)–>lowering of blood pH

23
Q

Tx of salicylism/ASA poisoning

A

-Reduce salicylate load (get rid of it)
~Increases urinary excretion (dextrose & sodium bicarb)
~Trap in urine pKa of salicylate is 3.0 –>ionized urine–>can’t go back
-Tx by correcting metabolic imbalance
-Supportive care

24
Q

Ibuprofen and Naproxen

A

-Potent reversible COX inhibitor
-Ibuprofen half-life: 2 hr
-Naproxen half-life: 14 hr (works faster)
-Better tolerated than ASA
-Inter-pt variation in response and adverse effects
**Ibuprofen is not much better than placebo for OA

25
Diclofenac
-Available as a gel (apply topically to joints) -Excellent alternative to naproxen and ibuprofen -Increased risk of peptic ulcer and renal dysfunction with prolonged use -Arthrotec (diclofenac + misoprostil) for chronic use to protect the lining of the gut and decrease peptic ulcer risk ~Misoprostil: PGE1 analog
26
Indomethacin
-One of the most potent reversible inhibitors of PG biosynthesis -High incidence and severity of SE long-term -Acute gouty arthritis, ankylosing spondylitis
27
Sulindac
-Less toxic derivative of indomethacin -Still significant SE -Rheumatoid arthritis & ankylosing spondylitis
28
Pharmacology of enolic acid NSAIDS
-Used to tx arthritis -Great joint penetration -One of the least GI SE -At low doses, meloxicam is COX-2 selective -Long half-life ~Meloxicam: 20 h ~Piroxicam: 57 h
29
Adverse events of NSAIDs
-Renal function ~Inhibition of renal PGE2 synthesis can lead to increased sodium reabsorption, causing peripheral edema (could lead to stomach ulcer) ~Higher risk with longer half-life NSAIDs ~Higher risk with long-term use -Transient inhibition of platelet aggregation ~Increased risk of GI bleeds -Inhibition of uterine motility ~Therapeutic use for delaying preterm labor -GI distress/ulceration ~Risk increases with age (>65 y/o) ~Less GI distress than salicylate NSAIDs ~Risk increases with long-term use ~20-50% depending on dose and duration >tx with misoprosol to induce labor
30
Acetaminophen (tylenol, paracetamol, APAP)
-Highly effective as an analgesic and antipyretic -Limited anti-inflammatory activity
31
Advantages of APAP compared to NSAID
-No GI toxicity -No effect on platelet aggregation -No correlation with Reye's syndrome -Liver disease pts using <2 gram/day is okay
32
Disadvantages of APAP compared to NSAID
-Little clinically useful anti-inflammatory activity -Acute OD may lead to fatal hepatic necrosis -MOA is still unclear
33
ADR with acetaminophen
-Renally toxicity, papillary necrosis ~Vasoconstriction by inhibition of PGE2 ~ greater risk than ASA, NSAIDs -Dose-dependent potentially fatal hepatic necrosis ~Dose limit: 4 g/day ~Increased risk with high EtOH consumption >hepatotoxic, nephrotoxic; alcohol increases CYP450 >Increase in toxic APAP metabolites (NAPQI) >Tx with n-acetylcysteine to detoxify NAPQI -Pts unaware that it is in multiple products
34
How does n-acetylcysteine detoxify NAPQI?
-Acts as a substitute for glutithione which normally reacts with NAPQI, but NAPQI eventually depletes glutithione and creates toxic agent
35
SE profile of non-selective COX inhibitors drove development of COX-2 selective inhibitors What was the first selective COX-2 inhibitor? Benefit of selectivity?
Rofecoxib -Reduced ulcers and GI bleeds -Withdrawn due to high chance of blood clots, strokes, and heart attack b/c inhibiting COX-2 decreases PGI2 Celecoxib -Used for arthritis -Black box label for serious CV thrombotic events, MI, and stroke which can be fatal
36
COX-2 selective NSAIDs
-Meloxicam -Diclofenac -Celecoxib -Valdecoxib -Rofecoxib -Etoricoxib -Lumiracoxib
37
NSAID contraindications
-ALL should be avoided in pts with CKD, PUD, and hx of GI bleed -ALL carry CV risk in pts with coronary heart disease in the short term, but this risk is the highest for diclofenac and lowest for naproxen -ALL, when used in high doses, can interfere with bone healing -NSAIDs can causes asthma exacerbation (clinically, not sure if this is huge) ~COX-2 selective are less likely to do this
38
Local anesthetics are ____
Sodium channel blockers
39
Lidocaine
-Sodium channel blocker -Local analgesia (dentistry), itch, burn -15 min onset; lasts 30-120 min
40
Bupivacaine
-Sodium channel blocker -Longer lasting (3.5 hours) -Epidural anesthesia
41
Benzocaine
-Sodium channel blocker -Topical numbing agent -OTC use, oral ulcers, ear pain -Esters have higher allergy risk -Blocking sensory conduction
42
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 ~PF-05089771 (Pfi zer) ~Passed phase II CT
43
Psychiatric drugs that are also sodium channel blockers
Anticonvulsant -Lamotrigine (Lamictal) ~Off label peripheral neuropathy, migraine -Carbamazepine (Tegretol) ~Trigeminal neuralgia -Oxcarbazepine (Trileptal) ~Fewer side effects TCA -Amitriptyline (Elavil) ~Post-herpetic neuralgia, polyneuropathy, fibromyalgia, visceral pain
44
Sodium channel blockers with SNRI functionality (block some sodium channels)
SNRIs increase norepinephrine levels -Can act on alpha2A-adrenergic receptors in spinal cord (plays a role in reflex arch) -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, but have use in chronic pain (esp neuropathic pain) -Milnacipran (Savella) ~Fibromyalgia -Tapentadol (Nucynta) ~NRI and MOR agonist ~diabetic neuropathic pain α2a adrenergic agonists -Clonidine
45
Overview of calcium channel blockers as possible analgesic
Major function=HR, BP -Diabetic neuralgia -Fibromyalgia and neuropathic pain >Gabapentin and Pregabalin -α2δ – Cav1, 2 selective -Not metabolized, not protein bound -No drug-drug interactions -T1/2=4-8hr >Ziconotide -Snail toxin -Use in opioid intolerant pt >Levetiracetam -Well tolerated -May cause mood sx

Therapeutics P2 Winter Semester (29 decks)

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