PHAR 733 Module 2 Flashcards
What is the Arrhenius equation?
k = Ae^(-Ea/RT)
or
ln k = ln A - (Ea/RT)
Ea = activation energy A = the total number of collision e^-Ea/RT = the probability that any given collision will result in a reaction K = reaction rate constant T = absolute temperature, in Kelvin
What is the universal gas constant?
R = 1.987 cal K^-1 mole^-1
What is the two point Arrhenius Equation?
A method to determine the activation energy for a given reaction from experimental data found at two different reaction temperatures.
log K(atT2)/K(atT1) = (Ea/2.303R)(T2-T1/T2T1)
K at what temperature is useful for calculating half and shelf life?
25 degrees celcius
When T is increased by ten, reaction increased by ____________?
2-fold, shelf life decreased by 2 fold(4-fold if T increased by 20; 8 if by 30)
Shelf-lives for different orders of reaction
Zero: t90 = o.1 Ao/Ko
First: t90 = .105/K1
Second: t90 = 0.111/(Ao*k2)
Define Q10
The factor by which the rate increases when the temperature is raised by 10 degrees
Q10 = K(T + 10) / K(T)
What Q10 value is most accurate when Ea is unknown?
Q10 = 3 is most likely (2 is smallest reasonable, or possible, and 4 is the largest reasonable, or conservative)
Define Q(delta T)
Used for an arbitrary temperature change.
Q(delta T) = k(T + delta T) / k (T) = Q10 ^ DeltaT/10
What is the equation for Q10 method of shelf life estimation.
t90(forT2) = t90(forT1)/Q10^deltaT/10
A positive deltaT reduces the shelf life, a negative deltaT will increase in the shelf life
High is osmolarity defined
By the number of osmoles (osm) of solute per liter of solution
ex. 1 mol/L NaCl = 2 osmol/L of NaCl solution
Hypertonic solution effect on the body
Irritation and dehydration since fluid is drawn out (administration of hypertonic is much more consequential than administration of hypotonic solutions)
Define iso-osmotic solution
has the same solute concentration as compared to another one and contains both penetrating and non-penetrating solutes.
Define isotonic solution
Has the same osmotic pressure and contains only non-penetrating solutes
What are normal blood serum osmolarity values?
Between 275 and 300 mOsm/L.
Osmolarity of pharmaceuticals should be close to 285 mOsm/L to minimize discomfort to eyes and nose
What do red blood cells, blood serum, tears and 0.9% NaCl solution all have in common?
Have the same number of solute particles per unit volume and are isotonic and iso-osmotic
How to calculate dissociation factor?
i = total number of particles after dissociation/number before
Define sodium chloride equivalent (E)
The amount of NaCl in grams that is osmotically equivalent to 1 g of the drug
Define Parenteral
A route of administration in to the body other than through the GI tract (injection)
Enteral involves absorption through the GI tract
Routes of parenteral administration include
IV, IM, Sub-q, and ID
Other routes include:
intraarterial, intraocular, intraperitoneal, intracardiac, intraartiular (into the joints), intrathecal (cerebrospinal fluid), intraspinal and intrasynovial
Describe the gauge of a needle
Used to designate the size of the lumen, ranges from 27 (the finest) to 13(largest)
What are the components of an IV administration set?
Plastic spike (to pierce seal on iv container), drip chamber (permits adjustment of flow rate and trips air), polyvinyl chloride tubing, flow regulator, injection port, connector
When is the butterfly catheter used?
Short term IV
What are the best peripheral veins for IV therapy?
The basilic and cephalic veins on back of hand and dorsal forearm
What is the max injection volume for adults?
3L/day
What are the 3 categories of IV administration?
- IV bolus (push) - immediate effects needed, toxicity may occur; usually 1-2mL
- Intermittent infusion - drug diluted into volume of parenteral fluid (25-100mL) and infused over course of hour typically at spaced intervals; safer than IV bolus but provides less consistent drug plasma level than continuous infusion
- Continuous infusion - drug added to large parenteral volume and slowly administered into vein; allows simultaneous fluid and drug therapy, provides excellent drug plasma level and minimized toxicity and irritation
What are the disadvantages of continuous infusion?
