Random Stuff to Memorize from All Classes Flashcards
Identify the class of drug depicted in the photo.
What is it indicated for?
Describe the MOA.
Bonus: what specific drug is it?
NK1 Receptor Antagonist
Indicated for the prevention of nausea and/or vomiting
Used in combination with 5-HT3 antagonists
MOA - selective high-affinity antagonist of substance P/neurokinin 1 (NK1) receptors
Arepitant (EMEND)
Identify the class of drug depicted in the photo.
What is it indicated for?
Describe the MOA.
Bonus: what specific drug is it?
NK1 Receptor Antagonist
Indicated for the prevention of nausea and/or vomiting
Used in combination with 5-HT3 antagonists
MOA - selective high-affinity antagonist of substance P/neurokinin 1 (NK1) receptors
Arepitant (EMEND)
Identify the class of drug depicted in the photo.
What is it indicated for?
Bonus: which drug is it?
5-HT3 Antagonist
Indicated for prevention of nausea and/or vomiting
Ondansetron (Zofran)
Identify the class of drug depicted in the photo.
What is it indicated for?
Bonus: Which drug is it?
5-HT3 Antagonist
Indicated for prevention of nausea and/or vomiting.
KYTRIL (Granisetron)
What is the purpose of the two tri-fluoro methyl groups in NK1 antagonists?
Enhance the activity and improves the metabolism
Describe the mechanism of action of proton pump inhibitors.
They form a covalent bond with their target receptor (proton pumps).
The sulfoxide group and a nitrogen group (that is a couple carbons removed from it) allow the structure to be arranged in such a way that it can form a disulfide bond with its traget.
They inhibit the final step in gastric acid production. In the gastric parietal cells, they bind to the H+/K+ ATP pump to inhibit secretion. The covalent binding prevents secretion for up to 24 hours or longer.
Identify the class of drug depicted in the photo.
What is it indicated for?
Bonus: name the drug.
Proton Pump Inhibitor
Indicated for short-term treatment of erosive esophagitis associated with GERD, maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger-Ellison syndrome.
Pantoprazole (Protonix)
Identify the class of the drug depicted in the photo.
What is it indicated for?
Bonus: name the drug.
Proton Pump Inhibitor.
Treatment in adults of duodenal ulcer and gastric ulcer, treatment of adults and children with GERD, and maintenance of healing of erosive esophagitis
Omeprazole (Prilosec)
List some drugs found in the PPI class.
Omeprazole (Prilosec)
Lansoprazole (Prevacid)
Pantoprazole (Protonix)
Esomeprazole (Nexium)
To which class of drug do ranitidine (Zantac) and famotidine (pepside) belong?
H2-receptor antagonist.
Identify the class of drug depicted in the photo
What is it indicated for?
Bonus: identify the drug.
H2 receptor antagonist (competitive inhibitor of histamine H2 receptors)
Short-term treatment of active duodenal ulcer, treatment of GERD
Pepside (Famotidine)
To which drug class does metoclopramide (reglan) belong?
Prokinetic agent (motility stimulant)
What is reglan indicated for?
Short-term treatment of GERD in adults who fail to respond to conventional therapy
Relief of symptoms in adults with acute and recurrent diabetic gastroparesis
Describe the structure in the picture, identifying the important aspects of its SAR.
It’s a catecholamine
The aromatic hydroxyl groups are required for H bonds to the target serine residues (especially in beta receptors)
The aromatic ring forms VDW interactions with the phenylalanine in the binding site
The alcoholic -OH forms H bonds with asparagine
The aminium ion forms an ionic bond with the aspartate
N-alkyl substituents lead to selectivity for beta receptors
What cofactor is found in the ACE enzyme?
Zinc
Identify the class of drug depicted in the photo.
Bonus: name each drug.
First generation beta blockers (non-selective)
Propranolol, Pindolol, Timolol
Identify the class of drug depicted below.
Bonus: name each drug.
Second generation beta blockers.
Acebutolol, Atenolol, Metoprolol, Betaxolol
Describe the SAR of the molecule in the photo. Which drug is depicted?
Enalaprilat
The carboxylate ion weakly binds with the zinc cofactor found in ACE.
