CHEM 455 EXAM 3 Flashcards
Drug resistance
formerly effective drug dose is no longer effective
drug synergism
synergism arises when the therapeutic effect of two or more drugs used in combination is greater than the sum of the effect of the drugs individually
5 types of drug synergism
- Inhibition of a Drug-Destroying Enzyme
- Sequential Blocking Inhibition
- Inhibition of Targets in Different Pathways
- Efflux Pump Inhibitors
- Use of Multiple Drugs for the Same Target
why is resistance a problem
it causes drugs to be inhibited and ineffective which can be costly and deadly
why is drug synergism important
important in order to both combat drug resistance and to improve effectiveness of drugs
what are the 8 mechanisms of drug resistance
- Altered target enzyme or receptor
- overproduction of the target enzyme or receptor
- overproduction of the substrate or ligand for the target protein
- increased drug destroying mechanisms
- decreased drug (prodrug) activating mechanism
- activation of new pathways circumventing the drug effect
- reversal of drug action
- altered drug distribution to the site of action-modified cell membrane
- altered drug distribution to the site of action-efflux pumps
Altered Target Enzyme or Receptor
mutation of AA residue→ drug binds poorly, but substrate binding is unchanged
Overproduction of the Target Enzyme or Receptor
- induction of extra copies of the same gene encoding the target protein
- taking a larger dose may help until is reaches toxic levels
Overproduction of the Substrate or Ligand for the Target Protein
-overproduction of the substrate for a target enzyme would competitively block the ability of the drug to bind at the active site
Increased Drug-Destroying Mechanisms
-resistance by induction of genes→ produce new enzymes, increase quantities of existing enzymes, or produce other substances to degrade or sequester the drug
Decreased Drug (Prodrug)-Activating Mechanism
Prodrug- compound that is converted to the active substance after its administration
Activation of New Pathways Circumventing the Drug Effect
-if the drug inhibits an enzyme that blocks production of a metabolite, the organism could induce a new metabolic pathway that produces the same metabolite
Reversal of Drug Action
-drug acts in the opposite way that it is supposed to
Altered Drug Distribution to the Site of Action- Modified Cell Membrane
- organism excludes the drug from the site of action by preventing cellular uptake of the drug
- adjust net charge of plasma membrane
Altered Drug Distribution to the Site of Action- Efflux Pumps
- Efflux pumps- transmembrane proteins that act as transporters to carry drugs out of the cell before they elicit their therapeutic effect
- multidrug resistance pumps- broad specificity transporters that efflux a wide range of drugs against microorganisms and tumor cells
what are the factors that affect metabolism
increased lipophilicity increases metabolism
species, strain, sex, age, hormones, pregnancy, liver diseases, other drugs you’re taking
what are the two primary routes of metabolism for drugs and how do they differ
- via mouth: it is absorbed through small intestine/stomach-> blood stream -> liver
drugs metabolized by liver enzymes are presystemic or first pass effect - avoid liver
-sublingual, rectal, IV, IM, subcutaneous injections, pulmonary absorption, topical application
how is drug metabolism studied
mass spectrometry, radioactive labels, HPLC/NMR
Principal steps in drug metabolism studies
- Sample preparation– extractions, ion exchange—sometimes omitted and urine injected directly into HPLC
- Separations – HPLC, gas chromatography (GC), and capillary electrophoresis (CE)
- Identification – mass spectrometry (MS), NMR: link to separation with LC-MS, GC-MS, or CE-MS; good for
why are prodrugs used
aqueous solubility, absorption and distribution, site specificity, instability, prolonged release, toxicity, poor patient acceptability, formulation problems, delivery of nucleoside drugs
what is carrier prodrug
a compound that contains an active drug linked to a carrier group that is removed enzymatically
types of carrier prodrug
bipartite: comprised of a carrier attached to a drug
tripartite: carrier connected to a linker that is connected to a drug
mutual (codrug): two usually synergistic drugs that are attached to each other
bioprecursor prodrug
a compound that metabolized by molecular modification into a new compound, which is a drug or is metabolized further to a drug- or just simple cleavage of a group from the product
why are esters the most frequently used prodrug moiety
- Esterases are ubiquitous
- can prepare esters with any degree of hydrophilicity or lipophilicity
- ester stability can be controlled by appropriate electronic and steric manipulations
- both alcohols and carboxylic acids can be esterified
- based on environment and what is needed you can slow down rate or increase it
to accelerate the hydrolysis rate of esters
- attach EWG if a base hydrolysis mechanism is important
- attach an electron donating group if an acid hydrolysis mechanism is important
to slow down hydrolysis rate
- make sterically hindered esters
- make long chain fatty acid esters
why does bodor’s redox tripartate prodrug delivery work so well for CNS drug delivery and why is it generally not toxic
oxidation of the dihydropyridine to the pyridinium ion prevents the drug from escaping out of the brain because it becomes charged
- this drives equil of lipophilic precursor throughout all the tissues of the body to favor the brain
why are McGuigan’s ProTides so effective
- Increases cellular delivery of the nucleoside
- Overcomes the rate-limiting monophosphorylation step- delivers the monophosphate form
- Pieces that form the ProTide prodrug are not toxic
- nucleosides/monophosphates are very polar and the ProTides masks this allowing it to cross the membrane
How does Rohypnol interact with GABA, the major inhibitor of neurotransmission in the brain?
