Science of Medicines Week 9 Flashcards
define elimination
the removal of a substance or termination of its biological action
In which two ways does elimination of substances in the body occur?
- metabolism
- excretion
define anabolism
the build-up of compounds
define catabolism
breakdown of compounds
Which organs are responsible for removal of substances?
- liver
- kidneys
- lungs
What are the aims of the phase I and phase II reactions in the liver?
to increase solubility of substances and enhance renal elimination
How do molecules reach the liver?
through the hepatic artery and portal vein
What are the steps of enterohepatic circulation?
- compounds from the liver are secreted into the bile
- most are then reabsorbed in the small intestine
- circulated back to the liver
What do liver enzymes do to lipophilic molecules?
metabolise them to form polar products so they can be excreted in the urine
What are the two stages of liver metabolism?
Phase I and Phase II
What happens in phase I to molecules?
catabolic reactions and introduction of a functional group which adds as a ‘tag’ to provide a point of conjugation for phase II
What are the main mechanisms of catabolism in phase I?
oxidation, reduction, hydrolysis
Which enzymes carry out the phase I reaction?
liver microsomal enzymes from the cytochrome P450 family (CYP enzymes)
What type of molecule does liver metabolism deal with? Why?
mainly applicable to lipid soluble molecules as polar molecules can be excreted at least partly unchanged
How does cytochrome P450 enzymes differ?
they have different..
1. amino acid sequences
2. substrate specificity
3. susceptibility to inducers and inhibitors
define polymorphic form (enzymes)
an enzyme that exist in multiple different forms within the same species
What determines your cytochrome P450 enzymes?
different alleles in your genes -> different amino acid sequences
What does an individuals cytochrome P450 enzymes affect?
the rate of activity of the enzymes, therefore creates differences in side effects and drug response
What happens in phase II?
anabolism and involves the addition of a subtituent group to inactive the compound
What are examples of substituent groups added?
glucuronyl, sulphate, methyl, acetyl
What happens to the product after phase II?
several hydrophilic products are secreted into the bile and delivered to the small intestine where the conjugation is removed and the drug is reabsorbed
What different processes do different enantiomers undergo?
- different pharmacological effects on receptors
- they are metabolised differently
What are the steps of pre-systemic first-pass metabolism?
- food and drugs are absorbed into small intestine and pass into the blood
- the blood is carried to the liver by the hepatic portal vein
- so hepatic microsomal enzymes can metabolise food or drugs before entering systemic circulation
For drugs administered by IV, is a higher or lower dose needed?
lower –> as there is no initial metabolism as drug goes straight into systemic circulation
For patients with less GI motility, is a higher or lower dose needed?
high dose as less absorption of drug into bloodstream
For patients with decreased liver function, is a higher or lower dose needed?
lower as there is less metabolism of the drug and metabolites may be toxic
define prodrug
a drug that is inactive when administered and is only activated when it is metabolised
define single nucleotide polymorphism
a DNA sequence variation with a different single nucleotide at a particular locus
What are the effects of SNPs on CYP450 enzymes?
the different nucleotide sequence may change the amino acid sequence
What do different polymorphic forms of enzymes lead to?
different rates of enzymatic activity and metabolism
fast metaboliser and active drug
higher dose needed
fast metaboliser and prodrug
lower dose needed as increased risk of toxic effect as fast activation
slow metabolisers and active drug
lower dose needed as metabolised slower -> may be toxic
slow metabolisers and prodrug
higher dose needed as prodrug will not be active for long
How are CYP450 profiles of patients roughly determined?
start patients on a low dose of the drug and take blood samples to find the amount of active drug in the blood and increase from there
Do CYP450 inducers make drugs work faster or slower?
faster as they increase the activity of the enzymes so drug is broken down and cleared quicker
What are 3 inducers of CYP450 enzymes?
brussel sprouts, smoking, St John’s Wort
What is an inhibitor of CYP450 enzymes?
grapefruit juice
How do co-administered drugs affect each other?
many drugs can compete as substrates for CYP450 enzymes so affect the metabolism of each other
What do CYP450 enzyme inducers do?
increased the activity of the enzymes, so increase rate of metabolism
What are the drawbacks of enzyme inducers?
