Drug Elimination II (metabolism and elimination) L6

Question 1

what is elimination

Answer 1

Metabolism + excretion = elimination

Question 2

what are the main elimination systems

Answer 2

kidneys
hepato-biliary system (liver and bile)
lungs

Question 3

what is metabolism

Answer 3

the processes of making a lipophilic drug more water soluble so it can be eliminated easier

Question 4

what type of modification is involved in metabolism and where does it take place
how many phases are there

Answer 4

enzymatic modification in the liver
2 phases

Question 5

describe the metabolism of asprin

Answer 5

phase 1: aspirin is modified by forming hydroxyl group
- asprin to salicyclic acid
- active metabolite
phase 2: salicyclic acid is conjugated to form glucuronide
- salicyclic acid to glucuronide

Question 6

what are the modifications used in phase 1

Answer 6

1. oxidation (most common)
2. reduction
3. hydrolysis

Question 7

which enzyme is mainly involved in phase 1
what is their function

Answer 7

cytochrome P450
introduce/expose a functional group- functionalism
Decrease lipid solubility but may increase pharmacological or toxicological activity

Question 8

what are pro-drugs

Answer 8

drugs that are inactive as the molecule they are taken as and become active once they have undergone P1 reaction

Question 9

outline basic CYP450 reaction

Answer 9

1. cyp450 forms complex with drug
   - needs NADPH to donate electron for this to happen
2. oxygen and more electrons combine with complex to form metabolite
   - uses enzyme NADPH-cyt-P450 reductase

Question 10

ethanol metabolism does not use CYP450
outline ethanol metabolism

Answer 10

occurs in liver
converted to acetaldehyde by 2/3 alcohol dehydrogenase and 1/3 by CYP2E1
with chronic administration, acetaldehyde is converted to acetic acid by alcohol dehydrogenase not acetate
- very toxic

Question 11

what are phase 2 reactions

Answer 11

Conjugation reactions
- functional group serves as a point of attack for conjugation systems
large groups attached e.g.
- glucuronyl,
- sulphate,
- acetyl
further decreases lipid solubility and almost always results in pharmacologically inactive metabolite
conjugate excreted in urine or bile

Question 12

what is the main type of conjugation system

Answer 12

Glucuronidation
- important for both endogenous compounds e.g. bilirubin and exogenous compounds
- mediated by UDP-glucuronyl transferases, an enzyme system with broad substrate specificity- conjugate many compounds
- due to their polar nature glucuronides are usually pharmacologically inactive and rapidly excreted

Question 13

describe paracetamol metabolism

Answer 13

mainly conjugated to form glucuronic acid
- detoxified
some conjugated to form sulfation
- detoxified
Only a minor proportion metabolised by CYP450 to a toxic metabolite

Question 14

what happens during a paracetamol overdose

Answer 14

Pathways of conjugation are saturated and co-factors are depleted and as such more paracetamol is metabolised via CYP450
Toxic metabolite reacts with liver proteins instead of glutathione (depleted)
Tissue damage occurs leading to hepatic necrosis
- phase 2 reactions cant happen only phase 1

Question 15

what type can factors affecting metabolism be

Answer 15

Endogenous:
- Genetics (including epigenetics)
- Age
- Disease
Exogenous:
- Drugs
- Smoking/Alcohol
- Environmental exposure including diet

Question 16

what is bimodal distribution of pharmacokinetic parameters within a population

Answer 16

Frequency distribution curve under the same conditions with drug Y, indicating a bimodal curve typical of a pharmacogenetic alteration
there are two modes

Question 17

explain how genetics affect metabolism

Answer 17

a person can either be a fast or slow metaboliser
this can have implications on therapeutic efficacy and/or toxicity of certain drugs

Question 18

describe fast and slow metabolisers

Answer 18

fast
- normal enzyme activity so have low plasma con of parent drug and a high concentration of metabolite
- have normal therapeutic response
slow
- slow enzyme activity so have high plasma con of parent drug and low con of metabolite
- may lead to exaggerated therapeutic response at normal doses

Question 19

what effects will poor metabolisers have

Answer 19

side effects
- drugs will be presented at higher concentration doses and/or during a greater length of time
- alterations such as mutations, deletions, or polymorphisms with loss of function in enzymes

Question 20

what effects will rapid metabolisers have

Answer 20

no effect
- genomic duplications and gain of function polymorphisms will increase the enzymatic activity, leading to lower active drug concentration (bottom).

