l10 pharm

what is drug elimination?

drug elimination is the process that removes drugs from the body

why is drug elimination important?

it determines how long drugs remain active in the body and whether they accumulate to toxic levels

what are the two processes that contribute to drug elimination?

metabolism and excretion

what is metabolism in drug elimination?

metabolism is the chemical modification of drugs, usually mainly by the liver

what is excretion in drug elimination?

excretion is the physical removal of drugs from the body, usually through urine or bile/faeces

what is the general pathway for drug elimination?

drug → metabolism in liver → excretion by kidney or bile

what are the main organs responsible for drug elimination?

the liver and the kidney

what is the liver mainly responsible for in elimination?

the liver chemically modifies drugs through metabolism and can excrete some drugs into bile

what is the kidney mainly responsible for in elimination?

the kidney excretes many water-soluble drugs and metabolites into urine

what is elimination rate?

elimination rate is the amount of drug removed per unit time

give an example of an elimination rate

20 mg/hour means 20 mg of drug is removed every hour

what usually happens to elimination rate when drug concentration is higher?

elimination is usually faster when drug concentration is higher

why are drugs often eliminated faster at higher concentrations?

because more drug molecules are available to meet enzymes and transporters

what is first-order elimination?

first-order elimination is when the elimination rate depends on drug concentration

what happens to elimination in first-order kinetics when concentration is high?

elimination is fast

what happens to elimination in first-order kinetics as concentration falls?

elimination slows down

what fraction is eliminated in first-order kinetics?

a constant fraction is eliminated per unit time

what does constant fraction eliminated mean?

the same percentage of drug is removed each time period, not the same amount

give an example of first-order elimination

if 50% is removed each hour, 100 mg becomes 50 mg, then 25 mg, then 12.5 mg

why does the amount removed get smaller over time in first-order elimination?

because the same fraction is removed from a smaller amount each time

what kind of decline does first-order elimination produce?

an exponential decline

what does exponential decline mean in drug elimination?

the concentration falls quickly at first, then more slowly over time

do most drugs follow first-order or zero-order elimination?

most drugs follow first-order elimination

what is clearance?

clearance is the volume of plasma cleared of drug per unit time

what are the units of clearance?

L/hour

what does high clearance mean?

the body removes the drug efficiently

what does low clearance mean?

the body removes the drug poorly, so the drug can accumulate

does clearance mean actual litres of plasma are removed from the body?

no, it means the body removes drug at a rate equivalent to clearing that volume of plasma

what does clearance help determine?

clearance helps determine the steady-state concentration of a drug

what is steady state?

steady state is when the rate of drug entering the body equals the rate of drug leaving the body

at steady state, what equals what?

elimination rate = dose rate

what does “drug entering body = drug leaving body” describe?

steady state

can two patients receiving the same dose have different plasma concentrations?

yes, because they may have different clearance

what happens in a patient with high clearance?

the drug is removed quickly, so steady-state concentration is lower

what happens in a patient with low clearance?

the drug is removed slowly, so steady-state concentration is higher

why can renal failure cause drug accumulation?

because the kidney cannot excrete drugs properly, so clearance decreases

what is the clinical risk of low clearance?

drug accumulation and toxicity

why does first-order elimination usually happen?

at normal doses, drug-clearing enzymes and renal transporters are not saturated

what does saturated mean?

saturated means the enzymes or transporters are working at maximum capacity

why does elimination increase with concentration when enzymes are not saturated?

more drug molecules are present, so more can meet enzymes or transporters and be cleared

what is half-life?

half-life is the time taken for the amount or concentration of drug to fall by 50%

what happens to half-life in first-order elimination?

half-life is constant

if a drug has a half-life of 1 hour, how much remains after 1 hour?

50% remains

if a drug has a half-life of 1 hour, how much remains after 2 hours?

25% remains

if a drug has a half-life of 1 hour, how much remains after 3 hours?