- a single co-administered drug may be metabolised too quick reducing its effect
- toxic metabolites will increase
What 3 main factors affect CYP450 enzymes?
genetic polymorphisms, diet and co-administered drugs
What are the 5 main functions of the kidneys?
- regulation of water, salts, acidity
- removal of metabolic waste
- removal of foreign chemicals e.g. drugs
- gluconeogenesis
- production of hormones and enzymes
Name 2 enzymes the kidneys produce
erythropoietin (controls RBC production and renin (controls blood pressure and Na+ balance)
What are the 4 regions of the kidney?
- capsule -> boundary separating it
- cortex -> outer region where nephrons sit
- medulla -> inner region
- pelvis -> feeds into the ureter
What happens in the Bowman’s capsule?
blood is filtered
What happens in the loop of Henle?
main site of water reabsorption
What are the 3 stages of nephron function and filtering by the kidneys?
- glomerular filtration
- tubular secretion
- tubular reabsorption
define tubular secretion
the process by which the kidneys move substances from the blood into the tubules
define tubular rebabsorption
the process by which the kidneys remove water and solutes from the filtrate and return them to the bloodstream
How does the structure of the glomerulus allow for much filtration to happen?
the vessel is ‘bunched up’, so blood spends a long time within the vessel inside the Bowman’s capsule
How are cells in the glomerulus adapted?
the endothelial cells have tiny pores, so are leaky
define podocyte
specialised cells on the outside of the glomerular capillary with many small projections to create sieve like structure
define glomerular filtration rate
the volume of fluid filtered from the glomeruli to the Bowman’s capsule per unit of time
How is the GFR regulated?
by the body adjusting the blood pressure on either side of the glomerulus
How is the glomerular filtration rate reduced?
constrict the afferent arteriole or dilate the efferent arteriole to reduce pressure
How is the glomerular filtration rate increased?
dilate the afferent arteriole or constrict the efferent arteriole to increase the pressure -> increases the excretion of water and salt
Where is Na+ (salt) reabsorbed?
- proximal convoluted tubule
- loop of Henle
- the collecting duct
Which regions does salt go through to be reabsorbed into the blood?
tubule fluid -> tubule cell -> interstitial space -> blood
How does reabsorption of Na+ from the tubule fluid to tubule cells occur (proximal convoluted tubule)?
via cotransporters and counter-transporters
define cotransporter
a membrane protein that moves two different molecules or ions across a cell membrane at the same time in the same direction
define counter-transporter
a membrane protein that moves two or more molecules in opposite directions across a cell membrane
What is the main counter-transporter found at this stage?
Na+ pumped into cell, H+ pumped out
How does rebabsorption of Na+ from the tubule cells to interstitial space occur (proximal convoluted tubule)?
active transport by Na+/K+ ATPase
What is Na+/K+ ATPase?
Na+/K+-ATPase pumps three sodium ions out of the cell into interstitial space and two potassium ions into cell -> Na K pump
How are K+ ions returned to interstitial space (proximal convoluted tubule)?
active transport into cell creates K+ concentration gradient, so they diffuse through K+ channels back into interstitial space
How is Na+ moved from the tubule fluid into tubule cells in the ascending loop of Henle?
using a cotransporter, Na-K-Cl transporter (NKCC)
How does Na-K-Cl transporter work?
Na+ is pumped into tubule cells through contransport with Cl- and K+
How is K+ returned to the tubule fluid?
eventually K+ has a high concentration in the cell and diffuses back into tubule fluid -> this keeps the transporter moving
How does Na+ move from tubule cells to interstitial fluid in the ascending loop of Henle?
Na+/K+ ATPase
How does Na+ move from the tubule fluid into the tubule cells in the collecting ducts?
diffusion
How does Na+ move from the tubule cells to the interstitial space in the collecting ducts?
Na+K+ ATPase moves Na+ into interstitial space and K+ back into cells
What is the hormone that controls rebabsorption of Na+?
aldosterone
What type of hormone is aldosterone?
a steroid hormone
How does aldosterone work?
it changes the number of ion channels and Na+K+ ATPase transporters to change how much salt is moved across
How long does aldosterone take to work?
hours as it is a steroid hormone
Where does water reabsorption occur?
