Metabolism Flashcards
Define Metabolism and where does it occur?
Enzymatic conversion of one chemical compound into another.
Most drug metabolism occurs in the liver
some processes occur in the gut wall, lungs and blood plasma.
How does metabolism work? What happens to a drug when the drug is metabolised.
Conversion of the drug into a more water-soluble compound by increasing its polarity
Essential for excretion in the body fluids
urine or bile
On the whole, as drugs are metabolised their therapeutic effect diminishes.
What factors affect metabolism?
Aging
decline in hepatocyte number and enzyme activity
Disease
reduced hepatic blood flow
heart failure or shock
reduce metabolic potential of the liver
Genetic
Over expression or deficiency of a particular enzyme
Other drugs, diet and environmental factors
grapefruit juice and St John’s Wort inhibit Cytochrome P450 activity.
Cigarette smoke and Brussel sprouts increase p450 activity
What do Phenytoin, salicylates and ethanol do to enzymes?
A small number of drugs are capable of saturating eliminating enzymes at therapeutic concentrations
Display ‘zero order or non-linear kinetics’ which means a constant amount of drug is lost per unit time.
Small increase in dose may cause a disproportionately
large increase in plasma concentration
The best known are:
Phenytoin
Salicylates
Ethanol
Most drugs display ‘first order or linear’ kinetics.
Phenytoin - It can treat epilepsy in children and adults and trigeminal neuralgia.
Salicylates - Salicylates are used as food preservatives and antiseptics and have bacteriostatic, fungicidal and keratolytic (skin peeling) properties. Salicylic acid and acetylsalicylic acid have analgesic ( pain relieving), anti-inflammatory, and antipyretic (temperature-lowering)
what is phase 1 Metabolism
Can involve reduction or hydrolysis of the drug, but the most commonly, oxidation.
Oxidation is catalysed by cytochrome P450 enzymes
results in the loss of electrons from the drug
After phase 1 reactions, the resulting drug metabolite may still be chemically active.
What is phase 2 metabolism?
Involves conjugation
the attachment of an ionised group to the drug
glutathione, methyl or acetyl groups.
These metabolic processes usually occur in the hepatocyte cytoplasm.
The attachment of an ionised group makes the metabolite more water soluble.
Facilitates excretion
decreases pharmacological activity
What enzyme is involved in Cytochrome P450? What reactions do Cp450 undergo? Where are they found?
Phase I oxidative reactions typically involve a cytochrome P450 monooxygenase (CYP)
Nomenclature based on nucleic acid and amino acid homology
Cytochrome P450 (CYP)
Family CYP2
Sub-family CYP2D
Specific gene CYP2D6
NOTE that this nomenclature is genetically based: it has NO functional implication
Found in gut wall in intestinal epithelium
How is Paracetamol metabolised?
Some drug metabolites can be toxic
E.g. Paracetamol
detoxified by phase 2 conjugation joining with glutathione.
However, in paracetamol OD where dose is very high
not enough glutathione to detoxify the metabolites
accumulation causing toxicity and can result in hepatitis
compounds then need to be administered to boost the levels of glutathione so that phase 2 metabolism can take place
What is Induction?
A increases the rate of metabolism
of B, blood concentrations of B fall
below normal therapeutic levels.
B becomes ineffective
Barbituiates drugs can substantially increase the rate at which warfarin is metabolized and thus reduce the effect of a previously adjusted dose.
What is Inhibition?
A reduces the rate of metabolism
of B, blood concentrations of B
increase above that which is safe.
B becomes toxic
Features of CYP450 in enzyme induction
Gradual onset and offset
Onset - accumulation of inducing agent and increase in enzyme production
Offset - elimination of inducing agent and decay of enzymes
Results in reduction of plasma concentration of substrate drugs
Some substrates may induce their own metabolism,
Carbamazipine
Give an example of a withdrawal of an inducer.
Barbituirates decrease the hypoprothrombinemic effect of warfarin.
Patient taking barbiturates and warfarin
Barbiturates cause induction - warfarin clearance increased
Warfarin dose titrated above normal dose, blood levels are now normal
Barbiturates suddenly withdrawn and replaced by valproate
Warfarin clearance falls - blood levels rise above normal
Patient dies
Give a beneficial use of induction
New born infants have poorly developed hepatic metabolic enzymes.
Conjugate bilirubin inefficiently - some become jaundiced
Small doses of barbiturates can be used to induce the liver enzymes and clear the bilirubin. is a yellowish pigment that is made during the breakdown of red blood cells.
What do CYP450 inhibitors and inducers do to CYP450?
Not simply the opposite of induction;
Induction – Additional CYP450 in the liver
Inhibition – No reduction in quantity of CYP450.
Existing CYP450 made less effective.
Probably the most significant of all interactions
- Potentially fatal
Example of inhibitor herbal remedies
Milk thistle (Silibinin)
Garlic
Peppermint oil (Menthol)
