The Importance of Modifying Opiod Structure to Enhance the Activity of These Drugs Within The Body Flashcards
What are the differences between opioids and opiates and how are they classified?
Opioids are drugs with opiate-like activity. Opiates are the natural plant based alkaloids from the opium poppy. Mainly classified as depressants.
Describe the structure of morphine, and its two variants codeine and heroin.
Morphine has a phenanthrene ring with two OHs on the left and a tertiary methyl Nitrogen. It’s a naturally occuring substance.
Codeine is also a naturally occuring substance and instead of 2OHs on the left it has OCH3 on the top left. Also a tertiary methyl N.
Heroin is a synthetic molecule which has no OH groups, instead it has OOCH3. Also has a tertiary methyl N.
How does the structure of heroin, morphine, and codeine influence their pharamacokinetics?
Heroin is the most lipid soluble as it has no polar OH groups, meaning it can access tissues very readily. Morphine is the least lipid soluble as it has 2 polar OH groups which allow less ready access to tissues. Codeine is intermediate with only one polar OH group.
What are the roles of the OH groups and the tertiary nitrogen in affinity and efficacy?
The top left OH (position 3) and the tertiary nitrogen act to anchor the molecule to the receptor, giving the molecule affinity for the receptor. The efficacy comes from the side chains attached to the tertiary N. If the side chain is 2 or fewer carbons on it, the molecule has efficacy. If the tertiary N has 3 or more carbons on its side chain, the molecule doesn’t activate the receptor.
How does the ratio of ionised:unionised morphine change in different body compartments? Morphine’s pKa is 8.0
In stomach (pH = 3) its 100,000:1, in blood and terminal ileum (pH = 7.4) it’s 4:1, in urine (pH = 8) it’s 1:1. So, in the blood, about 25% of the bioavailable morphine is free to diffuse into tissues. If the administration was IV, this would be 25% of 100%. If administration was oral, it would be lower as first pass metabolism would reduce bioavailability.
How does the metabolism of different opioids influence their effectiveness?
Heroin and Codeine must both be metabolised first as they don’t bind as effectively as morphine due to their lack of position 3 (top left) OH.
Describe the metabolism of Heroin
Heroin has no polar OH groups so cannot bind effectively to the receptor but is very lipid soluble. The major metabolite is 6-acetyl morphine which is the top left (position 3) replaced with an OH making it still relatively lipid soluble but also able to bind the receptor. It can be metabolised completely to morphine. When Heroin is injected IV, some will rapidly go to the brain where it’s metabolised to 6-am, but a larger part will be metabolised in the liver where it gains affinity and then travel to brain as it retains some lipid solubility. Heroin is more potent than morphine because of 6-am.
Describe the metabolism of Codeine
Can be metabolised to morphine and norcodeine. Morphine is responsible for all of the effects as norcodeine doesn’t have a tertiary N. Most opioids are metabolised in the liver by CYP450 subtypes CYP3A4 and CYP2D6. 3A4 responsible for fast metabolism which deactivates codeine. 2D6 is responsible for slow metabolism which activates codeine (pro drug). Only about 10% of codeine is activated which is why it’s a weak opioid.
Describe how opioids are excreted
Opioids are basic, meaning that in high pH (alkaline) urine conditions, they are unionised, so more lipid soluble, so will diffuse out of the tubule back into the bloodstream. They may accumulate in the body due to low excretion.
