Drug Metabolism Flashcards
Describe phase 1 metabolism
Creating/modifying functional group
Creation - oxidation
Modifying - hydrolysis
Describe phase 2 metabolism
Products:
Less active
More hydrophilic
Larger
Weak acids
More likely to bind albumin
Availability of co-factor determines reaction capacity
Define Drug Metabolism:
Biochemical modification to pharmaceutical substance by living organisms
Usually through activity of specialised enzymes
4 main sites of drug metabolism?
Liver
Lungs
Gut Lining
Kidneys
What is a prodrug?
Precursor to a drug
Activated by metabolism e.g. Codeine
What are the 3 outcomes of metabolism on a drug?
Production of toxic metabolites
Activation (prodrugs)
Deactivation/loss of activity
What does the “wide substrate specificty” of metabolic enzymes mean?
Many drugs can be metabolised by more than one enzyme
Substrate is specific to many different enzymes
What are the 3 types of phase 1 metabolism reaction?
Hydrolysis
Oxidation
Reduction
[HOR]
Whats the function of phase 1 metabolism?
Increase polarity of compound
Provide active site for phase 2 to occur
What family of enzymes carries out phase 1 metabolism?
P-450 family of enzymes
What is the Prefix for the enzymes in phase 1 metabolism?
CYP- is prefix followed by no.-letter-no.
3 enzymes in phase 1 metabolism?
CYP3A4
CYP2D6
CYP1A2
Where is CYP3A4 found?
In Liver
What does CYP2D6 metabolise?
Antidepressants
Antipsychotics
Converts codeine to morphine
How does smoking affect CYP2D6?
CYP2D6 is induced by Smoking
What does CYP1A2 metabolize?
Theophylline
Which phase 1 enzyme isnt induced by smoking?
CYP3A4 isn’t induced by smoking
What phase involves conjugation?
Phase 2 metabolism involved conjugation
What is conjugation?
Combining drugs with other substances to terminate their activity
How does conjugation make excretion of the drug easier?
Conjugated drugs have an increased water solubility
What substances are used to conjugate the metabolites formed in phase 1?
Glucuronic Acid
Glutathione
Sulphate
Acetate
Does conjugation deactivate all drug metabolites?
Most, but not all are inactivated
In what two ways do other drugs/herbal meds affect drug metabolism?
Other drugs/herbals can cause enzyme induction & inhibition, affecting metabolic rates
What is enzyme induction?
Substance causes increased synthesis of enzyme leading to greater metabolic rate
What are some commmon inducers?
Other drugs, herbals, smoking & alcohol.
How long does induction take to become apparent?
Weeks -> months
Is enzyme inhibition reversible?
Some enzyme inhibition is reversible but not all
What are some common substances that inhibit drug metabolising enzymes?
Erythromycin & Clarithromycin
(Grapefruit)
What is pharmacogenetics?
Wide genetic variability in pharmacokinetics
Role of genome in drug response
What are the consequences of ‘bad’ pharmacogenetics?
Therapeutic failure
Adverse reactions
How can genetic variation lead to drug toxicity?
Genetic variation can cause:
Absence/deficiency in enzymes
Overly high drug level
Drug toxicity
How can genetic variation lead to tehrapeutic failure without adverse effectS?
Over production of an enzyme
Overly high metabolic activity
Low drug conc. in blood
Failure of therapy
What two aspects of the liver can effect drug metabolism?
Liver Disease
Hepatic Blood Flow
What are the 2 main differnces in the drug metabolism of infants to adults?
Infants have:
- reduced or absent drug metabolizing enzymes
- Reduced renal function
How is a pubescant childs metabolism differnt to an adults?
By puberty a childs metabolism is faster than an adults
Which parameters affecting drug metabolism are affected in the elderly?
Lower liver weight, renal function, plasma protein & lean body mass
How does chronic disease in the elderly affect drug metabolism?
Chronically ill elderly people are on multiple meds which can interact or overpower the body.
How does gender affect drug metabolism?
It effects all 4 areas of pharmacokinetics:
- Absorption
- Distribution
- Metabolism
- Excretion
How does pregnancy effect drug metabolism?
Hormonal changes in 2nd/3rd trimester induce some drug metabolising enzymes
How does ethnicity effect drug metabolism?
Variation in expression of P-450 genes leads to different levels of drug metabolising enzymes between races
What is knowing ADME important for?
- Choosing method of administration
- Choosing safe & effect Doses/Frequency
- Making changes based on drugs, illness or physiological factors