Certain drugs can’t be administered like this due to extended run times, can’t be used if patient’s have restricted fluid intake, and can’t be used to admix poorly soluble drugs dissolved in water-miscible drugs
IM needle specs
1/2 inch to 1.5 inches long, 19-23 gauge (needle point should be far from nerves)
What is the benefit of IM route
Lower but more sustained blood concentrations than IV administration due to an absorption step
Sub-Q needle specs
3/8 to 1 inch long; 24-27 gauge
Why is absorption slower in sub-q injection compared with IM?
Poor vasculature in sub-q tissue
What are the most important drugs administered sub-q
Heparin and insulin
Injection site and limit for intradermal route?
anterior surface of forearm and limited to 0.1ml
Intradermal needle specs
3/8 inches long; 25-28 gauge
What agents are injected ID and what is the onset fast or slow?
Diagnostic agents, desensitization and immunization agents; onset slow
All parenteral products must be…
Sterile, pyrogen limited, free from extraneous insoluble materials
Define pyrogen
A substance, typically produced by bacterium, that produces fever and hypotension when introduced to the blood; could originate from microbes that get destroyed during sterilization
Max endotoxin level allowed by FDA: 0.2EU/kg for intrathecal, 5 for nonintrathecal, and .25-.5 for sterile water.
1 EU = 100pg of E.Coli lipopolysacharide
What various forms of parenteral products are available for use?
Solution, lyophilizied solids, emulsion, suspensions
Official types of injectable materials(USP)
Injections, for injection (dry solids that require vehicle for conversion to injection), injectable emulsion, injectable suspension, for injectable solutions (dry solid that requires addition of vehicle for conversion to injectable suspension)
What are the possible components of parenteral formulations?
Vehicles, buffering agents, preservatives, antioxidants, chelating agents, tonicity agents
Most common vehicle
Water
Describe water for injection, USP
Water for injection, USP (pyrogen free, purified and contains no more than 1mg/100mL of trace elements) - intended for use within 24hours, not required to be sterile but terminal products must be sterilized
Describe sterile water for injection, USP
Sterile water for injection, USP (water for injection that has been sterilized) - may contain more than 1mg/100ml of solids due to leaching from container during sterilization, stored in single dose not larger than 1L, and commonly used as vehicle for dry-powder injectable products
Describe bacteriostatic water for injection, USP
Sterile water for injection that contains one or more antimicrobial agents.
Packed in prefilled syringes not exceeding 30mL of water, container label must state names and proportions of preservatives, not widely used in large volume due to potential toxicity from preservatives, label must state “Note for use in Neonates”
Describe chloride injection, USP
Sterile isotonic solution of NaCl (0.9%) in water for injection, which contains no antimicrobial agents.
Often used as vehicle in parenteral solutions and suspensions, and also used as a catheter or IV lines flush to maintain patency
Describe bacteriostatic sodium chloride injection, USP
Sterile isotonic solution of sodium chloride (0.9%) in water for injection, which contains antimicrobial agents
Containers no larger than 30mL, often used as vehicle for preparing parenteral solutions and as catheter or IV line flush
Describe 5% dextrose injection, USP (D5W)
isotonic with blood and used as a water source and vehicle
Describe Ringer’s Injection, USP
Sterile solution of NaCl, potassium chloride and calcium chloride in water.
Used as a vehicle for other drugs or alone as an electrolyte replenisher and plasma volume expander.
What defines a hyper or hypotonic parenteral fluid? How are they used?
340
Hypotonic - to dilute excess serum electrolytes as in hyperglycemia
Hypertonic - to correct electrolyte imbalances, as in losses from excess vomiting and diarrhea
What are the 2 main uses for non-aqueous vehicles?
Limited water solubility of the drug and susceptibility to hydrolysis
Examples of water immiscible, non-aqueous vehicles
Fixed oils, ethyl oleate, isopropyl myristate, benzyle benzoate
Examples of water miscible, non-aqueous vehicles
Propylene glycol, glycerol, ethyl alcohol, polyethylene glycol
Consideration for barbiturates and digitoxin with water?
