MSPA: Analgesics, Pain Medication & Local Anesthetics

Question 1

Sharp and localised pain from mechanical or thermal stimuli are mediated by which caliber fibers ?

Answer 1

Small mildly myelinated A delta fibers.

Question 2

Dull, slow, diffuse or throbbing pain is mediated by what caliber fibers ?

Answer 2

The unmylinated C fibers.

Question 3

Mechanical non-noxius stimuli are processed by what caliber fibers ?

Answer 3

Heavily myelinated A-beta fibers.

Question 4

What are the four major process involved in pain physiology ?

Answer 4

transduction, transmission, perception and modulation.

Question 5

What is the anatomy of Spinothalmic tract ?

Answer 5

*https://youtu.be/-VYvEAudEgA
*https://youtu.be/oas7yemSG5g.

Question 6

what is the difference between opioid and opiates ?

Answer 6

Opiates refer to natural opioids such as heroin, morphine and codeine. Opioids refer to all natural, semisynthetic, and synthetic opioids.

Question 7

What are the 3 major class of opioid receptors ?

Answer 7

*μ – m1, m2, m3
*κ - κ1, κ2, κ3
*δ - δ1, δ2

Question 8

What is the signaling mechanism of opioid receptors ?

Answer 8

These are GPCRs consists of seven transmembrane spanning proteins that are couple to intracellular G proteins. opioid agonists inhibit the conversion of adenylyl cyclase to cAMP leading to reduced activation of PKA system. This results in opening of V-gated K channels which reduces neuronal excitability and inhibition of V-gated Ca2+ channels which inhibits neurotransmitter release.

Question 9

What are the major effects associated with main types of opioid receptors ?

Answer 9

• Induction of analgesia through supraspinal, spinal and peripheral mdoulation.
• respiratory depression through Mu and delta receptor activation.
• Physical dependence tthrough Mu and to some extent Kapaa receptor activity.

Question 10

What is the mechanism of supraspinal analgesia ?

Answer 10

Stage 01: A sub-tract of the Anterior spino-thalamic tract known as spino- mesenciphalic tract stimulates Enkephalin- releasing neurons(ERNs) at the PAG.

Stage 02: The ERNs project to activate serotonergic neurons(SN) at the dorsal Raphe nucleus (DRN).

Stage 03: The SNs projects to the Enkephalin and dynorphin releasing interneurons at the substantia gelatinosa.

Stage 04: The Enkephalin and dynorphin releasing INs activate Mu and Kappa receptors of C and delta fibers carrying pain input from peripheral nociceptors.

Stage 05: The activation of Mu and Kappa receptors inhibit release of substance P at first order synapses in the Dorsal column of the spinal cord. This results in inhibition of the peripheral pain signal transmission through the spino-thalamic and trigeminal-thalamic tracts to the VPL and VPM of the thalamus.

All these steps lead to supraspinal analgesia.

Question 11

what is the mechanism of spinal analgesia ?

Answer 11

Activation of opioid receptors in substantia gelatinosa causes opening of voltage gated K+ in post synaptic neurones leading to hyperpolarization of these neurones. It also inhibits the activation of Ca2+ channels leading to inhibition of pre-synaptic neurotransmitter release.

Question 12

Mechanism of Peripheral analgesia ?

Answer 12

Through local anaesthetic effect and COX pathways inhibitions as in NSAIDs.

Question 13

What is the action of μ-opioid receptors in pre-synaptic terminals ?

Answer 13

In the presynaptic terminal, μ-opioid receptor activation decreases Ca2+ influx in response to an incoming action potential
↓ neurotransmitter release

Question 14

What is the action of μ-opioid receptors in post-synaptic terminals ?

Answer 14

Postsynaptic μ-opioid receptor activation increases K+ conductance and thereby decreases the postsynaptic response to excitatory neurotransmission
↓AP generation

Question 15

What is Morphine ?

Answer 15

It is the gold standard, most valuable opioid for severe pain. It is a m, k and d receptor agonist.

Question 16

What are the effects of Morphine?

Answer 16

• Analgesic: Marked elevation in pain threshold without loss of consciousness (m and k receptors).
• Euphoria: pleasant, ‘floating’ sensation with freedom from anxiety(m receptors).
  *dysphoria in some subjects (k receptors)

Question 17

What are the modes and factors to consider in Morphine administration ?

Answer 17

*It can be administered through several routes.
*Usual starting dose 5 -10mg every 4 h – no ceiling dose.
*Sustained release oral preparations to increase duration of action (usually 12 h).
*Management of breakthrough pain (usually 1/6th of standard dose).
* Can be used for Patient-controlled IV analgesia.

Question 18

What is the half life and bioavailability of Morphine ?

Answer 18

Bio-avilability approx. 25% and modest 1/2 life of 3 to 4 hours.

Question 19

What are the side effects of Morphine?

Answer 19

*Sedation
*Respiratory depression: inhibits brain stem regulatory centre,
*Nausea, vomiting: due toChemoreceptor trigger zone.
*Constipation: increased GIT muscle tone, decreased propulsive movements, reduced sensory stimuli for defecation reflex.
*Miosis: due to μ and κ receptor mediated stimulation of Edinger-Westphal nuclei.
* Hyperalgesia: paradoxical nociceptive sensation suggesting loss of efficacy.
*Depression of cough reflex
*Histamine release

Question 20

What is the effect of Morphine on Biliary tract ?

