L19 Flashcards
Nociceptive pain
protective; response to the detection of noxious stimuli that can potentially cause tissue injury
Inflammatory pain
protective; caused by tissue damage; release of inflammatory mediators
Pathological pain
neuropathic pain
* caused by damage to the nervous system; e.g., spinal cord injury, diabetic neuropathy, multiple sclerosis
dysfunctional pain
- abnormal function of the nervous
system in the absence of damage or
inflammation
Inflammatory pain sensitisation simple
Tissue injury
↓
Production & release of a chemical soup
↓
Peripheral sensitisation to pain
↓
Central processing and sensitisation (Spinal cord)
↓
Signal sent to brain for final processing
What does PGE2 do with peripheral excitability
PGE2 increased peripheral excitability; evoked many action potentials,
* cAMP/PKA-dependent modulation of the tetrodotoxin-resistant sodium channel
Cyclooxygenase and prostaglandin synthesis
Membrane phospholipids
↓ – Phospholipase A2
Arachidonic acid
↓ –cyclooxygenase activity (COX)
Prostaglandin G2
↓ –peroxidase activity (COX)
Prostaglandin H2
↓
Prostaglandin E2
COX
Cyclooxygenase (COX)*
COX-1 stomach
COX-1 synthesises cytoprotective PGs (e.g., PGI2)→ protection on mucosal epithelium→ protection from peptic ulcer
Cox-1 Kidney
PGE2 production→ vasodilation and maintains renal blood flow
Cox-1 Platelet
production of thromboxane A2- platelet aggregation
COX1 CNS
distributed in neurons throughout the brain
COX-2 - inflam and CNS
- Can be induced by stimuli that are associated with inflammation
- CNS: restricted to parts of the CNS, e.g., spinal cord, hippocampus
What type of drugs inhibit COX
- steroids
- NSAID
- Diclofenac
- Aspirin
Diclofenac and COX
- Drug inhibits COX
- Compete with arachidonic acid for cyclooxygenase active site thereby blocking it
Aspirin and COX
- Unique MoA
- Acetyl group with acetylated the hydroxyl group serine → irreversible COX inhibition
- antiplatelet effects from inhibition of thromboxane A2 formation
Aspirin in asthma
- bronchospasm in aspirin-sensitive asthmatics (leukotrienes - airway constriction)
How aspirin produces leukotrienes
- Arachidonic acid
- 5-Lipoxygenase (5-LOX)
- 5-HPETE
- Leukotrienes
- bc aspirin irreversibly blocks prostaglandin formation
Reye’s Syndrome
- affect children - use aspirin to treat fever after viral infection; first described in 1963
- vomiting, hyperventilation→ hepatic failure, encephalopathy
- high mortality
Difference in structure of COX-1 and COX-2
- isoleucine to valine substitution at position 523 - a side pocket to accommodate bulkier substrates
- wider channel opening
- Only COX-2 has the side pocket not COX-1 which make it easier to make selective inhibitors
-coxibs are what type of drug
COX-2 selective inhibitors that fit into the side pocket of COX-2
Non-steroidal anti-inflammatory drugs uses
- analgesic effects - useful non-opioid analgesics
- anti-inflammatory effects - painful conditions with an inflammatory component
- anti-pyretic effects
Effects of using Non-selective COX inhibitors
- GI tract adverse effects
- bleeding
- acute renal dysfunction - ↓ renal blood flow
- problems in the elderly
Elderly patients and Non-selective COX inhibitors
- elderly patients
- history of previous GI ulcers
- patients with CV risk factors
- patients with renal risk factors
- make side effects worse
Effects of using selective COX-inhibitor compared to non-selective
- lower GI adverse effects
- reduced risk of bleeding
- no bronchospasm in NSAID-sensitive asthmatics
Paracetamol effects
- analgesic effects
- anti-pyretic effects
- lacks anti-inflammatory effects
Paracetamol deacetylation
By P-aminophenol to AM404
enzyme is a fatty acid amide hydrolase
Paracetamol MoA proposed
- COX-3 inhibition in dogs its different in humans
- Interaction with the endocannabinoid system
–AM404 inhibits endocannabinoid reuptake→ CB1 receptor activation → descending serotoninergic pathways→ inhibit pain sensitisation - Interaction with TRP (transient receptor potential) channels
– Paracetamol and metabolites - Inhibition of NO formation
– Inhibit NMDA receptor-mediated NO synthesis - NO conveys nociceptive information at the spinal level
Paracetamol metabolites
- NAPQI
- AM404
Paracetamol inactive at what sites
- kidney - no renal impairment
- GI tract - no peptic ulcer risk
- lacks anti-inflammatory effect
NAPQI is rapidly detoxified - how? (treatment of OD)
- intrinsic drug-induced liver injury- NAPQI accumulation
- antidote: N-acetylcysteine to replenish glutathione
What is antidote to Paracetamol OD
N-acetylcysteine
