Drug Elimination - Metabolism and Excretion Flashcards
What is Drug metabolism ?
is the biochemical modification of substances , in this case drug which is performed by specialist enzymes.
What is another term for drug metabolism ?
Xenobiotic Metabolism.
What is the ultimate aim of metabolsim?
most drugs are lipophilic which makes it difficult to excrete so metabolism converts them into hydrophilic molecules which will help the drug be excreted into the urine.
As drugs are metabolised the therapeutic effect decreases , is this true?
Yes for some drugs however there are some drugs will becomes active only after metabolism occurs - these are called prodrugs.
What are the products of the chemical reactions that take place in metabolism
Metabolites
Explain the two ways in which drug metabolism can be bought about by?
- Specialist Mechanisms - if drug is similar to another substance already in the body like a neurotransmitter the it will be broken down by specialist mechanisms eg - adrenaline = monoamine oxidase
- General Mechanisms - most drugs metabolised by enzymes present in the smooth endoplasmic reticulum of the liver.
What is microsomal metabolism
To reach SER of liver drugs need to be lipophilic = the products of the reaction = hydrophilic = process known as MM.
Where in the body is main site for drug metabolism?
Liver
- highly metabolically active
- large organ size
supplied with blood which contains most of absorbed drug from GI tract via hepatic portal system
- high conc of enzymes compared to other parts of the bosy.
State other sites of metabolism in the body
Wall of intestines
lungs
kidneys
plasma
What do you know about the liver?
- 1.5kg
- 4 lobes of unequal size and shape
- overlies the gallbladder which stores bile synthesized by liver
Where does the liver receive blood from?
oxygenated blood via hepatic artery
deoxygenated via hepatic portal vein.
blood drains from the liver by the
hepatic vein
Liver is made up of …
collection of hepatic lobules
Describe structure of a lobule
hexagonal
have central vein which leads ot hepatic vein - carry blood away from liver
each corner of lobule there are collection of structures
In each corner of lobule there are collection of structures - State what they are
branch of hepatic artery branch of hepatic portal vein bile duct lymphatic vessels branch of vagus nerve
what is a sinusoid
channels (enlarged capillaries)running through the lobule
blood flows from hepatic portal vein and artery in the corners of lobules draining it into the central vein
What surround the sinusoids
liver cells - hepatocytes
what is the main function of the smooth endoplasmic reticulum
biosynthesis of the phospholipids and cholesterol
hepatocytes - metabolism because it contains large amount of enzyme family - cytochrome p450
How many phases f metabolism are they and what are they names
two phases 1. Functionalisation includes oxidation , reduction hydrolysis 2. Conjugations with charged species
What is the purpose of phase 1 reactions
exposing or introducing a functional group - such as hydroxy; , amino or carboxyl
this will increase reactivity of the drug and slightly increase the hydrophilicity
What is the purpose of phase 2 reactions
metabolites are conjugated with charged species such as sulphate , glycine, glucuronic acid which will strongly increase hydrophilicity
attachment of ionised group will make it more water soluble
What is oxidation ?
- most common phase 1 reaction
- its the addition of a single o2 atom to drug moecule to form an OH(hydroxyl group)
- catylsed by cytochrome p450 in liver
- omeprazole ( used in tx of gastric disease)
- o2 split - one added to substrate and one combined with hydrogen to produce water
What does oxidation require to take place
molecular oxyGen and NADPH nicotinamide adenine dinucleotide phosphate
Where is cytochrome p450 located
within cells - mitochondria or ER
define cytochrome p450
cytochrome - coloured intracellular protein
450- contains heme pigment which absorbs light at 450nm when exopsed to co2
cytochrome p450 account for how much of the bodies metabolism
75%
Reduction reaction are catalysed by which system and in which conditions is this most likely to occur
p450
anaerobic respiration
Hydrolysis reaction are catalysed by …
Esterases and Amidases
What is hydrolysis ?
splitting of drug molecule by addition of water
Where does hydrolysis take place
plasma and tissues - small intestines mainly
what is the name of the enzymes that carry out phase 2 reactions
transferases
what is the name of the most common type of conjugation reaction
glucoronidation
State some names of groups that are coupled to parent drugs or phase 1 metabolite
glycine acetyl glucoronide glutathione sulphate methyl amino acid
paracetamol is also known as
aceteminophen
what is a common cause of acute hepatic failure
paracetemol overdose
Briefly explain what occurs when paracetamol is taken under normal doses
converted into non toxic metabolites by phase 2 metabolism
conjugation reactions occur with sulphate and glucoronide
small amount metabolised to create highly reactive intemediate metabolite known as NAPQI
UNDER NORMAL - napqi IS CONJUGATED WITH GLUTATHIONE
What happens when paracetemol overdose occurs
sulphate and glutathione pathways becomes saturated
only other route to metabolise is to produce more NAPQI
all of glutathione will be used up
NAPQI will begin damaging the cells of liver
how can you stop NAPQI damaging the cells of the liver
administer acetylcysteine which helps restore availability of glutathione
State factors which will affect drug metabolism
enzyme inducer enzyme inhibitor age nutrition liver disease genetic variation
What ids genetic polymorphism
inherited differences in the structures of the enzymes responsible for metabolism
state two reasons why the first pass effect can be problematic
1 - larger doses needed orally than by other routes
2. big variation in extent of first pass effect - unpredictable
what is a prodrug?
pharmacologically inactive when administered - remains like this until metabolised
State some reasons why prescribing a prodrug may be appropriate
Related to solubility
Ensure duration of action is enhanced
Toxicity problems
drug needed to work at specific site
give an example of a prodrug
Enalapril - enalaprilat
What is excretion?
removal of a drug and its matabolites from the bosy
what organ is responsible for excretion
kidneys
state other routes available for excretion
saliva
breastmilk
draw a simple illustration of the urinary system with labels
notes
where does the kidney receive its blood supply from
renal arteries which branch from abdominal aorta
state the role of the kidneys
filter blood
production of urine
regulate Ph of blood and regulate blood pressure
remove organic molecules form blood
what part of the kidneys form an important part in the formation of urine
nephrons
85% - cortical nephrons located near cortex
15% juxta medullary nephrons - cortex medulla junction
draw and label an image of kidney
notes
draw , label and explain how a nephron functions
notes
what restricts the passage of large molecules into the bowmans capsule
epithelial cells
Blood arrives at the nephron via the
afferent arteriole
What percentage of the plasma is filtered through the glomerulus
20%
what are the names of the two systems that transfer the drug molecules into tubules
basic drugs
acidic drugs
Active secretions is …
against the conc gradient
What is passive reabsorption
drugs enter tubules but reabsorbed back into the blood
no energy required
diffusion
basic drugs will be excreted in
acidic urine because low ph conditions favour ionisation of drug making it difficult to be reabsorbed
acidic drugs will be excreted in
alkaline urine
Renal excretion of drugs is affected by
molecular weight of drug solubility of drugs Kidney disease renal blood flow Age Plasma protein binding Dehydration
what would cause drugs to be excreted via the faeces
if it wasnt absorbed following administration
enterohepatic circulation
Notes
