Pharm 19 - Opiates/Opioids

Question 1

What is an opiate?

Answer 1

Alkaloid derived from Opiate poppy (Papaver somniferum)

Question 2

What are the 4 most common opiates

Answer 2

Morphine
Codeine
Thebaine
Papaverine

Question 3

Describe the structure of opiates

Answer 3

1. Tertiary N present - this is what gives opiates an analgesic effect
2. Hydroxyl groups on 3’ and 6’ positions - they help secure the molecule at the receptor

(OH group on 3’ is required for binding - hence

Question 4

What happens if the side chain on the tertiary N has more than a 3 C side chain?

Answer 4

It becomes an antagonist

Question 5

Heroin and codeine are what of morphine

Answer 5

Derivates/prodrugs

Question 6

Heroin is much more soluble than morphine. Why?

Answer 6

Because the 3’ and 6’ OH group is replaced by acetyl groups

Question 7

Fentanyl is a very potent opioid compared to morphine. One reason for this?

Answer 7

Morphine = quaternary carbon

Fentanyl = tertiary carbon

Question 8

Methadone conforms to the morphine rule in what sense?

Answer 8

It has a tertiary N, quaternary C, Phenyl group

Question 9

Opioids are weak bases. Where will they be most readily absorbed?

Answer 9

In the SI - as they are mainly unionised here.

In stomach, they are ionised so less absorption

Question 10

What process decreases the bioavailability of opioids?

Answer 10

First pass metabolism

Question 11

Blood has a pH of 7.4. Opioids have a pKa of >8. Therefore what state are they in the blood

Answer 11

Ionised

<20% of opioids are unionised in blood - it is these opioids that can access tissues

Question 12

pKa and pH must be roughly the same in order for the drug to be…?

Answer 12

Heavily unionised

Question 13

Rank the lipid solubility of the opioids

Answer 13

1. Fentanyl
2. Methadone
3. Heroin
4. Morphine

(more lipid soluble = more potent)

Question 14

Morphine is metabolised in the liver and excreted in the …?

Answer 14

Bile - undergoes enterohepatic cycling - returns to blood to have more of an effect

Question 15

What are the 2 main active metabolites of morphine?

Answer 15

1. Morphine-3-Glucuronide (M3G)

2. Morphine-6-Glucuronide (M6G)

Question 16

Most opioids aside from morphine are excreted by the…?

Answer 16

Kidneys

Question 17

Fentanyl is very addictive because?

Answer 17

It has a very fast clearance (because it is broken down in the blood by plasma cholinesterase’s)

Question 18

Why is methadone used to wean people off heroin?

Answer 18

It has a slow clearance - low addictive potential as it remains in blood for longer

Question 19

Why is methadone metabolised very slowly?

Answer 19

It is a poor substrate for CYP450

Question 20

Which 2 enzymes metabolise the majority of opioids in the liver.

In the case of codeine, what do these 2 enzymes do

Answer 20

1. CYP2D6 -activates codeine into morphine (slow process)
2. CYP3A4 - deactivates codeine into inactive metabolites (fast process)

Consequently, only 10% of codeine is converted into morphine - this is what gives codeine its analgesic effect

Question 21

A polymorphism in the CYP2D6 means what for people who take codeine?

Answer 21

Codeine cant be activated - doesn’t have much effect

Question 22

Name 3 types of endogenous opioid peptides (they act on opioid receptors)

Answer 22

1. Endorphins
2. Enkephalins
3. Dynorphins / neoendorphins

Question 23

Which type of opioid receptor do endorphins act on?

Answer 23

Mu receptors (or delta)

Pain/sensorimotor parts of the brain

Question 24

Which type of receptor do enkephalins act on?

Answer 24

Delta

Motor/cognitive function parts of the brain

Question 25

Which type of receptor do dynorphins act on?

Answer 25

Kappa Neuroendocrine part of the brain

Question 26

What are the 3 means through which opioids have a depressive effect?

