Drug elimination 2 (L7)

Question 1

what is elimination?

Answer 1

metabolism + excretion = elimination

Question 2

what are the major systems concerned with elimination?

Answer 2

• kidneys
• hepato-billiary system
• lungs

Question 3

what is metabolism of drugs?

Answer 3

when drugs are made more water soluble prior to elimination

enzymatic modification of drug

2 sequential phases: I and II

Question 4

phase I metabolism reactions usually consist of what?

Answer 4

• oxidation
• reduction
• hydrolysis
• cytochrome P450s
• functionalisation
• decrease lipid solubility but may increase pharmacological or toxicological activity

Question 5

what are cytochrome P450s?

Answer 5

• large superfamily of heme cofactor containing enzymes
• often called ‘CYPs’
• metabolise thousands of endogenous and exogenous compounds
• increase water solubility of drugs

Question 6

location of CYPs

Answer 6

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

Question 7

how can functionalisation affect a drug?

Answer 7

• changes the metabolite
• will bind in a different way
• different stereochemistry
• effects how well the drug binds

Question 8

ethanol metabolism

Answer 8

ethanol isn’t metabolised by P450s but by enzyme expression

process predominantly catalysed by alcohol dehydrogenase but also some CYP2E1

Question 9

phase II reactions

Answer 9

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

Question 10

glucuronidation

Answer 10

most common conjugation reaction

important for both endogenous and exogenous compounds

mediated by UDP-glucuronyl transferases - an enzyme system with broad substrate specificity

Question 11

paracetamol metabolism

Answer 11

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

Question 12

what is the toxic intermediary in paracetamol metabolism?

Answer 12

NAPQI

• the more active form of paracetamol
• if too much is produced we see liver damage
• can be detoxified to mercapturic acid by glutathione

Question 13

what happens in paracetamol overdose?

Answer 13

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

Question 14

internal factors affecting drug metabolism

Answer 14

endogenous factors
• genetics
• age
• disease

Question 15

external factors affecting drug metabolism

Answer 15

exogenous factors
• drugs
• smoking/alcohol
• diet

Question 16

genetic factors

Answer 16

a person is either a ‘fast’ or a ‘slow’ metaboliser

can have implications for therapeutic efficacy and/or toxicity of certain drugs

Question 17

fast metabolisers

Answer 17

• normal enzyme activity
• low plasma conc of parent drug
• higher conc of metabolite
• generally normal therapeutic response

Question 18

slow metabolisers

Answer 18

• low enzyme activity
• high plasma conc of parent drug
• low conc of metabolite
• may lead to exaggerated therapeutic response at normal doses

Question 19

how does age affect metabolism?

Answer 19

individuals at extremes of age are affected

neonates (premature)
elderly

Question 20

drug metabolism in neonates

Answer 20

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

Question 21

drug metabolism in the elderly

Answer 21

CYP activity declines with age

more variability of half-life of many drugs
• issues for drug development

Question 22

chemical exposure on a daily basis

Answer 22

• pharmaceuticals
• cosmetics
• food additives
• industrial chemicals
• pesticides
• smoking
• alcohol

these compounds either induce or inhibit drug metabolising enzymes

Question 23

what happens when drug metabolising enzymes are induced?

Answer 23

increased synthesis of enzymes (phase I and II)

results in increased metabolism of inducing agent and other drugs

smoking and ethanol are both inducers

Question 24

implications of induction

Answer 24

decreased drug effectiveness on chronic exposure

need to increase drug dose

may be issues when inducer is withdrawn from regime

Question 25

how is paracetamol metabolism effecting by ethanol consumption?

Answer 25

alcohol increases amount of CYP2E1 which increases amount of NAPQI increases liver damage happens when overdose is involved with alcohol consumption

Question 26

what happens when drug metabolising drugs are inhibited?

Answer 26

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)

Question 27

3 major processes in renal excretion

Answer 27

glomerular filtration tubular reabsorption tubular secretion

Question 28

what happens to water soluble drugs?

Answer 28

excrete unchanged through the kidneys

Question 29

what happens to lipid soluble drugs?

Answer 29

* filtered in the glomeruli * reabsorbed in the distal portion of nephron *  metabolised to more polar compounds * excreted in urine

Question 30

extent of tubular reabsorption depends on...

Answer 30

drug lipid solubility (pKa) pH of tubular fluid

Question 31

what happens if tubular fluid becomes more alkaline?

Answer 31

acidic drugs ionise and becomes less lipid soluble reabsorption diminishes elimination occurs

Question 32

what is pH portioning?

Answer 32

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

Question 33

where are weak bases ionised best?

Answer 33

at acid pH drug gets ionised and can't be reabsorbed

Question 34

where are weak acids best ionised?

Answer 34

at alkaline pH