12.5% remains

why is first-order elimination predictable?

because the same fraction is eliminated each half-life

what is zero-order elimination?

zero-order elimination is when a fixed amount of drug is removed per unit time, regardless of concentration

what is removed in zero-order elimination: fraction or amount?

a fixed amount is removed per time

give an example of zero-order elimination

if 10 mg is removed each hour, 100 mg becomes 90 mg, then 80 mg, then 70 mg

how does zero-order differ from first-order elimination?

first-order removes a constant fraction per time, while zero-order removes a constant amount per time

why does zero-order elimination happen?

it happens when metabolic pathways or enzymes are saturated

what does it mean if enzyme capacity is reached?

all enzymes are busy, so metabolism cannot speed up even if concentration increases

why can zero-order elimination be risky?

because extra drug cannot be cleared faster, so concentration can rise dangerously

what are examples of zero-order elimination drugs?

ethanol, phenytoin at high doses, and aspirin in overdose

what is the classic example of zero-order elimination?

ethanol/alcohol

how fast is alcohol metabolised according to the lecture?

about 7 to 8 g/hour

why is alcohol eliminated at a constant rate?

alcohol dehydrogenase requires NAD+ cofactors, and these become limiting

what enzyme metabolises alcohol?

alcohol dehydrogenase

what cofactor limits alcohol metabolism?

NAD+

why does drinking more alcohol not make alcohol elimination faster?

because the metabolic pathway is limited and already working near capacity

what is the main organ for drug excretion?

the kidney

what are the kidney’s main functions in drug excretion?

filter blood, remove water-soluble molecules, and regulate electrolytes

why are water-soluble drugs easier for the kidney to excrete?

they stay in watery urine and are less likely to diffuse back into the blood

what is the functional unit of the kidney?

the nephron

what part of the nephron is responsible for most renal drug elimination?

the proximal tubule

what does the proximal tubule do for drug elimination?

it secretes many drugs into the tubule for excretion

approximately how much drug secretion occurs in the proximal tubule?

about 90%

what is renal secretion?

renal secretion is movement of drugs from blood into the kidney tubule

what happens after a drug is secreted into the kidney tubule?

it can be eliminated in urine

what is reabsorption in the kidney?

reabsorption is movement of substances from the tubule back into the blood

what useful molecules are reabsorbed in the proximal tubule?

glucose, amino acids, and vitamins

why can lipid-soluble drugs diffuse back into blood?

because they can passively cross lipid membranes

what is passive diffusion?

passive diffusion is movement across a membrane without energy or transporters

which form of a drug is more likely to be reabsorbed from the tubule?

unionised drug

which form of a drug is more likely to be trapped in the tubule?

ionised drug

why are unionised drugs reabsorbed more easily?

they are uncharged and can cross lipid membranes more easily

why are ionised drugs trapped in the tubule?

they are charged and cross membranes poorly

what is ion trapping?

ion trapping is when an ionised drug cannot diffuse back into blood, so it stays in the tubule and is excreted

how can changing urine pH affect drug elimination?

it can change how ionised the drug is, altering reabsorption and excretion

why does ionisation increase excretion?

ionised drugs cross membranes poorly, so they stay in the tubule and are excreted faster

what is the principle behind using urine pH to increase elimination?

ionised drug → trapped in tubule → faster excretion

what does alkalinising urine mean?

increasing urine pH to make it more basic/alkaline

what drug overdose can be treated by alkalinising urine?

aspirin overdose

what is used to alkalinise urine in aspirin overdose?

sodium bicarbonate

why does sodium bicarbonate help in aspirin overdose?

it increases urine pH, making aspirin ionised so it cannot diffuse back into blood

what happens to aspirin in alkaline urine?

aspirin becomes ionised

why does ionised aspirin get excreted faster?

it is trapped in the kidney tubule and cannot easily diffuse back into the blood

what chemistry explains urine pH and ionisation?

the Henderson-Hasselbalch principle

what are weak acids like aspirin more ionised in?

alkaline/basic urine

what is biliary excretion?

biliary excretion is removal of drugs into bile, which can then leave in faeces

where is bile produced?

bile is produced by the liver

how much bile does the liver produce per day according to the lecture?

about 1 litre per day

what kinds of drugs are often excreted into bile?

drugs that are large, lipophilic, and conjugated/glucuronidated

why does glucuronidation help biliary excretion?

it makes drugs larger and more polar, which helps secretion into bile

how can drugs eliminated in bile leave the body?

through the intestine and faeces

what is enterohepatic circulation?

enterohepatic circulation is when a drug cycles between liver, bile, intestine, and reabsorption back into blood

what bacterial enzyme is involved in enterohepatic circulation?

beta-glucuronidase

what does beta-glucuronidase do?

it removes glucuronide conjugates from drugs in the intestine

what happens after beta-glucuronidase removes the conjugate?

the unconjugated drug can be reabsorbed

what is the clinical effect of enterohepatic circulation?

prolonged drug action