Physiology Analgesia and Analgesic Drugs

Question 1

what are the different mechanisms for analgesics reducing nociception

Answer 1

acting at site of injury (decrease nociceptor sensitisation in inflammation by blocking synthesis of prostaglandins)

suppressing nerve conduction (blocking/ inactivating v-activated sodium channels) (local anaesthetics)

suppressing synaptic transmission of nociceptive signals in dorsal horn (opioids and some antidepressants)

activating descending inhibitory controls (opioids and tricyclin ADs)

targeting ion channels upregulated in nerve damage (gabas)

Question 2

what is the who analgesic ladder

Answer 2

NSAID (aspirin, diclofenac, ibruprofen, naproxen) and/or paracetamol

weak opioid (codeine, tramadol, dextropropoxyphene)

strong opioid (morphine, oxycodone, hydromorphone, heroim, fentanyl)

Question 3

whats the difference between opiates and opioids

Answer 3

Opiates – substances extracted from opium, or of similar structure to those in opium
Opioids – any agent (including endogenous peptides, known collectively as endorphins/enkephalins) that act upon opioid receptors

Question 4

does paracetamol have anti inflammatory effects

Answer 4

no

Question 5

what mediates supraspinal anti-nociception

Answer 5

descending pathways from the brainstem:
-brain regions involved in pain perception (cortex, thalamus, hypothalamus) project to specific brainstem nuclei
-neurones of brainstem nuclei give rise to efferent pathways that project to spinal cord to moderate afferent input
(the gate theory)

Question 6

what areas of brain stem are important in supraspinal nociception

Answer 6

the periaqueductal grey (midbrain)
locus ceruleus (pons)
nucleus raphe magnus (medulla)

Question 7

what activates PAG

Answer 7

electrical stimulation
endogenous opioids (enkephalins) 
morphine/ related compounds (excite it by inhibiting inhibitory GABA interneurones)

Question 8

what does PAG activation cause

Answer 8

profound analgesia

Question 9

how doe PAG neurones work

Answer 9

activated PAG neurones project to the nucleus raphe magnus and excite serotonergic and enkephalinergic neurones
+ also project to dorsal horn causes suppressed nociceptive transmission

Question 10

what do locus coeruleus noradrenergic neurones do

Answer 10

project to the dorsal horn and inhibit nocicpetive transmission

excited by PAG neurones

Question 11

opioids also activate NRM neurones, what do these release

Answer 11

5-HT and enkephalins

Question 12

how do opioids suprpress pain

Answer 12

activate descending pathways which suppresses pain:

-excites PAG and NRM by disinhibition

Question 13

what are the resp adverse effects of opioids

Answer 13

apnoea:

-blunts medullary resp centre to CO2

Question 14

what are the cardio adverse effects of opioids

Answer 14

orthostatic hypotension:

• reduced sympathetic tone and bradycardia
• histamine evoke vasodilation

Question 15

what are the GI adverse effects of opioids

Answer 15

nausea
vomiting
constipation
increased intrabiliary pressure

• acts on chemoreceptor trigger zone
• increased smooth muscle tone
• decreased motility

Question 16

what are the CNS adverse effects of opioids

Answer 16

confusion, euphoria, dysphoria, hallucinations, dizziness, myoclonus, hyperalgesia (with excessive use)

Question 17

what are the agonist types of opioids and how do they work

Answer 17

morphine
diamorphoine 
codeine 
fentanyl 
pethidine 
buprenophine
tramadol 
methdone 

prolonged activation of μ-opioid receptors

Question 18

how is morphine metabolised

Answer 18

metabolised in the liver

excreted by the kidney

Question 19

how can morphine be administered

Answer 19

IV, IM, SC or orally

epidural, intrathecal

Question 20

what is oral morphine good for

Answer 20

immediate breakout pain

Question 21

what is morphine not good at

Answer 21

reducing neuropathic pain

Question 22

what is diamorphine used for

Answer 22

rapid onset- used in severe post op pain

Question 23

what is codeine used for

Answer 23

mild/ moderate pain

Question 24

how is codeine metabolised

Answer 24

in liver (metabolised into morphine)

Question 25

how is codeine administered

Answer 25

orally (not IV)