- the weaker interaction of the carboxylate is compensated for by extra binding interactions involving phenethyl and methyl groups
- the phenethyl group fits into the S1 pocket and the methyl group fits into the S1’ pocket
- the amine mimics the amide of the natural substrate
Bonus: enalapril is an ethyl ester prodrug for enalaprilat
Describe some features associated with statins.
Statins with hydrophilic character target liver cells and have lower side effects (ex. rosuvastatin); they don’t cross cell membranes easily so their liver uptake is OATP dependent
Lipophilic statins readily cross membranes and exert SE due to inhibition of HMGR in other cells (like muscle cells)
Common SE = myalgia (muscle pain)
What is the MOA of statins?
Competititive inhibitor of HMGR
Why can statins be considered transition state analogues?
They imitate the transition state of the first step of the reaction mechanism of HMG-CoA reductase
Which two type 1 statins are prodrugs?
Lovastatin and Simvastatin
The active site of renin contains…
two aspartyl residues
What are particulate carriers?
Nano or micrometer size lipid or polymeric drug delivery systems
Compare and contrast the size range of nanoparticles and microparticles.
Nano = 5-1000 nm range
Micro = 3-1000 micrometer range
What types of particulate carriers are there?
- sphere: drug is absorbed or dispersed in nanometer or micrometer sized polymeric matrix
-
capsule: particles are surrounded by a polymer; consists of a shell and a space in which the drug or any other substance is place
nanocarrier: nanocapsules and nanoparticles
What’s the difference between nanopharmaceutical and a nanomedicine?
NP - a drug product that uses nanocarriers as delivery vehicle
NM - science that deals with the use of nanocarrier based drug delivery or diagnostic or medical procedures
Micron size capsules that envelope solids, liquids, or gases
Microencapsulation
Describe some benefits of microencapsulation.
- protects the product against degradation by pH and light
- masks color and taste
- improves release profile and shelf-life
Polymers used in microencapsulation include…
Gelatin
Polyvinyl Alchol
Ethyl Cellulose
Polyvinyl Chloride
What is a liposome?
A vesicle-like structure composed of one or more lipid bilayers encapsulating an aqueous core
(phospholipids are usually used as lipids)
True or False: both water and lipid soluble drugs can be encapsulated into liposomes.
True
What types of lipids can be used to prepare liposomes?
Neutral (do not carry charge); examples: DSPE (distearoyl phosphatidyle-thanolamine), cholesterol, DSPC (distearoylphosphatidylcholine)
Anionic (negative charge); example: DMPG (dimyristoylphosphatidylglycerol)
Catioinc (positive charge); examples: DOTAP (dioleoyltrimethylammonium propane) and DODAB (dioctadecyldimethylammonium bromide)
Describe the preparation of liposomes.
- dissolve lipids in organic solvent (chloroform, or that + mixture)
- mix lipids with solvent
- use dry nitrogen or rotary evaporator to remove solvent & produce film
- evaporate residual solvent by placing on a vacuum pump
- dry film thoroughly
- film can be prepared by freeze drying
What is the purpose of sonication and extrusion?
Sonication and extrusion are done to reduce the size of the hydrated LMV suspension.
Describe how liposomes are classified.
Based on size and number of lamellae
- small unilamellar vesicles (SUV) are 20-100nm
- large unilamellar vesicles (LUV) are a few hunder nm to several micrometers
- large multilamellar vesciles (MLV) or multivesicular vesicles (MVV) are a few hundred nm to several microns
- the thickness of membrane measures about 5-6 nm
When classified based on composition and applications, what are the classifications of liposomes?
Conventional
Sterically Stabilized
Immunoliposomes (non-stealth and stealth)
Cationic
pH Sensitive
Identify the type of liposome:
- made of only phospholipids, negatively or positively charged lipids, and or cholesterol
- readily taken up by phagocytic cells of reticuloendothelial system (RES) <– this is a limitation
- localized predominantly in liver and spleen
- are made of natural lipids
Conventional
AmBisome and DaunoXome are…
Commercial liposomes
AmBisome is unilamellar
Identify the type of liposome:
- prepared by grafting polymer at the surface (increases circulation time in the blood; PEG is usually attached)
- PEGs create a barrier around them to reduce interactions with endogenous molecular and cellular components
- evades recognition by immune system because of PEG
Long-Circulating (Stealth)
Identify the type of liposome:
- prepared by grafting or coating the surface with antibodies or antibody fragments
- can be stealth or non-stealth
Immunoliposomes
Identify the type of liposome:
- antibody ocnjugation does not ahve long-circulating properties
- are just conventional liposomes coated with antibodies
Non-stealth immunoliposomes
Identify the type of liposome:
- antibody coated liposome with long-circulating properties
- antibodies are conjugated either on the surface of pegylated liposomes or with the PEG chain
Stealth Immunoliposomes
What are SEDDS and at what size ranges are they found?
