Exam 4 Flashcards
What yields the biological response?
signal transduction and signal amplification
How should a receptor be named?
after the endogenous agonist
What is the law of mass action?
rate of chemical reaction is proportional to the product of the concentrations of reactants
K(D)
equilibrium dissociation constant for the drug from the receptor
With respect to the law of mass action, what are things we have to assume?
- Magnitude of the effect is proportional to the amount of receptors bound or occupied
- Emax occurs when all receptors are bound
- Binding of the drug to the receptor exhibits no cooperativity (no allosteric binding)
define pharmacophore
portion of a drug that is responsible for its biological action
define affinity
the strength of the interaction/binding between the ligand and its receptor
Kd
concentration of drug required to occupy 50% of available receptor sites
Bmax
maximum number of receptors that can be bound by drug
K(A)
affinity; = 1/Kd
Define threshold concentration
minimum concentration required to elicit a measurable response
What does “ceiling effect” mean?
when Emax is reached; doesn’t matter how much drug you add, you will not see a response
Define potency
A measure of the amount of drug necessary to produce an effect of a given magnitude; consider EC50
Define efficacy
ability of drug to elicit response by binding to a receptor; consider Emax
What is intrinsic efficacy / activity?
describe the ability of a drug to activate a receptor after the drug-receptor complex has formed
What happens after a receptor gets activated?
-> 2nd messengers -> signal transduction cascade of events to produce the biologic effect
What is an agonist?
a molecule that binds to a receptor to activate it
What is an antagonist?
a molecule that binds to a receptor to prevent further binding
What is an inverse agonist?
a molecule that binds to an activated receptor and turns it inactive
Characteristics of an antagonist
- high affinity
- binds even in absence of agonist
- low dissociation
Two mechanism for irreversible antagonism
- bind covalently to active site of receptor
- bind to allosteric site
What are functional / physiological antagonists?
works on different receptors but physiological effects are opposite => cancel each other out
What are chemical antagonists?
antagonist that prevents binding of agonist by disturbing the molecule itself from binding
What are the ways in which chemical antagonists can take action?
- combine with inorganic substances
- combine with macromolecules
What are examples of physically active agents?
- magnesium sulfate
- mannitol
- hydrogen peroxide
What are pharmacokinetic antagonists?
- drug-drug interaction
- absorption of drug is decreased or metabolism and excretion of drug are increased
There were several examples of tolerance with pharmacotherapeutic agents. What were they?
- slow regeneration of inactive receptor
- formation of endogenous inhibitor
- negative cooperativity
- phosphorylation of receptor; uncoupling
- “down-regulation”; receptor internalization
- depletion of endogenously released factor
- increased metabolism to inactive form
Define desensitization
Receptors show a reduced ability to be activated again by their respective drug
What are the stages of GPCR desensitization?
- Phosphorylation
- Internalization
- Down-regulation (Degradation)
How does desensitization work?
- Clathrin-coated pit engulfs drug-receptor complex
- Goes to early and late endosome
- Goes to lysosome to be broken down
Can resistance be a heritable change?
Yes, it generally is
What does rifampin target?
RNA polymerase
How can you reduce threshold of intrinsic resistance with respect to rifampin targeting fungi?
- administer rifampin with low concentration of polyene
- it weakens the membrane which allows rifampin to get into the cell
What are some mechanisms for antibiotic resistance?
- alteration of target
- degradation of drug
- efflux of drug
What are the mechanism of resistance to β-lactams?
- porin mutation
- production of β-lactamase
Describe combination chemotherapy
- two drugs that target the same pathway
- one drug helps the other drug take effect
- one drug decreases resistance of the therapeutic drug
Define transformation
cells take up small bits of DNA and incorporate them into the chromosome
Define transduction
bacteriophage mediated transfer of resistance determinants
Define conjugation
cell-cell contact mediated transfer of genetic material
What are the mechanisms of resistance with respect to gene transfer?
- transformation
- transduction
- conjugation
What are the mechanisms of resistance with respect to gene amplification?
