Drug Elimination II (metabolism and elimination) L6 Flashcards
what is elimination
Metabolism + excretion = elimination
what are the main elimination systems
kidneys
hepato-biliary system (liver and bile)
lungs
what is metabolism
the processes of making a lipophilic drug more water soluble so it can be eliminated easier
what type of modification is involved in metabolism and where does it take place
how many phases are there
enzymatic modification in the liver
2 phases
describe the metabolism of asprin
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
what are the modifications used in phase 1
- oxidation (most common)
- reduction
- hydrolysis
which enzyme is mainly involved in phase 1
what is their function
cytochrome P450
introduce/expose a functional group- functionalism
Decrease lipid solubility but may increase pharmacological or toxicological activity
what are pro-drugs
drugs that are inactive as the molecule they are taken as and become active once they have undergone P1 reaction
outline basic CYP450 reaction
- cyp450 forms complex with drug
- needs NADPH to donate electron for this to happen - oxygen and more electrons combine with complex to form metabolite
- uses enzyme NADPH-cyt-P450 reductase
ethanol metabolism does not use CYP450
outline ethanol metabolism
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
what are phase 2 reactions
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
what is the main type of conjugation system
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
describe paracetamol metabolism
mainly conjugated to form glucuronic acid
- detoxified
some conjugated to form sulfation
- detoxified
Only a minor proportion metabolised by CYP450 to a toxic metabolite
what happens during a paracetamol overdose
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
what type can factors affecting metabolism be
Endogenous:
- Genetics (including epigenetics)
- Age
- Disease
Exogenous:
- Drugs
- Smoking/Alcohol
- Environmental exposure including diet
what is bimodal distribution of pharmacokinetic parameters within a population
Frequency distribution curve under the same conditions with drug Y, indicating a bimodal curve typical of a pharmacogenetic alteration
there are two modes
explain how genetics affect metabolism
a person can either be a fast or slow metaboliser
this can have implications on therapeutic efficacy and/or toxicity of certain drugs
describe fast and slow metabolisers
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
what effects will poor metabolisers have
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
what effects will rapid metabolisers have
no effect
- genomic duplications and gain of function polymorphisms will increase the enzymatic activity, leading to lower active drug concentration (bottom).
how does age affect metabolism
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
how do exogenous factors such as Drugs/Smoking/Alcohol/Chemicals affect metabolism
these compounds either INDUCE or INHIBIT drug metabolising enzymes
describe induction of drug metabolising enzyme and their implications
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
describe how ethanol acts as an inducer on paracetamol
ethanol induced CYP450 to turn paracetamol into toxic metabolite
describe inhibition of drug metabolising enzymes
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
give the types of excretion systems
URINE
Bile
lung
milk
sweat
- biochemical properties of drug determines how it is excreted
the rate of excretion from kidney is very
give the rates for penicillin and diazepam
P: cleared rapidly
D: cleared slowly
metabolites are cleared slower than parent compound
what are the 3 main processes that take place in renal excretion in the nephron
- glomerular filtrate
- tubular reabsorptions
3.tubular secretion
what happens to water soluble drugs/metabolites in the kidneys
excreted unchanged through the kidneys
what happens to lipophilic drugs/metabolites in kidneys
filtered in glomeruli, reabsorbed on the distal portion of nephron, metabolism to more polar compounds, excretion in urine
describe process of glomerular filtration
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
what does the rate of entry to glomerular filtrate depend on
- concentration of free drug in plasma
- molecular weight
describe ACTIVE TUBULAR SECRETION
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
what are the two carrier systems
- acidic drugs and endogenous acids e.g. penicillins, uric acid
- organic bases e.g. morphine
how does passive diffusion affect tubular reabsorption
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)
what does tubular reabsorption depend on
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
what is pKa
measures the strength of acid/base
what percentage of a drug is ionised when its pKa is the same as the pH
explain warfarin
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
when can acids pass and not pass through membrane
can pass when neutral, can’t pass when ionised e.g aspirin
bases can’t pass when ionised either
what is pH partitioning
acidic drugs accumulate in basic fluid compartments and visa versa
when is ionisation greatest for acids and bases
acids: when in alkaline conditions
bases: when in acidic conditions
how does pH partitioning impact excretion
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
what are the mechanisms of excretion
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)
