Metabolism and Excretion Flashcards
what is the main site of metabolism?
the liver
where else in the body are drugs metabolised?
the GI tract, skin, lungs, kidneys and the neurones and the blood
what are the two main effects of metabolism?
increases water solubility and reduces pharmacological activity
what property does a drug need to have to be excreted through urine?
water soluble
why can’t a lipophilic drug be excreted via urine?
the drug will be filtered through the glomerulus but will be passively absorbed back into the blood stream
what occurs in phase I metabolism?
functionalization
what is functionalization?
when a reactive group is added to a molecule to increase its reactivity
what type of reactions can functionalization occur in?
oxidation, reduction and hydrolysis
what is conjugation?
a reaction in which the drug or its metabolites are coupled with another molecule
how can conjugation produce a polar molecule?
a polar molecule is added at the reactive site on the metabolite to produce a water soluble product
how does CYP450 metabolise drugs?
oxidises the drug by adding a molecule of oxygen to the drug to form an OH group
where is CYP450 found?
In hepatocytes of the liver
what occurs in phase II metabolism?
the polar metabolites that are produced via conjugation are catalysed by specific transferases
where are transferases found?
in the ER and cytoplasm of hepatocytes
what is different about metabolites from phase I and metabolites from phase II?
phase II metabolites usually have lower pharmacological activity or toxicity
what are examples of polar molecules that phase I metabolites can be linked to?
glucoronic acid, glycine, sulphate, acetate, methyl or glutathione
what are active drug metabolites?
when the metabolites produced are not less toxic or less pharmacologically active
what are some examples of drugs that have active metabolites?
codeine when converted to morphine, imipramine to desipramine, enalapril to enalapriat
what drug has toxic metabolites?
paracetamol
what is paracetamol conjugated as at normal therapeutic doses?
glucoronide or sulphate
how can paracetamol be potentially toxic?
because a small amount is converted to a potentially toxic intermediate in phase I via an oxidation reaction
at normal doses, why does the toxic intermediate of paracetamol cause no damage?
because the intermediate quickly reacts with a scavenger molecule called glutathione and further converted to a non-toxic form and excreted via the kidney
how does an overdose of paracetamol cause damage to the body?
when high doses of paracetamol are ingested this depletes the levels of glutathione in the body and so the toxic intermediate causes hepatic and renal damage
what is the antidote for paracetamol overdose? how does it work?
N-acetyl cysteine (NAC) as it is a precursor to glutathione
how is a graph used to determine the toxicity of the drug dosage?
plot the drug concentration against the hours post ingestion and use this to determine what treatment should be given
what kind of substances are excreted through urine?
low molecular weight substances
what kind of substances are excreted through bile?
high molecular weight substances that are often conjugates
what kind of substances is excreted through faeces?
compounds that are excreted through bile and materials that have not been absorbed by the gut
what kind of substances are excreted through sweat?
water-soluble drug products
what kind of substances are excreted through breath and saliva?
breath excretes volatile substances such as gases and solvents and saliva I slow molecular weight substances
what kind of substances are excreted through breast milk?
lipid soluble and water-soluble products
what is the the relationship between rate of elimination and drug concentration?
the higher the concentration, the higher the rate of elimination, in most cases
what is first order kinetics?
rate of elimination is proportional to drug concentration
what is the half life of a drug?
the time taken to reduce the plasma concentration of the drug by half
what is the equation of half life and what does it tell us?
half life=0.693xVd/clearance, shows that the higher the Vd, the longer the half life will be
what is clearance?
volume of blood that is cleared of the drug per unit of time
what is zero order kinetics?
elimination is independent of drug concentration as the rate is unaffected by the increases of drug concentration
what kind of drugs show zero order kinetics?
alcohol, phenytoin, warfarin at high doses, aspirin
what causes a drug to show zero order kinetics?
when the enzyme system that is responsible for metabolism is fully saturated
