Pain Pharmacology Flashcards
What are the drugs for pain?
paracetamol
opioids
co-amoxiclav
lactulose
What are the possible opioids for pain?
Weak – codeine, tramadol
Strong – morphine, fentanyl, (heroin)
What is the drug target for paracetamol?
Unclear.
5HT3 receptors/Cannabinoid reuptake proteins/Peroxidase
What is the mechanism of action for paracetamol?
Still not totally clear.
At peripheral sites, may inhibit a peroxidase enzyme which is involved in the conversion of arachidonic acid to prostaglandins (1st step in this pathway involves the enzyme, cyclooxygenase). The ability of paracetamol to inhibit peroxidase can be blocked if excessive levels of peroxide build up (as is commonly seen in inflammation)
Activation of descending serotonergic pathways possibly via 5HT3 receptor activation.
Inhibits reuptake of endogenous endocannabinoids, which would increase activation of cannabinoid receptors - this may contribute to activation of descending pathways.
What are the main side effects of paracetamol?
Relatively safe drug with few common side effects.
OVERDOSE:
Liver damage and less frequently renal damage.
Nausea and vomiting early features of poisoning (settle in 24h).
Onset of right subcostal pain after 24h indicates hepatic necrosis.
What are the an/antis of paracetamol?
Analgesic and anti-pyretic.
Does NOT possess anti-inflammatory activity
What are the drug targets of opioids?
Opioid receptor
What is the mechanism of action of opioids?
Over-arching mechanism at a cellular level is a depressant effect on cellular activity. Multiple sites within pain pathway, where activation of the opioid receptor leads to decreased perception or increased tolerance to pain.
Antitussive effect due to decreased activation of afferent nerves relaying cough stimulus from airways to brain
What are the side effects of opioids?
Mild – nausea & vomiting (increase activity in chemoreceptor trigger zone) and constipation (opioid receptors in GIT can reduce gut motility)
OVERDOSE - respiratory depression (direct and indirect inhibition of respiratory control centre.)
What are the drug targets of co-amoxiclav?
Amoxicillin = penicillin binding proteins
Clavulanate = beta lactamase
What is the mechanism of action of co-amoxicillin?
Amoxicillin (like all penicillin like drugs) binds to bacterial penicillin binding proteins. This prevents transpeptidation (the cross linking process for bacterial cell wall synthesis)
Clavulanate is an inhibitor of beta lactamase. Beta lactamase is a bacterial enzyme that can degrade beta lactam anti-biotics and thus confer resistance to these anti-biotics.
What are the side effects of co-amoxiclav?
Amoxicillin is well tolerated. Most common side effects are nausea and diarrhoea.
What is amoxicillin?
Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms
What is hypersensitivity of penicillin associated with?
rash but can lead to anaphylactic reactions
What is the drug target of lactulose?
no drug target
What is the patient’s problem?
How would you give opioids dependent on pain?
WHO pain ladder
What are the therapeutic objectives?
If diagnosed with gastroenteritis…
Oral rehydration: Can manage oral fluids, but is at risk of dehydration due to consistent diarrhea and vomiting
Analgesia: Complaining of abdominal pain. Over the counter paracetamol is fine (no need to prescribe)
Most patients can manage gastroenteritis at home.
What is the treatment for this patient by the GP?
regular oral fluids and simple analgesia such as paracetamol
advised to stay off work for 48h and reminded of good hygiene to stop spread
told to seek advice if his symptoms persist, feels more unwell or has symptoms of dehydration?
Describe the pain pathway.
- peripheral receptor activated by pain stimulus
- nerve signal travels from peripheral sensory neurone to dorsal horn of spinal cord
- peripheral sensory neuron synapse with spinothalamic neuron
- spinothalamic neuron travels up to thalamus
- thalamus sends signal to cerebral cortex
- cerebral cortex decides how much to activate downstream inhibitor pathway
- downstream pathway modulates the signal
- signal goes back down to dorsal horn and signal (from peripheral to thalamus) is diminished
What is the difference between NSAIDs and paracetamol?
