Metabolism and Excretion Flashcards
define elimination
irreversible loss of drug from the body
metabolism
conversion of a drug to a metabolite
excretion
removal of drugs (chemically unchanged or metabolites) from the body
main site of metabolism
liver
main site of excretion
kidney
aim of metabolism
to make drug more water soluble and polar to be easily excreted.
if the drug is already polar…
doesnt need changing
what is a prodrug and give an example
inactive when administered but made more active by metabolism in the liver
e.g., aspirin is converted to salicylic acid.
first pass effect
occurs for oral drugs and is when drugs are metabolised by the liver after entering the gut by the hepatic portal vein. This reduces the drug available in the systemic circulation so there is a decrease in bioavailability.
Gut -> Hepatic portal vein -> liver
where else can first pass metabolism occur
in the gut by gut enzymes and the microbiota.
bypassing first pass effect
giving the drug by sublingual and buccal routes.
enterohepatic circulation
when drugs are metabolised by liver and bile and enter the gut but then reenter the liver for metabolism
compounds undergoing enterohepatic circulation
hormones eg oestrogen, NSAIDs
what do Abx do in relation to enterohepatic circulation
antibiotics that kill gut bacteria often reduce enterohepatic drug circulation and this requires a temporary increase of the drug’s dose until the antibiotic use is discontinued and the gut repopulates with bacteria.
do the 2 phases of drug metabolism act sequentially or independently
both
what are the phases of drug metabolism in the liver
Phase I
-Functionalisation reactions.
-Examples include oxidation, reduction and hydrolysis.
-Primarily mediated by CYP enzymes: 3A4, 2D6, and 1A2.
-Aim = make drug more water soluble so it be easily excreted by the liver
Phase II
-Detoxification reaction by conjugation
-Aim = Sometimes the metabolites from phase I are more toxic so phase II removes this and makes drug even more water soluble if needed.
-Examples include acetylation, methylation and sulfoconjugation, glucuronidation.
-Must have amino, hydroxyl or thiol group for conjugate to attach to.
what 3 groups do conjugates attach to in phase II
amino, hydroxyl or thiol
metabolism of aspirin
Phase I = hydrolysis to salicylic acid by esterases
Phase II = glucuronidation by UGT (UDP-glucuronosyltransferases)
why is aspirin administered and not salicyclic acid
because it causes GI irritation
more about CYP enzymes
450 nm wavelength.
family of haem containing monooxygenases.
Lungs have CYP enzymes and some are more highly expressed in lungs than liver e.g. enzymes capable of prostenoid metabolism
inhibition/induction of CYP enzymes:
grapefruit juice inhibits CYP3A4
St johns wort, cigarettes and brussel sprouts induce CYP3A4.
other phase I enzymes apart from CYP
Monoamine oxidase – inactivates biologically active amines
gut has microbiota and gut enzymes
alcohol is metabolised by alcohol dehydrogenase and aldehyde dehydrogenase and CYP2E1.
What does long term alcohol exposure do to the alcohol metabolising enzymes?
Acetaldehyde (metabolite of alcohol dehydrogenase) causes liver toxicity. Body deals with it by increasing expression of alcohol dehydrogenase. This increases the body’s tolerance to alcohol. Alcohol also damages liver.
list all the phase II reaction examples
glucuronidation
acetylation
methylation
amino acid conjugation
sulfoconjugation
Glutathione S-conjugation
2 examples of phase II reactions detailed
acetylation:
- Involves the transfer of acetyl moieties.
- Uses the N-acetyltransferases (NATs) e.g., NAT1, NAT2 which are expressed in the liver, bladder and placenta.
- Population can be divided into slow or fast acetylators.
glucuronidation:
-40-70% of drugs are metabolised like this
-Uses the UGTs (UDP-glucuronosyltransferase) enzyme
-Conjugation of UDP-hexose to a nucleophilic atom such as O, N, S, C
-products are secreted in bile and excreted in urine.
What happens if 2 drugs are taken by a patient which are metabolised by the same enzymes?
+If one drug enhances the metabolism of the other, it could reduce the therapeutic efficacy of the latter.
+If the metabolic pathway is overwhelmed or if the drugs are eliminated more slowly, there is an increased risk of drug accumulation in the body, potentially leading to toxicity.
prodrug example
codeine.
- Codeine is an analgesic and is inactive in itself. Oxidatively demethylated by CYP2D6 to produce morphine.