Barbiturates readily hydrolyzed by water; Digitoxin has poor solubility with water
Requirement for non-aqueous vehicles
Non toxic in amounts administered, nonirritating, non-sensitizing, it must not exert pharmacological activity
Considerations for non-aqueous vehicles
stability at various pH levels, viscosity (is it suitable for syringe), fluidity must be maintained over temp range, boiling point should be high to permit heat sterilization, constant purity or ease of purification
Fixed-oil considerations
Never administer by IV, typically IM; USP restricts oils for parenteral use if oil doesn’t remain clear when cooled to 10 C; can’t contain mineral oil or paraffin since these materials aren’t absorbed by body tissues; when vegetable oils are included, label must say so in case of allergy
Non-aqueous co-solvent considerations
Co-solvent concentration should be sufficient to render drug soluble with formulation but should not be irritating or toxic; formulation should not be diluted with water or precipitation may occur
Role of preservatives and USP requirements
Substances added to dosage forms to protect them from microbial contamination
At least 1 suitable preservative must be added to multi dose parenteral containers unless monograph says otherwise or if injection’s active ingredients are bacteriostatic themselves.
When are preservatives contraindicated?
Neonates and parenteral products with volume greater than 30mL
When is it not necessary to add preservatives?
Preparation will be used immediately, no water present, ph less than 3 or more than 9
Properties of idea preservatives
Effective at low concentration against wide variety of organisms, stable, soluble at required concentration, compatible with wide variety of drugs, non-toxic and non-sensitizing, free from odor, taste, color or stinging.
What is the acceptable pH range of parenteral products and IV preparations
3 to 10.5
4-9
pH above 10 can cause _______________
necrosis
pH below 3 can cause _____________________
pain
Buffering agent requirements
Nontoxic, nonirritating, sterile
Define antioxidants and reducing agents
substances added to dosage forms to protect against oxidative degradation; true antioxidants have lower oxidation potential than the drugs and are preferentially oxidized
reducing agents - reduce a drug or excipient that has been oxidized
Define chelating agents
Compounds that can form complexes with metal ions and inactivate their catalytic activity in the oxidation process
Define tonicity agents and provide primary examples
Used to achieve isotonicity in a parenteral formulation.
Dextrose, sodium chloride, potassium chloride
Methods of sterilization
- Use of sterile starting materials and equipment
- Aseptic technique
- Sterilization of post manufacture, preferable in final sealed containers
Methods include dry heat, steam, filtration, gas and radiation
Describe dry heat sterilization
Conducted at 150 - 170 celcius for 2 to 4 hours.
Used for thermostable powders, fixed oils and glass
Disadvantages: non-uniform heat distribution, requires high temperature and long time
Describe steam sterilization
Autoclave - airtight and designed to maintain high pressure and hot steam saturation (120 degrees C)
Advantages: microogranisms destroyed at lower temp with moisture, heat exchange by steam is more rapid than dry heat
Disadvantages: can’t be used for heat and moisture sensitive materials and those that aren’t penetrated by moisture (oil, fats)
Describe filtration
Physical removal of microorganism (0.22 micrometer pore size; 5 micrometer for particulate matter)
Advantages: simple and convenient; ability to sterilize thermoliable materials
Disadvantages: macromolecules like proteins may be damaged in filtration, some filters absorb drugs, time consuming for large volume solution
Different levels of filtration and what is removed with each
Micro (0.1 to 2 microns) - bacteria, fungi, parasites
Ultra (0.01 to 0.1 microns) - viruses
Nano (0.001 to 0.01) - organic compounds with MW 300-1000 DA (almost all pyrogens)
Reverse osmosis (under .001 microns) - also removes 90-99% of all ions
Describe gas sterilization
Typically uses ethylene oxide to kill microorganism.
Advantage: sterilization of thermoliable and moisture-sensitive materials
Disadvantages: some drugs lose potency
Describe radiation sterilization
Accomplished by UV light or high-energy ionizing radiation such as gamma rays.