- both work by preventing release of prostaglandins
- NSAIDs and paracetamol inhibit in different parts of the pathway
Mr Chow is admitted under the surgical team and made nil by mouth. He is given intravenous maintenance fluids as well as intravenous morphine (initially 5mg every 4 hours – dose adjusted based on response) and prophylactic antibiotics (intravenous co-amoxiclav -1.2g every 8h).
Explain what effect morphine would have at a cellular level using the diagram provided.
- inhibit calcium from binding → prevents release of neurotransmitters
- increases efflux of K+ → hyperpolarises the neuron
- prevents conversion of ATP to cAMP → depressant effect on the cell
What is the effect of morphine on the pain pathway?
- activates modulation pathway → increases the diminishment of pain pathway, by inhibiting the GABA receptors
- inhibiting an inhibiting factor is called disinhibition
- inhibits neurotransmission from peripheral sensory neurone to spinothalamic neurone
- inhibits peripheral sensory neurone from picking up on pain signal
In order for opioids (or any drugs) to produce effects within the brain, it needs to be able to access the brain tissue. The major route for drug permeation into the brain is via passive diffusion. Lipid solubility is the major determinant of passive diffusion.
Once inside the brain, opioids need to bind to opioid receptors in order to produce any effect. In this case, it is the chemical structure of the drug that determines the ability to bind to the receptor.
You have been provided with five different opioids below, with information on their structure and lipid solubility. Discuss the ability of each of these opioids to produce opioid like effects in the brain.
- a drug needs to be sufficient lipophilic AND have high affinity for receptor in order to be effective
- lipophilic → the oil-water partition coefficient is between 1.5-2.7
- high affinity → OH group at position 3 AND tertiary nitrogen
- 6-acetyl morphine is the only drug listed that is both lipophilic and has affinity to bind to receptor
Following a successful appendicectomy, Mr Chow is returned to the ward with patient-controlled analgesia containing IV morphine.
Later that day, Mr Chow is found unresponsive in his bed. An ABCDE assessment is done:
A – Patent.
B – Respiratory rate 6 breaths per minute, O2 sats 91%, chest is clear.
C – Heart rate 48 bpm regular, BP 74/59 mmHg, heart sounds normal.
D – Capillary blood glucose 4.7, AVPU unresponsive, pupils constricted bilaterally.
E – Temperature 36.7°C, abdomen surgical wound appears clean.
Mr Chow is suffering from opioid overdose. He is provided with ventilatory support (oxygen) and administered naloxone intravenously (0.5mg, repeat every 2 minutes with 0.2-0.4mg increments according to response).
what classical signs of opioid overdose is Mr Chow presenting with?
- decreased resp rate bc inhibition of central system
- constricted pupil
- opioids activates occulomotor nerve bc of gaba disinhibitation → constricts pupils
- VS in normal unresponsive patients pupils are dilated
- urea and creatinine raised → acute renal failure
- opioid overdose leads to rhabdomyolysis (breakdown of muscle tissue that releases muscle contents into blood → harmful to kidneys)
- makes the overdose worse bc morphine cannot be cleared from body due to renal failure
Compare the structure of morphine and naloxone.
Naloxone is an example of an opioid antagonist that is synthesized by replacing the methyl group (CH3) on the nitrogen (N) found in the structure of morphine with an allyl group (CH2CH=CH2)
As noted previously, codeine is primarily a pro-drug for morphine. As you can see in the figure below, codeine can be metabolized to both norcodeine (inactive metabolite) AND morphine (active metabolite). In the liver, cytochrome P450 enzymes are responsible for this metabolism. CYP3A4 is responsible for ‘fast’ metabolism of codeine to norcodeine and CYP2A6 is responsible for ‘slow’ metabolism of codeine to morphine.
What do you think is the significance of this?
- conversion of codeine to norcodeine (inactive) is fast, and abt 90% of the reactions
- conversion of codeine to morphine is slow, and abt 10% of the reactions
- need to do the math to figure out how much codeine to actually give him, bc switching from morphine to codeine
