LOADING AWESOME
LOADING AWESOME
LOADING AWESOME
physicochemistry of opioids
www.propofology.com
Dr. David Lyness
@Gas_Craic
Opioids = weak bases (pKa 6.5-8.7) - meaning they are more ionised in acidic environments = bad absorption in the stomach
Dissociate in solution to ionised and unionised fractions - proportions depend on pH of the solvent and the pKa of the opioid.
The pKa = the pH at which both forms exist in equal amounts - a low pKa means there's a higher unionised amount in acidic environment
Dissociate in solution to ionised and unionised fractions - proportions depend on pH of the solvent and the pKa of the opioid.
The pKa = the pH at which both forms exist in equal amounts - a low pKa means there's a higher unionised amount in acidic environment
Low protein binding in the plasma demonstrates large volumes of distribution - BUT you must take in to account the other properties.
UNIONISED = more diffusible than the ionised form - so you want most of the drug to be UNIONISED for it to work/diffuse
Highly acidic stomach = they are HIGHLY IONISED so don’t absorb as well, they absorb better in the alkaline small intestine (unionised)
Many opioids undergo large first pass metabolism in the intestinal wall and liver = low oral bioavailability.
HIGH LIPID solubility = better opioid transport into the site of action (biophase). More lipid soluble = more rapid onset
UNIONISED = more diffusible than the ionised form - so you want most of the drug to be UNIONISED for it to work/diffuse
Highly acidic stomach = they are HIGHLY IONISED so don’t absorb as well, they absorb better in the alkaline small intestine (unionised)
Many opioids undergo large first pass metabolism in the intestinal wall and liver = low oral bioavailability.
HIGH LIPID solubility = better opioid transport into the site of action (biophase). More lipid soluble = more rapid onset
HIGH LIPID SOLUBILITY + HIGH UNIONISED FRACTION or LOW PROTEIN BINDING = LARGE VOLUME DISTRIBUTION
A large Vd will mean they rapidly redistribute away from their sites of action (CNS) to other tissue.
Larger doses = longer duration of action as plasma levels are high beyond a threshold = slower elimination to become reduced.
THERE IS AN INTERPLAY BETWEEN ALL THESE FACTORS THAT GIVE EACH OPIOIDS THEIR UNIQUE CHARACTERISTICS
METABOLISED to active and inactive compounds by the liver that are excreted in bile and urine.
Excreted partly in the bile as water soluble glucuronides - in the gut these are metabolised by normal gut flora to the parent compound and reabsorbed (enters-hepatic-recirculation)
Excreted partly in the bile as water soluble glucuronides - in the gut these are metabolised by normal gut flora to the parent compound and reabsorbed (enters-hepatic-recirculation)
Highly lipid soluble opioids like fentanyl may diffuse from the circulation into the stomach mucosa and lumen where they are ionised and concentrated because of the low pH - these then pass into the small intestine which then absorbs them = 2nd peak effect (gastro-enteric recirculation).
The KIDNEYS help conjugate morphine.
Blood and Tissue Esterases metabolise REMIFENTANIL
Large variations in duration of action and complex. For example, the half-life of morphine is shorter than fentanyl yet lasts longer -
The KIDNEYS help conjugate morphine.
Blood and Tissue Esterases metabolise REMIFENTANIL
Large variations in duration of action and complex. For example, the half-life of morphine is shorter than fentanyl yet lasts longer -
This is due to its lower lipid solubility and slow diffusion out of the CNS tissue - once back in the blood it gets cleared more quickly.
Fentanyl moves out rapidly and is not at the site at which it can act to produce an effect.
IONISATION/LIPID SOLUBILITY/pKa/VOLUME OF DISTRIBUTION/CONTEXT-SENSITIVITY
KEY ISSUES
