Up to Midterm #1 Flashcards
(43 cards)
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
Beneficial and Toxic Effects of Drugs
* For the first one: hard to avoid toxicity because it is result of what you want drug to do
26
Therapeutic Index
* 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
Wide vs. Narrow Therapeutic Index Drugs
* 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
If TI≤ 2.0, the drug is considered to have NTI
* 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
Therapeutic Window
* 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
Classical Theory of Drug Action “Occupancy Model”
Assumptions and Exceptions
* 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
Drug-Receptor Theory
* EC50 and Kd relationship for
* Occupancy Model
* Spare Receptors
* Drug Threshold
* Occupancy model: EC50=Kd
* Spare receptors: EC50
Drug threshold: EC50>Kd
32
Pharmacogenetics vs. Pharmacogenomics
* 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
1000 Genomes Project
* International effort to produce a public catalog of human genetic variations
* Goal: Sequence 2500 unidentified people from 25 populations around the world
34
Concerns with Genome Projects
* 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
Pharmacogenetic Approach
* **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
Polymorphisms
* 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
G6PD Deficiency
* Primiquine in AA cause hemolytic anemia
* Less G6PD because less plasmodium replication
38
Pharmacogenetic in Clinical Practice
Requires 3 primary types of evidence
* 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
Thiopurine Methyltransferase (TPMT)
* 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
FDA Approved Pharmacogenetic Tests
* Gene→Drug→Consequence
* TPMPT→6-MP→Toxicity
* CYP2D6→Tamoxifen→Decreased efficacy
* UGT1A1→Irinotecan→Toxicity
* CYP2D6→Codeine→Ineffetive analgesia
* These genes all modulate pharmacokinetics
41
Tamoxifen
* 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
Monogenic vs. Multigenic Pharmacogenetics
* Monogenic: Activity determined by single gene
* Multigenic: Activity influence by many different genes
43
Conclusion on Genes and Pharmacy
* 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
