Drug elimination 2 (L7) Flashcards
what is elimination?
metabolism + excretion = elimination
what are the major systems concerned with elimination?
- kidneys
- hepato-billiary system
- lungs
what is metabolism of drugs?
when drugs are made more water soluble prior to elimination
enzymatic modification of drug
2 sequential phases: I and II
phase I metabolism reactions usually consist of what?
- oxidation
- reduction
- hydrolysis
- cytochrome P450s
- functionalisation
- decrease lipid solubility but may increase pharmacological or toxicological activity
what are cytochrome P450s?
- large superfamily of heme cofactor containing enzymes
- often called ‘CYPs’
- metabolise thousands of endogenous and exogenous compounds
- increase water solubility of drugs
location of CYPs
main locations: intestine and liver
• liver = hepatocytes
• intestine = enterocytes
small amounts in kidney, white blood cells and nasal passages
always in the endoplasmic reticulum of the cell
how can functionalisation affect a drug?
- changes the metabolite
- will bind in a different way
- different stereochemistry
- effects how well the drug binds
ethanol metabolism
ethanol isn’t metabolised by P450s but by enzyme expression
process predominantly catalysed by alcohol dehydrogenase but also some CYP2E1
phase II reactions
conjugation reactions
functional group serves as a point of attack for conjugation systems
large groups attached
• glucuronyl
• sulphate
• acetyl
further decreases lipid solubility and almost always results in pharmacologically inactive metabolites
conjugate excreted in urine or bile
glucuronidation
most common conjugation reaction
important for both endogenous and exogenous compounds
mediated by UDP-glucuronyl transferases - an enzyme system with broad substrate specificity
paracetamol metabolism
is metabolised and detoxified relatively quickly
mainly by conjugation with sulphate and glucuronic acid
only a minor proportion is metabolised by CYP450 to a toxic metabolite
what is the toxic intermediary in paracetamol metabolism?
NAPQI
- the more active form of paracetamol
- if too much is produced we see liver damage
- can be detoxified to mercapturic acid by glutathione
what happens in paracetamol overdose?
saturates the normal metabolic processes
pathways of conjugation are saturated and co-factors are depleted so more paracetamol is metabolised via CYP450 to make the toxic metabolite
toxic metabolite reacts with liver proteins into of glutathione
tissue damage occurs leading to hepatic necrosis
internal factors affecting drug metabolism
endogenous factors
• genetics
• age
• disease
external factors affecting drug metabolism
exogenous factors
• drugs
• smoking/alcohol
• diet
genetic factors
a person is either a ‘fast’ or a ‘slow’ metaboliser
can have implications for therapeutic efficacy and/or toxicity of certain drugs
fast metabolisers
- normal enzyme activity
- low plasma conc of parent drug
- higher conc of metabolite
- generally normal therapeutic response
slow metabolisers
- low enzyme activity
- high plasma conc of parent drug
- low conc of metabolite
- may lead to exaggerated therapeutic response at normal doses
how does age affect metabolism?
individuals at extremes of age are affected
neonates (premature)
elderly
drug metabolism in neonates
low CYP and conjugating activity
express metabolising enzymes in different ways - lack of enzymes
lack of use of morphine in labour - babies cannot metabolise it so causes respiratory issues
• baby goes blue
drug metabolism in the elderly
CYP activity declines with age
more variability of half-life of many drugs
• issues for drug development
chemical exposure on a daily basis
- pharmaceuticals
- cosmetics
- food additives
- industrial chemicals
- pesticides
- smoking
- alcohol
these compounds either induce or inhibit drug metabolising enzymes
what happens when drug metabolising enzymes are induced?
increased synthesis of enzymes (phase I and II)
results in increased metabolism of inducing agent and other drugs
smoking and ethanol are both inducers
implications of induction
decreased drug effectiveness on chronic exposure
need to increase drug dose
may be issues when inducer is withdrawn from regime
how is paracetamol metabolism effecting by ethanol consumption?
alcohol increases amount of CYP2E1 which increases amount of NAPQI
increases liver damage
happens when overdose is involved with alcohol consumption
what happens when drug metabolising drugs are inhibited?
reduced rate of metabolism and increased pharmacological effect
inhibition of the CYO system is caused by many drugs
• a component of grapefruit juice inhibits CYP3A4 so inhibits metabolism of CYP3A4 substrates (terfenadine and nifedipine)
3 major processes in renal excretion
glomerular filtration
tubular reabsorption
tubular secretion
what happens to water soluble drugs?
excrete unchanged through the kidneys
what happens to lipid soluble drugs?
- filtered in the glomeruli
- reabsorbed in the distal portion of nephron
- metabolised to more polar compounds
- excreted in urine
extent of tubular reabsorption depends on…
drug lipid solubility (pKa)
pH of tubular fluid
what happens if tubular fluid becomes more alkaline?
acidic drugs ionise and becomes less lipid soluble
reabsorption diminishes
elimination occurs
what is pH portioning?
impacts upon the rate at which drugs permeate membranes and distribution of drug between aqueous compartments
weak acids accumulate in compartments if relatively high pH, whereas weak bases tend to do the opposite
where are weak bases ionised best?
at acid pH
drug gets ionised and can’t be reabsorbed
where are weak acids best ionised?
at alkaline pH
