Analgesics Flashcards
Give some examples of NSAIDs.
- Aspirin
- Ibuprofen
- Naproxen
What is the mechanism of action of NSAIDs?
Competitive inhibition of COX-1 and COX-2.
Main Effect is via inhibition of COX-2
What are the effects of NSAIDs?
Analgesia
Anti-inflammatory
Antipyretics
What is the action of Aspirin?
- Irreversibly inhibits COX enzymes by acetylation
- Converted to salicylate.
Describe the pharmacokinetics of Aspirin?
- Lower doses show first order kinetics
- Higher doses show zero order kinetics
What are the specific uses of Aspirin?
- Cardioprotective functions
- Prophylactic for GI/Breast cancers
What are side effects of NSAIDs?
- Long term use in elderly has iatrogenic morbidity and mortality
- Renal ADR occur in compromised individual with hypovolaemia or HRH
- Stomach/GI tract ADRs. Includes varying degrees stomach pain, nausea, heartburn, gastric bleeding, ulceration.
- Vascular such as increased bleeding time and increased bruising haemorrhage
- Hypersensitivity
- Reyes syndrome which is a rare serious brain/liver injury
What causes Renal ADRs in compromised individuals as a result of NSAIDs?
- PGE2 and PGI2 maintain renal blood flow. if reduced by NSAIDs then GFR decreases which can lead to further risk of renal compromise
- Na+/K+/Cl- and H2O retention follow with increased likelihood of hypertension
What causes Stomach/GI tract ADRs as a result of NSAIDs?
- COX-1 PGE2 stimulates cytoprotective mucus secretion throughout GI, reduce acid secretion and promote mucosal blood flow
- Can be offset with PPIs or Misoprotolol
What are the features of Hypersensitivity as a result of NSAIDs?
- Skin rashes that are usually mild
- Bronchial asthma so care in asthmatics
Describe the pharmacodynamic of NSAIDS
- Mainly heavily bound to plasma protein (90-99%)
- In combination with low dose opiates extend therapeutic range for treating pain. Act by different mechanism to extend range
Which drugs can be affected by NSAIDs?
Can displace the drug into plasma
- Suphonylurea (hypoglycaemia)
- Warfarin (increased bleeding)
- Methotrexate (wide ranging serious ADRs)
What are some examples of non-narcotics?
Paracetamol
What is the mechanism of action of non-narcotics (paracetamol)?
Unknown mechanism but thought to be:
- Weak COX-1/COX-2
- Primarily acts in the CNS on the TRP channels
- Activation of serotogernic pathway
- Prostagladin inhibition
What are the uses of paracetamol?
Analgesia
How is paracetamol metabolised?
- Normally mainly use phase 2 conjugation to break down. Some Phase 1 oxidation occurs (10%) which forms NAPQI which is very reactive and toxic.
- At normal dose, NAPQI is detoxified by phase 2 conjugation with Glutathione. Conjugation is linear but limited by glutathione availability
What happens at high doses of paracetamol?
- At high doses, phase 2 metabolism is saturated. Leads to increased phase 1 production of NAPQI.
- Phase 2 conjugation of NAPQI with glutathione is rate limited and saturated.
- Unconjugated NAPQI is highly reactive and bind with cell macromolecules/mitochondria.
- This can lead to hepatic cell death. Can also lead to renal failure in paediatric and elderly patient primarily
Describe the pharmacokinetics of Paracetamol
- High dose, PKs become zero order
- Phase 2 metabolism saturated so phase 1 increases so more NAPQI.
- Conjugation of NAPQI with glutathione is rate limited. GLuthathione is also rapidly depleted.
How is paracetamol overdose treated?
- Treatment must be given as soon as possible.
- Delayed hepatoxic effect peak 72-96 hours post ingestion
- 0-4 hours, activated charcoal orally reduce uptake by 50-90%
- 0-36 hours, start with acetylcysteine. Methionine given by mouth if N- Acetylcysteine cannot be given promptly
What are some example of Narcotics?
- Oral codeine (metabolised to morphine)
- Oral tramadol
- Morphine
- Diamorphine
- Fentanyl patch
- Oxycodone
What is the mechanism of action of narcotics?
- Bind to opiate receptor
- Inhibits adenyl cyclase
- Decreases cAMP
- Cause decreased influx of Ca2+
- Reduced neurotransmitter release
- Reduced transmission of nociceptive impulses
What are the uses of narcotics?
Good agent for moderate to severe pain such as cancer pain, chronic pain and post-operative pain
-Used in Acute, Chronic, and Non analgesias
What are the side effects of narcotics?
- Constipation
- Reduced conscious levels
- Respiratory depression
- Nausea and vomiting
- Confusion
- Constricted pupils
What can be given to reverse the effects of opiates if needed?
Naloxone is an opiate antagonist that can be given in toxicity to reverse opiate overdose
What is the interaction when combination NSAIDS are used?
- Combination NSAIDs can affect PK/PD due to competition for plasma protein binding sites and therefore cause ADRs.
- NSAIDs + low dose aspirin compete for COX-1 binding sites which may interfere with cardio-protective action of aspirin
Which acute clinical cases require Narcotics?
-Acute: trauma, burns, perioperative, MI
Which Chronic Clinical Cases require Narcotics?
-Chronic: refractory pain, malignancy
Which non-analgesic situations use narcotics?
-Non analgesis: cough suppression, manage diarrhoea, breathlessness