Question 21

how does age affect metabolism

Answer 21

neonates (premature)
- low CYP and conjugating activity
elderly
- CYP activity declines slowly with age
- more variability in half-life of many drugs
issues for drug development
- increased half-life of diazepam causing memory impairment

Question 22

how do exogenous factors such as Drugs/Smoking/Alcohol/Chemicals affect metabolism

Answer 22

these compounds either INDUCE or INHIBIT drug metabolising enzymes

Question 23

describe induction of drug metabolising enzyme and their implications

Answer 23

increased synthesis of enzyme results in increased metabolism of inducing agent
- autoinduction
rifampicin, carbamazepine and ethanol act as inducers
chronic exposure to smoking and ethanol also act as inducers
implications
1. decreases effectiveness of drug if chronically exposed
- need to increase drug dose to get same response

Question 24

describe how ethanol acts as an inducer on paracetamol

Answer 24

ethanol induced CYP450 to turn paracetamol into toxic metabolite

Question 25

describe inhibition of drug metabolising enzymes

Answer 25

many drugs inhibit CYP
- Reduced rate of metabolism and increased pharmacological effect
- Basis of several drug-drug interactions e.g. terfenadine and ketoconazole
- A component of grapefruit juice inhibits CYP3A4 and as such inhibits the metabolism of CYP3A4 substrates including terfenadine and nifedipine
- Ethanol acts acutely to inhibit drug metabolism

Question 26

give the types of excretion systems

Answer 26

URINE
Bile
lung
milk
sweat
- biochemical properties of drug determines how it is excreted

Question 27

the rate of excretion from kidney is very
give the rates for penicillin and diazepam

Answer 27

P: cleared rapidly
D: cleared slowly
metabolites are cleared slower than parent compound

Question 28

what are the 3 main processes that take place in renal excretion in the nephron

Answer 28

1. glomerular filtrate
2. tubular reabsorptions
   3.tubular secretion

Question 29

what happens to water soluble drugs/metabolites in the kidneys

Answer 29

excreted unchanged through the kidneys

Question 30

what happens to lipophilic drugs/metabolites in kidneys

Answer 30

filtered in glomeruli, reabsorbed on the distal portion of nephron, metabolism to more polar compounds, excretion in urine

Question 31

describe process of glomerular filtration

Answer 31

most drugs have <20,000 MW so diffuse into filtrate whereas plasma albium is almost completely retained
highly ppb drugs found at lower concentration in filtrate than in plasma e.g. warfarin (98% ppb) concentration in filtrate is 2% that in plasma
- not affected by pH or lipid solubility

Question 32

what does the rate of entry to glomerular filtrate depend on

Answer 32

1. concentration of free drug in plasma
2. molecular weight

Question 33

describe ACTIVE TUBULAR SECRETION

Answer 33

80% of renal blood flow (and thus 80% of drug) passes onto the peritubular capillaries of the proximal tubule

drug molecules transferred to tubular lumen by two carrier systems which can transport against an electrochemical gradient
- most effective mechanism for drug elimination
- ppb is not a barrier to carrier mediated transport
- many drugs share same transporter which can lead to competition

Question 34

what are the two carrier systems

Answer 34

1. acidic drugs and endogenous acids e.g. penicillins, uric acid
2. organic bases e.g. morphine

Question 35

how does passive diffusion affect tubular reabsorption

Answer 35

volume of urine = ~1% of the filtrate
drug concentration increases as water is reabsorbed
highly lipid soluble drugs have high tubular permeability and are slowly excreted
- reabsorbed
highly water soluble drugs have low tubular permeability and concentrate in urine (100x that in plasma)

Question 36

what does tubular reabsorption depend on

Answer 36

Drug lipid solubility (i.e. pKa)
pH of tubular fluid.

If the fluid becomes more alkaline:
Then an acidic drug ionises, becomes less lipid soluble. Thus its reabsorption diminishes.

But a basic drug becomes un-ionised and its reabsorption increases

Question 37

what is pKa

Answer 37

measures the strength of acid/base

Question 38

what percentage of a drug is ionised when its pKa is the same as the pH
explain warfarin

Answer 38

50%
The acidic drug warfarin with a pKa of 5
- when pH is 5, 50% is ionised
- when pH is 7, 99% ionised
- when pH 3, it is unionised- reabsorbed the most

Question 39

when can acids pass and not pass through membrane

Answer 39

can pass when neutral, can’t pass when ionised e.g aspirin
bases can’t pass when ionised either

Question 40

what is pH partitioning

Answer 40

acidic drugs accumulate in basic fluid compartments and visa versa

Question 41

when is ionisation greatest for acids and bases

Answer 41

acids: when in alkaline conditions
bases: when in acidic conditions

Question 42

how does pH partitioning impact excretion

Answer 42

pH partition impacts upon the rate at which drugs permeate membranes and distribution of drug between aqueous compartments
Weak acids accumulate in compartments of relatively high pH, whereas weak bases tend do the reverse

A weak base is more rapidly excreted in acidic urine (the drug is largely ionised and thus not reabsorbed)
A weak acid is more rapidly excreted in alkaline urine

urinary acidification will accelerate excretion of weak bases and vice versa (important in overdose) - ion trapping

Question 43

what are the mechanisms of excretion

Answer 43

physiochemical properties
1. exhalation
- volatile gases
2. urine
- Water-soluble compounds are often eliminated to some degree unchanged in the urine
Also may be excreted in the bile
- Lipid-soluble compounds typically undergo metabolism to more water-soluble metabolites that are then excreted in the urine and/or bile
saturable elimination
- Elimination mechanisms (such as enzymes) are typically not saturated at therapeutic doses of drugs
- Increasing dose will disproportionately increase concentration (linear to non-linear kinetics)