pKa

between 6.5 - 8.7

They dissociate into their
unionised and ionised

forms - the proportion of
each depends on the pH of
their solvent and their pKa

The larger the value of pKa, the

smaller the extent of dissociation at
any given pH that is, the weaker the
acid.
'A high pKa = less acidic'
Lower a value than -2 = strong acid

UNIONISED drugs are more easily absored than

IONISED drugs - they diffuse more easily into

neural tissue.
The stomach is highly acidic - therefore the drugs are highly ionised and
poorly absorbed. Better in the alkaline small intestine.
Many opioids have a high first pass metabolism in the intestinal wall and
liver --> low oral bioavailability.

This facilitates transport into the site of action (biophase).

Opioid receptors are most commonly found in gut and neural
tissue. Opioids with high lipid solubility, high unionised fraction
or low protein binding have large volumes of distribution. Most
opioid's VD's exceed total body water. High VD's tend to last
longer.

Low dose short acting produce short duration of action because

plasma and BRAIN concentration remain above the threshold for
therapeutic action only for a short period before being
redistributed.
Larger doses produce longer lasting effects because plasma and
brain conc remain above the threshold at the completion of the
redistribution phase - their reduction therefore relies on the
slower elimination process.

Opioids --> Liver --> Active/Inactive products --> Excreted in urine and bile.

Morphine and other opioids are metabolised to gluconorides (like morphine-6gluconoride) and excreted in the bile. Extrahepatic metabolism can be important too the kidneys play a vital role in conjugated morphine, whereas blood and tissue
esterases are responsible for remifentanil metabolism.
ODDLY - in the GI tract, normal gut flora can metabolise gluconorides back into the
parent compound and you can get an 'entero-hepatic-recirculation'. Fentanyl is highly
lipid soluble -can re-enter the gut, become concentrated and unionised --> 2nd peak
effect as it enters the small intestine after gastric emptying... (gastro-enteric-recirc.)

From the poppy flower- properties discovered over 4000 yrs ago. Receptor sites
were discovered in a 1970's study on dogs - newly coined OP1, OP2, OP3 receptor
sites (old terms being Mu, Delta and Kappa). Opiates are all ANTAGONISTS at these
sites, naloxone being a pure AGONIST. They act to inhibit adenylyl cyclase (cAMP)
pathway which involved antagonising G1 protein coupled membrane-bound
receptors.
This action causes K+ efflux from the cell and restricts voltage gated calcium
movement across a membrane. This causes hyperpolarisation of the cell, blockade
of neurotransmission and therefore reduction in pain transmission.
They are external drugs that mimic endogenous opioid peptides found in the body
(anterior pituitary and hypothalamus) called ENDORPHINS. Beta-endorphin is the
most active - from the same precursor as ACTH.