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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
Q

Diclofenac

A

-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
Q

Indomethacin

A

-One of the most potent reversible inhibitors of PG biosynthesis
-High incidence and severity of SE long-term
-Acute gouty arthritis, ankylosing spondylitis

27
Q

Sulindac

A

-Less toxic derivative of indomethacin
-Still significant SE
-Rheumatoid arthritis & ankylosing spondylitis

28
Q

Pharmacology of enolic acid NSAIDS

A

-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
Q

Adverse events of NSAIDs

A

-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
Q

Acetaminophen (tylenol, paracetamol, APAP)

A

-Highly effective as an analgesic and antipyretic
-Limited anti-inflammatory activity

31
Q

Advantages of APAP compared to NSAID

A

-No GI toxicity
-No effect on platelet aggregation
-No correlation with Reye’s syndrome
-Liver disease pts using <2 gram/day is okay

32
Q

Disadvantages of APAP compared to NSAID

A

-Little clinically useful anti-inflammatory activity
-Acute OD may lead to fatal hepatic necrosis
-MOA is still unclear

33
Q

ADR with acetaminophen

A

-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
Q

How does n-acetylcysteine detoxify NAPQI?

A

-Acts as a substitute for glutithione which normally reacts with NAPQI, but NAPQI eventually depletes glutithione and creates toxic agent

35
Q

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?

A

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
Q

COX-2 selective NSAIDs

A

-Meloxicam
-Diclofenac
-Celecoxib
-Valdecoxib
-Rofecoxib
-Etoricoxib
-Lumiracoxib

37
Q

NSAID contraindications

A

-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
Q

Local anesthetics are ____

A

Sodium channel blockers

39
Q

Lidocaine

A

-Sodium channel blocker
-Local analgesia (dentistry), itch, burn
-15 min onset; lasts 30-120 min

40
Q

Bupivacaine

A

-Sodium channel blocker
-Longer lasting (3.5 hours)
-Epidural anesthesia

41
Q

Benzocaine

A

-Sodium channel blocker
-Topical numbing agent
-OTC use, oral ulcers, ear pain
-Esters have higher allergy risk
-Blocking sensory conduction

42
Q

Overview of sodium channels as analgesic target

A

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
Q

Psychiatric drugs that are also sodium channel blockers

A

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
Q

Sodium channel blockers with SNRI functionality (block some sodium channels)

A

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
Q

Overview of calcium channel blockers as possible analgesic

A

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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