Analgesics

Question 1

Describe primary nociceptive afferent A and C types in terms of:

• Diameter
• Location
• Shape

Answer 1

Diameter
• A delta nerves have a larger diameter than C fibres
• A delta are myelinated - thus, action potentials will travel very fast through these fibres
• C fibres are non- myelinated, thus action potentials travel very slowly. C fibres tend to exist in clusters

Location
• Dorsal ganglion of spine

Shape
• Axon has two parts; peripheral axon and the central axon (goes to spinal cord)
• Peripheral axons split up into many other fibres, and are termed as nocisensors.

Question 2

Explain the types of pain experienced in terms of A delta and C fibres

Answer 2

• Initially, A delta are the first fibres to be activated upon a painful stimulus. Thus, patients feel a very sharp pain (as A delta fibres transmit pain very fast due to their myelination)
• Eventually, the pain stimulus is transferred to C fibres, and this is when the patient will experience the onset of dull pain

Question 3

Describe how the pain scale works

Answer 3

• VAS numeric pain distress scale works by getting patients to describe their pain on a scale from 1 to 10
• This helps guide clinicians to prescribe analgesics accordingly

Question 4

State the signs of inflammation

Answer 4

• Calor (heat)
• Tumour (swelling, oedema)
• Rubor (redness, erythema)
• Dolor (pain)

Question 5

Explain the mechanism of inflammatory of pain

Answer 5

• The endothelial lining of capillaries/ the venous system contract upon the presence of an inflammatory stimuli
• This allows molecules such as leukocytes, to enter the peripheral inflammatory tissue. Under normal circumstances, these cells should not be in peripheral tissue
• These molecules form inflammatory millieu at the site, and this may activate the peripheral nociceptors

Question 6

Explain the COX 1 and COX 2 pathway, and how it leads to inflammatory pain

Answer 6

• In inflamed tissue, COX 2 production is upregulated (in normal circumstances, this does not happen. In normal tissue, only COX 1 is mainly being produced)
• Both enzymes produce prostaglandins that promote inflammation, pain, and fever; howeverCOX-1produces prostaglandins that activate platelets and protect the stomach and intestinal lining (essential for homeostasis)
• COX 2 catalyses the production of prostaglandins, such as PGE2 which activates nociceptive afferents, causing pain

Question 7

List some examples of NSAIDS and their MOA (3)

Answer 7

• Aspirin: binds to COX 1. This can leads to loss of the lining of the stomach. Thus it is not used very much.
• Ibuprofen: Higher affinity to COX 2.
• Naproxen

Question 8

List the side effects of Aspirin

Answer 8

• GI irritation (nausea, vomiting, gastric bleeding, heartburn, ulcers)
• Acid-Base/ electrolyte disturbances
• Causes hyperventilation
• Blood dyscrasia (blood disorders) and anaemia
• Allergic reactions

Question 9

Describe specific COX 2 inhibitors - COXIBS

Answer 9

• These drugs are specific COX-2 inhibitors; Celecoxib, is used against rheumatoid arthritis and osteoarthritis
• They have analgesic, anti-pyretic and anti-inflammatory effects
• However, some COXIBs (like Rofecoxib) lower the amount of PGs that inhibit clot formation via platelet aggregation
• So as a side effect, they result in thrombosis and myocardial infarction
• A number of specific COX-2 inhibitors have been withdrawn from the market because of this adverse effect

Question 10

Describe how bradykinin becomes a part of the inflammatory milieu and how it leads to pain

Answer 10

• When the endothelial cells contract, the molecule cofactor XII also enters the inflamed tissue
• Factor XII gets in touch with the collagen in the inflamed tissue and is converted into factor XIIa
• Factor XIIa then facilitates the conversion of prekallikrein into kallikrein
• Kallikrein then helps convert kininogen into bradykinin
• Bradykinin activates primary afferent nociceptors
• Thus stopping the production of bradykinin can help reduce the pain

Question 11

Explain the role of nerve growth factor and BDNF in pain production

Answer 11

• Primary nociceptive afferents have receptors on their surface called tyrosine kinase A (TrKA)
• Nerve growth factors binds to the TrKA, eventually forming a dimer
• This dimer goes into a vesicle, and this is transported from the peripheral tissue to the dorsal ganglion where the primary nociceptive afferent bodies are
• Then, through a molecular cascade, it will change gene expression which will sensitise receptors, thus causing hyperalgesia
• Brain derived neurotrophic factor (BDNF) is one of the molecules that are upregulated. BDNF and glutamate activate secondary neurones, thus activating pain conduction
• Thus, targeting NGF can help reduce pain by inhibiting the above pathways

