Metabolism and Pharmacokinetics Flashcards
What is drug metabolism?
Biochemical modification of pharmaceutical sibstances by living organisms usually through specialised enzymatic activity
What does metabolism limit?
The life of a substance in the body by rendering lipid soluble and non-polar compounds to water soluble and polar compounds than can be excreted
What substances are excreted?
Water soluble
What substances are reabsorbed back into the blood from renal sites?
Lipid soluble
What are some sites of drug metabolism?
Liver
Lining of gut
Kidneys
Lungs
What is the purpose of drug metabolism?
Increase water solubility and aid excretion
Deactivate compounds
What are prodrugs?
Drugs that may be activated following metabolism
What are examples of prodrugs?
Codeine
Enalpril
Simvastatin
Sacbitril
What are the effects of metabolism?
Loss of pharmacological activity
Decrease in activity, with metabolites that show some activity
Increase in activity, more active metabolites (activation of prodrug)
Production of toxic metabolites
What can different kinds of toxic metabolites do?
Direct toxicity
Carcinogenesis (formation of a cancer)
Teratogenesis (congenital malformations produced in an embryo)
What is carcinogenesis?
Formation of a cancer
What is teratogenesis?
Congenital malformations produced in an embryo
What happens to a prodrug during metabolism?
Inactive chemical compound is coverted into its active metabolite
What controls the metabolism of drugs?
Enzymes
What can you say about the specificity of enzymes that metabolise drugs?
They have a wide range of specificity so individual drugs are often metabolised by more than one
How can different enzymes be expressed?
Constitutively (constant amounts)
In the presence of particular substance
What are the 2 phases of metabolism?
Phase 1 (activation/inactivation)
Phase 2 (conjugation products)
What are different phase 1 reactions?
Oxidation
Reduction
Hydrolysis
What happens during phase 1?
Polar groups are introduced to the molecule
What does increasing the polarity of compounds during phase 1 do?
Provides an active site for phase 2 metabolism
What is the most important superfamily of metabolising enzymes?
Cytochrome P-450
What does drug specificity of an enzyme depend on?
Which isoform of cytochrome P-450 is being used
What are the 3 families of the cytochrome P-450 super family used in oxidative drug metabolism?
CYP1
CYP2
CYP3
What is CYP1A2 important in the metabolism of?
Theophylline
What is CYP1A2 induced by?
Smoking
What is CYP2D6 important for the metabolism of?
Some antidepressants, antipsychotics and conversion of codeine to morphine
What is CYP2D6 induced by?
Smoking
Where is CYP3A4 found?
In the liver and the gut
What is CYP3A4 important for?
Pre-systematic (first pass) metbaolism of several drugs
What are examples of drugs that CYP3A4 is important for the metabolism of?
Diazepam
Methadone
Simvastatin
CCBS
What can you say about smokers and drugs that are metabolised by the cytochrome P-450 family?
They require a higher dose of drugs than non-smokers to achieve the same desired effect
What does phase 2 metabolism involve?
Conjugation
What does conjugation during phase 2 do?
Increases water solubility and enhances excretion of the metabolised compound
Usually resulting in inactivation however a small number of drug metabolites may be active
What does conjugation involve?
Attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by phase 1 metabolism
What does a endogenous molecule do during phase 2 metabolism?
A molecule endogenous (inside) the body donates a portion of itself to the foreign molecule (the drug)
D+ENDOX→DX+ENDO
What does endogenous mean?
Inside
What are some factors that affect metabolism?
Other drugs
Genetics
Hepatic blood flow
Liver disease
Age
Sex
Ethnicity
Pregnancy
What is enzyme induction?
Process where a molecule (such as a drug) induces (enhances) the expression of an enzyme
What does enzyme induction result in?
Increased metabolism of the drugs metabolised by that enzyme, decreasing the drug effect
What are common enzyme inducers?
Alcohol
Cigarettes
What is enzyme inhibition?
Substances which inhibit the expression or function of metabolising enzymes
How may enzyme inhibitors bind to enzymes?
Reversibly or irreversibly
What are some common enzyme inhibitors?
Cimetidine
Erythromycin
Clarithromycin
Ketoconazole
CCBS
Grapefruit
What are possible consequences of there being a wide variation in the response to drugs between individuals?
Therapeutic failure
Adverse drug reactions
What is pharmacogenetics?
The study of inherited genetic differences in drug metabolic pathways which affects an individual’s response to a drug
What can gene mutations result in?
Deficiencies or absence of a particular metabolising enzyme
What does decreased activity in enzymes result in?
Increased drug toxicity
What does multiple expressions of a particular enzyme result in?
Reduced drug effect or drug resistance due to increased metabolism
What is polymorphism?
Discontinuous genetic variation resulting in the occurrence of several different forms or types of individuals amount the members of a single species
What are the 4 phenotype subpopulations of metabolisers?
Poor metabolisers (PM)
Intermediate metabolisers (IM)
Extensive metabolisers (EM)
Ultrarapid metabolisers (UM)
What is CYP2C9?
The gene that codes for cytochrome P450 2C9
What does cytochrome P450 2C9 do?
Metabolises 16 commonly used drugs such as warfarin and phenytoin
What is CYP2C19?
Gene that codes for cytochrome P450 oxidase 2C
How many allelic varients are there for cytochrome P450 oxidase 2C?
8
What can you say about all the allelic variants of cytochrome P450 oxidase 2C and what does this mean for dosage of drugs?
They are all non-functional and so dose adjustments must be made for poor metabolisers of drugs that these enzymes act on such as S-mephenytoin
What are some enzymes that exhibit genetic variation?
Pseudocholinesterase
N-Acetyltransferase
Cytochrome P450 2D6
Cytochome P450 2C19
TMPT
Dihydropyrimidine dehydrogenase
How do infants metabolise drugs compared to adults?
Slower
Why do infants metabolise drugs slower than adults?
Deficient enzymes
Worse renal function
When can children metabolise drugs faster than adults?
At 2 and at puberty
Why do the elderly metabolise drugs differently to adults?
Plasma protein
Lean body mass
Liver weight
More common chronic disease
What is responsiveness to certain drugs different between?
Men and woman
What causes a profound change to drug metabolism in woman?
Pregnancy
Why may race affect drug metabolism?
Due to differences in genetic expression of cytochrome P450 isoforms
Why is knowing about absorption, distribution, metabolism and excretion important?
Determining how to get the drug to the site of action
Determining the dose and frequency
Making sure the drug is present in an effective dose
Predicting and avoiding toxicity
Making changes based on other drugs, illness or physiological factors