SEDDS = self-emulsifying drug delivery systems
Isotropic mixtures of natural or synthetic oils, solid or liquid surfactants, and co-solvents/surfactants
- the emulsify spontaneous to produce fine oil-in-water emulsions in contact with the aqueous phase
Size range = 100-300 nm
What are the limitations of conventional drug delivery systems?
- whole body exposure
- affect non-target organs and tissues
- drug wastage and even toxic effects
What are some benefits of drug targeting?
- deliver drugs to target cells/tissues (or even intracellular)
- keep drug out of non-target areas
- reduce leakage
- protect drug from metabolism
- reduce premature clearance
- retain the drug at site for desired time
- facilitate entry into cells
- biocompatible, biodegradable, and non-antigenic
The 3 major components for a drug targeting system are
1 - the drug (for therapeutic effect
2 - carrier system (controls distribution and protects from metabolism and early clearance)
3 - homing device (delivers drug to specifc area)
Compare and contrast active and passive functional targeting.
Passive - exploits the natural distribution of the drug carrier in vivo; no homing device is used
- application: treatment of macrophage associated disease; Leishmaniasis; treatment of lysosomal enzyme deficiency
Active - has all 3 components (carrier, homing device, & drug); the homing device is attached ot the carrier or drug; molecules over-expressed in some diseases can be targeted
What is meant by the term “enhanced permeability and retention effect”?
EPR is that clearance from tumor tissue is delayed due to poor lymphatic drainage
(blood vessels in tumors are leakier than those in normal tissue; this traps macromolecules and prevents their escape)
What type of targeting utilizes polymer-drug conjugates?
Both active and passive.
In passive, the drug is conjugated with a water soluble polymeric backbone via a linker. This is useful with anticancer drugs because normal tissues will not allow the conjugate to enter, but tumors have the EPR effect.
In active, the polymer-drug conjugate is linked to a targeting moiety such as an antibody. (ex. conjugated with galatosamine (the homing device) to target certain cells)
What is pegylation and what is it used for?
It is used in passive targeting as a pay to prevent macrophages from phagocytosing drugs/drug carriers.
Carriers and/or drugs can be coated with PEG. The PEG coating reduces adsorption of opsonins and slows phagocytosis.
It also delays uptake by the liver and increases circulation time.
Describe what is involved with antibody directed enzyme prodrug therapy (ADEPT).
It uses tumor cell specific surface ligands.
Conjugates an enzyme, which is not present in the extracellular fluid or on cell membranes, with an anti-tumor antibody.
The enzyme-antibody conjugate is administered first, which then goes on to locate the tumor. Then, a prodrug is administered after the conjugate is eliminated from circulation.
The tumors’ enzyme-antibody converts the prodrug to the cytotoxic partent compound at the tumor site.
What kinds of particulate carriers can be used for active targeting?
Liposomes and polymeric micelles
the particle surface is modified with proteins, peptides, antibodies, or polymers.
Ligands used are: folate, transferrin, and epidermal growth factor receptor (EFGR) because they are overexpressed in many tumor surface cells
What are the limitations of the BCS?
Does not take into account the effects of uptake and efflux transporters and the route of elimination (disposition) that play important roles in drug absorption and bioavailability
What system was devised as an alternative to BCS?
Biopharmaceutics drug disposition classification system (BDDCS)
- takes into account the impact of metabolism and drug transporters (efflux and uptake/absorptive)
- when the major route of elimination is metabolism, permeability is high
- when the major route of elimination for a drug is renal and biliary excretion of unchanged drug, the permeability is low
Compare and contrast BCS and BDDCS.
BCS is the extent of absorption or permeability.
BDDCS is based on the rate of intestinal permeability, which is related to the extent of drug metabolism.