Used for thermoliable drugs like penicillin, streptomycine, thiamine, riboflavin
Disadvantages: highly specialized equipment required, some materials are sensitive to irradiation
Difference between large and small volume parenteral dosage forms
Large greater than 100
Uses for large volume parenterals
- Maintenance therapy - used for fluid and electrolyte balance
- Replacement therapy - replacement of fluid and electrolytes
- Drug vehicle for administering other drugs
Define physical incompatibility and list causes.
Interaction between 2 or more substances which lead to change insolubility, precipitation, color, odor, viscosity and morphology.
- pH
- dilution of mixed solvent systems
- cation-anion interactions
Describe the pH effect
The sodium salts of weak acids precipitate as free acids when added to intravenous fluids with an acidic pH
Describe dilution of mixed solvent systems
Precipitation on dilution in aqueous IV fluids is common with nonionized drugs that are formulated as injections with greater than 40% alcohol by volume (intermolecular h water-alcohol bonds deprive drugs of van der waals forces, solubilizing them)
Describe cation-anion interactions
Precipitation is likely when oppositely charged, organic drug ions that contain aromatic rings are combined in relatively strong concentrations.
Define chemical incompatibility
Decomposition of drug substance resulting from combination of parenteral dosage forms. Most result from oxidation, hydrolysis or other reactions.
Give examples of protein drugs
Insulin, erythropoietin
Stages of DNA recombination in E.coli
Plasmid removed and opened by restriction enzymes; DNA coding inserted into opened plasmid and plasmid then closed by ligase; introduction of recombined plasmid into E.coli host cells
Define biotechnology
Any technique that uses living organisms in the production or modification of products
How are biopharmaceuticals administered?
Parenteral due to their sensitive nature (would be degraded in GI if administered orally)
Describe insulin structure
Two polypeptide chains (subunit A and B) connected by two disulfide bridges.
Have a tendency to form dimers in solution due to H-bonding, which will form hexamers in presence of zinc ions in blood.
Insulin produced and stored as hexamer (diffuses poorly into blood), but the active form is the monomer (readily diffuses)
What are the general types of insulin?
Basal insulin (intermediate or long-acting) - the background insulin that is normally supplied by the pancreas and is present 24 hours a day, whether or not the person eats
Bolus insulin (rapid or short-acting) - the extra amounts secreted by the pancreas in response to food intake (depends on meal size)
What are the types of pre-mixed insulin?
70%NPH/30% regular: 30-60 min onset, peak 2-10 hours, duration 10-18 hours
50%NPH/50%regular: 30 minutes onset, 2-5 hour peak, duration 18-24 houros
75%NPL/25% Lispro: Onset 5 minutes, peak 7-12 hours, duration 16-20 hours
Define IU
International Unit - a unit of measurement for the amount of a substance, based on biological activity or effect
1 IU = 0.0347 mg of human insulin
What level of glucose in blood plasma indicates hyperglycemia?
Over 200 mg/dl
Describe Regular insulin
Clearly identical to human insulin synthesized through rDNA technology in a non-disease-producing lab strain of E.coli
Covers insulin needs for meals eaten within 30-60 minutes.
Can be given SC, IM or IV
Describe formulation of regular insulin
Human insulin - 100units/mL Glycerin (isotonic agent) Metacresol (preservative) Endogenouos zinc (stabilizer) Water for injection
Describe storage of short-acting insulin (regular insulin)
Stable if stored in cold place but freezing should be avoided since it reduces potency. Vial can can be stored at room temp for 28 days. Should appear clear.
Describe rapid-acting insulin
Analogue of human insulin of recombinant DNA origin. Changes in structure block the formation of insulin dimers and hexamers, allowing larger amount of active monomeric insulin immediately following injection.
Humalog adjusted to pH 7 - 8 and typically injected within 15 minutes of a meal. Typically used in combination with medium or long-acting insulin
Novolog adjusted to pH 7.2-7.6. Administered 5 to 10 minutes before meal. Used with long or intermediate acting insulin
Apidra (Generic Glulisine) adjusted to pH of 7.3 and usually given with long-acting insulin. Should be given with 15 minutes of starting or 20 minutes following a meal. Used with long or intermediate acting insulin
Describe Isophane insulin
Intermediate acting insulin.
