*Analgesics

Question 1

5 Cardinal signs of inflammation

Answer 1

• Heat
  
  • increased vascular perfusion delivers core blood to the affected region
    to facilitate optimal temperatures for enzymatic activity
• Red
  
  • local vasodilation facilitates swelling and immune cell infiltration to
    facilitate destruction or isolation of the pathogen and remove cell debris
• Loss of function
  
  • local pain reduces mobility of the affected body area which
    limits movements that could aggravate preparative steps in tissue repair
• Pain
  
  • physical swelling and released mediators from immune cells stimulate
    pain fibers
• Swelling
  
  • exudation of plasma and proteins from locally dilated capillaries
    isolates the wound and pathogen and facilitates immune cell access

Question 2

Inflammation

Answer 2

• NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a ”rapid acting” (preformed), first responder transcription factor residing in the cytoplasm of all cells
• In responsive to a variety of hyperosmolar tears(often associated with dry eye), harmful stimuli, and
  cytokines, NF-κB activation begins with the phosphorylation and
  subsequent degradation of its inhibitor proteins
• Once activated, NF-κB initiates transcription of genes involved in
  inflammation, T-cell activation; innate and adaptive immune responses,
  cell survival responses, and cellular proliferation
• Defective NF-κB activity is linked to cancer, inflammation, AI diseases,
  septic shock, and viral infection
• MMP-9, an inducible(has to be synthesized first) matrix metalloproteinase, is another key player in
  the inflammatory response

Question 3

Which autonomic responses are associated with pain?

Answer 3

(SNS, PNS shut down):

• Tachycardia
• Systemic hypertension
• Tachypnea
• Diaphoresis (cold sweat)
• Pallor
• Nausea

Question 4

Therapeutic relief mechanisms for treating pain

Answer 4

• Peripheral(directly at the source, i.e. hand),:
  
  • block pain mediators,
  • receptor sensitization
  • afferent neuronal discharge
• Central:
  
  • block pain receptors in the CNS

Question 5

Once activated NF-_KB initiates transcription of genes involved in…

Answer 5

• Inflammation
• T-cell activation
• Inate and adaptive immune responses
• Cell survival responses
• Cell proliferation

Question 6

Defective NF-_KB is linked to

Answer 6

• Cancer
• Septic shock
• Inflammation
• Viral infection
• Auto immune diseases

Question 7

Inflammatory pain mediators

Answer 7

• Nociception - reception/sensation of harm/pain
• Bradykinin, NE, and histamine stimulate pain fibers (likely a combination)
  
  • Bradykinin - RAAS → vasodilation, also produces pain
  • NE - SNS → pain linked to NE
  • Histamine - key molecule in allergic (type 1 sensitivity) reactions
• Allodynia (an exaggerated pain response) can result when pain fibers are (hyper)sensitized by low pH, bradykinin, prostaglandins (PGs), leukotrienes (LTs), and Substance P
  
  • Inflammation leads to ↓ pH
  • Clinical application: eye → painful to touch
• PGE2 & PGI2 (prostaglandins) promote pain and inflammation
• Other Mediators:
  
  • Cytokines (interleukins, interferons, tumor necrosis factors, growth factors and chemokines)
  • Nitric Oxide (for good and bad → inflammation-induced pain → inflammation leads to iNOS [produces lots of NO, that now stimulate pain fibers])
  • Platelet Activating Factor (PAF)

Question 8

Define allodynia

Answer 8

• An exaggerated pain response can result when pain fibers are sensitized by low pH, bradykinin,
  prostaglandins leukotrienes, and Substance P
  
  • PGE2 & PGI2 promote pain and inflammation

Question 9

Inflammation pathway

Answer 9

Leukotriene type 4 and Prostaglandin type 2 = pro inflammation

(even numbers = bad)

Leukotriene type 5 and Prostaglandin type 3 = anti-inflam

(Odd numbers = good)