Answer 26

1. Hyperpolarisation - increased K efflux 2. Reduce Ca influx - important for Neurotransmitter exocytosis 3. Reduce adenylate cyclase activity - general reduction in cellular activity

Question 27

What are the 7 main effects of opioids?

Answer 27

1. Analgesic 2. Euphoria 3. Anti-tussive (depression of cough centre) 4. Respiratory depression - most dangerous side effect 5. Pupillary constriction 6. Nausea/vomiting 7. GI effects

Question 28

Generally speaking, how do opioids have their analgesic effects?

Answer 28

Increase pain tolerance Decrease pain perception

Question 29

Where are the targets of opioids in terms of analgesia

Answer 29

1. Dorsal horn - increases inhibition of sensory neurones 2. PAG - enhances PAG firing 3. NRPG - activates this Opioids work by switching off GABA

Question 30

How do opioids cause euphoria

Answer 30

1. Binds to Mu receptors on GABA interneurones - inhibits GABA 2. Less inhibitory GABA input on dopaminergic neurones of the VTA 3. Increased dopamine release at the nucleus accumbens

Question 31

What are the 2 means by which opioids exert an antitussive effect?

Answer 31

1. Inhibits motor neurones linking the cough centre to the larynx. This Inhibition of 5HT1A receptor increases serotonin levels in the cough centre, decreasing cough reflex. 2. Preventing transmission of information from sensory nerves to vagus

Question 32

Where are 5HT1A receptors found?

Answer 32

Dorsal raphe nucleus

Question 33

How do opioids cause nausea and vomiting

Answer 33

1. Activate mu receptors in chemoreceptor trigger zone (CTZ) 2. Activates medullary vomiting centre 3. Stimulants from the stomach and intestines send signals to chemoreceptor trigger zone and medullary vomiting centre 4. Opioids switch off GABA receptors which inhibit CTZ

Question 34

Opioids cause pupil constriction. Why?

Answer 34

1. Oculomotor nerve is preganglionic PNS nerve to the eye - causes pupil constriction (nerve originates from Edinger-Westphal nucleus) 2. Opioid receptors present on GABA receptors on Edinger-Westphal nucleus 3. Less GABA inhibition of oculomotor nerve

Question 35

What is the pre-Botzinger complex and what does it do

Answer 35

Small area in the ventrolateral medulla - generates respiratory rhythm

Question 36

How can opioids cause respiratory depression

Answer 36

1. Inhibits pre-botzinger complex (which is active in inspiration) 2. Inhibits central chemoreceptors (chemoreceptors which provide tonic drive to respiratory motor output - sense changes in pH) Ultimately opioids depress firing rate of central chemoreceptors - interfering with ability of brain to control respiration

Question 37

What are the main effects that opioids have on the GI tract

Answer 37

1. Decreases gastric emptying 2. Decreases gastric motility 3. Less water absorption ALL CAUSE CONSTIPTAION

Question 38

Which opioid receptor types are found on myenteric neurones?

Answer 38

Kappa and Mu

Question 39

Why are opioids good for preventing diarrhoea?

Answer 39

Depress intrinsic nervous system of GIT

Question 40

Symptoms of opioid use include itching, hives, hypotension, though opioids do not cause an allergic response. Whats going on?

Answer 40

1. Opioids bind to mast cells in skin - promote histamine release 2. Hydroxyl group at position 6 vital in this - only if this present can histamine release occur

Question 41

How does tolerance to opioids occur?

Answer 41

Receptor internalisation due to arrestin upregulation (if long term use)

Question 42

Opioids have a powerful physical withdrawal. How?

Answer 42

Body compensates for decreased adenylate cyclase function (when opioids were used) by upregulating adenylate cyclase function ; leading to shakes, sickness, etc - withdrawal symptoms resemble flu

Question 43

What are features of opioid OD

Answer 43

1. Coma 2. Respiratory depression 3. Pinpoint pupils 4. Hypotension

Question 44

What is the treatment for opioid OD and why

Answer 44

Naloxone - opioid receptor antagonist (it has a tertiary N with extended side chain)