Rohypnol increases the affinity of GABA for its receptors, thus decreasing the excitation of nerve systems resulting in reduction of anxiety and alertness
What is the general role of benzodiazepines, such as Rohypnol?
Benzodiazepines like Rohypnol are central nervous system (CNS) depressants that result in sedative-hypnotic activity
What are the two key substituents of Rohypnol that contribute to its enhanced sedative-hypnotic activity?
The nitro group and the o-fluoro group of the phenyl group produce increased sedative-hypnotic activity compared to other benzodiazepines
Why did drug developers think that Mibefradil would be a better drug than its counterparts
It is highly selective for T type calcium channels
What alternative purposes is Mibefradil being studied for now? What further research is being done now
Its structural analogs are being studied, its anticancer properties are also being studied
Why was thalidomide initially taken off of the market and how did it affect drug safety regulations?
Thalidomide was taken off the market because it had been linked to birth defects. Drug safety regulations became stricter and required animal testing and tightly controlled human testing before going on the market.
List two conditions/ailments that thalidomide has been used to treat.
Leprosy (ENL), multiple myeloma, morning sickness, insomnia, Crohn’s disease, graft-versus-host disease, recurrent mouth ulcers, sarcoidosis
If the S-enantiomer isomer of thalidomide is the problem child, why can’t we just use its safer and effective R-enantiomer?
The R-enantiomer of thalidomide will racemize in the body, forming a racemic mixture.
Name three common symptoms of ADHD.
inattention, hyperactivity, impulsivity
Provide the name of at least one neurotransmitter that is up-regulated by Adderall
Dopamine, serotonin, norepinephrine
List two common side effects of Adderall use
difficulty sleeping, irritability, nausea/vomiting, loss of appetite/taste, restlessness and dry mouth, abnormal heart rate, high blood pressure, hallucinations, continued painful erections
What makes HUMIRA different than the other monoclonal antibodies?
HUMIRA is a fully human monoclonal antibody. The ones preceding Adalimumab (such as Etanercept) were combinations of a human and mouse antibody.
Why doesn’t HUMIRA have normal ADME studies?
you cannot perform traditional ADME studies on an antibody
Why does HUMIRA cause an increased risk of infection?
The drug acts as an anti-inflammatory agent by binding to TNF alpha, causing a weakened
immune response to xenobiotics and other pathogens, thus increasing risk of infection
Name two advantages and two disadvantages of Hetlioz
Advantages may include: Only one on the market Doesn’t affect receptors and enzymes Non-habit forming Disadvantages may include: Expensive Headaches Increased urinary and upper respiratory infections Need to take with food so poor patient compliance
Flibanserin acts as a full agonist to HTRA1 and as an antagonist to HTRA2. What ligand found in the brain normally binds to these receptors?
Serotonin
Identify if the following neurotransmitters are upregulated or downregulated by Flibanserin: dopamine, norepinephrine, and serotonin
Dopamine, upregulated| norepinephrine, upregulated| serotonin, downregulated
Does Flibanserin (the “female Viagra”) function in the same way as Viagra? In other words, does Flibanserin cause increased blood flow to the genital region? Explain in 1 sentence the major difference between the two.
No, Flibanserin affects the chemical balance in the brain while Viagra affects the flow of blood to the genital region.
Why shouldn’t Albuterol be used along with MAO inhibitors?
Taking Albuterol along with MAO inhibitors increases risk of tachycardia and agitation. Cheese Effect.
What role does cAMP play in the the regulation of Albuterol?
cAMP decreases Ca2+ concentration within the cell which leads to smooth muscle relaxation and bronchodilation.
Why does it make sense that Albuterol is distributed as a racemic mixture?
Both enantiomers fulfill a different role and work synergistically. Also, time and money spent isolating the enantiomers is avoided.
What is the function of esomeprazole magnesium?
Proton pump inhibitor
How does esomeprazole magnesium associate with its receptors?
Covalent disulfide bonds with cysteine
Which isomer of omeprazole functions best in humans?
S - isomer
List a combination of four side effects and common uses for doxycycline
- Increased photosensitivity, GI effects, discoloration of teeth in children, candidiasis
- Rocky Mountain Fever, Chlamydia, UTIs, acne, staph, cholera
What type of bacterial agent is doxycycline?
Bacteriostatic
What two functional groups are common to doxycycline’s pharmacophore
Ketones and Alcohols
What are the two receptors that esketamine targets?
Dopamine Reuptake Transporter
NMDA Receptor
How was ketamine administered and how is esketamine going to be administered?
Ketamine is administered as an IV, esketamine will be administered through a nasal spray
What was ketamine originally used as, and because of this, what are some of the side effects of esketamine?
Ketamine was originally used as an anesthetic, and because of this some of its side effects include hallucinations and dissociation/derealisation
