Pharmacokinetics - Metabolism Flashcards
(11 cards)
What are the stages of metabolism?
Metabolism is the process by which a molecule undergoes chemical change, usually to aid the process of excretion, but also includes activation of prodrugs. Largely in the hepatic endoplasmic reticulum, but also in kidneys, lungs, blood and other organs.
Phase I
Non-Synthetic phase designed to inactivate the drug - applies to most drugs. Examples include oxidation, hydrolysis & reduction. Mostly catalysed by CYP450 enzymes.
CYP2B6 - Propofol
CYP2C9 Propofol, parecoxib, losartan, S-warfarin
CYP2C19 Losartan, diazepam, phenytoin, omeprazole, clopidogrel
CYPD6 Codeine, flecainide, metoprolol
CYP2E1 Sevoflurane, methoxyflurane (produces fluoride ions causing AKI), isoflurane, paracetamol
CYP3A4 Diazepam, midazolam, temazepam, alfentanil, fentanyl, lidocaine, vecuronium
CYP3A5 Diazepam
Other examples of Phase I metabolism
Catecholamines metabolised by MAO
Atracurium undergoes Hofmann degradation (60%), and ester hydrolysis (40%) in plasma
Suxamethonium hydrolysed by non-specific plasma esterases
GTN inactivated by gastric mucosa
ACE inhibitors metabolised in the lung
Phase II
Synthetic phase, primarily to increase water solubility for urinary/biliary excretion.
Some drugs only undergo phase II.
Liver failure tends to affect phase I metabolism more than phase II.
Examples:
Glucuronidation - Propofol, morphine
Acetylation - Isoniazid
Methylation - Noradrenaline
Sulphation - Propofol
Identify some prodrugs and their active metabytes
Diamorphine to 6-monoacetylmorphine
Paracoxib to valdexocib
Enalapril to enalaprilat
Codeine to morphine
Losartan
Clopidogrel to 2-oxo-clopidogrel
How is codeine metabolised?
CYP2D6 and CYP2C9
CYP2D6 variation affects metabolism - a defective allele can prevent metabolism to morphine, and therefore preclude analgaesia
Multiple copies of codeine cause ultra-fast metaboism to morphine, and increased side effects
Approx:
80% are ‘extensive’ metabolisers
10% are poor metabolisers
5% are intermediate metabolisers
2% are ultra-rapid metabolisers
CYP2D6 also metabolises
Oxycodone, methadone, tramadol
SSRIs
Haloperidol
Amiodarone
Flecainide
How is ethanol metabolised, what pharmacokinetics does it demonstrate?
Alcohol dehydrogenase in cell cytoplasm to form acetaldehyde, then oxidised to acetic acid.
Alcohol dehydrogenase is easily saturated - initially demonstrating first order kinetics, then zero-order kinetics, with a rapid increase in plasma concentration if further ethanol ingested.
Other than the liver, where else does metabolism occur?
Esterases in multiple tissues (including muscle/liver)
Aspirin, atracurium, etomidate
Blood
Pseudocholinesterases (AK plasma cholinesterase or butyrylcholinesterase)
Suxamethonium
Hofmann degradation of atracurium (pH/temperature dependent)
Lung
Angiotensin converting enzyme - converts angiotensin I to II.
Also breaks down bradykinin - hence ramipril induced ‘bradykinin cough’
Acetylation (Phase II metabolism)
Spleen
Acetylation
What is genetic polymorphism? Give examples
Inherited enzyme structure differences that affect drug metabolism
Suxamethonium apnoea
Plasma cholinesterase hydrolyses suxamethonium in the plasma.
It is coded on Chromosome 3, with 4 alleles - usual, atypical, fluoride-resistant, silent.
Depending on homo/heterozygosity & which alleles are present, paralysis can last between minutes to hours.
Testing is with the dibucaine blood test, and treatment is with FFP or supportive measures.
May also be acquired during pregnancy, liver/renal/cardiac disease, thyroid disease, or certain cancers.
CYP2D6 & codeine metabolism
Approx:
80% are ‘extensive’ metabolisers
10% are poor metabolisers
5% are intermediate metabolisers
2% are ultra-rapid metabolisers
Acetylation
Phase II metabolism
N-Acetyltransferase 2 (NAT2) metabolised hydralazine and isoniazid - individuals may be slow or fast acetylators.
How can enzymatic drug metabolism be affected?
Increased activity
Enzyme inducers:
Carbamazepine, phenytoin, barbiturates, chronic alcohol intake, griseofulvin, rifampicin
Indirect via intermediary messengers
Direct positive allosteric modulation (a molecule binds to the enzyme, inducing a conformational change to make it more active), which may increase the Km, Vmax or both
Enzyme inhibitors
Omeprazole, fluconazole, valproate, disulfiram, cimetidine, chloramphenicol, isoniazid, clarithromycin, diltiazem (3A4 inhibitor)
Km = Michaelis constant (substrate concentration required for 50$ max enzyme rate)
Vmax = max enzyme rate
What factors influence hepatic metabolism of a drug?
Drug factors
Lipid solubility
Ionisation
Protein binding
Effects on enzymes (induction/inhibition)
Patient factors
Age
BMI
Pharmacogenetics
Liver disease
Pregnancy
Smoking
Hepatic blood flow
What is the hepatic extraction ratio?
Extraction ratio is the fraction of drug removed in one pass through the organ
Three categories
High extraction & metabolic capacity (Perfusion dependent)
Propofol & lidocaine
Free drug removed rapidly from plasma, and metabolised so quickly that protein-bound drug is also released, absorbed & metabolised. Protein binding is less important, and hepatic blood flow is vital.
These drugs usually have very low PO bioavailability due to high first-pass metabolism
Low extraction & metabolic capacity (High protein binding)
Phenytoin & diazepam
Limiting factor is the ability of the hepatocyte to metabolise the drug, not blood flow - small changes in the free fraction of the drug, such as changes in protein binding are very significant
Low extraction & metabolic capacity (Low protein binding)
Neither blood flow nor protein binding particularly impactful on hepatic metabolism
Factors affecting the hepatic extraction ratio:
Portal blood flow
Uptake into hepatocyte
Enzyme metabolic capacity (Michaelis constant)
Michaelis Constant - the substrate concentration that results in an enzme working at 50% max capacity
What is the entero-hepatic circulation & why is it relevant?
The mechanism by which the liver ‘recycles’ endogenous compounds & drugs via excretion in the bile into the duodenum.
Cholesterol is metabolised to cholic and chenodeoxycholic acids (bile acids), bound to glycine or taurine to form bile salts, which are stored in the gallbladder, and excreted into the duodenum to aid in fat digestion, with 95% re-absorbed in the ileum via the portal vein.
Many drugs undergo hepatic conjugation to glucuronic acid, with biliary excretion. Once in the GI tract, bacterial glucuronidases can release the active, original molecule, which may be re-absorbed via the liver.
This may be used to reduce the drug dose required for clinically effective plasma concentration, but can also result in toxic accumulation of drugs recirculating & causing liver damage.
This applies to
Chloramphenicol, aspirin, paracetamol, diazepam, lorazepam, morphine, and metronidazole, among others.
Changes to this circulation can affect drug levels - such as tetracycline killing gut bacteria, reducing enterohepatic recycling of the COCP
Another example - ciprofloxacin is a potent CYP1A2 inhibitor, and weak CYP3A4 inhibitor - which would be expected to increase the concentration of diclofenac.
However, as it kills gut bacteria, and diclofenac undergoes extensive entero-hepatic recycling, the plasma concentration instead decreases.