What is GER?
Gastric emptying rate - the speed with which substances leave the stomach after ingestion
Identify factors that affect gastric emptying rate.
1 - state of matter (liquids empty faster than solids and solids content slows down GER)
2 - food (presence slows GER, as does increased acidity)
3 - osmolarity (increased osmolarity decreases GER)
4 - temperature (if it’s abnormal, it slows)
5 - posture (faster standing than lying)
When does gastric pH have the most impact?
It is more predominant for weakly basic drugs that have high solubility at acidic pH. The bioavailability is dependent on their rapid dissolution into stomach acid
Motility of the GIT is characterized in terms of _____, which is define as…
transit time
the time taken for a dosage form to pass through a compartment
Most drugs (acidic or basic) are absorbed from the…
intestine (SI)
A weak acid ionizes more when the pH is _____ its pKa, and a weak base ionizes more when the pH is _____ its pKa
acid ionizes when pH is above pKa
base ionizes when pH is below pKa
What is meant by “ion trapping” after oral absorption?
when extracellular and intracellular pH is different, the ionized fraction of solute in and out of the cells becomes different.
- ionized fraction increases where pH favors ionization, so a drug may get trapped on one side of the cell membrane (in or out)
- when ionized fractions go up inside the cell, the intracellular drug concentration also goes up (this could be good or bad)
What is absorbed (mostly anyway) in the large intestine?
Water and electrolytes
Transit time in the large intestine is approximately…
why is this important?
20-30 HOURS
Modified release dosage forms can be designed to release the drug in the colon (LI)
For bioavailability, the general rule is that it decreases in the order ______ –> ______ –> ______ –> _____ –> _____
Solution –> Suspension –> Capsule –> Tablet –> Coated Tablet
Identify the purpose of megesterol acetate and how its formulation was designed.
Megesterol Acetate is a synthetic derivative of progesterone that is indicated for the treatment of appetite loss or unexplained, significant weight loss in AIDS patients.
The original formula was micronized, whereas this form has nanoparticles. The nanoparticles provide increase surface area for the drug, which lead to more rapid dissolution and increased absorption, leading to improved bioavailability.
How does milk affect the absorption of tetracycline?
It reduces absorption because tetracycline forms stable chelate complexes with metals, including calcium and magnesium, that are insoluble in water.
List some diseases that affect oral absorptions.
Parkinsons (due to disturbance of GI motility, which manifests as impaired emptying and constipation)
Depression (side effects of antipsychotics may cause anything from constipation to bowel obstruction due to decreased motility)
Achlorydria (absence of hydrochloric acid; weakly basic drugs remain undissolved in low HCl stomach)
Congestive Heart Failure (reduced blood flow and motility –> decreased absorption)
Crohn’s (inflammation causes decreased absorption)
Celiacs (inflammation of proximal small intestine, increased permeability of jejunal mucosa)
Compare and contrast the dictionary definition and pharmceutical convention definition of “parenteral”.
Dictionary - sites that are outside of or beside the alimentary tract
Pharmaceutical - medicines that are administered by means of an injection
Which routes of administration are “parenteral” routes?
Intravenous, Intraarterial, Intracardiac, Intraspinal, Intrathecal, Intraosseous, Intraarticular, Intrasynovial, Intracutaneous, Intradermal, Subcutaneous, and Intramusclar
True or false: subcutaneous implants are usually classified as parenterals.
True.
What are the components that make up a needle?
Shaft - lubricated metal portion (lubricated with sterile silicone coating for a smooth, easy injection THIS IS WHY WE DON’T SWAB THEM WITH ALCOHOL); The tip of the needle shaft is slanted to facilitate injection (this is the bevel)
Hub - attaches the needle to hte syringe and is often color-coded for a specifc gauge
What are the different bevel types?
Regular - most common; used for most applications
Short - designed to minimize injection depth and to obtain rapid withdrawal or dispersion of fluid
Intradermal - designed to allow for shallow and low angle insertion of the needle just below the epidermis for use in skin testing
How is needle size described?
Gauge - measure of the outside diameter of the shaft (27-13); the larger the number, the smaller the diameter. 18, 20, and 21 G are the most commonly used.
