Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Phcol 401 > Up to Midterm #1 > Flashcards

Up to Midterm #1 Flashcards

1
Q

Effect of Changes in Receptor Numbers

A
  • Antagonist increases total number of receptors
    • “Overshoot” Phenomena upon Drug Withdrawal
      • Withdraw antagonist→exaggerated responses to physiological [agonist]
  • Agonist causes receptor down-regulation
    • Withdraw agonist→too few receptors for effective endogenous stimulation
    • Clondine: alpha-adrenergic receptor→withdraw→hypertensive crisis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Drug Threshold

A

Minimum number of receptors that must be occupied before any drug effect is detectable

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Example of Drug Threshold

A

If there are multiple steps in a biochemical pathway, no effect will be detected until a normally fast step becomes the rate limiting step

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Example 2: Renal Carbonic Anhydrase-Acetazolamide

A
  • 50% of enzyme is bound, but there is hardly any effect
  • See 50% effect with 99% are bound
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Drug Threshold Decreases Agonist Sensitivity

A

With a drug threshold, EC­50>Kd

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Classical theory, Spare Receptors, Drug Threshold

  • When is max effect achieved
  • EC50 and Kd relationship
A
  • Classical Theory
    • Max effect requires all receptors to be bound
    • EC50=Kd
  • Spare Receptors:
    • Max effect is reached without all receptors being bound
    • EC50 is less than Kd
  • Drug Threshold:
    • No effect until a significant fraction of receptors are bound
    • EC50>Kd
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Receptor Regulation

A
  • Frequent/Continuous agonist exposure decrease receptor response
    • Tachyphylaxis
    • Desensitization
  • Prevents over stimulation leading to cell damage
  • Lead to drug tolerance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Drug Tolerance: 3 Kinds

A
  • PK Tolerance: change at the drug level
  • PD Tolerance: change at the receptor level
  • Cross-tolerance: repeated exposure to one drug decreases response to another drug
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

PK Tolerance:

A
  • Amount of drug reaching site of action is reduced
    • Decreased absorption
    • Decreased penetration to site of action
    • Increased metabolism
    • Increased clearance
  • ADME
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Metabolic Tolerance:

A
  • PK Tolerance
  • Enzyme induction
  • Continuous drug exposure induces enzymes that degrade/inactivate drug
    • Example:
      • Ethanol induces alcohol dehydrogenase (ADH)
      • Barbiturates induce synthesis of cytochrome P450s
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

PD Tolerance:

A
  • Change in receptor
  • Receptor uncoupled from signaling pathway
  • Total number of receptors in the system is decreased
  • Example:
    • Nicotinic Acetylcholine Receptor
      • Desensitized state caused by prolonged exposure to agonist.
      • Receptor undergoes conformational change that blocks responsive of receptor
        • Continuous exposure closes gate→ions not flow
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Response of beta-Adrenergic Receptor (GPCR) to Agonist Over Time

A
  • Receptor uncouples from receptor signaling pathway
  • Desensitization occurs within a few minutes
  • Re-sensitization occurs with removal of agonist for a few minutes
    • Fails if not a long enough gap
    • If give same concentration of agonist again, the effect will be smaller
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Mechanism of Desensitization, Re-sensitization, and Down-regulation of GPCR

A
  • Unique to GPCR’s; but not every GPCR does this
  • GRK=G-protein coupled receptor kinase, phosphorylates the GPCR
  • Phosphorylation then allow beta-arrestin to bind and the G protein cannot couple to the receptor anymore
  • Receptor internalized
    • Degraded
    • Taken back to the membrane
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Receptor Down-Regulation

A
  • Continuous exposure to agonist
  • Long-term reduction in receptor numbers
  • Mechanisms:
    • Increased degradation of receptor
    • Decreased synthesis of the receptor
  • Example: High BG causes increased insulin production, leading to down regulation of insulin receptor. Decrease BG, less insulin, receptor come back
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Stress Induced Desensitization

A
  • Osmotic stress
  • UV light
  • Acute psychological stress
  • Example: high anxiety people need more binding @ adrengeric receptors to get effect. Low anxiety people, about the same.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Dopaminergic Neurotransmission