- spontaneous duplication of essential gene
- over-production of ligand to overcome competitive inhibition
- mutation in molecule to alter drug-complex binding
- altered transport of drug into the cell
What are the mechanisms of resistance with respect to biochemical processes?
- inhibit bacterial protein synthesis
What is the TET protein?
pumps drug out of cell; slow in normal bacteria but produced a lot by resistant isolates
How does tetracycline get inside the cell?
- crosses outer membrane via passive transfer
- crosses inner membrane via active uptake
How does methotrexate get into the cell?
- at low concentrations, by energy dependent carriers
- at high concentrations, by passive diffusion
How do you treat cancer with methotrexate? (with respect to dose)
- give a high concentration so that passive diffusion into cell can happen
- rescue normal cells with folate analogue Leucovorin since cancer cells do not have (DHF?)
What are two drugs that cancer cells are resistant to?
- vincristine
- actinomycin D
How can cancer cells be resistant to drugs?
- P170 or P-glycoprotein
- overproduction of transporter -> drug efflux
What are examples of inactivation of drug?
- β-lactamase inactivation of penicillins
- Enzymatic modification of aminoglycosides
- Enzymatic modification of chloramphenicol
How can you have sulfonamide resistance?
- overproduction of metabolite PABA
- loss in feedback inhibition
How can you have resistance to flucytosine?
- loss of cytosine deaminase activity
- loss of feedback inhibition
How does flucytosine work?
converted to fluorouracil by cytosine deaminase
What is the purpose of autolysins?
- mutant cells contain autolysins
- makes bacteriostatic drug -> bacteriocidal
What are the characteristics of a “normal” patient?
- 18-65 years old
- weighs 70kg
- have normal body functions
What are types of therapeutic variability?
- gene difference
- Pharmacokinetic
- Pharmacodynamic
Characteristics of infants
- increased permeability
- greater %age of water
- decreased biotransformation; underdeveloped metabolic enzymes
- decreased renal clearance; reduced GFR
- lower rate of blood flow to most organs
Characteristics of the elderly
- decline in organ function
- absorption decreased compared to metabolism and excretion
- decreased liver and renal blood flow
- reduced # of nephrons
- increased sensitivity to drugs
Hormones that are secreted in the morning
cortisol, catecholamines, angiotensin and aldosterone
Hormones that are secreted at night
gastric acid, growth hormone, folliclestimulating hormone
Why does asthma symptoms get worst at night?
lowest levels of cortisol (antiinflammatory) and high levels of histamine (bronchoconstrictor)
Which drugs increase gastric emptying?
- phenytoin
- morphine
Which drugs decrease gastric emptying?
erythromycin
What effect does the normal flora have on effects of specific drugs that we talked about in class?
- converts digoxin into a more polar form; more excretd
- converts oral contraceptives into more lipophilic form to allow more to be reabsorb
What happens if you lower urine pH?
- pH lowered by ammonium chloride
- increases excretion of antihistamines and amphetamines
What happens if you increase urine pH?
- pH increased by sodium bicarbonate
- increases excretion of ASA and phenobarbital
Tubular secretion can be altered. Give a specific example in class that we discussed.
Probenecid (weak acid) blocks clearance of other drugs like penicillins and sulfonamides
Describe the tyramine drug-food interaction
- tyramine is found in cheese and drinks
- antidepressants reduce tyramine metabolism
- increased tyramine can lead to elevated NE
- can cause hypertensice crisis
What is an idiosyncratic response?
