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Possible essay questions/Learning objectives:
Emphasise the importance of genetic variation on diversity of an individual’s phenotype
Review major factors that can influence drug response
Describe the potential importance of genetic background on drug metabolism and drug
response
Provide specific examples of how genetic variation can influence drug responses
Definitions
Pharmacogenetics
Studying an individuals genetic make up in order to predict responses to a drug
Pharmacogenomics
Analysing entire genomes, across groups of individuals, to identify the genetic factors
influencing responses to a drug
Pharmacogenetics vs Pharmacogenomics

Personalised Medicine
Personalised medicine:
Tailoring healthcare to an individuals genetic makeup rather than 'one size fits all'
approach
The right dose of the right drug to the right person
Factors contributing to variability in drug response/compliance with drug prescription
Environmental
Climate
Parasites
Pollutants
Smoking
Alcohol
Drugs

Cultural factors
Attitudes
Beliefs
Family influence
Biological factors
Age
Gender
Weight
Disease
Genes
Pharmacogenetics
Pharmacogenomics
Cardiovascular drugs and racial/ethnic origin
Ace inhibitors
More effective in Caucasians than in African Americans
Beta - Blockers
More effective in Caucasians than in African Americans
Alpha - Blockers
More effective in Caucasians than in African Americans
Thiazide (diuretic)
More effective in African Americans than in caucasians
BiDil in African Americans with Congestive Heart Failure
Isosorbide/hydralazine combination
BiDil is the first drug approved for use in African-Americans only

*Drugs in bold = important for this course

Stevens-Johnson Syndrome
Rare, serious disorder of skin and mucous membranes
Reaction to medication or an infection
Medications that can cause the reaction:
Anti-gout medications
Pain relievers such as Paracetamol, ibuprofen
Penicillin
Anticonvulsants and antipsychotics
Radiation therapy

HLA-B 1502 gene associated with an increased risk of Stevens-Johnson syndrome
HLA-B 1502 major histocompatibility complex, class I, B
Risk increases with certain drugs for seizures or mental illness
Families of Chinese, Southeast Asian or Indian descent are more likely to carry this gene

ADME

Sources of pharmacogenetic variation
Pharmacokinetic
Variability in concentration of drug at site of drug effect [Plasma]
Pharmacodynamic
Variability of drug in affecting target
Underlying disease mechanisms
Variability in disease being treated

Categories of major cardiovascular pharmacogenetic variants

Genetic polymorphisms and drug response

Potential consequences of genetic variability in drug metabolism
Genetic polymorphisms can affect:
Metabolism may influence plasma drug levels
Fast metabolisers vs slow metabolisers
Efficacy of drug
Toxic vs non-toxic responses (safety)
Beta-blockers and hypertension
Beta-adrenoceptor antagonists (Beta-blockers) are
widely used agents in the treatment of hypertension
Marked variability in response to beta-blockers
30-60% of patients fail to achieve adequate blood pressure lowering with betablockers
Common beta-blockers used in hypertension
include:
Metoprolol*
Atenolol
*learn
Examples of genetic variants and drug response
Genetic polymorphisms
Affect metabolism
Metoprolol CYP2D6*
* Learn a few families - genes involved in drug response/metabolism

The cytochrome P-450 mono-oxygenate (highly
polymorphic) system is largely responsible for
catalysing phase 1 reactions
Complex supergene family ( > 40 enzymes
expressed in human tissues)
Enzymes located on smooth endoplasmic reticulum
CYP1A2, 3A4, 2C9, 2C19, 2D6, 2E1 exert a major
role in drug metabolism
Phase 1 reactions add or expose a functional group
through oxidative reactions:
N-dealkylation
O-dealkylation
Hydroxylation
N-oxidation
S-oxidation
Diminution

CYP 2D6*3
(*3) indicates type of different polymorphic
variant number
CYP2D6 is a cytochrome P450 enzyme
Representative drugs metabolised by CYP2D6:
Metoprolol
Debrisoquine
Sparteine
Nortryptiline
Codeine
Prozac
Overexpression of CYP = fast metabolism = decreased [plasma]
Underexpression (CYP) = slow metabolism =
increased
If metoprolol is metabolised too quickly, it may
decrease the drug's efficacy (e
...
when multiple
copies of CYP2D6 expressed)
Reduced function variants e
...
CYP2D6*4 results in
absence of CYP2D6 activity
Longer half life and greater systemic exposure
Carriers have higher systemic exposure to metoprolol
Greater reduction in HR and BP
Slow metabolism may also result in toxicity
Inherited Activity of CYP2D6 and drug dosing

Genetic variation can influence blood levels of the
drug
Dose may need to be adjusted according to genetic background
Common variant of CYP2D6 is CYP2D6*4 associated with absence of activity of
CYP2D6 (reduced function variant)
Genetic variation and effects on
pharmacodynamics/drug targets
Pharmacodynamics
Receptors
Ion Channels
Enzymes
Immune molecules
Pharmacodynamics
Clopidogrel: P2RY12
Simvastatin: HMGCR
Metoprolol: ADRB1

Beta-1 Adrenergic Receptor

ADRB1 allele frequency and functional consequences
Gly389 variants have ↓ response to metoprolol
Arg389 variants have increased response to metoprolol

Ser49Gly = Glycine replaces Serine
Burden of Respiratory disease - Mortality

Types of lung cancer

Epidermal growth factor receptor in NSCLC
EGFR is an important target in NSCLC
Most NSCLC express it at high levels
Associated with a worse prognosis
Results of numerous phase 2 trials testing EGFR tyrosine kinase inhibitors erlotinib and
gefitinib in unselected patients were modestly positive

EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib)

BR
...
7 vs 4
...
8% response rate
Led to FDA approval of erlotinib as second/third line treatment after chemotherapy (if it
didn't work)
BR
...
This is because a
substantial proportion of patients are prescribed medications that are, at an individual
level, either ineffective or dangerous



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