A
  • Dopamine is cleared from the synapse by reuptake transporter
  • Amphetamine competitively inhibit DA transport
    • Dopamine stuck in snapse
  • Interferes with VMAT fux and filling of synaptic vesicles with DA
  • Increases cytoplasmic DA and reverse direction of DAT
  • Increases extracellular DA
  • Development of Amphetamine Tolerance
    • Dopamine required for downstream stimulatory effect of amphetamine
      • The cellular dopamine becomes depleted from the cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Quantal Drug Effects

A
  • Choose a given magnitude for the desired effect
  • Treat as “All-or-none” effect
  • For each drug dose, either achieve desired magnitude or considered to have no effect
  • Test on a population of subjects
  • Differ from graded dose response where increase dose→increase effect
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Dose-Response of Different Individuals to Quantal Drug Effect

A
  • Hyperractive
  • Average
  • Hyperactive
  • No Effect
19
Q

Quantal Dose-Response

A
  • Frequency distribution curve
  • Determine minimum dose required to produce the specified effect for each member of the population
  • Peak of curve=average effective dose=µ
  • “Gaussian” distribution
20
Q

Quantal Dose-Response Curves

A
  • ED50=effective dose at which 50% of the subjects respond
  • Average effect dose in the population=Dose effective for 50% of the population=µ
  • µ=ED50
  • ED50 doesn’t compare or connect to EC50
  • Lower ED50, increased potency
  • ED50=population
  • EC50=individual
21
Q

Reasons for Variations in Drug Sensitivity

A
  • Physiological variables
    • Physical condition, age, weight, sex, genetic factors, taking other drugs
22
Q

Concentration of Endogenous Receptor Ligand Differs

A
  • Propranolol
    • Competitive antagonist at beta-adrenergic receptor
    • Slows heart rate in people with elevated catecholamines
    • No effect on heart rate of marathon trained runners with reduced catecholamines
  • Saralasin
    • Weak partial agonist at angiotensin II receptor
    • Lowers BP in HTN caused by increased angiotensin II production
      • Not the full effect
    • Raises BP in patient with normal angiotensin II levels
      • Partial effect is greater than their normal
23
Q

Variations of Drug Sensitivities in a Population

A
  • Shape of curve reflects degree of variability in the responsiveness of individuals to the drug
  • B less potent than A and C
  • Prescribe drug C
    • B is less potent
    • A is variable in effective doses….sharper peaks are easier to prescribe
  • In a cummulative curve
    • ED50 will be the same
    • Drug C will have a sharper slope
24
Q

Cumulative Quantal Dose-Response of a Population to Drugs A and B

A
  • B is less potent
  • Same percentage of population doesnt see desired effect
    • insensitive
25
Q

Beneficial and Toxic Effects of Drugs

A
  • For the first one: hard to avoid toxicity because it is result of what you want drug to do
26
Q

Therapeutic Index

A
  • Describes the relative safety of a drug in a population
  • TI=dose undesired effect/dose desired effect
  • In animal studies:
    • TD50/ED50=[D] toxic for 50% of population/[D]effective for 50% population
  • Higher the TI, the safer the drug
27
Q

Wide vs. Narrow Therapeutic Index Drugs

A
  • Good separations of two curves is best
  • Steep slope for adverse effects is undesirable
    • Adverse effects occur more frequently at lower doses
    • Little dose increase and lots of people sick
28
Q

If TI≤ 2.0, the drug is considered to have NTI

A
  • Digoxin, cyclosporine, theophylline, warfarin
  • Require regular measurement of drug levels to ensure therapeutically effective levels while avoiding excess toxicity
  • Cut off is 1 because toxic dose lower than the effective dose
29
Q

Therapeutic Window

A
  • Range of dose that is effective but within safety range
  • Ranges from minimum effective dose to minimum toxic dose
  • Below TW, treatment ineffective; Above TW, toxicity observed too frequently
  • More useful than TI as a clinical dosage guide
30
Q

Classical Theory of Drug Action “Occupancy Model”

Assumptions and Exceptions

A
  • Binding of drug to the receptor is a simple, bi-molecular reaction that is freely reversible
    • Exception: noncompetitive irreversible active site antagonists
  • The magnitude of the effect is proportional to the concentration of drug:receptor complexes formed
    • Exception: spare receptors and drug threshold
  • The maximal drug effect occurs when all receptors are occupied
    • Exception: spare receptors
31
Q

Drug-Receptor Theory

  • EC50 and Kd relationship for
    • Occupancy Model
    • Spare Receptors
    • Drug Threshold
A
  • Occupancy model: EC50=Kd
  • Spare receptors: EC50<kd>
    </kd><li>Drug threshold: EC50&gt;Kd</li>