- highly unusual and unpredictable response in an individual
- can be caused by enzyme deficiency
Define Pharmacogenetics
study of one gene as it relates to drug response
Define Pharmacogenomics
study of genome as it relates to drug response
What are the mechanisms for succinylcholine apnea?
have an abnormal amount of cholinesterase -> increased amount of succinylcholine -> prolonged muscle relaxation and apnea
How can you test levels of cholinesterase?
administering dibucaine in vitro
N-acetyltransferase (NAT) 1
metabolizes p-aminosalicylate and paminobenzoic acid
N-acetyltransferase (NAT) 2
- metabolizes isoniazid and other antiinfectives, caffeine
- slow and rapid acetylators
CYP2D6
responsible for the metabolism of ~25% of drugs
- 70 variant alleles
- Prozac inhibit this enzyme activity
CYP2C9
- primary pathway for metabolism of warfarin
- variants (2and3) are associated with excessive anticoagulation
Thiopurine Biotransformation
- XO and TPMT converts TP into non-toxic form
- HPRT converts it to toxic form
- normal dosing depends on how much gets converted to toxic form
How does Chronic Myeloid Leukemia come about?
- BCR-ABL fusion gene from chromosome 22 and 9 respectively
- treated with Imatinib (Gleevec) which inhibits cell division in the CML clones but does not affect growth of normal cells
How does cystic fibrosis come about?
- CFTR mutation; improper folding in ER
- treated by stabilizing misfolded proteins
How many percent of the genome actually codes for proteins?
1%
Define mutation
- permanent, structural change in the DNA
- the types are: insertions, duplications, single base substitution
Define polymorphism
- a gene that has more than one allele
- alleles that are present in at least 1% of the population
GWAS
- Genome Wide Association Study
- comparing DNA profiles with and without diseases to target locations of susceptible genes
Define haplotype
Segments of chromosomal DNA that usually remain intact during inheritance because they have not been broken up by meiotic recombination
Iressa
- used for non-small-cell lung cancer patients
- target protein is EGFR (epidermal growth factor receptor)
- mutations in EGFR can increase therapeutic effects
Define innate tolerance
tolerance which cannot be controlled
What are the types of learned tolerance?
- Behavioral tolerance
- Conditioned tolerance
Conditioned tolerance
Body’s physiology reacts to the environment.
What are the types of acquired tolerance?
- Pharmacokinetic tolerance
- Pharmacodynamic tolerance
- cross tolerance
How does pharmacokinetic tolerance happen?
- Body increases metabolism as a response to the drug.
- Tolerance by administering the same drug or other drugs.
How does pharmacodynamic tolerance happen?
Changes in receptor density, signaling pathway, and efficiency of the drug.
How does cross tolerance happen?
develops from repeated administration of another drug
What is the reward pathway?
- mesolimbic dopaminergic system in the brain
- causes addiction
What are the most common drugs of abuse?
- Opiates and narcotics
- CNS depressants
- CNS stimulants
- Hallucinogens
- Marijuana (Tetrahydrocannabinol)
GABA
inhibits release of dopamine from neurons
Opiates mechanism of action
inhibits GABA
Benzodiazepines and Alcohol mechanism of action
causes ion channels to open -> increase intracellular Ca2+ -> cause vesicles to be released into synaptic cleft
Cocaine and Amphetamine mechanism of action
breakdown transporter that reuptakes dopamine
What are the drugs used for therapy of drug addiction / overdose to opiates?
- methadone
- buprenorphine
- naltrexone
What are the drugs used for therapy of addiction / overdose to alcohol?
- disulfiram
- acamprosate
- naltrexone
- topiramate
What are the drugs used for therapy of addiction / overdose to tobacco?
- nicotine preparations
- varenicline
- bupropion
With respect to drug discovery, what is a lead?
a compound of interest
What are the compound-based approach?
- naturally occurring products
- purely synthetic drugs
- drug metabolites
What are the target-based approach?
- systemic approach to identifying targets
- screening method
How long does toxicity tests be done for?
for two years in two species: rodent and non-rodent disease model
What needs to be approved before clinical trials?
investigational new drug
What happens after application of IND?
FDA’s Center for Drug Evaluation and Research (CDER) decides within 30 days
Define priority drugs
Drugs that may be expedited if it considered a special and medical need
Define accelerated or fast-track drugs
Fast review of drugs that treat life-threatening diseases
Define orphan drugs
drugs that treat conditions which fewer than 200k people have
What process do generic drugs undergo?
ANDA = abbreviated new drug application