PGI₂ and TXA₂ are physiologic antagonists

Question 10

COX 1 vs COX 2

Answer 10

COX 1

• Constitutive (housekeeping, always active) enzyme; predominantly
  involved in PG & TXA2 production
  
  • GI mucosa, vasculature, platelets, macrophages, kidneys

COX 2

• Constitutive(pre-produced, ready to go) enzyme in the kidney
• Inducible enzyme; predominantly involved in PG production
  
  • Generates pro-inflammatory PGs and O2 radicals
  • Creates pain and pyresis from inflammatory focus

Question 11

Leukotrienes LTB₄ , LTC₄ and LTD₄

Answer 11

LTB₄

• chemotactic by activating phagocytes and
  promoting neutrophil adhesion
• key role in signalling to immune cells

LTC₄ and LTD₄

• enhance histamine effects(itch,pain), bronchoconstrict,
  and constrict coronary arteries and dilate vessels in
  regions of inflammation

Question 12

PG’s actions on kidney

Answer 12

PGE2 & PGI2 promote maintenance of renal blood flow by
stimulating renin release (ontributes to elevation in BP)

Question 13

PG’s an TXA₂ actions on vasculature

Answer 13

• PGE2 causes edema (swelling) and vasodilation (redness)
• PGI2 produces vasodilation
• TXA2 (Thromboxane A2) is a vasoconstrictor

PGI ₂ and TXA₂ physiologic antagonists

Question 14

PG’s and TXA2 actions on platelets

Answer 14

• TXA2 promotes platelet aggregation
• PGI2 inhibits platelets

Question 15

PG’s effect on GI tract

Answer 15

• PGE1 & PGE2: production of cytoprotective GI mucous

• PGI2 (Prostacyclin): decrease GI acid secretion

Question 16

PAFeffect on connective tissue

Answer 16

PAF (Platelet Activating Factor) activates matrix
metalloproteinases

Question 17

PGE₂ effect on CNS

Answer 17

PGE2 causes fever through the hypothalamus

Question 18

PGF2A effects on reproduction

Answer 18

PGF2a causes suppression of spermatogenesis & uterine
contraction

Question 19

Endogenous analgesics

Answer 19

• Endorphins
  
  • ​Induced by Tricyclic Antidepressants (TCADs)
  • Elevated in Cushing’s syndrome
• Serotonin
  
  • ​A mood regulator; linked to depression and arousal
  • A short-term analgesic; counteracts Substance P
  • Induced by paracetamol
  • Reuptake is inhibited by Tramadol, selective serotonin
    reuptake inhibitors (SSRIs), and selective norepinephrine
    serotonin reuptake inhibitors (SNRIs)

Question 20

** Acetylsalicylic Acid (Aspirin)

Dosing for

1. Anti-platelet activity
2. Analgesia
3. Anti-pyretic (fever)
4. Anti-inflammatory

Answer 20

1. Anti-platelet - 80-160 mg
   • Irreversible inhibition of COX-1 (TXA2) for life of platelets
2. Analgesia - 160-325 mg
   • Low intensity pain: central < peripheral
   • t1⁄2 2-3 hrs
3. Anti-pyretic - 160-325 mg
   • t1⁄2 2-3 hrs
4. Anti-inflammatory - 325-650 mg
   • t1⁄2 ~10 hrs

Question 21

Mechanism of action of ASA (aspirin/acetylsalilicylic acid)

Answer 21

Irreversibly, non-selectively inhibits COX, reducing PG and
TXA2 synthesis

Question 22

Adverse reactions of ASA (Aspirin/acetylsalicylic acid)

Answer 22

• Common:
  
  • bleeding time doubles, headache
• Serious:
  
  • Hypersensitivity: angioedema
• Special: Reye’s Syndrome (35% mortality)

Topical Ophthalmic Drug Interactions
• None

Contraindications
• Hemorrhagic disorders
• Pregnancy, esp 3rd trimester

Ocular: Corneal denervation, dry eye

Question 23

What medication is associated with corneal denervation?

