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]
- “Overshoot” Phenomena upon Drug Withdrawal
- Agonist causes receptor down-regulation
- Withdraw agonist→too few receptors for effective endogenous stimulation
- Clondine: alpha-adrenergic receptor→withdraw→hypertensive crisis
2
Q
Drug Threshold
A
Minimum number of receptors that must be occupied before any drug effect is detectable
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
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
5
Q
Drug Threshold Decreases Agonist Sensitivity
A
With a drug threshold, EC50>Kd
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
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
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
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
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
- Example:
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
- Nicotinic Acetylcholine Receptor
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
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
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
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.
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
- Dopamine required for downstream stimulatory effect of amphetamine
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
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>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
- SNPs
- 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
- Insertions/Deletions (Indels) in coding region
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