Length of the needle shaft; usually ranges from 3/8 inch to 3 inches
Which type of needle wall allows for a greater volume of fluid (than regular) to pass through it?
Which type provides the higher flow and requires less force to deliver the medication?
Greater volume only = thin wall
Higher flow AND less force = EXTRA thin wall
_______ are composed of a barrel and plunger. They are made of either ______ or _______.
Syringes
Glass or Plastic
When would you use a glass syringe? When would you use a plastic syringe?
Glass - used when medication is to be stored for an extended period of time and when stability requires
Disposable Plastic - costs less and used when the contact time is short, minimizing the potential for incompatibilty with the plastic
List and describe the types of syringe tips.
Luer-Lok - having a locking mechanism, which secures the needle with a threaded ring. Manipulation of hazardous drugs requires syringes with a locking mechanism.
Slip-Tip - allow the needle to be held on the syringe by friction
Eccentric Tip - features an offset nozzle that is on the edge of the barrel. This allows the needle to be closer in line with the wall so that the needle is nearly parallel with the injection surface
Catheter Slip Tip - used mostly with medical tubing like catheters and feeding tubes
How do needle free injections work?
Give an example.
They use high pressure to push the medication through the skin to the desired site.
Penjet - single use, disposable jet injector that comes prefilled with the proper drug dose. It is powered by a self-contrained compressed inert gas.
Injex - reusable injection device coupled driven by the power of a spring in the injector
Small Volume Parenterals are packaged in:
Small plastic bags (called a minibag of 50-100mL)
Ampules
Vials
Pre-filled syringes
______ are sealed glass containers that are used for liquid formulations only.
Ampules
What kind of needle should be used when drawing the contents of an ampule into a syringe?
Why?
A 5 micron filter needle should be used because glass particles may have fallen into the ampule when the top was snapped off
______ are used for both liquid and dry powder formulations. What are they made of?
Vials
They’re made of glass or plastic and sealed with a rubber stopper
What is lyophilization?
Freeze Drying
- many pharmaceuticals are unstable in solution
- lyophilization is a process in which the water is removed from the product using “sublimation”
- a vacuum is aplied to the frozen product so that water changes directly from solid to gas
Lyophilized powders can be filled in a special type of prefilled syringe called a _____________.
Dual chambered syringe
In what forms do single dose containers come in?
Ampules
Single Dose Vials
Pre-Filled Syringes
Large Volume Parenterals (LVPs) are generally administered via __________ as a means of…
Intravenous infusion
as a means of fluid replacement, electrolyte balance restoration, or for TPN
What must not be included in LVPs due to the large volume?
must not contain bacteriostatic agents or other pharmaceutical additives/excipients
Microdrop sets deliver ____ drops per mL while macro drop sets deliver ____ drops per mL
Micro = 60 drops/mL
Macro = 10, 15, or 20 drops/mL
What dosage forms can be used for parenterals?
Solutions
Emulsions
Suspensions
Dry Powders (once reconstituted)
List and describe the “official types” of small volume parenterals.
[drug] injection - liquid prep
[drug] for injection - dry solids that (upon addition of suitable vehicles) yield solutions
[drug] injectable emulsion - liquid prep of drug that’s dissolved/dispersed in a suitable emulsion medium
[drug] injectable suspension - liquid prep of solids suspended in suitable liquid medium
[drug] for injectable suspension - dry solids that (upon addition of suitable vehicles) yield suspensions
______ water is supplied for hand and equipment washing. ________ water must be used for compounding nonsterile drugs & rinsing equipment & utensils. It has a microbial limit of _______.
Water used to prepare a sterile prep must be either:
1 - _________
2 - _________
3 - _________
Potable water for hand and equipment washing
Purified water for nonsterile preps.
Microbial limit of less than or equal to 100 CFU/mL
1 - water for injection
2 - sterile water for injection
3 - bacteriostatic water for injection
What are the parameters required for WFI?
WFI (water for injection) - meets requirements for purified water (less than or equal to 100 CFU/mL),
What are the parameters required for sterile water for injection?
- made from WFI (water for injection) that has been sterilized (less than or equal to 10 CFU/100 mL) and packed in a single dose container of not greater than 1 liter in size
- no antimicrobial agents/added substances
What are the parameters required of bacteriostatic water for injection?
