(11/12) Autacoids I: Eicosanoids NSAIDs I: COX-I & COX-II inhibitors

Lecture 10 was skipped!!

Stages of inflammation

• Acute → local vascular changes

• Subacute/delayed → inflammatory-cell infiltration

• Chronic → tissue degradation + deformation

Tell me one class of inflammatory mediators released at the site of inflammation…

Eicosanoids

Eicosanoid pathway

This pathway is targeted by:

• NSAIDs

• corticosteroids/glucocorticoids

Eicosanoid pathway

Membrane phospholipids

→ PLA₂ → arachidonic acid

Then:

COX pathway

→ prostaglandins
→ prostacyclin
→ thromboxane

LOX pathway

→ leukotrienes

Eicosanoid pathway

Drug targets where?

Corticosteroids → inhibit PLA₂

NSAIDs → inhibit COX

Eicosanoids in…

a. fever

b. pain

a. PGE₂

b. PGE₂ + PGI₂

Eicosanoids in fever - process

Stimulus / pyrogens

→ COX

→ PGE₂

→ ↑ hypothalamic temperature set point

→ fever.

Eicosanoids in pain - process

make pain nerves more sensitive + histamine/bradykinin/serotonin→ more pain

NSAIDs and chronic inflammation connection…

NSAIDs do NOT stop tissue damage in chronic inflammation.

They relieve symptoms such as:

• pain

• inflammation

• swelling

But they do not modify disease progression.

Pain/inflammation →

Fever →

Platelets →

Pain/inflammation → PGE₂ + PGI₂

Fever → PGE₂

Platelets → TXA₂

SHARED PROPERTIES OF NSAIDs

The teacher specifically divided this into:

1. MOA/COX selectivity

2. 4 pharmacological actions + mechanisms

3. 5 side effects + mechanisms

4. shared contraindications/precautions

SHARED PROPERTIES OF NSAIDs

COX selectivity

Most NSAIDs

→ nonselective

→ inhibit COX-1 + COX-2

COX-1 AND COX-2: Roles?

→ both have physiological and inflammatory roles.

Reclassified COX-2-preferring drugs

	Drug
M	Meloxicam
E	Etodolac
D	Diclofenac

COX-2 selective drugs

Celecoxib

SHARED PROPERTIES OF NSAIDs

4 pharmacological actions + mechanisms

Action	Mechanism you need to know
Anti-inflammatory	↓ PGE₂ + PGI₂ → ↓ vasodilation/edema; also ↓ inflammatory-cell migration + stabilizes lysosomal membranes
Analgesic	↓ PGE₂ + PGI₂ → ↓ sensitization of pain nerves
Antipyretic	↓ PGE₂ → ↓ elevated hypothalamic set point
Antiplatelet	aspirin: ↓ TXA₂ → ↓ platelet aggregation. Do NOT assume all NSAIDs have a strong antiplatelet effect. celecoxib lack it.

SHARED PROPERTIES OF NSAIDs

5 side effects + mechanisms

Side effect	Why
GI ulceration/injury	↓ protective PGE₂/PGI₂
Delayed labor/prolonged gestation	↓ contractile uterine PGs
Renal (kidney)effects	NSAID → ↓ PGE₂/PGI₂ → unopposed renal vasoconstriction → ↓ renal blood flow/GFR → salt + water retention this all leads to… Edema + HTN + hyperkalemia
Hypersensitivity	COX blocked → LOX pathway becomes exaggerated
↑ CV events	↓ PGI₂ + TXA₂ active (clotting risk ↑) + renal effects

Order I remember in:

• GI injury

• Hypersensitivity

• Delayed Labor

• Renal (Kidney Effects)

• CV Effects

SHARED PROPERTIES OF NSAIDs

shared contraindications/precautions

• Peptic ulcer disease → GI injury

• Pregnancy/delayed labor

• NSAID hypersensitivity → hypersensitivity reaction

• caution in patients with compromised renal/CV status because of renal effects

SALICYLATES / ASPIRIN

what we need to know?

1. Unique MOA

2. 8 pharmacologic actions,

3. pharmacokinetics

4. 5 side effects

5. 6 contraindications

6. intoxication

7. therapeutic applications

SALICYLATES / ASPIRIN

unique MOA?

IRREVERSIBLE COX INHIBITOR

Why?

→ aspirin acetylates COX

→ forms irreversible inhibition.

