Applying PD/PK theory to opioids

Question 1

Name three opioids

Answer 1

morphine, codeine and heroin

Question 2

Structural similarity between the 3 opioids

Answer 2

contains a phenanthrene ring

Question 3

compare the lipid and polar solubility between the 3 opioids and why

Answer 3

morphine is the most polar and least lipid soluble as it has 2 OH groups and heroin is the least polar and most lipid soluble as it does not OH group .

Question 4

rank which drugs can cross lipid membranes more readily and why

Answer 4

heroin > codeine> morphine as heroin is the most lipid soluble and it can cross lipid membrane more readily

Question 5

Which molecule in the drug is important for anchoring the molecule to the receptor and determines the efficacy/ affinity

Answer 5

tertiary nitrogen and the hydroxyl at position 3

Question 6

what is the antagonist of morphine and how the structure of it affects activation

Answer 6

naloxone, if side chain contains 2 or less C -> activate the receptor
if side chain contains 3 or more C -> drug cannot activate the receptor

Question 7

what kind of bindings do morphine binds to opioid receptor

Answer 7

hydrogen bind, van der waal’s and ionic bond

Question 8

what is the kind of administration of heroin, morphine and codeine

Answer 8

heroin is intravenous, codein is oral and morphine can via both

Question 9

Compare the efficacy between the 3 opioids

Answer 9

As
heroin and codeine do not possess the -OH at position 3, they have a lower affinity for the
receptor than morphine despite having more accessibility to the brain and, by extension,
the receptor.

Question 10

Why is hepatic first metabolism required for oral administration of opioids

Answer 10

Oral administration is more complicated as only a portion of the drug can be absorbed in
the lower parts of the small intestine when the pH is sufficiently basic. The drug must then
undergo hepatic first-pass metabolism that reduces bioavailability as opioids undergo
complex metabolism which yields a mixture of active and inactive metabolites.

Question 11

describe the product of metabolism of heroin

Answer 11

Heroin is metabolised to produce 6-acetyl-morphine which has one less acetyl
group than heroin and possesses a position 3 hydroxyl group. However, it still
possesses one acetyl group which makes it more lipid soluble than morphine,
which means it can penetrate the brain more rapidly and bind strongly to the
receptor, which is why heroin is considered to be more potent than morphine.

Question 12

What enzyme metabolise heroin

Answer 12

esterases

Question 13

Describe the product after metabolising codeine

Answer 13

codeine convert to norcodeine by N-demethylation or convert to morphine by O-demethylation

Question 14

What enzyme metabolise codein

Answer 14

• CYP3A4 - fast metabolism which deactivates codeine to norcodeine
  
  • CYP2D6 - slow metabolism which activates codeine to morphine (only 10%)

Question 15

describe the excretion of opioids

Answer 15

Opioids are excreted in the urine but if they are unionised (which they are in
alkaline urine) and lipid soluble, they are more likely to diffuse back into the
bloodstream from the kidney tubules. Thus, opioids tend to accumulate in the body due to
low excretion levels.

Question 16

What are the three subtypes of opioids receptor

Answer 16

mu, detal and kappa receptor

Question 17

What are the endogenous agonists

Answer 17

endorphins (mu), enkephalins (delta), dynorphine (kappa)

Question 18

Describe the different mechanism of depressant effect when opioids bind

Answer 18

1. Inhibit adenylate cyclase and thus prevent production of cAMP
   - Decrease in cellular activity
   
   2. Inhibit calcium entry into the cell
      
      • This can have a very specific depressant effect in terms of decreasing the stimulus for exocytosis
   3. Enhance potassium efflux from cell
      
      • Specific depressant effect in terms of increasing hyperpolarisation
        § Thus reducing cell depolarisation (consequent activation)

Question 19

Describe how thalamus receive pain signals

Answer 19

1. Peripheral pain signals activate sensory neurons which relay the signal into dorsal horn of the spinal cord
   
   2. These neurons synapse onto spinothalamic neurons which relay the signal from spinal cord into the brain - thalamus
   3. Sympathetic system diminish pain signals in order to stop them distracting an individual during fight or flight response
   4. Thalamus receives pain signals and redirects them to other regions to minimise the pain felt

Question 20

Describe the PAG pathway

Answer 20

1. Thalamus directly activate Periaqueductal grey region (PAG) upon receiving the pain signal from periphery
   
   2. Signals are simultaneously sent to the cortex, which regulates the PAG’s response and access memories of pain to modulate the level of pain signal sent to the PAG
   3. PAG can accordingly activate the nucleus raphe magnus (NRM) which acts as the effector arm of the pain tolerance pathway and decreases the transmission of the pain signal from the periphery sensory neurons to the spinothalamic neurons.
   4. It does this by projecting onto substantia gelatinosa within the dorsal horn which is the region through which periphery sensory neuron relay their signal into the spinal cord
   5. Activation of substantia gelatinosa by NRM allow modulation of these pain signals to diminish pain
   6. Hypothalamus can modulate PAG activity depending on state of health as good health causes increased pain tolerance pathway activation

Question 21

Describe the NRPG pathway

Answer 21

1. The nucleus reticularis paragigantocellularis (NRPG) is directly activated by ascending spinothalamic neurones
   
   2. NRPG can activate NRM leading to a quick, abeit minor, diminishing of pain before brain can finish processing the complete pain tolerance pathway
   3. Thalamus can also signal to Locus coeruleus which can directly inhibit pain transmission to spinothalamic neuron
      • Considered as effector arm of the SNS due to its use in reducing the distraction of pain during fight or flight response

Question 22

What effect do opioids have on region of the pain pathway

Answer 22

Opioids increase firing rate in NRPG and PAG and decrease firing rate in thalamus, peripheral sensory neuron and spinothalamic neuron

Question 23

Describe the activation of the reward pathway

Answer 23

GABA inhibitory neurons normally suppress the dopamine pathway. When opioids bind to opioid receptor,, the receptor is activated and swtiches off this GABA negative effect. This causes a disinhibtiion effect and dopaminergic neuron fire at much high rate due to loss of gaba suppression

Question 24

what further classical effect do opioids have

Answer 24

1. anti-tussive effect which prevent cough by decreasing activation of afferent nerves which relay cough stimulus from airway to brain
2. Nausea inducing effect by increasing activation of neurons projecting from chemorecpetor trigger zone which stimulate feelings of nausea

Question 25

How does opioids cause suffocation

Answer 25

• The respiratory control centre is a region found within the medulla which alters the rate and depth of breathing based on information received from the central chemoreceptors such as changes to CO2 levels following carbonic anhydrase activity.
• Opioid receptors depress these central chemoreceptors which decreases the information relayed to the respiratory control centre and inhalation/exhalation stimuli to the lungs.

Question 26

Why are partial opioid agonist less dangerous

Answer 26

• Partial opioid agonist cannot induce a maximal response and cannot cause respiratory depression
• Opioid addict could be given a partial agonist which is less dangerous than a full agonist like morphine or heroin