Wk 21 Flashcards
Oxidised substances=
Reduced substances=
Lose electrons/ energy
Gain electrons/ energy
Free radical=
Have an unpaired electron in outer shell which makes them very unstable and reactive and want to steal an electron from another atom (but this makes that atom a free radical)
What is ROS?
What are ROS derived from?
What does excess ROS oxidise?
Reactive oxygen species (free radicals and peroxides)
Derived from metabolism of O2
oxidizes protein/ lipids/ DNA
How is iron related to ROS?
It catalyzes the reaction that forms ROS
Antioxidants=
What are the main antioxidants from diet?
What is the main antioxidant in the body?
a substance that inhibits oxidation or reactions promoted by oxygen, peroxides or free radicals
Vitamin A, C, E
Glutathione (GSH)
How does the liver detoxify?
(What cells remove forgein material from blood?)
Where does the liver remove waste to?
Cytochrome P450 enzymes convert toxic insoluble compounds into less toxic water sol metabolites that can easily be excreted
Kupffer cells
Gall bladder and kidneys
How does the liver clean the blood?
Kuppfer cells= phagocytic macrophages digest bacteria and other foreign matter in blood
What does the liver synthesize? (6)
Acronym to help remember
What does the liver store? (4)
Acronym to remember
Synthesis= Look left, go back, point up
Lipids (cholesterol, TGs, ketone bodies) Lipoproteins (VLDL) Glucose Bile Proteins Urea
Store= Give fat men (a) try
Glycogen
Fat sol vitamins (D,E,A,K) and vit B12
Metals (iron/ copper)
Triglycerides
What is dangerous about a vit K deficiency?
How does warfarin work?
Can’t ‘K’lot (clot) without vit K so increased risk of haemorrhage
it is an anticoagulant that antagonises the activity of vit K
What are the proteins made by the liver?
5
Albumin (main liver protein) and other carrier proteins
Haemostasis proteins (clotting)
Hormones and prohormones
Apolipoproteins
Enzymes (cytochrome P450)
Bile proteins
What is the main protein in the blood plasma?
What is a marker of liver damage?
What is the most important function of this protein?
What are 6 other cool functions of this protein?
(acronym)
Albumin
Serum albumin
regulate the oncotic pressure of the blood
(To brilliant Albumin, what a duuuude) Transport Buffering Anticoagulant Wound healing/ inflammation Antioxidant Detoxification
How does the liver breakdown/ catabolize Amino Acids?
First step= removal of amine group
Carbon skeleton –> ketoacid–> metabolism
Nitrogen skeleton portion -> ammonia (ammonia converted to less toxic form, urea, in liver)
What is transamination?
What is deamination?
Transfer of amino group from an amino acid to a keto acid (generates a new non-essential AA)
The removal of the amine group as ammonia (ammonia then converted to less toxic form, urea, in liver)
What is urea?
waste product formed from protein breakdown
What is pharmacokinetics?
what the body does with a drug
ADME
(picture a tic tac going through body)
What are xenobiotics?
Examples?
Forgein substances not natural to body (drugs, food additives, processed food, cosmetic products etc)
What is bioavailability?
Fraction of administered drug that reaches systemic circulation
What is the aim of metabolism?
Make drug less active and more hydrophilic
What are the 2 main classes of metabolism?
Phase 1: oxidation, reduction, hydrolysis of drug
Phase 2: conjugation of drug (or phase 1 product) with another molecule
Describe phase 1 of metabolism:
Add functional groups such as: -OH, -COOH, -SH, -O, or NH2 to alter biological properties of drug (usually drug inactivation and makes it more water sol so can be excreted)
Also prepares drug for conjugation to functional group
What are 3 types of enzymes in phase 1 and what do they do?
- haem protein mono-oxygenases cytochrome P450 (CYP) enzymes= mixed function oxygenases
- flavin-containing monooxygenases (FMO)
- Epoxide hydrolases (EH)
What enzymes do 75% of all drug metabolism?
CYP enzymes
How do CYP enzymes work?
Drug binds to oxidised Fe CYP to form complex
NADPH donates electrons to create reactive oxygen atom and this reactive oxygen atom transferred to drug
This results in oxidised drug product plus water
What is Phase 2 metabolism?
Attachment of substituent group (GST, NAT, SULT, TPMT) to make it very soluble in water
(faster than phase 1 oxidation)
What happens to drug’s therapeutic efficacy if…
Drug is metabolised too quickly?
Too slowly?
Lose therapeutic efficacy
increased therapeutic efficacy or adverse drug reactions or toxicity
What happens if drug A and drug B are metabolised by the same enzyme?
They compete for enzyme -> drug plasma levels are determined by which drug binds to enzyme with higher affinity (or which drug has higher conc)
What is an example of drug A inhibiting an enzyme involved in the conversion of prodrug B to drug B (causing less formation of drug B)?
PPI Omeprazole inhibits CYP enzyme which is needed for antiplatelet drug to activate so taken together= increased risk of thrombus formation
What happens when xenobiotics and drugs activate transcription and induce expression of genes encoding drug-metabolising enzymes? (2)
Can induce its own metab
Can induce metab destruction of other drugs
What antibiotic induces transcription of CYP 3A4 which increases metabolism of contraceptive pill (making it ineffective)
Rifampicin
What can happen if there are polymorphisms or mutations in gene encoding a metabolic enzyme?
Can enhance, reduce or eliminate enzyme activity (so changes in plasma levels of drug)
What is the metabolism of opiods?
codeine prodrug converted by CYP2D6 into morphine
What are the different steps of alcohol metab?
Ethanol absorbed in mouth, stomach and SI
Ethanol metabolised in liver by sequential hepatic oxidation
- First to acetaldehyde by alcohol dehydrogenase
Then to acetic acid by aldehyde dehydrogenase
(then to Acetyl CoA, then Fatty Acids)
What is acetaldehyde and why is it bad to have excess?
It is a reactive and toxic compound
Excess= flushing, tachycardia, hyperventilation and considerable panic and distress (and nausea because CTZ activated)
How is paracetamol metabolised…
Primarily which phase?
Normal Metabolism:
If conjugation saturated:
In overdose:
Predominantly in phase 2
Normal: non-toxic conjugates are added (glucuronide and sulfate conjugates) and then excretion in urine
Conjugation saturated: CYPs make toxic metabolite (NAPQI) which binds to glutathione so it can be excreted in urine
In overose: glutathione depletion so NAPQI increases -> cell death and hepatic necrosis
What does N-acetylcysteine (NAC) do?
Increases glutathione synthesis in liver (so helps NAPQI get excreted in urine)
What are the 4 stages of liver cirrhosis?
Normal -> Inflamed -> Fibrotic -> Cirrhotic
High levels (outside of the hepatocytes) of what enzymes indicate significant liver cell damage:
Transaminase enzymes:
- Alanine aminotransferase (ALT) [lard/ viral]
- Aspartate aminotransferase (AST) [scotch]
What is cholestasis?
Buildup of bile in liver because blockage to bile flow
What is hyperbilirubinemia?
Jaundice
What is pruritis?
Itchy skin due to: Increase in bile salts
What are 4 common clinical signs of cirrhosis?
Palmar erythmia
Spider hemangiomas/ naevi
Ascites (fluid in abdomen)
Finger clubbing