Compare:

Aspirin → irreversible

Other NSAIDs → reversible

SALICYLATES / ASPIRIN

8 pharmacologic actions: overview

1. Analgesic

2. Antipyretic

3. Antiplatelet

4. Anti-rheumatic / anti-inflammatory

5. Respiratory effects

6. Metabolic effects

7. Endocrine effects

8. Uric-acid effect

SALICYLATES / ASPIRIN

8 pharmacologic actions: Analgesic

→ inhibits: PGE₂ + PGI₂

→ ↓ sensitization to pain

→ useful for low-intensity pain.

SALICYLATES / ASPIRIN

8 pharmacologic actions: Antipyretic

→ inhibits: PGE₂

→ resets elevated hypothalamic set point.

SALICYLATES / ASPIRIN

8 pharmacologic actions: Antiplatelet

→ inhibits: TXA₂

→ ↓ platelet aggregation.

SALICYLATES / ASPIRIN - 8 pharmacologic actions: Antiplatelet

How much aspirin is needed for each effect?

Lowest dose
→ Antiplatelet

Higher dose
→ Analgesic = antipyretic

Much higher dose
→ Anti-inflammatory

SALICYLATES / ASPIRIN

8 pharmacologic actions: Anti-rheumatic / anti-inflammatory

Requires large doses.

Anti-inflammatory dose >5× analgesic dose

SALICYLATES / ASPIRIN

8 pharmacologic actions: Respiratory effects

Both cause: Hyperventilation

Direct Aspirin

→ directly stimulates respiratory center in medulla

→ hyperventilation.

Indirect Aspirin

→ uncouples oxidative phosphorylation

→ ↑ O₂ consumption

→ ↑ CO₂ + heat

→ further hyperventilation.

SALICYLATES / ASPIRIN

8 pharmacologic actions: Metabolic effects

Aspirin uncouples oxidative phosphorylation

Normal = energy → ATP
Uncoupled = energy → heat instead of ATP

Carbohydrate metabolism — large doses

May cause:

• hyperglycemia

• glycosuria

• depletion of liver/muscle glycogen

Fat metabolism

→ ↓ lipogenesis.

SALICYLATES / ASPIRIN

8 pharmacologic actions: Endocrine effects

• large doses → ↑ ACTH

• long-term administration → decrease in thyroid iodine uptake

SALICYLATES / ASPIRIN

8 pharmacologic actions: Uric-acid effect

Aspirin dose	Effect on uric acid
Low: 1–2 g/day	↓ urate excretion → urate retaine) (HOLD)
Intermediate: 2–3 g/day	No effect
Large: >5 g/day	↑ urate excretion → uricosuric (OUT)

SALICYLATES / ASPIRIN

Pharmacokinetics

1. Low-dose salicylate → FIRST order → elimination system NOT saturated

   1. aspirin t½ ≈ 15 min

   2. salicylate t½ ≈ 2–3 h

2. High-dose salicylate (>4 g) → ZERO order → system saturated

   1. salicylate t½ may become 15–30 h

SALICYLATES / ASPIRIN

Five salicylate side effects: overview

1. GI effects - extra info

2. Hypersensitivity

3. Hepatic/renal effects

4. Acid-base/electrolyte pattern

5. CNS effects

SALICYLATES / ASPIRIN

Five salicylate side effects: GI effects

Aspirin has the general NSAID mechanisms (↓ protective PGE₂/PGI₂) PLUS direct irritation.

1. Direct irritant effect because salicylate is acidic

2. Loss of PG-mediated inhibition of gastric-acid secretion

3. ↑ LOX-pathway products

→ epigastric distress, nausea/vomiting, ulceration/bleeding.

SALICYLATES / ASPIRIN

Five salicylate side effects: Hypersensitivity

→ LOX pathway exaggerated

→ ↑ leukotriene-related effects.

Possible:

• rash/urticaria (hives)

• angioedema

• asthma/bronchospasm

SALICYLATES / ASPIRIN

Five salicylate side effects: Acid-base/electrolyte pattern

LOW toxic dose
→ hyperventilation
→ ↓ CO₂
→ respiratory alkalosis

HIGH toxic dose
→ acids build up
→ metabolic acidosis and respiratory acidosis

SALICYLATES / ASPIRIN

Five salicylate side effects: CNS effects

High-dose salicylates:

→ CNS stimulation

→ eventually CNS depression.