- meets requirements for sterile water for injection
- contains 1 or more antimicrobial agents (0.9% benzyl alcohol) for use when a preserved solution is desired
- packaged in pre-filled syringe or vials containing no more than 30mL
- should NOT be used when large volumes are needed
- NOT FOR USE IN NEONATES
When would a non-aqueous vehicle be used for parenteral formulations?
Give examples of both fixed oils (non-volatile) and water-miscible (non-aqueous) solvents that may be used.
- drug has very limited solubility in water
- drug is susceptible to hydrolysis
Fixed Oils - cottonseed, sesame, olive, and corn
Water-Miscible - glycerin, ethyl alcohol, propylene glycol, polyethylene glycol
The majority of licensed products (for parenterals) have a pH of between ____ and ____.
What pH adjusting agents may be used?
3 and 9
NaOH, HCl, and ethylenediamine
What are the most commonly encountered buffers in parenteral products?
Phosphate - used when buffering around physiological pH
Citrate & Acetate - used when the required pH is lower
In most cases, sodium salts of acidic buffers are used, although potassium salts are occasionally encountered
When is a preservative required for parenterals?
When can antimicrobial agents NOT be used (for serious)?
In all multi-dose parenterals
Not used in LVP or preservative free preps and some cannot be used in pediatric/neonatal formulations at all (alcohol, benzyl alcohol, and propylene glycol)
Which tonicity adjusting agents are most commonly used in parenterals?
Dextrose, glycerin, sodium chloride, and mannitol
What is a protectant and why would it be added to a parenteral preparation?
It is a substance added to a formulation to protect against loss of activity of active ingredients by some stress (such as freeze drying)
- they can be cryoprotectants (freezing stress) and lyoprotectants (drying stress)
- examples: PEG, mannitol, glucose, and trehalose
What are the functional classifications of protein therapeutics?
Group 1 - enzymes and regulatory proteins (includes hormones; replacing a protein that is deficient or abnormal; augmenting an existing pathway; providing a novel function/activity)
Group 2 - targeted proteins (antibodies; interfering with a molecule or organism; delivering other compounds or proteins)
Group 3 - protein vaccines
Group 4 - protein diagnostics
Most therapeutic compuonds are now produced by _________.
Recombinant DNA technology
What are the 3 ways a recombinant plasmid can be introduced into a cell?
Transformation - insertion of the plasmid into prokaryotic cell
Transfection - insertion of a plasmid into a eukaryotic cell
Transduction - foreign DNA is introduced into another cell via viral vector
Most marketed therapeutic proteins are produced in ______
cultured mammailian cells (chinese hamster ovary (CHO) cells)
What are two of the more important post translational modifications (PTM)?
1 - formation of disulfide bonds (between two cysteine moieties), which is crucial for stabilizing tertiary structures
2 - glycosylation (attachment of oligosaccharides to an amino acid)
What is the aim of downstream processing?
To purify the therapeutic protein from (potential) endogenous and extraneous contaminants
What are the technical classifications of protein drugs by source?
1 - nonrecombinant (purified from natural sources)
2 - recombinant (produced from recombinant DNA technology); this kind allows for modification of a protein to improve the function or specificity
(first gen - unmodified/naive proteins; second gen - engineered proteins and chemically altered proteins)
RHI (regular human insulin) is considered a _________ insulin, with an onset of __________. Which molecule is required for insulin to be stored as dimers or hexamers in the pancreas?
Short acting
30-60 minutes
zinc
Crystalline zinc insulin (lente) and neutral protamine Hagedorn (NPH) insulin are both types of
intermediate-acting insulins
Compare and contrast the modifications made to insulin lispro, insulin aspart, and insulin glulisine.
They’re all rapid-acting (bolus) insulin analogs.
Lispro - similar to RHI except the sequence has been reversed at positions B28 (proline) and B29 (lysine) (it’s now lys-pro instead of pro-lys)
Aspart - formed by replacing B28 proline with aspartic acid
Glulisine - formed by replacing B29 lysine with glutamic acid and B3 asparagine with lysine (glu and lys were added…)
How does insulin glargine compare to RHI?
it has two arginine residues added to the B chain and glycine replaces an asparagine at A21
the result is an insulin with an isoelectric point of 6.7 (instead of 5.3-5.35). This results in reduced solubility at physiological pH, so the insulin is more slowly absorbed into the bloodstream.
