Pharmacodynamics and Genetics

Question 1

PK Factors ADME lead to

Answer 1

Inactivation, activation or change in bioavailability which leads to no response or a response

Question 2

PD Factors lead to

Answer 2

Enzymes, receptors, or transporter changes which leads to toxicity or no toxicity

Question 3

GPCR Targets/Drugs

Answer 3

B-adrenergic receptors (beta-blockers)
Serotonin (antipsychotic/antidepressants)
Mu-opioid receptor (analgesics)

Question 4

Transportor and Ion channels targets/drugs

Answer 4

Sodium & potassium (anti-arrhythmics)

Serotonin

Question 5

Nuclear Hormone Receptors targets and drug

Answer 5

Estrogen (hormone)
Androgen (hormone)
Glucocorticoid

Question 6

Enzymes targets and drugs

Answer 6

ACE (ACEI)

Question 7

Effects of polymorphisms can be seen?

Answer 7

Binding sites
Signal transduction
Biologic (adaptive) response (tolerance)

Question 8

Beta agonists do?

Answer 8

Reactive airway disease; target Beta 2 receptors

Question 9

Beta blockers do?

Answer 9

CV disease; target Beta 1 receptors

Question 10

B2 adrenergic receptor polymorphisms?

Answer 10

12 SNPs –> 5 AA changes

Question 11

Clinical implications of B2 adrenergic polymorphs

Answer 11

Enhance receptor down regulation (tolerance- 50%)
Resistant to down regulation (maintain efficacy - 25%)
Reduced affinity (decreased efficacy- 6%)

Question 12

Asthma Therapy

Answer 12

Montelukast
Zafirieukast
Zileuton
Pranleukast

Question 13

Arachidonic acid is converted to?

Answer 13

Leukotrienes (high inflammation) via 5-lipoxygenase)

Question 14

Decrease expression in promoter region?

Answer 14

Less response to leukotriene inhibitors –> disease is not mediated by leukotrienes

Question 15

Increased expression in promoter region?

Answer 15

More responsive to leukotriene inhibitors –> leukotrienes have a major role in disease

Question 16

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

Answer 16

D. Response to leukotriene inhibitors

Question 17

Serotonin is implicated in?

Answer 17

Depression
Anxiety
OCD
Psychosis
Eating disorders
Substance abuse
Dependence

Question 18

Clozapine is used in?

Answer 18

Schizophrenia 50% response rate

Question 19

Cloazpine side effects?

Answer 19

Agranulocytosis
Seizures
Myocarditis

Question 20

Polymorph of importance?

Answer 20

Tyr/Tyr: drugs almost never work but they have bad side effects

Question 21

Avoiding Clozapine in patients with Tyr/Tyr means?

Answer 21

Limit unnecessary drug exposure and risk of sever toxicities

Selection of alternative therapy that is more effective

Question 22

Do you genotype with clozapine?

Answer 22

YES

Question 23

Clinical relevance of Opioid Receptors

Answer 23

Pain therapy

Substance abuse

Question 24

Toxicity with Opioid Receptors?

Answer 24

N/V
Respiratory depression
Constipation

Question 25

Opioid mutation

Answer 25

Mutation in the receptor at the receptor → decreased binding affinity → efficacy decreases and less side effects --- requires higher doses

Question 26

CYP2D6

Answer 26

codeine --> morphine

Question 27

Ultra metabolizers lead to

Answer 27

toxicity

Question 28

Poor metabolizers lead to

Answer 28

Decreased efficacy

Question 29

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

Answer 29

b. CYP2D6 poor metabolizer and mu-opioid receptor mutation

Question 30

Genotype in Codeine?

Answer 30

No because you can just slowly titrate up and avoid ADRs

Question 31

Risk Factors for QT prolongation

Answer 31

``` Female Concomitant meds (also affect QT like calrithro or compete for metabolism) Hereditary LQTS (mutation in ion channels ```

Question 32

LQTS Genetics affect

Answer 32

Potassium and sodium ion transporters

Question 33

Therapeutic consideration with LQTS

Answer 33

K supplementation and K channel openers as well as Na channel openers

Question 34

Abacavir Hypersensitivity

Answer 34

NRTI in HIV | 5-7% hypersensitivity reaction

Question 35

HLA-B genetics

Answer 35

MHC Class I | Presents the peptide to the immune cells

Question 36

Define Haptenation

Answer 36

Drug has to complex with an endogenous protein → when the two get together and gets processed is now immuno-reactive

Question 37

Abacavir Genotype and Reaction

Answer 37

HLAB*5701 | Fatal

Question 38

Carbamazepine Genotype and Reaction

Answer 38

HLAB*1502 SJS Toxic --> fatal

Question 39

Allopurinol Genotype and Reaction

Answer 39

HLAB*5801 | Rash

Question 40

Abacavir has a black box warning for?

Answer 40

Genotyping before use

Question 41

Carbamazepine has a FDA alert for?

Answer 41

Genotyping because of SJS