Answer 23

Aspirin / acetylsalicylic acid

Question 24

What is Reye’s syndrome and which drug can cause it

Answer 24

nie vir kinders onder 16 aanbeveel

Reye’s syndrome

Adverse reaction in children taking ASA to reduce fever
in viral infections (eg. chicken pox or influenza)
• GI disturbances
• Liver degeneration
• Encephalopathy

35% mortality

Question 25

Indications of Celecoxib (COX 2 inhibitor)

Answer 25

Osteoarthritis: • Rheumatoid arthritis: • Ankylosing Spondylitis: • Dysmenorrhea: • Acute Pain:

Question 26

Mechanism of action of Celecoxib

Answer 26

Selectively inhibits COX-2 and reduces PG synthesis **\*Sulpha based drug\***

Question 27

Adverse reactions of Celecoxib (selective COX 2 inhibitor)

Answer 27

* Common: headache * GIT: Bleed, ulceration/perforation * **Black Box: Stroke, CHF, MI** CHF- congestive heart failure MI - myocardial infarction

Question 28

Topical Ophthalmic Drug Interactions of Celecoxib (COX2 inhibitor)

Answer 28

* Bromfenac, diclofenac, flurbiprofen, ketorolac, nepafenac: additive hemorrhage risk * • Naphazoline, tetrahydrozyline, phenylephrine: additive hypertensive risk * Cautions * Hypertension, smokers

Question 29

Indications of Acetaminophen (Paracetamol)

Answer 29

Pain and fever

Question 30

Mechanism of action of Acetaminophen (Paracetamol)

Answer 30

* Acts by inhibiting COX and enhancing 5-HT release (attenuates pain mediator generation) * Regulates body temperature by acting centrally at the hypothalamus; PG synthetase inhibition

Question 31

Adverse effects of acetaminiphen (paracetamol)

Answer 31

Common: headache Topical Ophthalmic Drug Interactions • None Contraindications/Cautions • No applicable ophthalmic conditions or findings

Question 32

ASA VS ACETAMINOPHEN

Answer 32

ASA VS ACETAMINOPHEN Antiinflammatory Yes No Antipyretic Yes Yes Platelet inhibitor Yes No Analgesic Yes Yes Site of action Peripheral Central GI irritant Yes No Pregnancy Safety D B

Question 33

Neurogenic pain responds best to which type of medications

Answer 33

Anticonvulsants and antidepressants

Question 34

Different pain killer profiles

Answer 34

Question 35

Other than analgesia, what can hydrocodone be used for

Answer 35

As an antitussive(cough)

Question 36

Hydrocodone mechanism of action

Answer 36

* Act through Gi -Protein-Coupled Mu, Kappa & Delta ‘opioid’ receptors; inhibit adenylyl cyclase activity; enhance K+ outflow/Ca++ inflow; hyperpolarize nerves affecting neuronal excitability and muscle tone * Stimulate prolactin and growth hormone release

Question 37

Adverse effects of hydrocodone

Answer 37

* Common: pruritus & flushing (histamine release [little tolerance]) * Ocular: miosis [no tolerance] * CNS: **elevated intracranial pressure (enhanced with head injury)** Topical Ophthalmic Drug Interactions * None Cautions * Mydriatic Procedures (antagonized)

Question 38

Mechanism of action of tramadol

Answer 38

* Agonist at mu receptors; effect is greater with active metabolite * Weak inhibitor of NE & 5-HT reuptake Tramadol antagonizes ACh receptors

Question 39

Indications of tramadol (non-conventional opioid)

Answer 39

Moderate to severe pain

Question 40

Adverse reactions of tramadol (opioid)

Answer 40

* headache, * pruritus, * flushing **Unlike most opioids, miosis is not listed as an adverse effect; mu selectivity effect**