How does insulin detemir compare with RHI?
The threonine in B30 is omitted and lysine is instead bonded to myristic acid
this causes the insulin to self-associate and bind to albumin, which leads to prolonged action
which insulin analogs are long acting?
glarging
detemir
degludac
ulralente
Fusion proteins (aka ______ proteins) are made from parts of different sources.
chimeric proteins
________ (________) is a second gen recombination protein. It is an enzyme substitution therapy indicated for the treatment of PKU.
It a pegylated derivative of the enzyme __________________.
Pegvaliase (Palynziq)
Phenylalanine ammonia-lyase
What’s the difference between chimeric and humanized antibodies?
Chimeric - combination of human and rodent chimeric antibodies (the main part of the rodent mAb is replaced with the corresponding human sequence)
Humanized - non-human antibody with a protein sequence that has been modified to increase the similarity to human antibodies (it is generated by grafting only the complementarity-determining regions (CDRs) of the rodent antibody to the human light and heavy chains)
Which of the following is a chimeric antibody? Which is humanized? Human?
Adalimumab
Infliximab
Rituximab
Trastuzumab
Bevacizumab
Ranibizumab
Ranibizumab, Bevacizumba, and Trastuzumab are humanized (zu)
Adalimumab is human (u)
Rituximab and Infliximab are chimeric (xi)
During what process are introns removed from the pre-mRNA sequence, exons joined together, and a finished mRNA molecule is formed?
RNA splicing
Explain what an oligonucleotide and an antisense oligonucleotide are.
Oligonucleotide - (oligomer) a short DNA or RNA-like molecule (50 or fewer bases in length)
Antisense Oligonucleotide (ASO) - single-stranded DNA or RNA oligonucleotides that bind to complementary (“sense”) mRNA sequences (following Watson-Crick base pairing rules)
How can ASO’s be classified?
What is RNase H?
1 - RNase H-_dependent_ ASOs (those that bind to complementary mRNA by base pairing and induce cleavage of target mRNA by RNase H enzyme)
2 - RNase H-_independent_ ASOs (those that alter mRNA translation without causing cleavage)
RNase H (ribunuclease H) is an endoribonuclease that specifically hydrolyzes the phosphodiester bonds of RNA (when hybridized to DNA, i.e. an endonuclease that degrades RNA in an RNA-DNA duplex)
What are some of the unfavorable properties of oligonucleotides?
- poor extracellular and intracellular stability (vulnerable to degradation)
- poor penetration due to negative charge
- suboptimal binding affinity
- off-target/toxicity effects
Explain how a 1st gen phosphorothioate (PS) modification works.
It is the replacement of a non-bridging phosphodiester oxygen by sulfur (this is the most widely used alteraction in NA drug development)
- this protects the oligonucleotide from degradation by nucleases
- it promotes RNase H-mediated cleavage
Drawback - if this is the only mod, it binds poorly
What are involved in 2nd gen modifications for ASOs?
Modifications to the sugar moiety at the 2’ position. Can be
- 2’ -o-methyl
- 2’ -fluoro
- 3’ -o-methoxyethyl (MOE)
these all increase stability toward digestion by nucleases and increase the binding affinity
(they don’t support RNase H cleavage)
How do “gapmers” help to get around the fact that alkyl substitutions don’t support RNase H-mediated cleavage for mRNA targets?
a central DNA “gap” is flanked on both sides by RNA “wings” made of 2’ alkyl modified nucleotides
the gap permits the formation of a DNA/RNA hybrid that allows RNase H1 to execute degradation
What is the purpose of 3rd gen modifications to ASOs? What are some examples of 3rd gen mods? Are they RNase H independent or dependent?
- enhance affinity and resist degradation
- LNA (locked nucleic acid): form a locked bridge
Phosphoroamidate morpholino oligomer (PMO, aka “morpholinos”): replace the sugar with a morpholino ring
Peptide nucleic acid (PNA): have N-(2-aminoethyl)-glycine units on repeat
are RNase H INDEPENDENT ASOs
Why would you want to avoid RNase H cleavage of mRNA?
To provide steric blocking (inhibits translation of undesirable proteins)
for splice-switching oligonucleotides (modulates splicing)