DESCENDING loop of Henle and the collecting ducts
How does water move into the interstitial space in the descending loop of Henle?
- the descending loop is permeable to water, so it can freely move into the interstitial space
- reabsorbtion of salt occurs at the ascending loop, so creates a hypertonic solution (high salt concentration) in the interstitial fluid surrounding the loop of Henle
- this causes water to diffuse out of the descending loop of Henle by osmosis
How does countercurrent flow work in the loop of Henle?
- blood flow around the loop of Henle is counter to flow through the loop of Henle
- the freshly filtered blood (low in salt) goes next to ascending LOH first, encouraging salt reabsorption
- the salt-rich blood circulates around descending loop
- so water is reabsorbed into the blood
- maintains concentration gradient
How is water absorbed into the collecting ducts?
diffusion through aquaporins as the interstitial space will be full of salt from Na+ reabsorption
Which hormone controls water re-absorption?
vasopressin
What type of hormone is vasopressin?
a protein that acts on g protein-coupled receptord
How does vasopressin work?
causes vesicles with aquaporins to fuse with plasma membrane of tubule cells, increasing water reabsorption
Why is the action of vasopressin much quicker than aldosterone?
vasopressin has aquaporins already made in vesicles, aldosterone involves making more transporters
What are the 3 functions of the nephron?
glomerular filtration, tubular secretion, tubular rebabsorption
What is the equation for ‘amount excreted’ from the kidneys?
amount excreted = (amount filtered + amount secreted) - amount reabsorbed
How do the kidneys regulate body pH?
the kidneys regulate HCO3- levels, therefore regulate pH
Equation for carbonic acid
CO2+ H2O -> H2CO3 -> HCO3- + H+
How do the kidneys make sure net gain/loss of carbonate is 0?
- carbonate is freely filtered into tubules from the blood
- carbonic acid made in tubule cells breaks down into H+ and HCO3-
- the H+ is transported to the tubules, where it combines with filtered HCO3- to form carbonic acid and break down into CO2 and H2O
- the HCO3- from the tubule cells is reabsorbed into blood
- HCO3- reabsorbed into the blood replaces that filtered, so NO net loss or gain
Which 2 ways do the kidneys increase HCO3- levels?
H+ secretion and glutamine metabolism
How does H+ secretion increase HCO3- levels?
- carbonic acid in tubule cells breaks down into H+ and HCO3-
- H+ moves into tubule and combines with filtered phosphate instead of carbonate and is excreted
- HCO3- is transporter into bloodstream
- increased of HCO3-
How does glutamine metabolism increase HCO3- levels?
- the amino acid glutamin enters tubule cells either from the blood or filtrate
- it is metabolised to NH4+ and HCO3-
- ammonia is secreted into the tubules to be excreted
- HCO3- is transported into the body
- net gain of HCO3-
define acidosis
when the body gains hydrogen ions and pH decreases becoming more acidic
define alkalosis
when the body loses hydrogen ions and pH increases becoming more alkali
How does the body respond to acidosis?
- lots of H+ is secreted into the tubules as there is too much in the body
- H+ ions react with filtered HCO3- and H2PO4- to cause reabsorption
- glutamine metabolism is increased to generate more HCO3- to react with H+
How does the body response to alkalosis?
- less H+ entering the tubules
- H+ secretion into tubules cannot keep up with filtered HCO3-
- so excess HCO3- will be excreted to lose carbonate, allowing H+ to increase and lower the body’s pH
- glutamine metabolism is decreased to reduce HCO3- generation so there are more H+ ions around
How does urine play a role in drug excretion?
- in alkaline urine, acidic drugs will be ionised
- in acidic urine, alkaline drugs will be ionised
- ionised drugs are less likely to be reabsorbed, so more is excreted
How is aspirin poisoning treated?
- patient is given an IV infusion of sodium bicarbonate, increasing pH of the urine
- the active metabolite salicylic acid becomes ionised, reducing its rebabsorption
- aspirin is excreted quicker, lowering the plasma concentration