Also called NPH, has neutral pH around 7.1-7.4 and is an equivalent balance between insulin and protamine.
Onset 1-2 hours, peak 6-10 and duration 16-20 (basal insulin needs for about half the day)
Suspension for SC injection, may be mixed with both rapid and short acting human regular insulin.
Describe long-acting insulins
Analogues of human insulin of recombinant DNA origin.
Glargine: onset 2 hours, no peak and 20-24 duration
Detemir: onset 3-4 hours, peak 6-8 and duration up to 24
Describe Lantus
pH 4 due to isoelectric shift caused by structural modifications. Precipitation shortly after injection allows for hexamer stabilization, allowing slow absorption into systemic circulation.
Injected once daily. Should not be mixed with other insulins. If used with rapid-acting, injection must be separate.
Describe detemir
Neutral solution. Attached to fatty acid which causes binding to albumin, preventing fast transport into cells.
Dosed once or twice daily (duration dose dependent).
Should not be diluted or mixed with any other insulin preparations. Short or rapid-acting insulin should be given in a separate syringe.
Describe pre-mixed insulin
Combination of rapid or short-acting and intermediate-acting insulin in a fixed proportion.
Twice daily injections and helps avoid administration errors if the two were injected separately.
Humulin 70/30, Novolin 70/30, Humulin 50/50
Humalog Mix 75/25, Humalog Mix (NPL/Lispro) 50/50 75/50 mix provides lower response than 50/50 SC only
Define lipohypertrophy
Lump under the skin caused by accumulation of extra fat at the site of many SC injections of insulin
Describe any disadvantages to use of insulin pens
More expensive, 1-2 units lost when pen is primed, not all insulin types are available in pen, pens do not let you mix insulin types.
Describe Inhaled insulin
Exubera; removed from pharmacy shelves in 2007
Afrezza (Technosphere insulin) - FKDP reassembly in acidic environment to form microspheres for inhalation; proteins can be incorporated into microspheres
- uses rapid acting with peak levels within 12-15 minutes
- available in 4 and 8 unit and can be used for 15 days
- not recommended for smokers
Describe growth hormone deficiency
A medical condition caused by problems arising in the pituitary gland, in which the body does not produce enough growth hormone (or somatotropin)
In adults results in alteration of physiology of different systems, manifesting as altered lipid metabolism, increased SC visceral fat, decreased muscle mass, decreased bone density and low exercise performance.
Brand name products for Somatotropin
Humatrope, Genotropin, Norditropin, Nutropin, Saizen
Describe somatotropin
Lyophilized powder for SC after reconstitution for Bacteriostatic Water for injection, USP; Stable in refrigerator for 14 days following dilution with preservative containing dilutent; if sterile water for injection used for reconstitution, each vial should be refrigerated and used within 24 hours; administered SC at 0.16 to 0.24 mg/kg/week
Describe Lepirudin
Anticoagulant drug; Brand Refludan.
Recombinant hirudin (peptide with blood anticoagulant properties) derived from yeast cells and is a highly specific direct inhibitor of thrombin
Supplied as sterile, white, freeze-dried powder for injection or infusion and is freely soluble in sterile water for injection USP or 0.9% sodium chloride for injection USP
Describe tPA
Tissue plasminogen activator - protein that breaks down blood clots (only acts at clot)
Plasminogen converted to plasmin which breaks down fibrin
Generic Alteplse; Brand Activase (used in acute MI, stgroke or embolism)
Comes in sterile, white to off-white powder for IV admin after reconstitution with Sterile Water for Injection USP
Describe clotting factor replacement medication
Generic: Anitihemophilic Factor (Recombinant) (rAHF)
Brand: Kogenate; Recombinate
Synthesized by genetically engineered Chinese Hamster Ovary cell line; sterile water for injection used as dilutent
Describe Colony-stimulating factors
Glycoproteins that stimulate stem cells in bone marrow to form a specific kind of white blood cells that defend body against infection.