Question 41

**TRAMADOL (opioid)** Topical Ophthalmic Drug Interactions

Answer 41

* Betaxolol, carteolol, levobunolol, timolol: additive hypotension risk * Brimonidine for glaucoma: additive CNS/respiratory depression and hypotension risk * **Atropine, homatropine, tropicamide (anticholinergics): additive constipation effects**

Question 42

OPIOID OVERDOSE ANTIDOTE

Answer 42

Naloxone

Question 43

Mechanism of action of Naloxone (opioid antagonist)

Answer 43

Competitive antagonist of various opioid receptors

Question 44

Adverse reactions of naloxone

Answer 44

Hypertension

Question 45

NSAIDS vs OPIOIDS

Answer 45

Question 46

Types of headaches

Answer 46

Question 47

MIGRAINE HEADACHES

Answer 47

* Recurrent moderate-severe intensity pulsating headaches lasting 2-72 hours affecting ~15% of people * Migraines are a neurovascular disorder * Often unilateral (migraine = Gr. hemikrania) * Up to 1/3rd of patients experience a visual aura * High levels of serotonin are associated with migraines * Disturbances in vision are characteristic of retinal migraines52

Question 48

Migraine treatments

Answer 48

Question 49

Indications of SUMATRIPTAN

Answer 49

* Acute migraine * Acute cluster headache

Question 50

Mechanism of action of sumatriptan

Answer 50

* Selectively activates vascular serotonin 5HT-1 receptors, producing intracranial vasoconstriction * Stimulate neuronal serotonin receptors, decreasing the release of peptides including Substance P and Calcitonin Gene-Related Peptide (CGRP), a potent vasodilator and pain stimulus

Question 51

Adverse reactions of sumatriptan (migraine treatment)

Answer 51

* Serious * Hypersensitivity: angioedema * Ocular: partial vision loss, transient/permanent blindness * Topical Ophthalmic Drug Interactions * None * Cautions * Hypertension

Question 52

Indications of ERGOTAMINE (abortive migraine treatment)

Answer 52

* Migraine * Cluster headache acute * • Cluster headache chronic

Question 53

Mechanism of action of ergotamine (abortive migraine therapy)

Answer 53

* Structurally similar to biogenic amines * Stimulates serotonin receptors producing: * Intracranial vasoconstriction; caffeine enhances vasoconstriction * Inhibition of CN-V (trigeminal nerve) pain transmission

Question 54

Adverse effects of ergotamine

Answer 54

* Serious * Hypertension * Topical Ophthalmic Drug Interactions * None * Cautions * No applicable ophthalmic conditions or findings

Question 55

Indications of topiramate (anticonvulsant)

Answer 55

* Migraines * seizures

Question 56

Mechanism of action of topiramate

Answer 56

* Blocks voltage-gated sodium channels * Augments GABA activity * Antagonizes glutamate receptors * Inhibits carbonic anhydrase

Question 57

Adverse effects of topiramate

Answer 57

* Bleeding Ocular side effects * Nystagmus, * diplopia, * visual disturbance * **Angle closure glaucoma,** * **myopia,** * **maculopathy** * **Hemorrhage,** * **anemia**

Question 58

Topical opthalmic interactions with topiramate

Answer 58

* Brinzolamide, dorzolamide: additive risk of adverse effects * Brimonidine for glaucoma: additive CNS depression Cautions • Hemorrhage

Question 59

Indication of ERENUMAB

Answer 59

* Migraine prophylaxis

Question 60

Mechanism of action of erenumab (migraine prophylaxis)

Answer 60

* Blocks calcitonin gene-related peptide (CGRP) activity

Question 61

Adverse reactions of erenumab(migraine prophylaxis)

Answer 61

* Constipation * Cramps * Muscle spasm * Serious * Anaphylaxis, hypersensitivity * Constipation * Hypertension

Question 62

Topical opthalmic drug interactions with erenumab

Answer 62

* Bevacizumab, celecoxib, ketorolac: additive HTN risk * Belladonna alkaloids, antihistamines: additive constipation risk * Cautions • HTN