- 80% of codeine is converted to morphine-6-glucuronide by glucuronidation. 60% of the analgesic effect of codeine is because of this compound.
- 15% is converted to norcodeine.
- Less than 5% is converted to morphine.
factors affecting drug metabolism rates
genetics
age
liver disease
heart failure (less blood perfusion)
drug interactions
Why might heart failure affect drug metabolism?
Congestive heart failure is associated withhypoperfusion to various organs including the sites of drug clearance, i.e. the liver and kidneys. It also leads to organ congestion as seen in the liver and gut.
different excretion routes
faeces - hepatobiliary system
urine - kidneys
air - inhalation
Sweat
Bile
Saliva
Tears
Breast Milk.
where does metabolism occur within the liver
sinusoids are lined with hepatocytes (where it occurs).
divisions of liver
lobes - lobules - sinusoids
nephrons are divided into
cortical - rest (renal cortex)
juxtamedullary - 12% (have glomeruli in junction between medulla and cortex)
role of kidney
maintain composition and vol of blood. urine is a byproduct
how much urine output
1.5L
first order vs zero order kinetics
First order:
-constant proportion of drug eliminated per time
-exponential
-metabolism can keep pace with drug concentration.
-enzymes are not saturated
-specific half life
Zero order:
-fixed amount of drug eliminated per time
-linear
-enzymes are saturated
-no specific half life
mixed order kinetics
in reality, mixed order kinetics occurs.
- At high concentrations metabolism may be zero order, when the system can be saturated
- As drug concentration decreases it may display first-order kinetics (so no longer working at maximum capacity)
steady state vs loading dose
Steady state = occurs within 3-5 half lives after repeated dosing of drugs. But for conditions which need rapid treatment a loading dose may be given.
3 steps of kidney excretion
1) Glomerular filtration
2) Tubular secretion
3) Tubular reabsorption
glomerular filtration process
-glomerulus acts like a sieve.
-first interface between the blood and kidneys.
-site of filtration
-fluid is driven from the capillaries by hydrodynamic force.
-molecules smaller than 20kDa pass through but anything bigger has trouble.
-limit 30-60kDa.
-excludes RBC and large proteins.
-forms primary urine/clear filtrate
-plasma proteins such as albumin don’t pass through which is why the efferent arteriole has higher plasma conc. than the afferent.
what percentage of renal blood is filtered through the glomerulus
20%
what percentage of renal blood is filtered through the tubules
80%
tubular secretion
-involves transporters which can become saturated.
-OAT anion = acidic
-OCT cation = basic
penicillin and OCT
penicillin is transported into tubule by an OCT and is rapidly excreted into urine. to prolong half life of penicillin, probenecid is administered as it competes for the same OCT.
What is the consequence of drugs competing for transporters?
reduce the uptake of a drug into target cells or tissues, decreasing its therapeutic efficacy.
can lead to higher concentrations of drugs in certain tissues or organs, potentially increasing the risk of toxicity.
tubular reabsorption
-some drugs are reabsorbed back into the bloodstream.
-passive diffusion so no ATP
-as water is reabsorbed some drugs are reabsorbed with it.
-drugs with high lipid permeability are poorly excreted.
what is ion trapping
- inhibit reabsorption of drugs across the renal tubular membranes = “captures” the drug in the urine, where it is expelled in its ionisedstate = basic drugs are more rapidly excreted in acidic urine.
For example, in cases of phenobarbital overdose — a weak acid — treatment with bicarbonate is used to alkalinise the urine. This action ionises the drug, impeding its reabsorption. The ionised form of the drug is not able to be reabsorbed across the renal tubule into the bloodstream.
how does the pH of a drug and urine affect excretion?
drug ionization changes depending on the alkaline or acidic environment. Increased excretion occurs with weakly acidic drugs in basic urine and weakly basic drugs in acidic urine.
define clearance
rate of elimination from plasma
renal clearance formula
CL (renal) = conc (urine) x vol (urine)/conc (plasma)
Vd
volume of distribution = Concentration of Drug in the Plasma/Amount of Drug in the Body
ratio
bioavailability
% of drug in systemic circulation and available for bioactivity
bioequivalence
comparison of different drug formulations/brands at same conc.
T1/2
elimination half life= time taken for plasma conc to fall by 50%
what is the consequence of reabsorption of drugs?
increases drug half life and can cause toxicity
loading dose?
quickly achieve therapeutic drug concentrations or prompt an immediate clinical response. A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life.
