PED1003/L06 Drug Elimination II Flashcards
Give the 3 major systems of elimination in the body.
Kidneys
Hepato-biliary system
Lungs
Which group of enzymes is a key player in Phase I reactions?
Cytochrome P450s
Which kind of drug are Phase I reactions particularly important for?
Pro-drugs
Describe a basic CYP reaction. (5)
Drug enters cycle
Forms complex with CYP450
Through series of e- donations with NADPH as cofactor
Produces a metabolite
CYP regenerated
Give an exception to the CYP cycle.
Ethanol metabolism
What is the most common conjugation reaction?
Glucuronidation
How is glucuronidation mediated?
By UDP-glucuronyl transferases
Why are glucuronides usually pharmacologically inactive and rapidly excreted?
They are polar
What is NAPQI?
Toxic metabolite of paracetamol
What happens in paracetamol overdose? (2)
Tissues become saturated with glutathione
Reacts and damages liver proteins
Give 3 internal factors that affect how an individual responds to a drug.
Genetics
Age
Disease
Give 3 external factors which affect how an individual responds to a drug.
Drugs
Alcohol
Environmental exposure including diet
Give 4 features of fast metabolisers.
Normal enzyme activity
Lower plasma conc.
Higher metabolite conc.
Generally normal therapeutic response
Give 4 features of slow metabolisers.
Low enzyme activity
Higher plasma conc.
Lower metabolite conc.
May lead to exaggerated therapeutic response at normal doses
Describe induction of drug metabolising enzymes. (2)
Increased synthesis of enzymes
Increased metabolism
Give 3 implications of induction.
Decreased drug effectiveness
Need to increase drug dose
In MDT may be problems when inducer is withdrawn from specimen
Basis of many drug-drug interactions
Give a drug which is rapidly and slowly cleared from blood.
Rapid - penicillin
Slow - diazepam
Give the 3 major processes of the kidney.
Glomerular filtration
Tubular reabsorption
Tubular secretion
Describe glomerular filtration.
Molecules of certain size pass from blood into nephron to be excreted (in glomerulus)
Describe tubular reabsorption.
In PCT
Acidic/basic molecules transferred from blood into nephron to be excreted
Describe tubular secretion.
Water is reabsorbed into body
Describe the path of a lipid soluble drug in the kidney. (4)
Filtered in glomeruli
Reabsorbed on distal portion of nephron
Metabolism to more polar compounds
Excretion in urine
Which plasma binding protein is almost completely retained?
Albumin
What does the rate of entry in glomerular filtration depend on? (2)
Concentration of free drug in plasma
Molecular weight
Which two carrier systems transport against an electrochemical gradient during tubular secretion?
For acids
For bases
More water-soluble drugs have what features during tubular reabsorption? (2)
Low tubular permeability
Concentrate in urine (100x that in plasma)
What si the extent of absorption dependent on?
Drug lipid solubility
pH of tubular fluid
What happens as fluid becomes more alkaline during tubular absorption? (3)
Acid drugs ionise
Become less lipid soluble
Reabsorption diminishes
(Basic drug un-ionised = reabsorption increases)
At what pKa is half of a substance ionised?
0
What is pH partitioning?
Acidic drugs accumulate in basic fluid compartments and vice versa
What is saturable elimination?
Elimination mechanisms are typically not saturated at therapeutic doses of drugs, with few exceptions
What is the purpose of Phase II reactions?
Increase water solubility to improve excretion