Question 12

Describe the role of NMDA receptors in pain conduction and hypersensitivity of 2nd order neurones

Answer 12

• Primary afferents are activated by noxious stimuli (action potential). This causes the release of glutamate
• Glutamate will bind to the NDMA and AMPA receptors on the post synaptic neurone
• This causes activation of the receptors, opening up their ion channels. Na will enter into the AMPA receptor. It will not enter the NMDA receptor immediately as the NMDA receptor will be blocked by Mg ions
• Thus constant entry of Na will change the voltage to -20mv which will cause Mg to unbind from the NMDA receptor
• Na and Ca can begin entering from the NMDA receptor
• Once Ca begins entering into the NMDA receptor, it will cause 2nd order neurones to be in a constant, active state (hypersensitivity).
• Hence, even a small signal from first order neurones will cause excitability of 2nd order neurones

Question 13

Describe how ketamine works to block pain conduction

Answer 13

• Ketamine will bind to NMDA receptors and remain there even if Mg falls off
• Thus, it will not allow Na, and thus Ca to enter the neurone
• Holistically, it will prevent long-term potentiation

Question 14

Describe why cocaine is not a good local anaesthetic, and why lidocaine is a good local anaesthetic

Answer 14

• Cocaine’s molecular structure is ester linked
• Plasma cholinesterase’s readily cleave this ester link, causing swift deactivation of cocaine’s analgesic effects
• Lidocaine is a good anaesthetic because it has amide links, which is not easily cleaved by the body

Question 15

Describe how local anaesthetics (LA) work

Answer 15

• LA molecules penetrates through the phospholipid bilayer of the neurone and goes into the cytoplasm (does not reside in extracellular area)
• From the cytoplasm, the LA molecule will travel up to voltage gated Na channels and block it from the inside
• Thus, the voltage gated Na channel goes into an inactivation state, where its inactivation gate closes the channel off.
• Then, it will go back to its open state briefly, but since the lidocaine is still blocking the channel, it will eventually go into a closed state
• If action potentials (pain signals) keep coming in, the lidocaine molecule will remain sitting in the pore. In addition, more lidocaine molecules will block more pores. It is a positive feedback loop
• However if no action potentials are coming for some time, lidocaine will fall out.

Question 16

Describe how endogenous opioids (enkephalins) block pain signals

Answer 16

• The brainstem contains the medulla, pons and midbrain
• In the midbrain, there is an area called the periaqueductal grey (PAG)
• Special neurones called enkephalinergic neurons reside in the PAG
• Enkephalin is an opioid neurotransmitter that is released during stressful situations
• When enkephalin is released, it will bind to the neurones in the PAG, activating them
• These neurones then send their action potential projections to two places in the brain; the pons and medulla
• In the pons, they send their projection to a place called locus coerelius (LC). Enkephalins are released in the LC and they bind to the new opioid receptors
• In the pons, projections are sent to the Nucleus Raphe Magnus (NRM) which has new opioid receptors which are activated when enkephalins bind to them
• The activated neurones in the pons and medulla will then send their projections to a place in the spinal cord called the substantia gelitanosa (lamina II)
• The substantia gelitanosa is a place in the spinal cord where primary neurones synapses with secondary neurones
• Neurones which are sending projections from the LC in the pons will release noradrenaline as its neurotransmitter
• Neurones which are sending projections from the NRM medulla will release serotonin as its neurotransmitter
• These neurotransmitter will activate special neurones in this area called enkephalin containing interneurons
• This interneuron will release enkephalins and it will bind to opioid receptors on the primary neurone and secondary neurone
• This will inhibit the release of neurotransmitters and in the second order neurones, and it will inhibit post- synaptic excitatory current

Question 17

Explain how morphine works to inhibit pain

Answer 17

• Morphine is an agonist of the opioid receptors in the thalamus and limbic system (works how enkephalins work)
• It produces sedation, lethargy, muscle relaxation and euphoria
• Produces inhibitory effects on the CNS and body by hyperpolarising cells
• Though, the higher the morphine dose, the higher the risk of death

Question 18

Explain the side effects of morphine (7)

Answer 18

• Neurons producing enkephalinsare spreadout and are found in different brain regions
• Enkephalins are involved in several biological processes (cardiovascular system, gastrointestinal functions, respiration, pain perception)

Morphine works by blocking all opioid receptors in the body. Thus, some side effects of morphine include:
• Depressed cough reflex 
• Stimulated vomiting reflex centre
• Pupillary constriction 
• Smooth muscle spasm 
• Decreased GI motility = constipation 
• Urinary retention 
• Histamine release, causing bronchoconstriction

