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

Leukotrienes LTB4 , LTC4 and LTD4

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 Pro-inflamation - 2 & 4 Anti-inflam - 3 & 5 (PGI2 is not pro-inflamatory

PG's an TXA2 actions on vasculature

PGE2 causes edema (swelling) and vasodilation (redness) PGI2 produces vasodilation TXA2 (Thromboxane A2) is a vasoconstrictor PGI 2 and TXA2 physiologic antagonists

\ \ Acetylsalicylic Acid (Aspirin) Dosing for 1. Anti-platelet activity 2. Analgesia 3. Anti-pyretic (fever) 4. Anti-inflammatory

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 Lowdose-1st order High dose- zero order

*Analgesics Flashcards by Jacomien Bingham

5 Cardinal signs of inflammation

Heat
- increased vascular perfusion - 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

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Inflammation

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

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Which autonomic responses are associated with pain?

(SNS, PNS shut down):

Tachycardia
Systemic hypertension
Tachypnea
Diaphoresis (cold sweat)
Pallor
Nausea

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Therapeutic relief mechanisms for treating pain

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

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

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

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Defective NF-_KB is linked to

Cancer
Septic shock
Inflammation
Viral infection
Auto immune diseases

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Inflammatory pain mediators

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)

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Define allodynia

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

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Inflammation pathway

Leukotriene type 4 and Prostaglandin type 2 = pro inflammation

(even numbers = bad)

Leukotriene type 5 and Prostaglandin type 3 = anti-inflam

(Odd numbers = good)

PGI₂and TXA₂are physiologic antagonists

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COX 1 vs COX 2

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

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Leukotrienes LTB₄ , LTC₄and LTD₄

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

Pro-inflamation - 2 & 4

Anti-inflam - 3 & 5

(PGI₂is not pro-inflamatory

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PG’s actions on kidney

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

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PG’s an TXA₂ actions on vasculature

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

PGI₂ and TXA₂ physiologic antagonists

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PG’s and TXA2 actions on platelets

TXA2 promotes platelet aggregation
PGI2 inhibits platelets

NSAIDS and OMEGA 3 prevent TXA₂

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PG’s effect on GI tract

PGE1 & PGE2: production of cytoprotective GI mucous

• PGI2 (Prostacyclin): decrease GI acid secretion

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PAFeffect on connective tissue

PAF (Platelet Activating Factor) activates matrix
metalloproteinases

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PGE₂ effect on CNS

PGE2 causes fever through the hypothalamus

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PGF2A effects on reproduction

PGF2a causes suppression of spermatogenesis & uterine
contraction

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Endogenous analgesics

Endorphins (natural opioid)
- 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(acetaminophen)
- Reuptake is inhibited by Tramadol, selective serotonin
  reuptake inhibitors (SSRIs), and selective norepinephrine
  serotonin reuptake inhibitors (SNRIs)

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** Acetylsalicylic Acid (Aspirin)

Dosing for

Anti-platelet activity
Analgesia
Anti-pyretic (fever)
Anti-inflammatory

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

Lowdose-1st order

High dose- zero order

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Mechanism of action of ASA (aspirin/acetylsalilicylic acid)

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

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Adverse reactions of ASA (Aspirin/acetylsalicylic acid)

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

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What medication is associated with corneal denervation?

Aspirin / acetylsalicylic acid

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

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

Indications of Celecoxib (COX 2 inhibitor)

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

Mechanism of action of Celecoxib

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

Adverse reactions of Celecoxib (selective COX 2 inhibitor)

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

Topical Ophthalmic Drug Interactions of Celecoxib (COX2 inhibitor)

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

Indications of Acetaminophen (Paracetamol)

Pain and fever Max dose per day : 4000mg

Mechanism of action of Acetaminophen (Paracetamol)

* 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

Adverse effects of acetaminiphen (paracetamol)

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

ASA VS ACETAMINOPHEN

Neurogenic pain responds best to which type of medications

Anticonvulsants and antidepressants

Different pain killer profiles

Other than analgesia, what can opioids be used for

As an antitussive(cough) Anti-diarrheal

Hydrocodone mechanism of action | (combined with acetaminophen)

* 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

Adverse effects of hydrocodone

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

Mechanism of action of tramadol (Only Shedule 4 opioid drug)

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

Indications of tramadol (non-conventional opioid)

Moderate to severe pain

Adverse reactions of tramadol (opioid)

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

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

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

OPIOID OVERDOSE ANTIDOTE

Naloxone

Mechanism of action of Naloxone (opioid antagonist)

Competitive antagonist of various opioid receptors

Adverse reactions of naloxone

Hypertension

NSAIDS vs OPIOIDS

Cellular Phase of Acute Inflammation

* Phagocytic extravasation from circulation: facilitates infiltration of the affected tissue site (swelling) * Chemotactic signalling serves to guide phagocytes to the inflammatory focus * Phagocytosis: of microbes, foreign bodies, and damaged cells * Formation of an exudate

Neurogenic(nerve) pain responds best to:

Anticonvulsants Antidepressants (Cross BBB, affecting neurologic function and tramsmission)

Nociceptive pain responds well to

NSAIDs, paracetamol, and opioids | (inhibit COX)

Essential fatty acids

Omega 6 - pro inflammatory-prostaglandins_2,TXA_2,Leukotrines₄ Omega 3- anti-inflam- prostaglandin₃ TXA_3,Leukotrine₅ _{Pro-inflammatory eicosanoids are series 2 and 4
- Anti-inflammatory eicosanoids are series 3 and 5} * _{Linoleic acid: vegetable, safflower oils} * _{Y-Linolenic acid (GLA): evening primrose oil supplement} * _{Arachidonic acid (AA): meat} * _{Alpha-linolenic acid (ALA): green leafy vegetables, flax seed, canola, walnut, soybeans
o ALA are less efficient in anti-inflammatory than EPA} * _{Eicosapentaenoic acid (EPA): oily fish, krill oil and algae} * _{Taking EPA doesn’t slow down the Omega-6 pathway but they do quickly turn into anti-inflammatory products} * _{Docosahexaenoic acid (DHA): a common supplement
- Delta-5-desaturase = much greater affinity for ETA than DGLA
o If you consume more omega-3 then the omega-6 pathway will essentially get shut down}

Topical NSAIDs

* Indications include intraoperative miosis prevention, post-op inflammation & CME, allergic conjunctivitis, inflammatory dry eye, corneal pain * Cystoid macular edema (CME) has an incidence of 0.1% following uncomplicated phacoemulsification cataract surgery * CME is linked to disruption of the BRB by PGs and other inflammatory mediators

Topical NSAID's adverse reactions

* Burning, stinging * Corneal toxicity: superficial punctate keratopathy * Corneal infiltrates * **Corneal melt** (promoted w/ desensitization) * Vitreous detachment * Delayed wound healing * Prolonged bleeding time * Elevated IOP\*

Since ASA works peripherally ans acetaminophen works centrally, do they both work for treating fever?

Yes

Which topical opthalmic drugs can cause corneal melt?

NSAIDs

Which classification of NSAIDs is most common to topicals?

Acetic acid derivatives (bromfenac, diclofenac, amfenac)

NSAIDs vs Steroids

Which of the following is a prodrug: 1. Flubiprofen 2. Nepafenac 3. Bromfenac 4. Ketrolac

Nepafenac