Drug metabolism Flashcards
Reactions in phase I metabolism
oxidation
reduction
hydrolysis
Adds a functional group to the drug which increases its polarity and provides a site for phase II reactions
N.B. Some oxidations do not involve P450 enzymes, e.g. ethanol metabolised in the cytosol. Hydrolytic reactions occur in the plasma and many tissues
Mixed function oxidase system
combination of molecular oxygen, NADPH and NADPH cytochrome P45o reductase.
Required for cytochrome P450 enzymes to function
Oxidation of a drug by cytochrome P450
The process of drug oxidation involves both oxidation and reduction.
CYP450 catalyses the transfer of one oxygen atom to the substrate (drug) while the other oxygen atom is reduced to water. Occurs in a P450 cycle of reduction and oxidation
Overall reaction:
DH+O2+NADPH+H > DOH+H2O+NADP
Major cytochrome P450 isoforms
CYP3A
CYP2D6
CYP2C
CYP2E1
CYP1A2
Isoforms of CYP450 involved in drug metabolism
CYP3A is the major enzyme involved in drug metabolism and is the most abundant in the liver
CYP2D6 is the second enzyme involved in metabolism but is found in significantly lower quantities.
Phase II reactions
Involve conjugation of a large chemical group to a functional group on a drug molecule.
The resulting conjugate is almost always pharmacologically inactive and is more hydrophilic and more easily excreted from the body.
Drug molecules that possess a suitable site what was present before, or as a result of phase I reactions are susceptible to phase II metabolism.
Examples of chemical groups used for conjugation in the liver
Glucoronyl
Acetyl
Methyl
Glutathione
Conjugation occurs mainly in the liver but other tissues e.g. lung and kidney are involved. Product is inactive
Factors affecting drug metabolism
Age
Genetics
Drug interactions and environmental influences e.g. herbal medication
Liver disease
How does age affect drug metabolism?
Neonates: Hepatic drug-metabolising enzyme systems are immature. Renal clearance is also inefficient. Lower doses of all drugs are needed
Children: Metabolic clearance can be quicker in children than in adults (CYPs are mature and their relative liver mass and hepatic blood flow are higher. Therefore doses of medicines may be need to be higher, using body surface area and age as a guide.
Elderly: Overall capacity of hepatic drug metabolism is reduced because relative liver mass and hepatic blood flow are lower (phase I reactions particularly affected). Simultaneous use of drugs in the elderly is also common due to co-morbidities. Start drug treatment with smallest effective dose and minimise number of drugs used.
How does genetics influence drug metabolism
The population may have differential expression of some CYP450 enzymes, Some patients will metabolise poorly which causes a polymorphic distribution.
e.g. some patients do not metabolise codeine to morphine. There is very little pain relief but patients experience slow, shallow breathing, nausea and vomiting, constipation, conscious depression.
Describe drug interactions at the level of Hepatic metabolism.
Normally due to interaction of phase I, CYP450 enzymes than phase II. Risk of interactions increases exponentially with 4 or more medications
Name 5 drug classes metabolised by CYP3A
Calcium channel blockers
Benzodiazepines
HIV protease inhibitors
HMG-CoA reductase inhibitors
Cyclosporine
Oral contraceptives
Name 3 drugs which inhibit drug metabolism of CYP3A
Anti-fungal drugs (azole drugs)
Cimetidine (H2 histamine receptor antagonist)
Macrolide antibiotics (e.g. Erythromycin)
Interactions that inhibit CYP3A lead to reduced clearance and higher blood levels of the primary drug. Potentially toxic drug levels and adverse effects can result.
Drugs which induce CYP3A enzymes
Carbamazepine: anti-convulsant
Rifampicin: anti-TB
Ritonavir: antiviral
St. John’s Wort: herbal
This leads to increased clearance and lower blood levels of the primary drug. Lack of therapeutic efficacy can result.
Why is it important to ask about herbal medications in a drug history?
St John’s Wort available over the counter - induces the activity of CYP3A and inhibits other CYP450 enzymes.
Inducing CYP3A increases metabolism, and therefore reduces plasma concentration of drugs such as warfarin, anti-epileptics and oral contraceptives.
Where in the liver are drugs metabolised?
Hepatocytes
Drugs and toxins in the GIT enters the liver via the portal vein. The majority of drugs metabolised by hepatocytes re-enter the blood via the central vein and pass to the kidneys to be excreted. Drugs with high Mw and hydophobicity re excreted in bile
Aim of drug metabolism
To make the drug less active and less lipid soluble sot aht it can be easily excreted from the body.
Phase I reactions add functional groups to the drugs
Phase II reactions add large molecules to functional groups of the drugs so they can be excreted.
Where are CYP450 enzymes found?
SER of hepatocytes
Hundreds of isoforms exist which have different specificities of reactions they catalyse. Some are constitutive, other are present when synthesized in response to an appropriate stimulus.
Describe the mechanism of paracetamol-induced liver injury following an overdose
Paracetamol can be lethal at 2-3 times the theraputic dose due to accumulation of its metabolite NAPBQI.
Paracetamol is normally metabolised by the phase Ii pathway by conjugation to glucaronic acid or sulphate. NAPBQI is a product of phase I metabolism (5%) and is normally inactivatd by glutathione.
When high doses of paracetamol are ingested, these pathways become saturated and more NAPBQI is produced. When glutathione is depleted, the toxic metabolite reacts with the cell leading to necrosis in the liver and kidneys within 48-72hrs.
Initial treatment for paracetamol overdose
Acetylcysteins and methionine. Increase the synthesis of glutathione in the liver.
Patient’s most at risk of paracetamol-induced liver damage
Patients taking P450 inducing drugs e.g. St Johns Wort, alcohol
Patients with gluathione depletion eg. eating disorders
Side effects of codeine
Slow, shallow breathing
Nausea and vomiting
Constipation
Conscious depression/mood alteration
Effects of liver disease on drug action
Liver disease impairs liver function which causes increased bioavailability of drugs and decreased protein binding.
How does cirrhosis affect drug action
In cirrhosis chronic inflammation causes scarring and fibrosis of the the liver tissue. Hepatocytes regenerate but the structure of the lobules is lost and nodules are formed.
Nodule formation impairs blood flow and causes portal hypertension, and may result in porto-systemic shunting so drugs are directed away from the liver as a result.
Dead and damaged hepatocytes also decrease the drug-metabolising capacity of the liver.
How does liver disease influence response to treatment?
Increased bioavailabiltiy: Orally administered drugs are normally absorbed in the small intestine and metabolised by 1st pass metabolism so less active drug is available in the body. In liver disease 1st pass metabolism is reduced (due to damaged hepatocytes and shunting) and therefore more active drug is available
Decreased protein binding: liver disease causes loss of plasma proteins, clotting factors and binding proteins synthesised by the liver. Therefore more unbound drug is available for distribution and binding to receptors in tissues.
Give 2 examples of drugs whose bioavailability is increased in cirrhosis
nicardipine (calcium channel antagonist)
paracetamol
propranolol (b-adrenoceptor antagonist)
verapamil (calcium channel antagonist)
What is the effect of liver disease on prodrugs?
Some drugs are activated by phase 1 metabolism. Therefore in liver damage activation of pro-drugs may be slowed or reduced e.g. ACEi.
Describe the functional zones in the liver lobule
Zone 1: periportal hepatocytes, receive the most oxygen, and specialise in oxidative metabolism.
Zone 2: intermediate zone
Zone 3: pericentral hepatocytes, least oxygenated, specialise in drug metabolism.