Question 19

Describe the side effects of the opioids codeine and heroin

Answer 19

• Codeine causes constipation
• Heroin is 3 times more potent than morphine and produces a high level of physical dependency. It is no longer used in Australia

Question 20

List the drug administered when there is respiratory arrest due to opioid overdose

Answer 20

• Naloxone (works VERY fast)

* Naltrexone

Question 21

Explain neuropathic pain in terms of Nav 1.3

Answer 21

• When neurones are injured, they express a special type of voltage Na gated channel called Nav 1.3
• Nav 1.3 is only found in foetal tissue - they tend to form very dense clusters
• Thus even a slight flicker, which may not be a noxious stimuli, will cause voltage to rise very quickly
• All these gated channels will open up, allowing a huge influx of Na to enter, causing powerful action potential

Question 22

Explain how nerve damage and/or repair leads to pain

Answer 22

• If you cut the periphery of a nerve, that part will degenerate
• The part of the nerve that is still vital will try to regrow, forming a bundle of nerves
• Since they are not growing properly, they will fuse with sympathetic nerves. This is called an ephapse
• Thus when the SNS is activated, they will send action potentials, but instead of the action potential going to the tissue, it will go back to the primary nociceptive afferent due to the connection
• Thus, this will activate the primary nociceptive afferent, causing pain

Question 23

Explain how neuropathic pain is treated and the MOA of the drugs

Answer 23

• It is treated through Gabapentin, especially pregabalin
• These drugs bind to the α2-δ subunit of the voltage-gated calcium channels in central nervous system tissues
• Thus, pregabalin reduces calcium influx at nerve terminals, which may inhibit the release of excitatory neurotransmitters such as glutamate.

Question 24

Explain the causes of trigeminal neuralgia and its management

Answer 24

• Develops due to a blood vessel pressing against the trigeminal nerve (superior cerebellar artery and basilary artery), located at the brain stem
• This compression may damage the nerve and cause excess bursts of neurological activity
• Carbamazepine is used to treat trigeminal neuralgia. It binds to Na gated voltage channels (like LA)

Question 25

State why tricyclic antidepressants are used to treat neuropathic pain

Answer 25

• Neurones which are sending projections from the LC in the pons will release noradrenaline as its neurotransmitter
• Neurones which are sending projections from the NRM medulla will release serotonin as its neurotransmitter
• Thus, tricyclic antidepressants will block norepinephrine transporters.
• Thus, noradrenaline will remain longer in the post synaptic cleft
• Serotonin and Norepinephrine reuptake inhibitors will work the same way on the stress- induced pain pathway

Question 26

Explain how endogenous cannabinoids work

Answer 26

• Ca enters the primary nociceptive afferent, and causes the post-synaptic release of neurotransmitters such as glutamate
• Glutamate will then activate NMDA receptors and AMPA receptors on the post- synaptic neurone
• Endocannabinoids are produced from the phospholipids at the post- synaptic neurone (second order neurone)
• When Ca enters the cytoplasm of the secondary neurone, it will trigger the conversion of the phospholipids into endocannabinoids
• These endocannabinoids will be released into the pre-synaptic cleft and bind to cannabinoids receptors (CB1)on the primary nociceptive afferent
• The CB1 is a g-protein coupled receptors. It will undergo its cascade which eventually results in blockage of the Ca channels
• It works in a reverse manner; it is generated in the post-synaptic neurone and then it will the Ca channels that block the presynaptic neurone

Question 27

Explain how paracetamol (acetaminophen) works

Answer 27

• Paracetamol (a pro-drug) enters the liver and is converted into its active form AM404
• AM404 is structurally similar to the endogenous cannabinoids, and it activates CB1 receptor
• Though, it is weaker than endogenous cannabinoids
AM404 also binds to transporter of cannabinoids - therefore, other endogenous cannabinoids such as anandamide cannot be reabsorbed in the pre-synaptic neurone. It will remain longer in the synaptic cleft, activate more CB1 receptor and result in prolonged blockade

Question 28

State the disadvantages (2) and adverse reactions (3) of paracetamol

Answer 28

Disadvantages
• IT IS NOT AN ANTI- INFLAMMATORY DRUG - the presence of hydrogen peroxide in inflamed tissue prevents its binding with COX enzymes in these inflamed tissues
• Does not block COX2

Adverse reactions
• It can cause methemoglobinemia
• Liver and kidney damage
• Leukopenia