Pharmacodynamics and Genetics Flashcards
PK Factors ADME lead to
Inactivation, activation or change in bioavailability which leads to no response or a response
PD Factors lead to
Enzymes, receptors, or transporter changes which leads to toxicity or no toxicity
GPCR Targets/Drugs
B-adrenergic receptors (beta-blockers)
Serotonin (antipsychotic/antidepressants)
Mu-opioid receptor (analgesics)
Transportor and Ion channels targets/drugs
Sodium & potassium (anti-arrhythmics)
Serotonin
Nuclear Hormone Receptors targets and drug
Estrogen (hormone)
Androgen (hormone)
Glucocorticoid
Enzymes targets and drugs
ACE (ACEI)
Effects of polymorphisms can be seen?
Binding sites
Signal transduction
Biologic (adaptive) response (tolerance)
Beta agonists do?
Reactive airway disease; target Beta 2 receptors
Beta blockers do?
CV disease; target Beta 1 receptors
B2 adrenergic receptor polymorphisms?
12 SNPs –> 5 AA changes
Clinical implications of B2 adrenergic polymorphs
Enhance receptor down regulation (tolerance- 50%) Resistant to down regulation (maintain efficacy - 25%) Reduced affinity (decreased efficacy- 6%)
Asthma Therapy
Montelukast
Zafirieukast
Zileuton
Pranleukast
Arachidonic acid is converted to?
Leukotrienes (high inflammation) via 5-lipoxygenase)
Decrease expression in promoter region?
Less response to leukotriene inhibitors –> disease is not mediated by leukotrienes
Increased expression in promoter region?
More responsive to leukotriene inhibitors –> leukotrienes have a major role in disease
Genetic polymorphisms in 5-lipoxygenase is most likely to affect:
A. Risk of agranulocytosis from clozapine
B. Response to beta-agonists therapy
C. Response to clozapine
D. Response to leukotriene inhibitors
D. Response to leukotriene inhibitors
Serotonin is implicated in?
Depression Anxiety OCD Psychosis Eating disorders Substance abuse Dependence
Clozapine is used in?
Schizophrenia 50% response rate
Cloazpine side effects?
Agranulocytosis
Seizures
Myocarditis
Polymorph of importance?
Tyr/Tyr: drugs almost never work but they have bad side effects
Avoiding Clozapine in patients with Tyr/Tyr means?
Limit unnecessary drug exposure and risk of sever toxicities
Selection of alternative therapy that is more effective
Do you genotype with clozapine?
YES
Clinical relevance of Opioid Receptors
Pain therapy
Substance abuse
Toxicity with Opioid Receptors?
N/V
Respiratory depression
Constipation
Opioid mutation
Mutation in the receptor at the receptor → decreased binding affinity → efficacy decreases and less side effects
— requires higher doses
CYP2D6
codeine –> morphine
Ultra metabolizers lead to
toxicity
Poor metabolizers lead to
Decreased efficacy
Which patient would have the least analgesic effects with codeine?
a. CYP2D6 extensive metabolizer and mu-opioid receptor mutation b. CYP2D6 poor metabolizer and mu-opioid receptor mutation c. CYP2D6 poor metabolizer and mu-opioid receptor wildtype d. DYP3D6 extensive metabolizer and mu-opiod receptor wildtype
b. CYP2D6 poor metabolizer and mu-opioid receptor mutation
Genotype in Codeine?
No because you can just slowly titrate up and avoid ADRs
Risk Factors for QT prolongation
Female Concomitant meds (also affect QT like calrithro or compete for metabolism) Hereditary LQTS (mutation in ion channels
LQTS Genetics affect
Potassium and sodium ion transporters
Therapeutic consideration with LQTS
K supplementation and K channel openers as well as Na channel openers
Abacavir Hypersensitivity
NRTI in HIV
5-7% hypersensitivity reaction
HLA-B genetics
MHC Class I
Presents the peptide to the immune cells
Define Haptenation
Drug has to complex with an endogenous protein → when the two get together and gets processed is now immuno-reactive
Abacavir Genotype and Reaction
HLAB*5701
Fatal
Carbamazepine Genotype and Reaction
HLAB*1502
SJS
Toxic –> fatal
Allopurinol Genotype and Reaction
HLAB*5801
Rash
Abacavir has a black box warning for?
Genotyping before use
Carbamazepine has a FDA alert for?
Genotyping because of SJS
