Opioids

Question 1

Define an opioid (1)

Answer 1

any drug that mimics endogenous opioid peptides by causing prolonged activation of opioids receptors

Question 2

Define an opiate (1)

Answer 2

any synthetic morphine-like drug without a peptide structure

Question 3

Endogenous opioids are derived from 3 different peptides (3)

Answer 3

B-endorphins, Encephalins, Dynorphins

Question 4

Describe opioid receptor activation (3)

Answer 4

G-protein coupled

opens K+ channels and closes Ca++ channels

causes hyperpolarisation and inhibits NT release

Question 5

What is the variation between Diamorphine and Morphine (1)

Answer 5

Diamorphine is more lipid soluble so has a more rapid onset of action when given IV

Question 6

Which opioid can be given transdermally for pain? (1)

Answer 6

Fentanyl

Question 7

Describe the specific use of Pethidine and why (2)

what are the downsides (1)

Answer 7

Used for childbirth pain

does not inhibit contractions, rapid onset + shorter duration of action

neonate may need nalaxone to treat respiratory depression

Question 8

Describe the variations of buprenorphine from other opioids (1)

Which receptor does it act upon and how (1)

Answer 8

Has a longer duration and a slower onset and can therefore cause prolonged vomiting

partial agonist of Mu receptors

Question 9

Can weak opioids cause tolerance? (1)

Answer 9

Yes but to a lesser extent

Question 10

What are the effects of opioids use? (4)

Answer 10

Euphoria

sedation

analgesia

respiratory depression

Question 11

Name the opioid receptors and state what activates them (8)

Answer 11

Mu - acted on by B-endorphins

Delta - acted on by B-endorphins and enkephalins

Kappa - acted on by dynorphins

ORL1 - non classical receptor acted on by nociceptin/OFW
has shared homology and also uses Gi/Go and has an endogenous ligand

Question 12

What are B-endorphins made from? (1)

Answer 12

Propriomelanocortin

Question 13

What are enkephalins made from? (1)

Answer 13

Proenkephalin

Question 14

What are dynorphins made from? (1)

Answer 14

Prodynorphin

Question 15

What is nociceptin made from? (1)

Answer 15

Pronociceptin

Question 16

Where are Mu receptors located? (4)

Answer 16

Rostral and caudal cortex and motor regions eg caudate

Limbic structures eg amygdala and stria terminalis

Reward areas eg accumbens

Pain Processing areas eg Thalamus and colliculi

Question 17

Where are the Delta receptors located? (3)

Answer 17

Limbic structures eg amygdala and stria terminalis

Reward areas eg accumbens

Pain Processing areas eg Thalamus and colliculi

Question 18

Where are the Kappa receptors located? (3)

Answer 18

Limbic areas

Sensory and Motor Structures

Some expression in endocrine areas such as the hypothalamus - KEY

Question 19

Effects of opioids and their mechanisms (8)

Answer 19

Analgesia (tissue injury and tumour growth) no as effective at neuropathic pain as it effects the limbic system

Euphoria - strong contentment and decreased anxiety from pain

Resp Depression - less sensitivity to CO2 centre via Mu receptors - most damaging

Cough Reflex - reduces, unknown mechanism (low doses pre analgesia)

N&V - action in area postrema by delta and area prostrema by Mu

Pupil constriction - pinpoint pupils sign of poisoning

GI Tract - increase tone and low motility cause constipation

Itching - morphine release histamine from mast cells

Question 20

Opioid Tolerance (2)

Answer 20

develops rapidly and needs to be increased reapidly

less for GI symptoms

Question 21

Physical opioid dependence symptoms and facts (3)

Answer 21

irritable, weight loss,, shakes, writhing, jumping and aggression

less intense with gradual withdrawal

rarely progresses to addiction

Question 22

Gi/Go receptor activation (4)

Answer 22

increase K+ channel opening causing hypoerpolarisation

decrease opening of VGCC

inhibition of AC, decrease in Ca++ and PKA

opioids decrease excitation in dorsal spinal cord from peripheral neurons

Question 23

Descending control system of opioids (4)

Answer 23

opioids excite PAG neurons and neurons of nucleus reticularis paragigantocellularis (NRPG)

stimulates neurons in nucleus raphe magnus (NRM)

5-HT and enkephalin neurons of NRM run to dorsal horn and inhibit transmission

opioids act directly on dorsal horn also on peripheral terminals

Question 24

Receptor and effects of Diamorphine (2)

Answer 24

MOP

pain relief for tissue injury and tumour growth

Question 25

Receptor and effects of Pethidine (2)

Answer 25

DOP analgesia in labour

Question 26

Receptor and effects of Fentanyl (2)

Answer 26

MOP rapid onset and shorter action - patient controlled

Question 27

Effects of Codeine (3)

Answer 27

readily absorbed oral analgesic for mild pain no euphoria constipation

Question 28

Use of Dihydrocodeine and why (2)

Answer 28

useful in 10% resistant to codeine lack demethylating enzyme that connects codeine to morphine

Question 29

Receptor effect of Tramadol (2)

Answer 29

opioid agonist weak NA reuptake inhibitor

Question 30

Nalaxone effect and unique factor (2)

Answer 30

antagonist does not cross BBB

Question 31

Chronic Pain and Addiction to opioids (2)

Answer 31

properly managed short term medical used rarely leads to addiction, just physical dependence risk increases when used in ways other than prescribed (increase dose, different administration, combine with alcohol, history of psychiatric disorder, genetic polymorphisms, age (adolescents/older)

Question 32

Morphine in MOP KO mice (4)

Answer 32

demonstrated that MOP is the primary receptor for morphine - Keiffers et Al mice have a preference to morphine in WT in KO they no longer self administrate MOP is a mediator of positive reinforcement

Question 33

Effect of KOP KO in mice (3)

Answer 33

WT spent 400 seconds longer in non-KOP against the injection chamber KO mice had none of this suggesting KOP is aversive or dysphoric KO mice had increased dopamine suggesting KOP decreases dopamine

Question 34

Mechanism of opioid dependence (4)

Answer 34

homeostatic compensatory neuradaptation - adaptive changes to oppose drug action, withdrawal causes rebound effect HPA axis is hyporesponsive in heroin and cocaine addicts CRF increased in amygdala CRF antagonists block withdrawal in animals

Question 35

Treatment for dependence symptoms and mechanism (2)

Answer 35

Lafexidine central a2 agonist that suppresses some withdrawal components

Question 36

Treatment for opioids by substitution and mechanism (4)

Answer 36

Methadone long acting drug causes no euphoria to morphine duration 24-36h 30-40mg stops withdrawal but leaves craving 80-100mg is more effective at lowering opioid use as it lowers craving

Question 37

Treatment for opioids that aims to prevent Euphoric feelings and mechanism (4)

Answer 37

Naltrexone opioid agonist that prevent impulsive use by blocking agonist effects dose is 50mg daily, 100mg every 2 or 150mg every 3 side effects involve hepatotoxicity so LFTs required every 3 months and not currently approved for opioid dependence

Question 38

Treatment for opioids by substitution and mechanism (4)

Answer 38

Burpenorphine partial MOP/KOP agonist and KOP antagonist lower risk of respiratory depression used with nalaxone