Pharmacology of non-narcotis analgesics Part 1

Question 1

How do non steroidal anti-inflammatory drugs (NSAIDs) work?

Answer 1

They act primarily by inhibiting the cyclooxygenase enzymes → block 1st step in prostanoid biosynthesis

It’s actually second step because membrane phospholipids to AAs is the first step and that is enzymatically acitvated by phospholipase A2

Decreasing prostanoid synthesis has beneficial and unwanted effects.

Question 2

What forms prostaglandins and thromboxanes?

Answer 2

arachidonic acid, and a couple other ones. this is catalyzed by cyclooxygenase to prostaglandins and thomboxanes.

Question 3

Is there a COX 1 and Cox 2? what are they for?

Answer 3

yes

COX-1: constitutively expressed → house keeping tasks
COX-2: constitutively in some tissues, but largely inducible →↑ Prostaglandins

Non selective COX inhibitors inhibit formation of COX 1 and Cox2. Selective Cox 2 inhibitors obviously inhibit COX 2. So intheory selective COX-2 inhibitors would be better.

Question 4

What is the role of prostaglandins in pain and inflammation?

Answer 4

PGs sensitize nociceptors to:
Many chemical mediators of pain such as:
Bradykinin
Cytokines
Substance P
- Thermal stimuli
- Physical Stimuli

PGs and prostacycline (PGI2) → ↑ blood flow to injured tissues → ↑ leukocyte infiltration
Edema and inflammation

Peripheral inflammation → ↑ COX-2 expression in dorsal horn of the spinal cord

Question 5

what is the role of prostanoids in peripheral and central pain pathways?

Answer 5

PGs work on PG receptors (EP: PGE2 receptor, IP: PGI2 receptor) -> hypersensitization of Bradykinin receptors, increased PKA -> activation of SNS channels -> enterance of cations -> depolarization, activation of VR-1 -> increased transduction of painful stimuli. Same receptors and channels are activated by PGs in central nervous system (spine in this case) + inhibition of Glycine receptor (an inhibitory neurotransmitter -> increased pain perception).

Question 6

what do non steroidal anti-inflammatory drugs non-selective COX inhibitors do?

Answer 6

Acetylsalicylic Acid (ASA) or Aspirin, T1/2 ≈ 0.5 hours.
Ibuprofen, T1/2 ≈ 2 hours
Inhibit cyclooxygenase I and II (aspirin irreversibly) reducing the formation of prostaglandins and thromboxanes
Inhibit pain sensory transmission in peripheral and central nervous system (spine and the brain).

for aspirin it binds irreversibly to the enzyme until the body makes new enzyme so the aspirin that is free will be gone in half an hour but the aspirin with the cyclooxygenase that binds with aspirin willl die and so the anti-platelet effect may last for about 7 days.

Question 7

what is the role of prostaglandins (PGs) in fever-effect of NSAIDs on fever?

Answer 7

Viruses and bacterial endotoxins → ↑COX II in the preoptic nuclei of the hypothalamus, the thermoregulatory center of the body
PGE2 is particularly a potent pyrogen
NSAIDS reduce elevated body temperature but do not alter normal body temperature appreciably
May re-set the thermoregulatory mechanism in the hypothalamus
It is seldom necessary to lower mild to moderate fever

It only works when the temperature is up. If someone has a regular temperature it won’t do anything to that.

Question 8

what occurs in the NSAID adverse effects?

Answer 8

Adverse effects due to inhibiting COX I
1- GI effects:
- PGI2 → ↓ Acid, PGE2 →↑ stomach protective mucus
- NSAIDs → ↓ PGI2 and PGE2 → Gastrointestinal irritation and ulceration
2- ↓ blood coagulation: (decreased platelet stickiness or aggregation)
1+2 → May cause GI perforation and severe GI bleeding in elderly (both increased in combination with alcohol)
→ Ibuprofen has less adverse GI effects compared to ASA
3- Kidney effects:
- ↓ renal blood flow: when there are circulating vasoconstrictors
- Interstitial nephritis

Question 9

What happens with the the NSAIDs if there is ASA (asparin) overdose?

Answer 9

• The analgesic activity occurs at lower doses
• The anti-inflammatory dose is higher
• At anti-inflammatory doses, hepatic enzymes are saturated producing a zero order kinetic pattern (up to a certain dose you go in a linear fashion and then you go exponentially)

Low toxicity = Salicylism

• Nausea/ vomiting
• Hyperventilation (due to metabolic acidosis, to ↓ CO2)
• Lethargy
• Tinnitus

Severe toxicity

• Restlessness
• Hallucinations
• Seizures
• Coma
• Respiratory and metabolic acidosis (start breathing fast to try to get rid of acid)
• Respiratory failure

Acidosis usually not a problem in adults, may lead to fatal acidosis in children. Also acute hepatic failure in children (Reye’s syndrome) with viral disease
Alkalinization of urine →↑ water solubility → ↑ clearance (weak acid: pKa = 3.5)

Figure 36-5 NSAIDs produce their therapeutic effects and many side effects by inhibiting the cyclooxygenase (COX) enzymes. Drugs that inhibit COX-2 selectively may produce fewer adverse side effects than do those that inhibit both isoforms of the enzyme.

Question 10

What are the NSAIDs - COX II inhibitors?

Answer 10

• Celecoxib (Celebrex®), T1/2 = 11 hours
  
  • Rofecoxib (Vioxx®), T1/2 = 17 hours
  • Are selective COX II inhibitors
  • Inhibiting COX II reduces various mediators of the inflammatory process, but does not alter GI mucosal defense or platelet aggregation
  Caution:
  • Found increased clots and myocardial infarcts in patients with pre-existing CV risk factors who took rofecoxib for more than 18 months.
  • Thromboxane A2 made by COX I increases platelet stickiness.
  • PGI-2 made by COX I and COX II reduces platelet stickiness and induces vasodilatation.
  • Chronic rofecoxib reduces PGI-2 but not TBX-A2, which results in increased platelet stickiness and reduced vasodialation.
  • Rofecoxib was withdrawn from market
  • Celecoxib may cause rash as it is a sulfonamide

Question 11

What is acetaminophen (Tylenol)?

Answer 11

• Acetaminophen, T1/2 ≈ 2 hours
• Weak inhibition of prostaglandin formation in peripheral tissues, lacks anti-inflammatory actions, and no antiplatelet
• Aanalgesic and anti-pyretic actions are comparable to Aspirin
• Less GI distress than Aspirin
• Recommended therapeutic doses are generally safe
• Acetaminophen is included in so many OTC products that it’s easy to inadvertently take too much which can produce liver damage which can be severe when combined with ethanol.
• Overdose (more than 10 to 15 grams) may be fatal due to highly hepatotoxic metabolites (20 tablets of 500 mg per tablet-extra strength)
• N-acetylcysteine (®Mucomyst) is the antidote