</kd>

32
Q

Pharmacogenetics vs. Pharmacogenomics

A
  • Pharmacogenetics
    • Study of the genetic basis for the variation in drug responses
    • One to one relationship with genes
    • study of single genes in variable drug response
  • Pharmacogenomics
    • Use of genomic methods to assess how variations in the human genome affects the response to drugs
    • Whole genome
    • Study the function and interaction of all genes in the genome on the variability of drug responses
33
Q

1000 Genomes Project

A
  • International effort to produce a public catalog of human genetic variations
  • Goal: Sequence 2500 unidentified people from 25 populations around the world
34
Q

Concerns with Genome Projects

A
  • Generation and storage of a patient’s genetic information
  • Cost
    • Is it worth sequencing every person’s DNA
  • Ethics of maintenance and use of the data
    • Who should have access?
    • Who owns and controls the information?
    • Reproduction issues
    • Commercialization of data
35
Q

Pharmacogenetic Approach

A
  • Forward genetics: phenotype-to-genotype approach
    • Identify “normal” individuals and “outliers” for a give drug response
    • Genetic comparison of the two groups to identify a gene
  • Reverse genetics: Genotype-to-phenotype approach
    • Identify differences in genomes (genotype) between individuals
    • Assess contribution to variability in drug response (phenotype)
36
Q

Polymorphisms

A
  • Variations in DNA sequence that occurs at a frequency ≥ 1% in a population
    • SNPs
      • Single base pair change
      • Occur every 300-1000 nucleotides
      • ~10*106 SNPs/person
  • Nonsynonymous
    • Different amino acid (missense) or stop codon (nonsense)
  • Synonymous: same amino acid
    • Insertions/Deletions (Indels) in coding region
      • Change amino acids
      • Introduce extra amino acids
      • Remove amino acids
      • Shorten a protein
37
Q

G6PD Deficiency

A
  • Primiquine in AA cause hemolytic anemia
  • Less G6PD because less plasmodium replication
38
Q

Pharmacogenetic in Clinical Practice

Requires 3 primary types of evidence

A
  • Screens of multiple human tissues linking the polymorphism to a trait
  • Complementary preclinical functional studies indicating the polymorphisms is possibly linked to a phenotype
  • Multiple supportive clinical phenotype/genotype association studies (people who have the genotype and then link the phenotype o them)
39
Q

Thiopurine Methyltransferase (TPMT)

A
  • Metabolizes cancer drugs like 6-MP and azathioprine
  • Thiopurine drugs converted to thioguanine nucleotides, which are cytotoxic to cells
  • Deficiency in TPMT activity leads to severe hematopoietic toxicity associated with treatment and potential mortality
  • Enzyme activity is high, medium and low in population
  • Saw that decreased the dosage and the incidence of relapse didn’t increase
    • In heterozygotes and wildtype
  • TPMT is enzyme that leads away from toxic pathway
40
Q

FDA Approved Pharmacogenetic Tests

A
  • Gene→Drug→Consequence
  • TPMPT→6-MP→Toxicity
  • CYP2D6→Tamoxifen→Decreased efficacy
  • UGT1A1→Irinotecan→Toxicity
  • CYP2D6→Codeine→Ineffetive analgesia
  • These genes all modulate pharmacokinetics
41
Q

Tamoxifen

A
  • Needs to be converted to endoxifen to be active
  • Conversion catalyzed by polymorphic enzyme cytochrome P450 2D6 (CYP2D6)
    • Need metabolism for activation
    • >70 CYP2D6 alleles described
    • Categories: Extensive metabolizers, IM and PM
    • CYP2D6 is a major player in drug metabolism
  • Efficacy of tamoxifen likely low in 6-10% of European population deficient in enzyme activity
42
Q

Monogenic vs. Multigenic Pharmacogenetics

A
  • Monogenic: Activity determined by single gene
  • Multigenic: Activity influence by many different genes
43
Q

Conclusion on Genes and Pharmacy

A
  • Genetic variation contributes to inter-individual difference in drug response phenotype
  • Through individualized treatments, pharmacogenetics and pharmacogenomics are expected to lead to
    • Better, safer drugs the first time
    • More accurate methods of determining appropriate drug dosages
  • Pharmacogenomics offers unprecedented opportunities to understand the genetic architecture of drug responses

Phcol 401 (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions