Pharmacology Flashcards
What are the various mechanisms that analgesics use to reduce pain?
- act at site of injury to decrease nerve sensitisation
- suppress nerve conduction
- suppress synaptic transmission in dorsal horn
- activate descending inhibitory controls
- targeting ion channels upregulated in nerve damage
How do NSAIDs reduce nociception and pain at the injury site?
- blocking synthesis of prostaglandins (PGE2 and PDE2)
- prostaglandins usually make afferent nerve terminal more sensitive to pain signals
How do local anaesthetics suppress nerve conduction to reduce pain and nociception?
blocking/inactivating voltage-activated Na+ channels
How do opioids and some anti-depressant drugs work to relieve pain and nociception?
- suppress synaptic transmission of nociceptive signals in dorsal horn of the spinal cord
- activate descending inhibitory controls
What are the three levels on the WHO analgesic ladder and give an example of drugs in each level.
3) STRONG opioid (e.g. morphine, oxycodone, heroin, fentanyl)
2) WEAK opioid (e.g. codeine, tramadol)
1) NSAIDs (e.g. aspirin, diclofenac, ibuprofen, naproxen)
+ paracetamol
What levels of the WHO ladder are appropriate to combine?
1+2
1+3
Don’t combine 2 and 3 as these act on ame receptors => combination makes little difference
WHat is the difference between Opiates and Opioids?
Opiates - substances extracted from opium
Opioids - any agent acting on opioid receptors (including substances made in the body)
What is Supraspinal anti-nociception?
Descending controls which are modifying th eperception of pain and nociception
What areas of the brain are involved in Supraspinal anti-nociception?
- parts involved in pain perception and emotion
=> cortex, amygdala, thalamus, hypothalamus
These project signals to specific brainstem nuclei
WHat areas of the brainstem are involved in creating the efferent signals to the spinal cord (which will eventually modify afferent inputs)?
- the periaqueductal grey matter (PAG) (midbrain)
- locus ceruleus (pons)
- nucleus raphe magnus (NRM) (medulla)
Excitation of the PAG in the brainstem by what two components has the potential to inhibit nociceptve transmission in the spinal cord?
Electrical signals from neurones or by opioids (these can even be endogeneous)
After its own excitation, PAG excites the NRM in the medulla to send signals along what neurones?
serotonergic and enkephalinergic neurones (=> ones releasing serotonin (5HT) and enkephalins)
These project to the dorsal horn resulting in nociceptive suppression
What type of receptor is the opioid receptor?
G protein-coupled receptors
signal to Gi or Go
What are the main functions of binding to the opioid receptor?
- Prevent neurotransmitter release (less Ca2+ intake)
- hyperpolarise post synaptic terminal => less likely APs
What are the main classifications of opioid receptor?
μ - responsible for most opioid analgesic action
- BUT these can have major adverse effects
δ - contributes to analgesia but can cause convulsion
κ - contributes to analgesia at spinal and peripheral level
- activation associated with sedation, dysphoria and hallucinations
What is the main adverse effect of opioids?
Respiratory depression
Morphine can be used for both acute severe pain and chronic pain. TRUE/FALSE?
TRUE
Describe how morphine is metabolised?
- metabolised in the liver at positions 3 and 6 on molecule
- yields M3G that is inactive
- also yields M6G which retains analgesic activity and is excreted by the kidney
Give an example of immediate and sustained release preparations of morphine
Immediate (e.g. Oramorph) Sustained release (e.g. MST Continus)
How long do sustained release morphine preparations usually last for?
12-24 hours
What opioids are agonists of the opioid receptor?
AGONISTS: morphine heroin Codeine Fentanyl Pethidine Buprenorphine Tramadol Methadone
What opioids are antagonists of the opioid receptor?
Naloxone Naltrexone (longer 1/2 life)
What is diamorphine (heroin) used for clinically?
- more lipophilic than morphine
=> when administered IV it enters CNS rapidly
=> can be used for severe post-operative pain
How is codeine metabolised and what is it metabolised to?
- hepatic metabolism to morphine
- completed by CYP2D6 and CYP3A4
=> if patients have low levels of these, they may struggle to metabolise the drug to the active form
How is codeine normally delivered?
Orally
What other functions can codeine have?
anti-diarrhoeal (opiates cause constipation)
antitussive activity => relieves cough
When is fentanyl used?
- Given IV during some surgeries to reduce the amount of general anaesthetic required
- Transdermal patches used in chronic pain
How much more potent is fentanyl than morphine?
75-100 times more potent
When is Pethidine used for pain, and how is it delivered?
- acute pain, particularly labour
- short duration of action => not suitable for chronic pain
- Given IV, IM, or SC
What drug class should not be given in combination with Pethidine and why?
MAO inhibitors (powerful antidepressant)
Combination causes excitement, convulsions, hyperthermia
What is buprenorphine used for and how is it given?
- chronic pain with patient-controlled injection systems
- may have slow onset, but used due to long duration of action
- Given by injection or sublingually
Tramadol should be avoided in what group of patients?
Epileptic patients
What is methadone used for, and why is it helpful that the half life is long?
- assists in withdrawal from ‘strong opioids’ e.g. heroin
- short acting opioids = more addictive => this helps patients to withdraw
- given orally
- long duration of action also useful in treating patients with chronic pain in terminal cancer
Naloxone is an antagonist at which of the opioid receptors?
antagonist at μ-receptors
When is naloxone used?
- reverse opioid toxicity associated with ‘strong opioid’ overdose
- may be given to a newborn with opioid toxicity due to administration of pethidine to mother during labour
Why is the short half life of naloxone impractical if a patient has opioid toxicity?
- may need frequent dosing of naloxone to completely reverse toxicity (=> dont leave patient)
- beware of opioid addicts as short duration of naloxone may trigger a very acute withdrawal response
What are the side effects of NSAIDs and COX-2 inhibitors?
NSAIDs - gastrointestinal damage
COX-2 - prothrombotic
What conditions can cause neuropathic pain?
- trigeminal neuralgia
- diabetic neuropathy
- post-herpetic neuralgia
- phantom limb pain
How do neuropathic pain drugs such as Gabapentin and pregabalin act to reduce pain and nociception?
- reduce expression of a subunit (α2δ) of some voltage-gated Ca2+ channels
- These channels are upregulated in damaged sensory neurones => release more neurotransmitter/signals
=> less upregulated channels = decrease of neurotransmitters (glutamate and substance P) from nociceptive neurones
Hod do tricyclic antidepressants aim to deal with neuropathic pain?
- E.g. Amitriptyline, nortriptyline
- act centrally by decreasing the reuptake of noradrenaline
- duloxetine and venlafaxine also decrease reuptake of 5-HT
What drug is used to control pain in trigeminal neuralga and how does it achieve this?
Carbemazepine
- blocks subtypes of voltage-activated Na+ channel that are upregulated in damaged nerve cells
- prevents number of attacks in TN
