CPT S7 - Analgesics Flashcards
Outline the pathway for the production of prostaglandins
Cell membrane phospholipids are converted by the enzyme phospholipase A2 to arachidonic acid
Arachidonic acid is then converted by COX1 or COX2 to prostaglandins G and H
These prostaglandins can be then converted to PGs D, E, F and I by specific enzymes
What is the role of COX1?
Major cytoprotective role in: -Gastric mucosa -Myocardium -Renal parenchyma Due to production of PGs
What is the role of COX2?
Expression is induced by bradykinin
Main therapeutic effects of NSAIDs occur via COX2 inhibition
How do the differences in structures of COX1 and COX2 affect the drugs that can act on them?
COX1 has a small opening for arachidonic acid, whereas COX2 has a larger opening. Larger drugs can only fit in the opening of COX2. Smaller drugs like aspirin can fit in both and act on both.
What are the effects of prostaglandins on nociception?
Following injury, tissues release PGs
These bind to C fibre GPCRs
Activation results in:
-Increased neuronal sensitivity to bradykinin
-Inhibition of K+ channels
-Increased Na channel sensitivity
In combination, these act to increase C fibre activity
PGs may also activate previously silent C fibres
Define allodynia
A painful response to a normally innocuous stimulus
Define hyperalgesia
An increased response to a painful stimulus
How do prostaglandins cause sensitisation of central nociception?
Increased sustained nociceptive signalling peripherally results in increased cytokine levels in the dorsal horn
This causes increased COX2 synthesis and PG synthesis
These act via local GPCRs to increase sensitivity and discharge rate of secondary interneurones
How do PGs cause pyrexia?
Inflammatory states stimulate macrophage release of IL-1
IL-1 causes PG synthesis within the hypothalamus
The PGs interact with GPCRs, resulting in both increased heat production and decreased heat loss
What are the general pharmacological effects of NSAIDs?
Main therapeutic effects mediated via COX2 inhibition
Nearly always competitive inhibition
Prevents arachidonic acid occupation
Very high protein binding
What preparations are common for NSAIDs?
Typically PO
Many topical options for soft tissue injury
What are the clinical uses of NSAIDs?
Anti-inflammatories - ie in MSK disorders; rheumatoid/osteoarthritis
Analgesia - for mild-moderate pain. Less effective than opiates but better ADR profile
Give some common ADRs for NSAIDs
GI: stomach pain, nausea, heartburn, gastric bleeding, ulceration
Renal: Most likely in HRH compromised patients. Reduced GFR, fluid and electrolyte retention, hypertension.
Vascular: Increased bleeding time and bruising
Hypersensitivity: Rashes (usually mild but can be very serious - Stevens Johnson syndrome). Bronchial asthma
Reyes syndrome: paediatric, liver/brain injury
Give the primary therapeutic effects of NSAIDs
Analgesia
Anti-inflammatory
Antipyretic
Are there any serious DDIs for NSAIDs?
Highly protein bound so can displace other highly protein bound drugs. This cold be a problem when there’s a narrow therapeutic window ie warfarin, methotrexate, sulphonylurea
Other NSAIDs: patients who take aspirin will lose its cardioprotective effect if they take other NSAIDs
In what way is aspirin different in comparison to other NSAIDs?
It irreversibly inhibits COX enzymes by acetylation: all other NSAIDs are competitive inhibitors.
What are the effects of paracetamol?
Mild-moderate analgesia and fever
Into which drug class does paracetamol fall?
It’s own: Non NSAID Non Opiate Analgesic.
This is because it exhibits almost no anti-inflammatory effects.
What is mechanism of action of paracetamol?
We don’t know yet.
Weak COX1&2 inhibitor
Give some ADRs for paracetamol
Very few, only one big one
Toxicity- phase II metabolism saturates very quickly, leading to phase I metabolism
This causes NAPQI production, a hepatotoxin whose conjugation is rate limited by glutathione supply
How is paracetamol toxicity treated?
If seen 0-4h, give activated charcoal PO to reduce uptake
If seen 0-36h, start N-acetylcysteine IV and adjust the dose based on plasma concentration of paracetamol.
By what mechanisms do we understand pain?
Physiological: nociception
Psychological: phantom limb pain, intractable pain, gate control theory.
What are the actions of opioids?
Central effects: psychoactive
Peripheral effects: gate control theory
Briefly describe the pain pathway
Stimulus activates a nociceptor
Action potential travels through a nociceptive nerve fibre (type A, C, etc)
Synapse in dorsal root
Goes through thalamus and primary sensory cortex before returning to interneurons in the substantia gelatinosa to deliver descending inhibition
Give some examples of endogenous opioid peptides
Enkephalins
Endorphins
Dynorphins
What are the types of opioid receptors?
μ mu (MOP)
δ delta (DOP)
Κ kappa (KOP)
Where are the opioid receptors expressed?
μ mu: supraspinal
δ delta: widely distributed
Κ kappa: spinal cord
What are the mechanisms of action of the opioid receptors?
μ mu: increases efflux of K
δ delta: decreases cAMP synthesis
Κ kappa: reduces influx of Ca via channels
Give some ADRs for opioids
μ mu: nausea, vomiting, constipation, drowsiness, miosis, respiratory depression, hypotension
Κ kappa: dysphoria
All have the potential to cause dependence and tolerance
Give an example of an opioid receptor agonist
Morphine
Give an example of a drug which can act as both an opioid receptor agonist and antagonist
Nalbuphine Pentazocine Butorphanol Buprenorphine Meptazinol
Give an example of an opioid receptor antagonist
Naloxone
Naltrexone
What are some clinical uses of opioid agonists?
Analgesics- relief of moderate to severe pain, particularly of visceral origin
Maintenance during dependence (eg methadone)
Anti-diarrhoea
Anaesthetics
Anti-convulsants
What are some clinical uses of opioid antagonists
Opioid toxicity
Reversal of respiratory depression
Treatment of dependence