Answer 20

contraction of biliary sphincter muscle, increased pressure in bile duct and gall bladder, colic, caution: gallstones.

Question 21

What is the Neuroendocrine effect of Morphine ?

Answer 21

Inhibit hormones in Hypothalamic Pituitary Adrenal (HPA) axis, lower testosterone, menstruation irregularities.

Question 22

What are the limitations in the clinical use of Morphine?

Answer 22

*Gradual loss in effectiveness due to desensitisation of opioid receptors.
*Cessation of chronic therapy due to dependency.
* Withdrawal syndrome- Which presents as hypertension, agitation, diarrhoea, pupil dilation.

Question 23

What is Fentanyl ?

Answer 23

It is an extremely potent Highly lipid soluble synthetic opioid. administered either Parental or transdermal routes due to poor oral absorption. It has a rapid onset and offset of effects. It can cause Respiratory depression.

Question 24

What is sufentanil ?

Answer 24

It is a fentanyl variant ~ 1000 times more potent than morphine.

Question 25

What is Methadone?

Answer 25

It is a Mu receptor agonist and an NMDA receptor antagonist which has Similar potency to morphine. It has >24hr 1/2 life and is administered orally. It is used for the Treatment of opioid addiction, cough suppression, palliative care.

Question 26

What is codeine?

Answer 26

It is a Weak opioid agonists with higher affinity for Kappa than Mu receptors. It is a pro-drug with ~ 10% converted to Morphine. It is used as mild analgesic, anti-Tussive and anti- diarrhoeal

Question 27

What is the effect of Genetic polymorphism in the CYP2D6 gene on Codeine metabolism ?

Answer 27

This is seen in 10% of Caucasian population and can variably affect the conversion of pro-drug codeine to morphine.

Question 28

What is tramadol ?

Answer 28

It is a Weak μ agonist metabolised to O-desmethyltramadol and inhibits uptake of 5-HT and NA. The side effects are respiratory depression, Increased risk of seizures, serotonin syndrome and physical dependence.

Question 29

What is Buprenorphine ?

Answer 29

It is an Opioid partial agonists because it has agonistic action on Mu receptors and antagonistic action on kappa and delta receptors. It can display full antagonism when used with a full agonist. It causes less euphoria, less sedation, milder withdrawal symptoms.

Question 30

What are the indications for Buprenorphine ?

Answer 30

*It can be given sublingually with naloxone for the Tx of opioid addiction. * It can be given transdermal/sublingual for moderate pain in non-opioid tolerant individuals.

Question 31

What is Naloxone ?

Answer 31

It has more affinity to μ than k receptor and is a competitive antagonists with a very rapid onset of action. It is used to rapidly reverse opioid overdose.

Question 32

What is the indication for Naloxone ?

Answer 32

* It can be given to reverse opioid actions e.g. alleviate respiratory depression in acute opioid overdose. However, repeated dosing maybe needed as it has a short half life (1-2 hours) compared to morphine. * It can be given with Oxicontin to reduce constipation.

Question 33

What is the contraindication for aspirin in > 16 year olds ?

Answer 33

Kawasaki disease.

Question 34

What are the pharmacological treatments for neuropathic pain ?

Answer 34

TCA – inhibit NA reuptake, independent of AD activity Gabapentin and pregablin – bind to Ca2+ channel inhibiting neurotransmitter release Lidocaine – topically or IV, analgesic activity unclear Other drugs – ketamine, cannabinoids, botulinium

Question 35

What is cocaine ?

Answer 35

It is a Weak bases with a pKa of 8-9, partially ionised at physiological pH which makes it capable of penetrating the nerve sheath and axon membrane. The cocaine subtypes with the Ester bonds are rapidly inactivated in plasma and tissues by non specific esterases (shorter half life). whereas, the ones with Amide bonds are more stable with longer half life's (metabolised in the liver).

Question 36

what are the examples of Cocaines with ester bonds ?

Answer 36

Benzocaine, Chloroprocaine, Cocaine, Proparacine, Procaine and Tetracaine.

Question 37

what are the examples of Cocaines with amide bonds ?

Answer 37

Articaine, Bupivacaine, Lidocaine, Levobupivacaine, Ropivacine.

Question 38

What is the key to identify whether a cocaine is ester or amide by looking at its name ?

Answer 38

The presence of 'I' before caine.

Question 39

What is the mechanism of action of Cocaine ?

Answer 39

It acts by Blocking the initiation and propagation of APs by preventing voltage dependent increase in Na+ conductance. It has more affinity for small than large fibers and can cause vasodilation, ergo, Addition of vasoconstrictor diminishes local blood flow - slows absorption - prolonged effect.

Question 40

Why is lidocaine used as surface anaesthetic?

Answer 40

Because it is a lipid soluble amide bond cocaine and can be absorbed from the mucous membrane and subcutaneous fat. It has a short half life of 1-2 hrs.

Question 41

What are the side effects of cocaine derivative local anasthetics?

Answer 41

Accidental administration into the blood vessels can cause: *Agitation, confusion, tremor progressing to convulsions and respiratory depression. * myocardial depression, conduction block and vasodilation. * allergic dermatitis and acute anaphylactic reactions (rare), mainly ester bond.