Pharmacological changes of dysfunctional hepatic system Flashcards
Where do drug-drug interactions occur?
the liver
how are drugs metabolised?
- enzyme mediated modification of chemical structure of a molecule
- primary purpose is to make fat soluble chemicals water soluble
- then drug is removed from systemic circulation
Consequences of drug metabolism?
- metabolite can be more active than parent product
- metabolite can be toxic
- metabolite can be carcinogen
Where does metabolism occur?
liver is the main organ but nearly all tissue have the capacity to metabolise.
When does SI metabolism come in handy?
For metabolising orally ingested chemicals
How many reactions/steps are involved when dealing with a drug with many metabolites?
- phase I
- phase II
- phase III
What happens during phase I reactions?
- parent compound is converted into a chemically active more polar metabolite through adding or masking functional groups. This is to enable it to be excreted.
- Reactions are oxidative and CYP-mediated.
What happens during phase II reactions?
- conjugation of parent compound with endogenous substrate (e.g. glucoronide, sulphate, amino acid etc) to increase aqueous solubility. –The metabolites produced are usually inactive.
- Three key enzymes for this phase: Glucuronyl transferases, Sulfotransferases, Glutathione-S-Transferases
What happens during phase III reactions?
-Efflux of metabolites and sometimes unchanged parent molecule into bile and urine.
Which part of the body is responsible for most Phase I biotransformations(reactions)?
The haem-containing proteins in the smooth ER
Factors that affect drug metabolism?
- physico-chemical factors (drug structures)
- Biological factors (age, gender, genetics, state of health)
- Environmental factors (diet, drug-drug interactions, stress, season)
During drug-drug interactions drug A can competitively inhibit Phase I metabolic enzyme (CYP450). What does this mean for drug B?
It means it won’t be able to interact with CYP450 so drug A is reducing the clearance of drug B which will increase drug B toxicity
If Drug A induces the expression or activity of phase I metabolic enzymes, what does this mean for drug B?
it increases the elimination of drug B. But also increase the production of toxic drug B metabolites
If drug A alters the metabolic route of drug B, what will happen?
-different metabolites will be formed and their clearance will be altered resulting in toxicity
How can drug interactions affect the pharmacokinetics of a drug?
one drug can alter the rate/extent of ADME of another drug.
How can drug interactions affect the pharmacodynamics of a drug?
one drug can change a patients response to another drug without altering the drugs pharmacokinetics
Ways that drugs interefere with each other’s pharmacodynamics?
- potentiation/antagonism at target receptor or off-target receptor.
- alteration of fluid/electrolyte environment
- interference with transport mechanism
How can drug interactions affect the pharmaceutics of a drug?
interactions occurring before systemic administrations e.g. mixing drugs in IV fluid.
How can drug interactions affect the absorption of a drug?
One drug alters the absorption of another drug via:
- changing GI pH
- binding in GI tract
- changing GI motility
- Malabsorption caused by drug
How can drug interactions affect the excretion of a drug?
Drug A can increase or decrease the excretion of drug B.
How are metabolic enzymes induced?
CYP substrates induce CYP transcription. More CYP produced as a result, therefore drug metabolism increases.
Induction is specific for one or only a few CYPs. (slide 21 for which CYPs are induced by which substrate)
Drugs that commonly inhibit CYPs?
- macrolide antibiotics
- antifungal agents
- HIV protease inhibitors
- St John’s Wort
Explain the drug-drug interaction between St John’s Wort and warfarin?
- St John’s Wort binds to CYP3A4 inhibiting warfarin from binding
- results in increased blood warfarin levels
- this increases prothrombin time
- results in spontaneous bleeding
Where else in the body can CYP3A4 be found besides the liver?
in the mucosa small intestines
What type of juice can inhibit CYP3A4?
Grapefruit juice
describe the 1st pass metabolism of felodipine and its interaction with grapefruit juice?
extensive metabolism of felodipine in intestinal enterocyte by CYP3A4 and further metabolism in liver. overall reduction in the bioavaiability of the drug.
-Grapefruit juice inhibits CYP3A4 in intestines so bioavailability of drug will increase as less is metabolised.
how is alcohol metabolised in the body?
- alcohol dehydrogenase initiate detoxification of alcohol to acetaldehyde
- acetaldehyde dehydrogenase converts acetaldehyde to acetic acid (harmless)
What drug inhibits acetaldehyde dehydrogenase and what is the consequence of this inhibition?
- Disulfiram
- consequence of this is a build up of acetaldehyde in the system and acetaldehyde is responsible for hang-over symptoms.
4 ways drugs can induce liver injuries?
- direct hepatocyte damage
- mitochondrial toxicity
- metabolite activity
- cholestasis
What is the periportal region of the hepatocyte(zone 1)?
- point of highest oxygenation with most O2 coming from hepatic artery and rest from deoxygenated blood of portal vein.
- least sensitive to ischaemia
- specialised for oxidative function
- most susceptible to viral hepatitis.
What is the centrilobular region of the hepatocyte(zone 3)?
- point of lowest oxygenation
- affected during ischaemia
- major role in glycolysis, lipogenesis, CYP450 drug detoxification.
Factors that can cause Drug Induced Liver Injuries (DILI)?
- drug toxicity
- higher dose
- chemically active drug metabolites
- genetic polymorphism
what is targeted in order to cause mitochondrial toxicity?
ATP synthesis is inhibited which results in failure to generate ATP to sustain cells and tissues.
-also results in changes to glucose and lipid homeostasis.
Where does Mitochondrial impairment typically affect?
- most aerobically active tissues
2. tissues exposed to high drug concentrations
How do tissues respond to mitochondrial failure?
- increases glycolysis resulting in increased lactate production.
- this results in abdominal pain, nausea, vomitting, dyspnea (breathing difficulties), tachypnea (rapid breathing)