Question 26

what are the extra effects of codeine

Answer 26

anti diarrhoeal (constipation) and antitussive

Question 27

what is fentanyl

Answer 27

agonist opioid | more potent that morphine

Question 28

what for and how is fentanyl used

Answer 28

maintenance anaesthesia | IV (in acute), transdermal (in chronic pain states)

Question 29

what for and how is pethidine used

Answer 29

acute pain (labour) IV, IM, SC not suitable for chronic pain should not be given with MAO inhibitors

Question 30

what for and how is buprenophine used

Answer 30

chronic pain patient controlled injection systems long duration can be given via injection or sublingually

Question 31

how is tramadol given

Answer 31

orally | avoid in epilepsy can cause seizures

Question 32

what for and how is methadone given

Answer 32

orally has long duration of action so used in opioid withdrawal used in chronic cancer pain

Question 33

what are the antagonist opioids and how do they work

Answer 33

naloxone naltrexone alvimopan methylnaltrexone competitive antagonist at μ-opioid receptors

Question 34

what are antagonist opioids used for

Answer 34

to reverse opioid toxicity associated with strong opioid overdose

Question 35

how are antagonist opioid given

Answer 35

incrementally IV. IM and SC routes are alternatives if IV is not practical

Question 36

why is the half life of naloxone important

Answer 36

short half-life – very important since opioid toxicity can recur to ‘strong opioid’ agonists with a longer duration of action. Clinically, you must monitor the effect of naloxone very carefully, titrating the individual dose, and frequency, to that required to reverse opioid toxicity and do not leave the patient unattended

Question 37

what is the advantage of naltrexone

Answer 37

oral availability and a much longer half-life

Question 38

what is the advantage of alvimopan and methylnaltrexone

Answer 38

do not enter CNS, reduce G.I. effects of surgical and chronic opioid agonist use

Question 39

how do NSAIDs work

Answer 39

diminish nociceptor sensitisation by inhibiting the synthesis and accumulation of prostaglandins (cause hyperalgesia, allodynia and pain) by COX enzymes 1 and 2 suppress the decrease in the activation threshold of the peripheral terminals of nociceptors that is caused by prostaglandins decrease recruitment of leukocytes that produce inflammatory mediators if they cross the BBB, suppress the production of pain-producing prostaglandins in the dorsal horn of the spinal cord (that, for example, reduce the action of the inhibitory neurotransmitter, glycine)

Question 40

what are all the effects of NSAIDs

Answer 40

analgesic antipyretic anti inflammatory

Question 41

what are the non specific NSAIDs

Answer 41

``` aspirin ibruprofen naproxen diclofenac indometacin ```

Question 42

what are the specific COX 2 NSAIDs

Answer 42

ones ending in ib etoricoxib celecoxib lumiracoxib

Question 43

when are COX enzymes active

Answer 43

COX-1 is constitutively active, COX-2 is induced locally at sites of inflammation by various cytokines

Question 44

does paracetamol act peripherally or centrally

Answer 44

only centrally

Question 45

what can long term administration of non selective NSAIDs cause

Answer 45

GI damage | (PGE2 produced by cox-1 protects against acid/ pepsin environment(

Question 46

what can paracetamol damage

Answer 46

kidney- cox 2 inhibition here can compromise renal hemodynamics

Question 47

what is the downside of selective cox 2 NSAIDs

Answer 47

are prothrombotic

Question 48

does neuropathic pain respond to NSAIDs

Answer 48

no

Question 49

what is used to treat neuropathic pain

Answer 49

gabapentin and pregabalin (antiepieptics) amitriptyline, nortyptiline and desipramine (tricyclic antidepressants) carbamazepine

Question 50

how do gabapentin and pregabalin work

Answer 50

DO NOT WORK VIA GABAERGIC SYSTEMIC reduce the expresison of V activated Ca2+ channels which are upregulated in damaged sensory neurones this causes a decrease in neurotransmitters (glutamate and substance P) from central terminal of nociceptive neurones

Question 51

what is gabapentin used in

Answer 51

migraine prophylaxis

Question 52

what is pregabalin used in

Answer 52

diabetic neuropathy

Question 53

how do tricyclic antidepressants work

Answer 53

work centrally | decrease the reuptake of noradrenaline

Question 54

how does carbamazepine work

Answer 54

blocks subtypes of v activates Na+ channels that are upregulated in damaged nerve cells

Question 55

what is the first line Tx to control pain intensity and frequency of attacks in trigeminal neuralgia

Answer 55

carbamazepine