Also:

stimulate CTZ → nausea + vomiting

SALICYLATES / ASPIRIN

Five salicylate side effects: Hepatic/renal effects

1. Compromised adult/patient → renal effects

   1. salt + water retention

   2. edema, hyperkalemia, hypertension

2. Child + viral infection + aspirin → Reye syndrome = liver + brain injury

SALICYLATES / ASPIRIN

Six salicylate contraindications + WHY

Contraindication	Why
1. Hemophilia	Aspirin antiplatelet effect → excessive bleeding
2. Peptic ulcer disease	GI irritation/ulceration/bleeding
3. Children/adolescents with viral infection	Reye syndrome → hepatic injury + encephalopathy
4. Gout	Low doses ↓ urate excretion → uric acid retained
5. Pregnancy	delayed labor + excessive bleeding
6. CHF / cirrhosis / chronic renal disease / hypovolemia	edema, hyperkalemia, worsened HTN,

Order:

1. GI/PUC

2. Pregnancy

3. CV/Renal

4. 3 NEW:

   1. Hemophilia

   2. Children/adolescents with viral infetion

   3. Gout

SALICYLATES / ASPIRIN

intoxication / aspirin toxicity

As aspirin exposure ↑	What to know
Low therapeutic	Antiplatelet effect — 81 mg discussed
Higher therapeutic	Analgesic + antipyretic
Still higher	Anti-inflammatory
🔴 Early toxicity (1)	TINNITUS = ringing in ears → one of the earliest signs
Mild toxicity (2)	Hyperventilation + nausea/vomiting
Low toxic level (3)	Hyperventilation → respiratory alkalosis → compensated respiratory alkalosis
Increasing/severe toxicity (4)	Hyperpyrexia, excessive sweating → dehydration
🔴 High toxic level (5)	Respiratory acidosis + metabolic acidosis
Very severe toxicity	CNS depression → coma
🔴 End stage	Respiratory failure → death

SALICYLATES / ASPIRIN- intoxication / aspirin toxicity

Aspirin toxicity treatment

1. Aspirin → no specific antidote

   1. but supportive treatment is available:

      1. Activated charcoal / gastric measures → ↓ absorption

      2. IV fluids → correct acid-base problems

      3. Hemodialysis → severe toxicity cases

2. Acetaminophen → NAC antidote

SALICYLATES / ASPIRIN

Therapeutic applications

• Aspirin = pain + fever + inflammation + antiplatelet

• Low-dose aspirin = antiplatelet

UNIQUE PROPERTIES OF THE OTHER NSAID CLASSES

Drug/class	What you need to know
Diclofenac	Reclassified → COX-2-preferring
Etodolac	Reclassified → COX-2-preferring
Indomethacin	Unique CNS effects (Psychiatric disorders) + PDA closure (patent ductus arteriosus)
Propionic acids	Better tolerated (in GI); commonly used
Ibuprofen	Alternative for PDA closure
Meloxicam	COX-2-preferring + long acting
Meclofenamate	Blocks PG receptors in addition to COX
Nabumetone	Only non-acid NSAID and prodrug
Celecoxib	COX-2 selective; no antiplatelet effect/CV issue (PGI₂ ↓ and TXA₂ unaffected ); sulfur-allergy caution

1. MEMORY TOOL:

• MED, C

• IPIMN (I PEED IN MY NIGHTGOWN)

Acetaminophen vs NSAIDs

• Acetaminophen = Pain + Fever, but NOT much inflammation

• And compared with aspirin, acetaminophen has basically:

  • NO antiplatelet effect

  • NO respiratory effects/NO acid-base effects

  • NO effect on uric acid excretion

  • NO gastric irritation/bleeding

Acetaminophen

metabolism

→ 60% glucuronidation ✅
→ 35% sulfation ✅
→ tiny amount CYP450 → toxic intermediate ⚠

• but glutathione grabs it and makes it safe ✅

Acetaminophen

At normal therapeutic doses, professor said there are…

few side effects, although occasional allergic/skin reactions can occur.

Acetaminophen

toxicity

APAP Overdose → ↓ glutathione → toxic metabolite ↑ → liver necrosis

Acetaminophen

toxicity treatment?

• N-ACETYLCYSTEINE = NAC

  • Mechanism:

    • replenishes hepatic glutathione

    • helps detoxify toxic metabolite.