Generic: Filgrastim; Brand: Neupogen, Imumax or Grafeel
Used in cancer patients who have low white blood cell counts, putting them at risk of infection.
Describe erythropoietine
Glycoprotein hormone that stimulates the production of red blood cells by stem cells in bone marrow (EPO) and is mainly produced by the kidneys. Released in response to decreased oxygen in tissue.
Generic: Epoetin Alfa
Brand: Epogen; Procrit
Approved for anemia as related to cancer chemo and chronic kidney disease
Describe Monoclonal antibodies
Monospecific antibodies that are the same because they are made by identical immune cells that are clones of a unique parent cell, in contrast with polyclonal antibodies which are made from several different immune cells.
Produced by Hybridoma technology in almost unlimited quantities.
Generation 1: Murine MAbs - limited therapeutic value; recognized by human body as foreign and illicit immune response
Generation 2: Chimeric MAbs - contains human constant and murine variable region; HAMA reactions much lower
Generation 3: Humanized MAbs - 90% human, 10% mouse protein
Generation 4: Human MAbs
Types of MAbs based on function
Trigger the immune system to attack cancer cells.
Generic: Rituximab
Brand: Rituxan
Block the growth of cancer tumor
Generic: Trastuzumab
Brand: Herceptin
MAbs stop new blood vessels from forming.
Generic: Bevacizumab
Brand: Avastin
Delivery of radiation drugs to cancer cells.
Generic: Ibritumomab Tiuxetan
Brand: Zevalin
Delivery of chemo drugs to cancer cells
Generic: Ado-trastuzumab Emtansine
Brand: Kadcyla
Cancer diagnosis.
Generic: Satumomab Pendetide
Brand: OncoScint
Used to reduce the body’s natural immunity in patients with organ transplants
Generic: Muromonab-CD 3
Brand: Orthoclone OKT3
Rheumatoidf Arthritis caused by overproduction of tumor necrosis factor (TNF)
Generic: Adalimumab
Brand: Humira
Pregnancy testing (by binding to hCG)
Describe Antisense Drugs
Used for genetic disorders or infections. Nucleic acid strand used to bind to mRNA of gene known to cause disorder, inactivating it.
Formivirsen Sodium (Brand: Vitravene) blocks translation of viral mRNA - Indicated for cytomegalovirus (CMV) retinitis in patients with AIDS
Diseases of the eye
Myopia (nearsightedness) Hyperopia (farsightedness) Astigmatism (irregular cornea) Presbyopia (lens can't bring close objects to sharp focus) Cataracts Glaucoma (fluid pressure) Conjunctivitis (inflammation of conjunctiva) Keratitis (inflammation of cornea)
Describe Astringents
Used in treatment of conjunctivitis. Shrinks or constricts body tissues.
Describe Miotics
Treats glaucoma. Lowers intraocular pressure by increasing drainage of aqueous humor.
Describe mydriatics
Allows examination of the fundus by dilating the pupil. Cycloplegics paralyze the ciliary muscles.
Topical administration advantages and disadvantages
Advantages: convenient, easy, noninvasive, fewer systemic drug effects.
Disadvantages: Low bioavailability, ineffective in treatment of posterior segment diseases
What factors effect bioavailability (ocular)
- Precorneal factors/fluid drainage (eye maintains volume of 7 to 10 microliters; can take 30; optimal volume 7 to 10)
Solution usually flushed from eye in 1-2 minutes with less than 1% ocular absorption. Drainage influenced by viscosity and pH (excessive tear secretion). Drugs can also bind to tear proteins (0.7% of total body proteins)
- Corneal factors: lipophilic corneal epithelium acts as major barrier for hydrophilic drugs, hydrophilic stroma for lipophilic
- Postcorneal factors: Melanin binding and drug metabolism by eye enzymes
Characteristics of Topical Formulations
Sterile, free from foreign particles, clarity, nonirritating, proper preservatives, pH, tonicity, viscosity, stability
